case study child with global developmental delay

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Case Study: Child With Global Developmental Delay

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PURPOSE. This case study focused on the care of a child with global developmental delay.

DATA SOURCES. Data were obtained through the author's clinical practice in long-term care pediatric rehabilitation and literature sources.

DATA SYNTHESIS. NANDA-International Classifications, the Nursing Interventions Classification (NIC), and Nursing Outcomes Classification (NOC) were used to identify the appropriate nursing diagnosis, nursing interventions, and patient outcomes.

CONCLUSIONS. This case study provides the pertinent nursing diagnoses, interventions, and outcomes for a child with global developmental delay. The interdisciplinary team approach and family involvement is addressed.

IMPLICATIONS FOR NURSING. Use of NANDA, NIC, and NOC outcomes constructs for enhancing the care of a child with global developmental delay.

Search terms: Global developmental delay, nursing diagnosis, nursing interventions, health outcomes

© (2010) The Authors, Journal compilation © (2010) NANDA International

doi: 10.1111/j.1744-618X.2010.01159.x

JT, a 5-month-old male infant, was admitted from an acute care hospital setting to the long-term care pediatric rehabilitation unit with a diagnosis of global developmental delay secondary to prematurity. Global developmental delay is a genetic disability that affects all areas of development, including motor, speech, language, cognitive, and social skills (Tervo, 2006).

JT had been institutionalized since birth. He was born at home at 28 weeks' gestation by spontaneous vaginal delivery precipitated by an altercation between his parents. His mother stated that she did not know she was pregnant He was born in the sack and reportedly experienced respiratory arrest prior to transport to the hospital neonatal intensive care unit. He weighed less than 2 lbs at birth. While hospitalized, he developed and was treated for pneumonia with periods of apnea.

The nurses and interdisciplinary team members evaluated JT's delayed development. The areas addressed were speech and language delay, motor delay, fine motor adaptive delay, and personal and social delay (Tervo, 2006). On admission to the longterm care facility,...

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A novel case of global developmental delay syndrome with microdeletion at 10p14–p15.3 and microduplication at 18p11.31–p11.32

Editor(s): Thachangattuthodi., Anish

a Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University)

b Population and Family Planning Science and Technology Research Institute/Key Laboratory of Birth Defects and Reproductive Health of The National Health and Family Planning Commission

c Department of Pediatrics, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, PR China.

∗Correspondence: Yun Bai, Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing, PR China (e-mail: [email protected] ); Yuping Zhang, Department of Pediatrics, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, PR China (e-mail: [email protected] ).

Abbreviations: aCGH = comparative genomic hybridization, CMA = chromosomal microarray analysis, CNVs = copy number variations, DD = developmental delay, FISH = fluorescent in situ hybridization, GDDS = global developmental delay syndrome, MLPA = multiplex ligation-dependent probe amplification, MR = mental retardation, OMIM = Online Mendelian Inheritance in Man.

DZ, LD, YZ, and XF contributed equally to this work.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

This work was supported by the National Natural Science Foundation of China (No. 81172723), and the Fundamental Research Funds for Non-profit Public Scientific Research Institutions of Chongqing (No. 2015cstc-jbky-01703 and 2016cstc-jbky-01703), Foundation of Chongqing Health Commission (No. 2017MSXM069), Natural Science Foundation Project of CQ CSTC (No. 2009CA5001 and 2017jcyjAX0478).

The authors declare that they have no conflict of interest.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

To characterize the etiology underlying a novel case of global developmental delay syndrome (GDDS) identified in a female child, aged 3 years old. This syndrome is a common pediatric presentation estimated to affect 3.65% of children aged 3 to 17 years.

The proband's detailed family history was used to infer a likely mode of inheritance for the GDDS. Genomic DNA samples collected from the proband and her parents were evaluated using conventional karyotyping, multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization microarray (aCGH), and fluorescent in situ hybridization (FISH) analysis techniques.

An analysis of the proband's family history suggested that she inherited the GDDS from her father. The conducted conventional karyotyping and MLPA methods failed to identify a causative defect for the GDDS; however, the aCGH analysis revealed both a 6.6-Mb deletion at p14–p15.3 of chromosome 10 (arr[hg19]; 100,026–6,710,183), and a 6.3-Mb duplication at p11.31–p11.32 of chromosome 18 (arr[hg19]; 136,226–6,406,733) in the proband. The conducted FISH analysis subsequently determined that these mutations resulted from a balanced translocation t(10;18)(p15.3; p11.32) carried by the proband's father. Finally, a bioinformatic analysis of the proband's mutations revealed ZMYND11 as a promising candidate causative gene for this case of GDDS.

The present study demonstrates that the aCGH method can be used to effectively identify the location and approximate size of microdeletions and/or microduplications, but not balanced reciprocal translocations. The nonconventional analysis methods used in the present study may be applicable to other GDDS cases with elusive etiology, and likewise, ZMYND11 should be considered as a potential causative gene during the investigation of future GDDS cases.

1 Introduction

Global developmental delay syndrome (GDDS) is a common pediatric presentation estimated to affect approximately 3.65% of children aged 3 to 17 years. [1] For children aged less than 5 years, it is characterized as the exhibition of a significant delay in 2 or more developmental domains (ie, intelligence, language, social communication, cognition, and/or daily motor activities). [2] Currently, there is no consensus neuroimaging method used to study and/or diagnose this condition, and furthermore, causes of developmental delay (DD) are difficult to elucidate using only routine diagnostic techniques and detailed clinical information. The chromosomal microarray analysis (CMA) technique facilitates the detection of small chromosome imbalances that are unable to be unidentified via microscope-guided karyotyping. In fact, CMA is already established as a major platform for the identification of copy number variations (CNVs) in patients with autism spectrum disorder and/or mental retardation (MR). [3,4]

In the present study, comparative genomic hybridization array (aCGH) and fluorescence in situ hybridization (FISH) techniques were used to investigate the etiology and pathogenesis of GDDS in a female child aged 3 years old.

2 Materials and methods

2.1 proband family history.

The study participants comprised members of a Chinese-Han family, who were identified and enrolled at the Department of Pediatrics at the Xinqiao Hospital (Third Military Medical University). The proband was a female child aged 8 months, who was diagnosed with GDDS. She was unable to either sit or crawl without assistance. The conducted physical examination of the proband identified no cortex thumb syndrome; however, she was found to exhibit bilateral ankle clonus, a poor active-conscious grip in both hands, grade-IV lower-limb muscle tension and strength, and the ability to support a prone position. Her bilateral knee-jerk and Achilles tendon reflex were found to be normal, and she was also assessed for Babinski (+), Kernig (−), Brudzinski (−), and Auspitz (−) signs. The proband was calculated to have a mental developmental index of 70, and a psychomotor developmental index of 63. The results of the generated electroencephalogram report were abnormal, comprising a small number of sharp waves, and slow spike waves in the central region.

The proband's mother reported a history of 3 spontaneous miscarriages. A chromosomal karyotype analysis did not reveal any positive findings for either the proband or her parents.

2.2 Ethics statement

A written statement of informed consent was obtained from the proband's guardians for her and their participation in the study, which was approved by the Ethics Committee of the Third Military Medical University (Chongqing, China), and by the Population and Family Planning Science and Technology Research Institute.

2.3 DNA extraction

Venous blood samples were collected in vacutainer tubes containing EDTA, and genomic DNA was extracted using the Wizard Genomic DNA Purification Kit (Promega, WI), according to the manufacturer's instructions. The quantity and quality of the extracted DNA were determined using a NanoDrop 1000 spectrophotometer (Thermo, MA).

2.4 Multiplex ligation-dependent probe amplification

Multiplex ligation-dependent probe amplification (MLPA) was performed at numerous sites of the proband's genome using the SALSA MS-MLPA kit P245-B1 (MRC-Holland), according to the manufacturer's instructions. This kit includes 40 probes that target chromosomal regions known to be altered in 23 multiple-microdeletion syndromes (including Prader-Willi/Angelman, Cri-du-chat, DiGeorge, Langer-Giedion, and Miller-Dieker syndrome, among others).

2.5 Array-CGH

The proband's extracted DNA was screened via an aCGH analysis conducted by the KingMed Diagnostics Corporation (Guangzhou, China), using the Affymetrix Genome-Wide CGH CytoScan HD array (ThermoFisher Scientific), according to the manufacturer's instructions. This array includes more than 2,000,000 copy-number and 750,000 SNP probes. Genotype and CNV identification, and an assessment of genotyping integrity were conducted using Affymetrix Chromosome Analysis Suite software (ThermoFisher Scientific).

A blood sample was accordingly collected from the proband's father, and the extracted DNA was used to conduct a FISH analysis of chromosomes 10 and 18. This analysis used 2 probe pairs, one of which comprised an Agilent SureFISH 18p11.32 red fluorescent (R) and a Chr18 CEP green fluorescent (G) label, and the second of which comprised an Agilent SureFISH 10p15.3 red fluorescent (R) and a Chr10 CEP green fluorescent (G) label.

The conducted MLPA analysis of the proband's genomic DNA did not identify any genetic abnormalities. Similarly, while the conducted aCGH analysis detected the proband to harbor a 6.6-Mb deletion between p14–p15.3 of chromosome 10 (arr[hg19]; 100,026–6,710,183), and a 6.3-Mb duplication at p11.31–p11.32 of chromosome 18 (arr[hg19]; 136,226–6,406,733), both mutations were not identified in her healthy parents ( Fig. 1 ).

By analysis of the provided family history, we determined that proband's paternal aunt had a child who exhibited similar symptoms to those displayed by the proband, and that the proband's paternal grandmother reported several spontaneous miscarriages. Taken together, these observations suggest that the proband's genetic disorder was likely paternally inherited. The proband's father was conducted a FISH analysis of chromosomes 10 and 18 ( Fig. 2 ). The results in 10 middle split like cells indicated that a translocation event happened. Furthermore, this translocation was shown to be balanced, as evidenced by the normal aCGH analysis result and phenotype exhibited by the proband's father. Thus, the proband's father was determined to harbor a t(10;18)(p15.3; p11.32) balanced translocation, from which the proband inherited her chromosome 10 p14–p15.3 deletion and chromosome 18 p11.31–p11.31 duplication.

4 Discussion

Balanced reciprocal translocations are the most common chromosomal rearrangements affecting humans, and are estimated to occur in 0.16% to 0.20% (1/625–1/500) of live births. [5] The great majority of cases with apparently balanced structural rearrangements exhibit a normal phenotype; however, 0.6% of patients with MR harbor these balanced structural rearrangements, which likely cause a deleterious phenotype by inducing gene disruption/dysregulation, microdeletion/duplication, and/or position effects at the chromosome breakpoint. Theoretically, balanced reciprocal translocation-carriers can produce 18 types of gametes, including only 1 normal and 1 balanced reciprocal chromosomal translocation, but 16 cytogenetically abnormal gamete types. As a result, the probability of such carriers producing healthy offspring is relatively low, and many carriers are clinically infertile, experience a high rate of miscarriage, and/or produce offspring affected by chromosomal disease. In the present study, the proband's father was identified to carry the balanced translocation t(10;18)(p15.3; p11.32), which was likely the cause of the multiple spontaneous miscarriages reported by his wife.

The proband was identified to harbor a 6.6-Mb deletion at p14–p15.3 of chromosome 10 (arr[hg19]; 100,026–6,710,183) and a 6.3-Mb duplication at p11.31–p11.32 of chromosome 18 (arr[hg19]; 136,2266,406,733), via the conducted aCGH analysis. A literature search using the University of Santa Cruz genome browser ( http://genome.ucsc.edu/ ) and Online Mendelian Inheritance in Man (OMIM) database ( http://www.omim.org/ ) identified ZMYND11 and TGIF1 (located at 10p15.3 and 18p11.3, respectively) as potential causative genes for the proband's observed GDDS phenotype. Coe et al recently reported loss-of-function mutations in ZMYND11 in 7 individuals from 6 families. [6] One of these familial cases comprised a male individual observed to exhibit GDDS, as well as delayed speech, social and behavioral difficulties, and dysmorphic facial features. Moreover, his father exhibited a milder version of this phenotype, comprising GDDS, and behavioral difficulties including aggressive childhood behavior and mood swings. In general, patients with mutations in ZMYND11 exhibit a mild intellectual disability, and subtle facial malformations that may include hypertelorism, ptosis, and/or a wide mouth. Both of the females studied by Coe et al were described as having autistic tendencies, and 3 of the 4 studied males exhibited increased aggression. Taken together, these results support those of the present study, and suggest that ZMYND11 is a promising candidate causative gene for GDDS. In contrast, TGIF1 is a dosage-sensitive gene, and TGIF1 haploinsufficiency is established to induce various human disorders (OMIM: 142946). [7] However, the proband in the present study harbors a chromosome 18 duplication that includes TGIF1 , while she was not observed to exhibit any related clinical phenotypes.

The aCGH technique is routinely used to detect chromosomal imbalances since it enables researchers to achieve a very high level of resolution without requiring specific probes for target sub-regions. It is well established to be effective in detecting CNVs, long-term continuous homozygosity, and chimeras (at a rate of greater than 20%), but it is unable to detect balanced chromosomal translocations such as reciprocal and/or Robertson translocations, inversions, and balanced insertions. [8] It is also unable to detect point mutations, and/or pathogenic tandem repeats (as observed in Fragile-X Syndrome). In the present study, the proband's father was identified as a chr18p–10p-balanced translocation carrier; however, the results of his karyotype and aCGH analyses showed no cytogenetic abnormalities. This is because while large balanced translocations can be identified via a conventional karyotype analysis, small balanced translocations must be detected via more sensitive methods than aCGH. Importantly, this emphasizes the fact that failure of these techniques to detect chromosomal lesion sites in the clinical setting should not be considered sufficient to exclude the possibility of their contribution to disease pathogenesis.

The American College of Medical Genetics (ACMG) has made a guideline on the cytogenetic evaluation of the individual with DD or MR in 2005. And it also made guidance for constitutional cytogenomic microarray analysis to explain CNV. For any child with unexplained MR/DD, even in the absence of dysmorphic facial features, other clinical features or positive family history, routine chromosome analysis is indicated according to these advices of ACMG. FISH or other molecular techniques should be performed before or at the same time as with chromosome analysis for children with clinical features suggestive of a particular microdeletion/microduplication syndrome. [9] In general, unaffected parent carried the detected CNV in patient with MR/DD, which it may be taken as evidence that supports the CNV as unrelated to the clinical features and likely benign in the patient. [10–12] In our study, no abnormal findings were present in karyotype analysis for all individuals, but a microdeletion of chromosome 10 with a microduplication of chromosome 18 was found in patient. For this situation, some doctors may regard the parents as normal individuals, while the patient carried a de novo variation of CNV. Notably, minor balanced translocation between chromosome 10 and 18 may be present in proband's parents, and the results of FISH confirmed our speculation in proband's father. Although our study only involved a rare case, it was important supplementary information to the current guidelines, especially in some special families similar to our case, where the results of FISH in proband's parents will help us identify the genetic pathogenesis.

The present study also demonstrates that the efficacy of genetic counseling in advising patients and their relatives of the risks and consequences associated with an inherited disorder, (particularly with regards to fertility management and family planning), is highly dependent upon the provision of an accurate patient medical history. The present study was initially hampered because the proband's parents did not disclose their full family medical history until a potential genetic basis of the observed GDDS was identified.

Ensuring that accurate genetic counseling is available to the families of patients with GDDS is essential, since the identification of the underlying disease pathogenesis in each GDDS case may facilitate the provision of tailored symptomatic treatment and/or rehabilitation services, thus ensuring that affected individuals are adequately supported. [13] In fact, children with GDDS are usually able to learn in a similar way to most children unaffected by the disorder, but take longer, and require additional support to acquire and develop new skills. Effective genetic counseling may allow the families of patients with GDDS to anticipate their current and future needs, and to thus to psychologically and financially prepare for the provision of future treatments and rehabilitation. This may, in turn, reduce the familial stress caused by the high level of care required to support patients in daily activities (such as eating, dressing, communicating, etc), and by parental anxiety for the future wellbeing of patients with this disorder.

Author contributions

Conceptualization: Danyan Zhang.

Data curation: Yijian Zhu, Xuefei Feng, Letian Zhao, Yuping Zhang.

Formal analysis: Limeng Dai.

Investigation: Xuefei Feng.

Methodology: Danyan Zhang, Mingfu Ma, Lianbing Li.

Project administration: Yijian Zhu, Hong Guo.

Resources: Limeng Dai, Hong Guo, Yuping Zhang.

Supervision: Danyan Zhang, Xuefei Feng, Limeng Dai, Mingfu Ma, Yun Bai.

Validation: Yijian Zhu, Xuefei Feng, Letian Zhao.

Visualization: Lianbing Li.

Writing – original draft: Danyan Zhang, Yun Bai.

Writing – review and editing: Danyan Zhang.

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comparative genomic hybridization; developmental delay; microdeletion; microduplication

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• Child with global developmental delay presenting with autistic features
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• http://orcid.org/0000-0002-9987-4255 Ruziana Masiran 1 , 2 and
• Mohamad Nizam Adha Ilias 2
• 1 Department of Psychiatry , Universiti Putra Malaysia , Serdang , Selangor , Malaysia
• 2 Department of Psychiatry , Hospital Sultan Abdul Aziz Shah , Serdang , Selangor , Malaysia
• Correspondence to Dr Ruziana Masiran; ruziana_m{at}upm.edu.my

https://doi.org/10.1136/bcr-2023-257293

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• Child and adolescent psychiatry
• Developmental paediatrocs

Description

A school-aged girl with underlying global developmental delay (GDD) diagnosed during her early childhood presented to the psychiatrist with repetitive disruptive behaviour of hitting her face with her own hands for one year duration. Her parents noticed that these behaviours would often be triggered when she was introduced to a new place or left alone in her room. She also had insomnia. During examination, the child appeared distracted and could not form meaningful eye contact. She was crying as she was entering the consultation room. She repeatedly placed her palms over her mouth, sometimes licking her palms (see video 1 ). There was also an increasing frequency of hitting one hand with another palm of her hand. She was not able to verbalise any comprehensible words. Antenatally, her conception was unexpected, as her mother had earlier performed bilateral tubal ligation after her fifth delivery. There was evidence of intrauterine growth retardation, but she was born at term via elective caesarean section, weighing only 2 kg. She then developed severe neonatal jaundice and received phototherapy. She developed epilepsy when she was three year-old, which was controlled with syrup epilim 200 mg twice a day. Her last seizure was one year before the psychiatric contact. She had hypothyroidism when she was four year-old, controlled with oral L-thyroxine 25 mcg once a day. There were gross motor, fine motor, and social communication development delays. There is no family history of neurodevelopmental problems. Following psychiatric assessment, the child was diagnosed with intellectual disability (ID) with autistic features. This diagnosis was based on the marked social communication deficits and stereotypical patterns of behaviours that were similar to stimming in autism spectrum disorder (ASD) developed recently. She was prescribed oral risperidone 0.5 mg at night, with which her sleep and disruptive behaviours improved.

Patient’s perspective

“We have resorted to applying medicated oil on her hand to prevent her from using it to hit hear head, and also putting on gloves, but these were unsuccessful” – from the child’s mother.

Learning points

Clinicians may find diagnosing autism spectrum disorder(ASD) in a child with globally developmentally delay (GDD) an arduous task.

A child having both features of GDD and ASD may present with more challenging disruptive behaviours requiring aggressive pharmacotherapeutic interventions.

Managing disruptive behaviours in children on the spectrum requires a collaborative approach with parents and families.

Ethics statements

Patient consent for publication.

Consent obtained from parent(s)/guardian(s).

• Jung HJ , et al
• Wang T-T , et al
• Bulgheroni S ,
• Toffalini E , et al
• Miller LE ,
• Robins DL , et al
• Fehlings DL ,
• Donner EJ , et al

Contributors RM and MNAI co-managed the case. MNAI prepared the preliminary manuscript draft and RM completed the final draft.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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• DOI: 10.1111/j.1744-618X.2010.01159.x
• Corpus ID: 22024437

Case study: child with global developmental delay.

• Pearline Okumakpeyi , M. Lunney
• Published in International Journal of… 1 July 2010

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Nursing diagnoses and theoretical frameworks in neonatal units: a literature review., 2 references, the redefinition of failure to thrive from a case study perspective., identifying patterns of developmental delays can help diagnose neurodevelopmental disorders, related papers.

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• Published: 18 May 2020

Clinical Characteristics of Developmentally Delayed Children based on Interdisciplinary Evaluation

• S. W. Kim 1 ,
• H. R. Jeon 1 ,
• H. J. Jung 2 ,
• J. A. Kim 2 ,
• J.-E. Song 3 &
• J. Kim   ORCID: orcid.org/0000-0003-4693-8400 4  

Scientific Reports volume  10 , Article number:  8148 ( 2020 ) Cite this article

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• Autism spectrum disorders
• Risk factors

The aim of this study is to examine the clinical characteristics of children suspected to have neurodevelopmental disorders and to present features that could be helpful diagnostic clues at the clinical assessment stage. All children who visited the interdisciplinary clinic for developmental problems from May 2001 to December 2014 were eligible for this study. Medical records of the children were reviewed. A total of 1,877 children were enrolled in this study. Most children were classified into four major diagnostic groups: global developmental delay (GDD), autism spectrum disorder (ASD), developmental language disorder (DLD) and motor delay (MD). GDD was the most common (43.9%), and boys were significantly more predominant than girls in all groups. When evaluating the predictive power of numerous risk factors, the probability of GDD was lower than the probability of ASD among boys, while the probability of GDD increased as independent walking age increased. Compared with GDD and DLD, the probability of GDD was increased when there was neonatal history or when the independent walking age was late. Comparison of ASD and DLD showed that the probability of ASD decreased when a maternal history was present, whereas the probability of ASD increased with male gender. To conclude, the present study revealed the clinical features of children with various neurodevelopmental disorders. These results are expected to be helpful for more effectively flagging children with potential neurodevelopmental disorders in the clinical setting.

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Introduction.

Developmental disabilities caused by dysfunction of the central nervous system, including the brain, are called neurodevelopmental disorders, and children with neurodevelopmental disorders have difficulties in various fields including physical, linguistic, behavior and learning 1 . According to a previous study conducted in the United States, 5–17% of children suffer from developmental disabilities, and recent trends have shown a gradual increase 2 . Limitations due to neurodevelopmental disorders might continue throughout life, and individuals with these disorders may require special services, health care and support 3 . These factors cause enormous social costs to a country as well as economic and psychological burdens for the families of children with developmental disabilities 4 .

The cause of neurodevelopmental disorders varies, and it is difficult to distinguish between children with neurodevelopmental disorders and typically developing children in early infancy. Even if the neurodevelopmental disorder is caused by nonprogressive factors, the clinical phenotype may change over time as the central nervous system matures 5 . Therefore, children’s symptoms are different according to their age and severity, and the necessary interventions will vary accordingly. As a result, the diagnosis of a neurodevelopmental disorder can vary greatly depending on the clinician’s perspective, and the treatment or intervention or social support offered may differ according to diagnosis. The time at which an expert is consulted varies widely from newborn to school-aged 6 . As shown in previous studies 7 , 8 , intervention during the period when the brain is developing rapidly can minimize disabilities and reduce the gap in developmental delay; as such, it is important to start precise intervention early. Neurodevelopmental disorders express various features, and the degree of influence by developmental domain varies from case to case. Because of the multi-morbidity feature, attempting to intervene by focusing on only one problem can lead to not only overlooking other accompanying problems but also a problem of inefficient use of limited intervention resources.

To compensate for difficulties in dealing with the complexity of neurodevelopmental disorders, an interdisciplinary clinic named the Developmental Delay Clinic (DDC) has been operating in our hospital. In this clinic, three specialists (a pediatric neurologist, pediatric physiatrist and pediatric psychologist) work together to provide comprehensive diagnoses and intervention plans. The three specialists, depending on area of expertise, each examine children, prescribe necessary tests, share and discuss the results of physical and neurological examinations and various tests and produce a precise diagnosis with a balanced intervention plan for each child. In this study, the authors aimed to identify meaningful factors for diagnosis and to determine if it is possible to distinguish major neurodevelopmental disorders at the clinical assessment stage.

Children who visited the DDC in our hospital with complaints of any developmental problems from May 2001 to December 2014 were included in this study. The total number of subjects was 1,877. Approval to perform this retrospective study was obtained from our Institutional Review Board (IRB) and research ethics committee (National Health Insurance Medical Center, NHIMC 2015-09-016). The need for informed consent was formally waived by the IRB and research ethics committee. All methods were performed in accordance with relevant guidelines and regulations.

All patients who visited the DDC for the first time had a history taken, and data were gathered according to the prescribed protocol. Data such as birth history, prenatal history, family history and other medical history were collected from a paper questionnaire. Birth history included intrauterine period and birth weight. Prenatal history included fetal distress, problems related to amniotic fluid or placenta, intrauterine growth retardation (IUGR), and fetal movement abnormality. Events such as fetal apnea, meconium aspiration and neonatal seizures were considered in the neonatal history. Postnatal history included infections such as sepsis, infantile spasm, and febrile convulsion. The presence of family history, such as language delay, autism spectrum disorder, and intellectual disability, and maternal history during the pregnancy period, such as anxiety or insomnia, depression, smoking and drinking, were also assessed in the survey.

After assessing histories through the questionnaire, the three specialists examined the child and prescribed necessary tests according to protocol. The diagnostic protocol was composed of two categories: required tests applied to all children and selective tests applied to some patients who needed those tests, based on each specialist’s judgment 9 (Fig.  1 , Supplementary 1).

Diagnostic protocol for children visited developmental delay clinic.

The diagnosis was determined by discussion among the three specialists in reference to each child’s clinical findings and standardized developmental assessment results. The diagnoses were divided into two categories: either a phenomenological diagnosis based on the child’s current condition or an etiological diagnosis based on the pathophysiology of the condition. All these phenomenological diagnoses were classified into four major groups according to the child’s main features: global developmental delay (GDD), autism spectrum disorder (ASD), developmental language disorder (DLD) and motor delay (MD). The GDD group included diagnoses such as GDD and intellectual disability. GDD refers to children with significant delays in more than two of the following developmental domains: gross motor/fine motor, speech/language, intelligence, social interaction and self-care. In general, children under five years of age who met the requirements were diagnosed with GDD, while older children who could be examined using a reliable and formal intelligence test were diagnosed with intellectual disability 10 . Diagnoses such as reactive attachment disorder and social communication disorder were included in the ASD group. Those in the ASD group were diagnosed based on diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition (DSM-IV) 11 . However, since it has been updated from DSM-IV to DSM-V, the term ASD is used in this paper to prevent confusion. MD was defined as significant impairment of gross and/or fine-motor function compared with other developmental domains. Cerebral palsy and developmental coordination disorder were included in this group. DLD was defined as significant impairment of speech and language ability compared with other developmental domains. In this context, “significant” meant more than two standard deviations below the average value for the same age 10 . Etiological diagnoses included chromosomal and genetic anomalies, myopathy, and metabolic disease, among others.

Statistical analysis

SAS ver. 9.2 (SAS Institute, Cary, NC, USA) was used for statistical analysis. The results of the survey were obtained using the Kruskal-Wallis test with Bonferroni correction and logistic regression analysis. The level of significance was set at p < 0.05.

A total of 1,877 children were enrolled in this study. When divided into classes according to major phenomenological diagnosis, GDD accounted for the largest number, with 824 children (43.9%), followed by ASD with 430 (22.9%), DLD with 389 (20.7%) and MD with 72 (3.8%). Only 16 children (0.9%) were finally diagnosed as developing normally after all tests and examinations were given. Boys were more predominant than girls, with 1,316 (70.1%) and 561 (29.9%), respectively (p < 0.05). The age at which children visited the DDC ranged from 2 months to 192 months, and the average age was 50.9 ± 30.0 months. The corrected age was used for preterm children until they reached two years old. Two hundred thirty-four children (12.5%) out of the total could be diagnosed with an etiological diagnosis. Among these, hypoxic ischemic encephalopathy accounted for the largest number, with 58 children (24.8%), followed by chromosomal and/or genetic abnormalities with 53 children (22.6%) and congenital anomalies of the brain with 33 children (14.0%). Among the children who underwent a brain MRI, abnormal findings were mostly found in MD with 27.8%, which was significantly higher than ASD and DLD (p < 0.05) (Table  1 ).

With respect to preterm birth (gestational age less than 37 weeks), the history of preterm birth was the most prevalent in MD (29.2%), which was significantly higher than that in GDD (12.5%), ASD (10.9%) and DLD (8.7%) (p < 0.05). A history of low birth weight (LBW, birth weight less than 2,500 grams) was most common in MD (44.4%), which was significantly higher than that in ASD (20.9%) and DLD (25.4%) (p < 0.05) but not GDD (32.5%) (p = 0.426). Prenatal histories were most prevalent in MD (5.6%), which was significantly higher than in ASD and DLD (p < 0.05). Neonatal histories were also most prevalent in MD (29.2%), which was significantly higher than in the other three groups (p < 0.05). GDD and MD had a significantly higher prevalence of postnatal history compared with ASD and DLD (p < 0.05), but the difference between GDD and MD was not significant. Among family histories, language delay was the most common across all diagnosis groups, but the prevalence of having a family history did not differ significantly among the groups (p = 0.445). With regard to maternal histories, a maternal history of having anxiety or insomnia was the most common type in GDD, ASD and DLD, but drugs or drinking alcohol were the most common in MD. The percentage of cases with a maternal history did not differ significantly across the groups (p = 0.294) (Table  2 ).

Among the various risk factors mentioned above, logistic regression analysis performed to compare the groups and to determine if certain risk factors contributed to being diagnosed with GDD, ASD and DLD. When comparing GDD with ASD, the risk of having GDD decreased with boys and the presence of family history, while the risk increased with the presence of neonatal, postnatal and maternal history, later independent walking age (a representation of delayed motor milestone) and abnormal findings in the brain MRI. After controlling for confounders, gender and independent walking age showed significant between-group differences. When comparing GDD with DLD, the risk of having GDD was lower in boys and with the presence of a family history, while the risk increased with presence of the prenatal, neonatal and postnatal history, later independent walking age and abnormal findings in the brain MRI. After controlling for confounders, neonatal history and independent walking age showed significant between-group differences. When comparing ASD with DLD, the risk of having ASD was higher in boys, while the risk decreased with the presence of maternal history. The results were the same after controlling for confounders (Table  3 , Fig.  2 ).

Distinctive clinical features among different diagnosis.

When receiver operating characteristic (ROC) curve analysis was performed to confirm the predictive power of these models, the model comparison of GDD vs. ASD and the model comparison of GDD vs. DLD showed good predictive power, while the model comparison of ASD vs. DLD had poor predictive power. Hosmer and Lemeshow’s Goodness-of-Fit Test revealed that all three logistic regression models were fit to predict the risk factors (Table  4 ).

The prevalence of developmental disabilities has risen in recent years with increases in high-risk pregnancies such as aged pregnancy, improved survival of high-risk infants due to medical technology advancement, and improved awareness and diagnosis of developmental disabilities 2 . The goal of early intervention for children with developmental disabilities is to prevent or minimize delays in all developmental domains, and early intervention allows children to achieve developmental milestones through the provision of enriched environments. Additionally, such interventions help caregivers cope efficiently with their children in daily life 12 . As seen in this study, the symptoms of children with neurodevelopmental disorders are very diverse, and the timing and symptoms of caregivers’ perception of something wrong in their children also vary. In addition, during the brain development period, one developmental domain affects the development of other domains, thus indicating multi-morbidity features. Proper intervention is important, but intervention is not always necessary. In some cases, it is more important to educate parents and modify the home environment than to use special resources. To effectively use limited resources, it is important to accurately diagnose neurodevelopmental disorders, which represent a multi-morbidity feature.

Among the patients who visited the DDC during the past 14 years, boys outnumbered girls in all diagnostic groups, which is consistent with previous studies 2 , 13 . Regarding etiological diagnosis, hypoxic ischemic encephalopathy was the most prevalent, followed by chromosomal and genetic abnormalities and congenital anomalies of the brain. These three factors accounted for 61.5% of the total etiologic causes. This outcome is similar to that of a study conducted by Shevell et al . 14 indicating that four causes, i.e., the three causes mentioned above plus poisoning, accounted for 68.9% of total cases with a known etiological basis. There were no children with poisoning in the present study, which could be due to differences in socio-cultural backgrounds. However, more attention to antenatal poisoning might be needed, based on the recent increase in poisoning cases in Korea 15 .

In cases of preterm birth and LBW, which are known as the strongest risk factors for developmental disabilities 16 , a history of preterm birth was significantly more common in MD than in GDD, ASD and DLD. In contrast, a history of LBW was not significantly different between MD and GDD. It could be posited that the risk of GDD increased in cases of small for gestational age even in full-term births. Arcangeli et al . 17 reported that compared with children of appropriate size for their gestational age, children who had a history of being small for their gestational age or who had fetal growth retardation, even in full-term births, showed lower neurodevelopmental scores. Takeuchi et al . 18 reported that being small for gestational age is a risk factor for developmental disabilities, even in full-term babies. These results were consistent with the present study, and more attentive follow-up regarding developmental course is needed for children with a history of being small for gestational age.

Kumar et al . 19 reported that the prevalence of neurodevelopmental disorders was higher in groups having family histories of neurodevelopmental disorders, such as epilepsy, GDD, MD, vision or hearing defects, compared with groups without such histories. Among the types of family histories, a history of language delay was seen the most in all diagnostic groups in this study. This finding could be explained by several factors: language delay is often present in various neurodevelopmental disorders, and the recognition and diagnosis of various neurodevelopmental disorders has improved in recent years, but this was not the case before. It may have been diagnosed as language delay 13 . In addition, it is possible that ASD has been diagnosed as other diseases, such as GDD or language delay, due to negative social perception of the diagnosis in Korea. Several studies have previously revealed that delay in one developmental domain often correlates with delay in other domains. Rechetnikov et al . 20 stated that there was a correlation between motor impairment and speech and language disorder. Wang et al . 21 reported that motor skill and communication skill were correlated with each other and that the motor skill of a one-and-a-half-year-old could predict the communication skill of a three-year-old. Language delay was predominant among the chief complaints of children who visited the DDC, but their final diagnosis was not limited to DLD. Shevell et al . 22 reported that approximately three-quarters of children who were diagnosed with DLD before their fifth birthday showed some limitation of not only language but also communication, motor skill and social function at an early school age. Overall, the physicians would carefully assess all of the developmental domains, even if the chief complaints of parents were language delay, and would also give them a proper intervention plan focusing on the other domains.

This study has a few limitations. First, it is a single-center study, and most of the included children were from a metropolitan area in the Northern Gyeonggi territory. Second, children suspected to have cerebral palsy often visited the outpatient clinic of the rehabilitation department instead of the DDC for their initial evaluation, so the proportion of children with cerebral palsy was low in this study. Third, although the diagnosis may change over time, the study was conducted based on the initial diagnosis. Nevertheless, this study is meaningful in that it is the first study to present a probabilistic model in the clinical evaluation of children with suspected neurodevelopmental disorders. Several papers on the diagnosis of neurodevelopmental disorders that suggest diagnostic steps for GDD and ASD have been published thus far 23 , 24 , 25 , 26 , 27 . However, in contrast to the present study, there were no articles suggesting probabilistic models that included comprehensive history taking and clinical diagnosis. Additionally, most previous studies were confined to one diagnosis, such as cerebral palsy or intellectual disabilities, whereas this study represents the many children who visited interdisciplinary clinics for 14 years with various chief complaints about development.

In conclusion, the present study revealed the clinical characteristics of children who have developmental problems. In this study, we present a feature that can aid diagnosis in the stage of clinical evaluation for children with suspected neurodevelopmental disorders. These results are expected to be helpful for more effectively identifying children with potential neurodevelopmental disorders in the clinical setting.

Kaufmann, W. E., Capone, G. T., Carter, J. C., Lieberman, D. N. & Disability, G. I. Capute and Accardo’s Neurodevelopmental Disabilities in Infancy and Childhood . (Paul H. Brookes Publishing Company Baltimore, 2008).

Boyle, C. A. et al . Trends in the Prevalence of Developmental Disabilities in US Children, 1997–2008. Pediatrics 127 , 1034–1042 (2011).

Article   Google Scholar  

Boulet, S. L., Boyle, C. A. & Schieve, L. A. Health care use and health and functional impact of developmental disabilities among US children, 1997-2005. Arch. Pediatr. Adolesc. Med. 163 , 19–26 (2009).

Anderson, D., Dumont, S., Jacobs, P. & Azzaria, L. The Personal Costs of Caring for a Child with a Disability: A Review of the Literature. Public Health Rep. 122 , 3–16 (2007).

Kaplan, B. J., Dewey, D. M., Crawford, S. G. & Wilson, B. N. The Term Comorbidity Is of Questionable Value in Reference to Developmental Disorders: Data and Theory. J. Learn. Disabil. 34 , 555–565 (2001).

Article   CAS   Google Scholar  

Yeargin-Allsopp, M., Oakley, G. P., Murphy, C. C. & Sikes, R. K. A multiple-source method for studying the prevalence of developmental disabilities in children: the Metropolitan Atlanta Developmental Disabilities Study. Pediatrics 89 , 624–630 (1992).

CAS   PubMed   Google Scholar  

Morgan, C. et al . Effectiveness of motor interventions in infants with cerebral palsy: a systematic review. Dev. Med. Child Neurol. 58 , 900–909 (2016).

Zwaigenbaum, L. et al . Early Intervention for Children With Autism Spectrum Disorder Under 3 Years of Age: Recommendations for Practice and Research. Pediatrics 136 , S60–S81 (2015).

Kim, S. W. et al . Diagnosis and Clinical Features in Children Referred to Developmental Delay Clinic. J. Korean Acad. Rehabil. Med . 28 , 132–139 (2004).

Shevell, M. I. et al . Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology 60 , 367–380 (2003).

Segal, D. L. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). In The Corsini Encyclopedia of Psychology 1–3, https://doi.org/10.1002/9780470479216.corpsy0271 (American Cancer Society, 2010).

Majnemer, A. Benefits of early intervention for children with developmental disabilities. Semin. Pediatr. Neurol. 5 , 62–69 (1998).

Baio, J. Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators; Centers for Disease Control and Prevention (CDC). Prevalence of autism spectrum disorder among children aged 8 years—Autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill. Summ. 63 , 1–21 (2014).

ADS   Google Scholar  

Shevell, M. I., Majnemer, A., Rosenbaum, P. & Abrahamowicz, M. Etiologic yield of subspecialists’ evaluation of young children with global developmental delay. J. Pediatr. 136 , 593–598 (2000).

Yoon, M. S. The current situation and developmental direction of Korean addiction service delivery system. Ment Health Soc Work 35 , 234–266 (2010).

Google Scholar  

Salas, A. A. et al . Gestational age and birthweight for risk assessment of neurodevelopmental impairment or death in extremely preterm infants. Arch. Dis. Child.-Fetal Neonatal Ed. 101 , F494–F501 (2016).

Arcangeli, T., Thilaganathan, B., Hooper, R., Khan, K. S. & Bhide, A. Neurodevelopmental delay in small babies at term: a systematic review. Ultrasound Obstet. Gynecol. 40 , 267–275 (2012).

Takeuchi, A. et al . Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese population-based study. Brain Dev. 38 , 529–537 (2016).

Kumar, R., Bhave, A., Bhargava, R. & Agarwal, G. G. Prevalence and risk factors for neurological disorders in children aged 6 months to 2 years in northern India. Dev. Med. Child Neurol. 55 , 348–356 (2013).

Rechetnikov, R. P. & Maitra, K. Motor impairments in children associated with impairments of speech or language: A meta-analytic review of research literature. Am. J. Occup. Ther. 63 , 255–263 (2009).

Wang, M. V., Lekhal, R., Aarø, L. E. & Schjølberg, S. Co-occurring development of early childhood communication and motor skills: results from a population-based longitudinal study. Child Care Health Dev. 40 , 77–84 (2014).

Shevell, M. I., Majnemer, A., Webster, R. I., Platt, R. W. & Birnbaum, R. Outcomes at school age of preschool children with developmental language impairment. Pediatr. Neurol. 32 , 264–269 (2005).

Moeschler, J. B. & Shevell, M. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics 117 , 2304–2316 (2006).

Moeschler, J. B. & Shevell, M. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 134 , e903–e918 (2014).

Bélanger, S. A. & Caron, J. Evaluation of the child with global developmental delay and intellectual disability. Paediatr. Child Health 23 , 403–410 (2018).

Charman, T. & Gotham, K. Measurement Issues: Screening and diagnostic instruments for autism spectrum disorders–lessons from research and practise. Child Adolesc. Ment. Health 18 , 52–63 (2013).

Charman, T. & Baird, G. Practitioner review: Diagnosis of autism spectrum disorder in 2-and 3-year-old children. J. Child Psychol. Psychiatry 43 , 289–305 (2002).

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S.W., H.J. and J.-E. conceived of the presented concept and revised the article. J.K. and H.R. developed the theory, interpreted of data and drafted the article. J.A. collected and analyzed the data and drafted the article. All authors discussed the results and contributed to the final manuscript and had complete access to the study data that support the publication. All authors read and approved the final manuscript.

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Kim, S.W., Jeon, H.R., Jung, H.J. et al. Clinical Characteristics of Developmentally Delayed Children based on Interdisciplinary Evaluation. Sci Rep 10 , 8148 (2020). https://doi.org/10.1038/s41598-020-64875-8

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Child with Global Developmental Delay

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Global developmental delay (GDD) is a common finding in the pediatric population and is found in 1–3% of children under the age of 5 years. GDD is etiologically diverse. A comprehensive assessment with thorough history and physical examination can help determine the next best diagnostic steps for evaluating these patients. Up to 25–50% of children with GDD will have an identified genetic etiology. Specific guidelines exist for recommended genetic testing in this population, though these are likely to change with recent advances in genetic medicine. Early diagnosis of GDD and identification of the specific etiology can help improve outcomes in many cases, allowing for earlier therapeutic intervention and identifying other associated health issues that may be subsequently managed.

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Diagnosis and management of global development delay: consensus guidelines of growth, development and behavioral pediatrics chapter, neurology chapter and neurodevelopment pediatrics chapter of the indian academy of pediatrics.

Moeschler JB, Shevell M, Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014;134(3):e903–18.

Article   Google Scholar  

Brown KA, Parikh S, Patel DR. Understanding basic concepts of developmental diagnosis in children. Transl Pediatr. 2020;9(Suppl 1):S9–22.

Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the quality standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2003;60(3):367–80.

Article   CAS   Google Scholar  

American Psychiatric Association. Intellectual disabilities [Internet]. 2013. https://www.psychiatry.org/psychiatrists/practice/dsm/educational-resources/dsm-5-fact-sheets .

Chen I-C, Chen C-L, Wong M-K, Chung C-Y, Chen C-H, Sun C-H. Clinical analysis of 1048 children with developmental delay. Chang Gung Med J. 2002;25(11):743–50.

Google Scholar  

Srour M, Mazer B, Shevell MI. Analysis of clinical features predicting etiologic yield in the assessment of global developmental delay. Pediatrics. 2006;118(1):139–45.

Han JY, Jang W, Park J, Kim M, Kim Y, Lee IG. Diagnostic approach with genetic tests for global developmental delay and/or intellectual disability: single tertiary center experience. Ann Hum Genet. 2019;83(3):115–23.

Mithyantha R, Kneen R, McCann E, Gladstone M. Current evidence-based recommendations on investigating children with global developmental delay. Arch Dis Child. 2017;102(11):1071–6.

Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil. 2011;32(2):419–36.

Jimenez-Gomez A, Standridge SM. A refined approach to evaluating global developmental delay for the international medical community. Pediatr Neurol. 2014;51(2):198–206.

Liao L-H, Chen C, Peng J, Wu L-W, He F, Yang L-F, et al. Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China. Chin Med J. 2019;132(13):1533–40.

Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–64.

Miclea D, Peca L, Cuzmici Z, Pop IV. Genetic testing in patients with global developmental delay/intellectual disabilities. A review. Clujul Med. 2015;88(3):288–92.

de Ligt J, Willemsen MH, van Bon BWM, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367(20):1921–9.

Hamdan FF, Srour M, Capo-Chichi J-M, Daoud H, Nassif C, Patry L, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014;10(10):e1004772.

The Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519(7542):223–8.

Hersh JH, Saul RA, Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127(5):994–1006.

Sempere A, Arias A, Farré G, García-Villoria J, Rodríguez-Pombo P, Desviat LR, et al. Study of inborn errors of metabolism in urine from patients with unexplained mental retardation. J Inherit Metab Dis. 2010;33(1):1–7.

Engbers HM, Berger R, van Hasselt P, de Koning T, de Sain-van der Velden MGM, Kroes HY, et al. Yield of additional metabolic studies in neurodevelopmental disorders. Ann Neurol. 2008;64(2):212–7.

Papavasiliou AS, Bazigou H, Paraskevoulakos E, Kotsalis C. Neurometabolic testing in developmental delay. J Child Neurol. 2000;15(9):620–2.

Srour M, Shevell M. Genetics and the investigation of developmental delay/intellectual disability. Arch Dis Child. 2014;99(4):386–9.

Lehner DC, Sadler LS. Toddler developmental delays after extensive hospitalization: primary care practitioner guidelines. Pediatr Nurs. 2015;41(5):236–42.

US Department of Health and Human Services. Toxicological profile for lead. North Charleston: Createspace Independent Publishing Platform; 2014.

American Academy of Pediatrics Committee on Environmental Health. Lead exposure in children: prevention, detection, and management. Pediatrics. 2005;116(4):1036–46.

Stoltzfus RJ. Iron-deficiency anemia: reexamining the nature and magnitude of the public health problem. Summary: implications for research and programs. J Nutr. 2001;131(2S-2):697S–700S; discussion 700S–701S.

Saloojee H, Pettifor JM. Iron deficiency and impaired child development. BMJ. 2001;323(7326):1377–8.

Firth HV, Hurst JA, editors. Congenital hypothyroidism. In: Oxford desk reference: clinical genetics and genomics. 2nd ed. London: Oxford University Press; 2017. p. 116–8.

Bélanger SA, Caron J. Evaluation of the child with global developmental delay and intellectual disability. Paediatr Child Health. 2018;23(6):403–19.

Silove N, Collins F, Ellaway C. Update on the investigation of children with delayed development: investigation of developmental delay. J Paediatr Child Health. 2013;49(7):519–25.

Naughton AM, Maguire SA, Mann MK, Lumb RC, Tempest V, Gracias S, et al. Emotional, behavioral, and developmental features indicative of neglect or emotional abuse in preschool children: a systematic review: a systematic review. JAMA Pediatr. 2013;167(8):769–75.

McDonald JL, Milne S, Knight J, Webster V. Developmental and behavioural characteristics of children enrolled in a child protection pre-school: child development in maltreatment. J Paediatr Child Health. 2013;49(2):E142–6.

Murias K, Moir A, Myers KA, Liu I, Wei X-C. Systematic review of MRI findings in children with developmental delay or cognitive impairment. Brain Dev. 2017;39(8):644–55.

Presson AP, Partyka G, Jensen KM, Devine OJ, Rasmussen SA, McCabe LL, et al. Current estimate of Down Syndrome population prevalence in the United States. J Pediatr. 2013;163(4):1163–8.

Jones KL, Jones MC, del Campo M, editors. Recognizable patterns of malformation. In: Smith’s recognizable patterns of human malformation: Expert consult—online and print. 7th ed. London: W B Saunders; 2013. p. 7–23.

Flore LA, Milunsky JM. Updates in the genetic evaluation of the child with global developmental delay or intellectual disability. Semin Pediatr Neurol. 2012;19(4):173–80.

Firth HV, Hurst JA, editors. Fragile X syndrome (FRAX). In: Oxford desk reference: clinical genetics and genomics. 2nd ed. London: Oxford University Press; 2017. p. 424–6.

Vissers LELM, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17(1):9–18.

Eun S-H, Hahn SH. Metabolic evaluation of children with global developmental delay. Korean J Pediatr. 2015;58(4):117–22.

Committee on Children with Disabilities. Developmental surveillance and screening of infants and young children. Pediatrics. 2001;108(1):192–6.

Riou EM, Ghosh S, Francoeur E, Shevell MI. Global developmental delay and its relationship to cognitive skills. Dev Med Child Neurol. 2009;51(8):600–6.

Hoyme HE. Minor malformations. Am J Dis Child. 1987;141:947.

Firth HV, Hurst JA, editors. Coarse facial features. In: Oxford desk reference: clinical genetics and genomics. 2nd ed. London: Oxford University Press; 2017. p. 106–8.

Lisi EC, Cohn RD. Genetic evaluation of the pediatric patient with hypotonia: perspective from a hypotonia specialty clinic and review of the literature: review. Dev Med Child Neurol. 2011;53(7):586–99.

Schaefer GB, Bodensteiner JB. Radiological findings in developmental delay. Semin Pediatr Neurol. 1998;5(1):33–8.

van Karnebeek CDM, Jansweijer MCE, Leenders AGE, Offringa M, Hennekam RCM. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet. 2005;13(1):6–25.

Tremblay I, Janvier A, Laberge A-M. Paediatricians underuse recommended genetic tests in children with global developmental delay. Paediatr Child Health. 2018;23(8):e156–62.

Borch LA, Parboosingh J, Thomas MA, Veale P. Re-evaluating the first-tier status of fragile X testing in neurodevelopmental disorders. Genet Med. 2020;22(6):1036–9.

Weinstein V, Tanpaiboon P, Chapman KA, Ah Mew N, Hofherr S. Do the data really support ordering fragile X testing as a first-tier test without clinical features? Genet Med. 2017;19(12):1317–22.

Stojanovic JR, Miletic A, Peterlin B, Maver A, Mijovic M, Borlja N, et al. Diagnostic and clinical utility of clinical exome sequencing in children with moderate and severe global developmental delay/intellectual disability. J Child Neurol. 2020;35(2):116–31.

Clark MM, Stark Z, Farnaes L, Tan TY, White SM, Dimmock D, et al. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. npj Genom Med [Internet]. 2018;3(1). https://doi.org/10.1038/s41525-018-0053-8

Wetterstrand KA. DNA sequencing costs: data from the NHGRI genome sequencing program (GSP) [Internet]. Genome.gov . [cited 2020 Dec 18]. http://www.genome.gov/sequencingcostsdata .

Srivastava S, Love-Nichols JA, Dies KA, Ledbetter DH, Martin CL, Chung WK, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med. 2019;21(11):2413–21.

Cloet E, Leys M, De Meirleir L. Access to early diagnostics, intervention, and support for children with a neurobiological developmental delay or disorder. Dev Med Child Neurol. 2017;59(12):1215–6.

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Flore, L.A., Campbell, S. (2022). Child with Global Developmental Delay. In: Kamat, D.M., Sivaswamy, L. (eds) Symptom-Based Approach to Pediatric Neurology . Springer, Cham. https://doi.org/10.1007/978-3-031-10494-7_3

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Article Contents

Etiology of gdd and id, additional investigations, recommendations, acknowledgements, canadian paediatric society mental health and developmental disabilities committee.

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Evaluation of the child with global developmental delay and intellectual disability

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Stacey A Bélanger, Joannie Caron, Evaluation of the child with global developmental delay and intellectual disability, Paediatrics & Child Health , Volume 23, Issue 6, September 2018, Pages 403–410, https://doi.org/10.1093/pch/pxy093

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Global developmental delay (GDD) and intellectual disability (ID) are common concerns in the paediatric setting. Etiologies of both conditions are highly heterogeneous. The American Academy of Pediatrics, the American Academy of Neurology and the British Columbia-based Treatable Intellectual Disability Endeavor (TIDE) protocol have each proposed multitiered investigations of GDD/ID to guide physicians toward an understanding of etiology that optimizes therapeutic yield. This statement provides a framework for the clinical investigation of GDD/ID in children, along with an updated protocol for Canadian physicians to follow in the etiological investigation of GDD/ID. The revised protocol is based on current knowledge and existing guidelines. Key elements of investigation include formal vision and hearing testing, chromosomal microarray, Fragile-X DNA testing and first-tier testing for treatable inborn errors of metabolism. Brain imaging is recommended in the presence of specific neurological findings.

Global developmental delay (GDD) and intellectual disability (ID) affect up to three per cent of the paediatric population ( 1 , 2 ). The diagnosis of GDD is limited to children younger than 5 years old, but these children often evolve to meet diagnostic criteria for ID and probably represent the same population ( Table 1 ). Because the etiological diagnoses of GDD and ID overlap, it is natural that investigations in pursuit of a definitive diagnosis for either disorder are similar. Early detection is crucial for initiating rehabilitation services and treatment as soon as possible. The etiology of GDD/ID can be identified in many cases (40% to 80%) ( 3 ). Therefore, it is essential that general paediatricians in Canada coordinate the etiological evaluation of this patient population with subspecialists, using an integrative approach.

Diagnostic criteria

Data taken from refs. ( 1 , 2 ). SD Standard deviation

*The various levels of severity are no longer based on the intellectual quotient (IQ) but are, rather, defined by adaptive functioning ( 1 ).

A diagnosis is critical because it allows for ( 2 ):

Timely initiation of causal treatment or supportive management,

Prevention of complications,

Improved prognostication,

Accurate genetic counselling regarding recurrence risk and prenatal/preimplantation genetic diagnosis, when indicated,

Better access to services in the community, and

Resolution of a diagnostic odyssey or (better still) avoidance of inappropriate, costly and traumatizing tests.

The goal of this statement is to provide a framework for etiological investigation of GDD/ID in children that helps clinicians to implement evidence-based guidelines. We also propose a stepwise approach suited for clinical practice in Canada, always understanding that it must be tailored to the specific clinical context and availability of local resources.

The probability of finding an etiological diagnosis varies in different studies and according to the kind of investigation and the severity of GDD/ID. In severe ID (as defined in DSM-5), an identifiable cause was detected in up to 80% of cases ( 4 , 5 ). The yield appears to be lower in mild ID, with a cause identified in approximately 24% of cases ( 6 ). The categories of etiological diagnosis and proportion of diagnostic yield for the most common diagnoses are presented in Table 2 .

Causes of global developmental delay/intellectual disability

Data taken from ref. ( 3 ).

*Percentage of total cases of GDD/ID with an identified etiologic diagnosis who fall into this specific category.

Etiological investigation

Algorithms recommended by the American Academy of Pediatrics (AAP) ( 2 ), the American Academy of Neurology (AAN) ( 4 ) and the Treatable Intellectual Disability Endeavour (TIDE) protocol ( 5 ) are intended to simplify investigation of GDD/ID by limiting tests that are time-consuming or not clinically relevant and to promote efficient use of limited health care resources.

Each algorithm was developed to screen for the most common or treatable etiologies first. By contrast, other pathways propose an approach based on checklists and likelihood ratio models, stopping investigation when the clinician feels that it would not alter outcome, even without a diagnosis ( 3 ). One important ‘clinical pearl’ is to look for clinical characteristics pointing toward a specific etiology and order testing for that diagnosis first. When no apparent cause can be identified, a stepwise approach—conducted in collaboration with a geneticist—is recommended, with paediatricians leading the investigation whenever possible. See Figure 1 for a suggested approach to testing.

Algorithm for investigating global developmental delay or intellectual disability. Figure available in colour online. EEG Electroencephalogram; GDD Global developmental delay; ID Intellectual disability; MRI magnetic resonance imaging; XLID X-linked intellectual disability

History and physical examination

In one recent review, an etiological diagnosis based on history and physical examination was found in 12.5% to 38.6% of cases ( 3 ), confirming that these steps mark the most important phase of investigation ( 2 , 3 , 7 , 8 ). A three-generation family history, a psychosocial history, detailed prenatal and birth histories and the timing of major milestones should be recorded as accurately as possible ( Table 3 ). A neurodevelopmental assessment, including current developmental level and a systematic physical examination ( Table 3 ) can either point toward a specific diagnosis or guide laboratory testing. When a specific etiology is suspected at that point or when a family history of disorder associated with GDD/ID has been established, specific testing for this disorder should be ordered first ( Figure 1 ).

History and physical and neurodevelopmental exams

GDD Global developmental delay; ID Intellectual disability

Sensory evaluation

According to the AAN ( 4 ) and other reviews ( 5 , 7 , 9 ), children with GDD/ID should be referred for a formal assessment of their vision (optometry or ophthalmology) and hearing. Identifying a sight or hearing deficit can alter management course and guide further investigation.

Genetic testing

Chromosome microarray.

The use of chromosome microarray (CMA, also referred to as comparative genomic hybridization or CGH) as a first-line investigation in children with GDD/ID, is endorsed by the AAP, the AAN, the International Standard Cytogenetic Array and the American College of Medical Genetics ( 2 , 4 , 9 , 10 ). It is the single test with the best diagnostic yield ( 7 , 8 ) (at 8% to 20%), exceeded in efficacy only by clinical evaluation from an experienced clinician specializing in GDD/ID ( 2 , 4 , 11 ). The variation in yield reported in different studies can be explained by the absence of stratification for severity and the presence of other anomalies. Therefore, it remains uncertain whether CMA is useful in mild (according to DSM-5) familial ID. Those patients could simply represent the lower percentiles of the IQ Gauss curve and the etiologies are often multifactorial. When multiple congenital anomalies are present, the American College of Medical Genetics still recommends CMA as a first-line investigation, unless a specific diagnosis is being considered ( 10 ).

The use of standard karyotyping is not recommended as a first-line test, because its sensitivity is less than one-half that of CMA in children diagnosed with GDD/ID. The resolution of conventional chromosomal analysis is 5 Mb to 10 Mb compared with 0.05 Mb to 0.1 Mb with CMA. However, karyotyping is recommended instead of CMA for clinically suspected aneuploidy (e.g., Turner syndrome, trisomy 21) or a family history of chromosomal rearrangements or multiple spontaneous abortions ( 4 , 12 ). For the latter scenario, parental chromosome karyotyping should be ordered first.

Fragile X DNA testing

For children with ID, Fragile X is the most common genetic cause, representing 2% to 6% of affected boys and 1% to 4% of affected girls. Because the clinical phenotype is often nonspecific in infants and young children with Fragile X, AAP and AAN guidelines both recommend that Fragile X DNA (FMR1) testing be considered as part of first-line investigation for boys and girls with GDD/ID as defined in the DSM-5 ( 1 , 2 , 4 , 9 , 12 , 13 ). Panels for X-linked ID exist but should only be considered for families with two or more affected males. They should be guided by a geneticist ( 2 ).

Rett syndrome testing

Rett syndrome is found in 1.5% of girls with moderate-to-severe ID ( 2 ). According to the AAP and the AAN, MECP2 molecular analysis should be ordered when characteristic symptomatology is present (i.e., initially normal development followed by loss of speech and purposeful hand use, stereotypical hand movement, gait abnormalities) or for moderately-to-severely affected girls ( 2 , 4 ).

Whole-exome or -genome sequencing

Whole-exome sequencing permits analysis of coding regions for known genes and the identification of causal mutations in up to 40% of patients with severe ID ( 14 ). This relatively new technique is becoming clinically accessible at lower cost in some regions of Canada. Variations of unknown significance are still a challenge and need to be interpreted with caution. Given these limitations, exome or genome sequencing is not actually recommended for primary care physicians but may become a first-line investigation in the near future. Use of this test by medical geneticists in moderate-to-severe ID or in syndromic cases is endorsed by the Canadian College of Medical Geneticists ( 15 ).

Metabolic workup

Red flags suggestive of an inborn error of metabolism (IEM) are listed in Table 4 . Even if these findings, when present, raise the diagnostic yield of a metabolic workup, some IEMs present in a more subtle manner ( 5 ). In 2011, the AAN recommended that metabolic testing be performed only in the presence of strong clinical suspicion, in the absence of neonatal screening or after genetic testing and neuroimaging have not been diagnostic ( 4 ). As Canada does not have a universal newborn screening panel for hereditary disorders, neonatal screening programs vary among provinces/territories. Even with an effective screening program, some IEMs are easy to miss ( 2 , 5 ).

Red flags suggestive of inborn errors of metabolism

Data taken from ref. ( 5 ).

IEM Inborn error of metabolism ; SD Standard deviation.

While rapid access to a clinical geneticist or metabolic specialist for an evaluation identifying the most probable IEM would be ideal, it is not a reality in most of Canada. Also striking is that as much as two-thirds of children with GDD/ID have no recognizable pattern of symptoms pointing toward a specific diagnosis. Nonspecificity often precludes the timely identification of a potentially treatable disorder, especially in late-onset disorders or in milder cases, where complete symptomatology has not developed. The typical metabolic workup (lactate, ammonia, chromatography of plasma amino acids and urinary organic acids) has a diagnostic yield of less than 1% to 5% ( 7 ), therefore supporting testing only when clinical red flags are present. However, previous studies were designed to identify an etiological yield and ignored the ‘therapeutic yield’ (i.e., the identification of a treatable disorder). Series with a more extended metabolic workup revealed a yield of more than 5% ( 5 ). It is also known that many treatable causes of GDD/ID do not present with developmental regression ( 5 ). One Canadian initiative from the B.C. Children’s Hospital ( 5 ), based on a review of the literature ( 16 , 17 ) identifying 89 IEMs amenable to treatment ( 17 ), aims to identify diseases before they become severe or irremediable complications develop. This protocol proposes a two-tiered algorithm. Tier 1 comprises a group of tests capable of identifying at least three IEMs, along with being readily accessible, minimally invasive and economical (in Vancouver, the whole test group costs about $528).

First-tier tests can identify 60% of currently known treatable IEMs causing ID. TreatableID.org is a web app ( www.treatable-id.org ) containing an algorithm that is regularly updated and describes 81 treatable IDs by their biochemical defects, diagnostic tests, clinical features and treatment modalities ( 17 ). The algorithm developers recommend tier-1 testing before genetic testing and neuroimaging, emphasizing the treatable nature of the disorders included and the relative urgency to identify them. The AAP recommends considering a metabolic workup at the same time or soon after CMA and Fragile X DNA testing ( 2 ). Tier-1 content is the same for both groups, except for the addition of copper and ceruloplasmin in the TIDE protocol. The AAN adds basic metabolic tests that can guide further testing: blood sugar, blood gas, lactate and creatine kinase. Table 5 and Figure 1 summarize first-tier laboratory investigations that should be ordered for all patients whose GDD/ID presents without a recognizable constellation of symptoms. An evaluation or a discussion with a metabolics specialist should be considered in the presence of red flags to tailor the laboratory investigation to that specific patient.

Tier-1 laboratory investigations for unexplained GDD/ID

ALT Alanine aminotransferase; AST Aspartate aminotransferase; GDD Global developmental delay; ID Intellectual disability; TSH Thyroid-stimulating hormone .

*Perform testing after 4 h to 8 h of fasting. **Recommended tier-1 test in the TIDE protocol, but not by AAP, AAN. Consider as a first-line investigation when hepatomegaly, dystonia, abnormal liver function findings are present. ***Clinical expert recommendation only. Consider biotinidase testing when severe hypotonia, seizures are present.

Thyroid testing

Hypothyroidism is a common, reversible cause of GDD/ID, with an incidence of approximately 1 out of 3,500 live births. Many study authors recommend screening for thyroid function ( 9 ), but the AAN states that the test does not need to be repeated when newborn screening is present ( 4 ). It is included in tier 1 ( Table 5 ) whether or not newborn screening is performed, such that acquired cases and hypothyroidism cases of hypothalamic or pituitary origin are not missed.

Iron, vitamin B12

An Australian group ( 9 ) recommends including complete blood count, ferritin and vitamin B12 in the initial workup of children with GDD/ID, especially when there is a history of pica or feeding restrictions. Iron deficiency anemia is an easily identifiable and treatable cause of altered development.

Lead poisoning can affect mental and physical development severely, especially in children younger than 5 years of age, leading to conditions such as autism spectrum disorder, loss of milestones (particularly related to language) and encephalopathy ( 18 ). The AAN is the only association to recommend lead level dosing in children with risk factors for exposure.

Testing for congenital infections

One study ( 9 ) suggests evaluating for congenital infections (TORCH: toxoplasmosis, others, rubella, CMV, herpes) when neurological anomalies, microcephaly, hearing and/or vision loss are present. Consider consulting with infectious disease specialists whenever a congenital infection is suspected.

Neuroimaging

Neuroimaging studies, including computed tomography or magnetic resonance imaging (MRI) reveal nonspecific abnormalities in approximately 30% of children with GDD/ID ([6], anywhere between 2% and 80%, depending on the study), but neuroimaging contributes to understanding the etiology underlying GDD/ID in only 0.2% to 2.2% of cases ( 2 ). The diagnostic yield for neuroimaging improves when an abnormal neurological examination, seizures or macro- or microcephaly are present. MRI is preferred to computed tomography because it is more sensitive for identifying clinically significant structural abnormalities and anomalies related to myelination and neuronal migration ( 2 , 4 , 9 ). Because sedation is often required to perform an MRI and finding an abnormality rarely leads to an etiological diagnosis, the AAP does not recommend neuroimaging as a routine investigation for children with GDD/ID. While the AAN recommends performing an MRI on all patients when chromosomal microarray, Fragile X testing and MECP2 (if indicated) have been inconclusive ( 4 ), others recommend this test only when neurological findings are present ( 9 ). According to expert opinion, a brain MRI with spectroscopy is indicated in all cases of intractable epilepsy or developmental regression.

Electroencephalogram

Uncontrolled epilepsy or epileptic syndromes, such as Landau-Kleffner syndrome, can be associated with developmental delays or regression. Seizures are a common symptom of IEMs. An electroencephalogram is justified when there is clinical suspicion of seizures, speech regression or neurodegenerative disorder ( 9 ).

A testing algorithm

A stepwise approach, based on the AAP’s 2014 policy statement, AAN’s 2011 guidelines and the TIDE protocol, with some modifications arising from the literature and expert consensus, is outlined above ( Figure 1 ).

GDD and ID are common disorders in children, and paediatricians are often involved in the etiological workup needed for diagnosis and next steps. Even if early identification and stimulation are of paramount importance, establishing an etiological diagnosis can help relieve family stress, limit invasive and inappropriate testing, guide prognosis and, in some cases, alter management and treatment and prevent complications. ‘Therapeutic yield’ is gaining on pure diagnostics as grounds for testing in this rapidly evolving field, and children with suspected GDD/ID are sure to benefit from the newer approaches described here.

The following recommendations are based on evidence-based clinical practice guidelines and expert opinion.

History and physical examination are still the best first steps for establishing a diagnosis and should be systematically conducted for each child with suspected global developmental delay (GDD) and intellectual disability (ID). When a more specific diagnosis is suspected following clinical evaluation, investigation to confirm that etiology should be ordered first.

When a specific diagnosis is not suspected following clinical evaluation, consider a stepwise approach to investigation. The scope of investigation will depend on paediatric experience, the accessibility of subspecialists and the availability of resources.

To promote an evidence-based approach to evaluating children with GDD/ID, coordinating physician efforts with testing at provincial/territorial or regional referring centres is essential.

Formal vision and hearing testing is critical for all patients with suspected GDD/ID.

When no etiological diagnosis has been identified following history and physical examination, Fragile X, chromosomal microarray, Tier-1 metabolic testing, +/- brain imaging is recommended. If the diagnosis is not established, consider consultation with genetics/metabolic specialist.

Chromosomal microarray and Fragile X DNA testing are first-line investigations for children with unexplained GDD/ID.

Evidence supports Tier-1 ( Table 5 ) testing for treatable inborn errors of metabolism (IEMs) in children with unexplained GDD/ID, even when clinical red flags are absent and a normal newborn screen has been obtained.

Brain imaging is recommended as a first-line investigation for patients with microcephaly, macrocephaly, seizures or abnormal neurological findings. For others, imaging may be postponed until first-line genetic and metabolic investigations have been performed. Consider the risks and benefits of sedation in each case. Magnetic resonance imaging (MRI) is the modality of choice.

Order lead level and iron studies for children at risk.

Whole-exome or -genome sequencing may be indicated in the clinical setting in future, when these tests are more readily available

All Canadian Paediatric Society position statements and practice points are reviewed regularly and revised as needed. Consult the Position Statements section of the CPS website www.cps.ca/en/ documents for the most current version. Retired statements are removed from the website.

This position statement has been reviewed by the Community Paediatrics Committee and the Early Years Task Force of the Canadian Paediatric Society.

Members: Debra Andrews MD (Chair), Stacey A. Bélanger MD (past Chair), Alice Charach MD, Brenda Clark MD (past member), Mark Feldman MD (Board Representative), Benjamin Klein MD, Daphne Korczak MD (past member), Oliva Ortiz-Alvarez MD

Liaisons: Sophia Hrycko MD, Canadian Academy of Child and Adolescent Psychiatry; Angie Ip MD, CPS Developmental Paediatrics Section; Aven Poynter MD, CPS Mental Health Section

Principal authors : Stacey A. Bélanger MD PhD, Joannie Caron MD

American Psychiatric Association . Intellectual disabilities . In: Diagnostic and Statistical Manual of Mental Disorders , 5th edn. Washington, D.C .: American Psychiatric Publishing, 2013 .

Google Scholar

Google Preview

Moeschler JB , Shevell M ; Committee on Genetics . Comprehensive evaluation of the child with intellectual disability or global developmental delays . Pediatrics 2014 ; 134 ( 3 ): e903 – 18 .

Jimenez-Gomez A , Standridge SM . A refined approach to evaluating global developmental delay for the international medical community . Pediatr Neurol 2014 ; 51 ( 2 ): 198 – 206 .

American Academy of Neurology . Evaluation of the Child with Global Developmental Delay . 2011 . www.aan.com/guidelines (Accessed March 17, 2017 ).

van Karnebeek CD , Stockler-Ipsiroglu S . Early identification of treatable inborn errors of metabolism in children with intellectual disability: The Treatable Intellectual Disability Endeavor protocol in British Columbia . Paediatr Child Health 2014 ; 19 ( 9 ): 469 – 71 .

Shaffer LG ; American College of Medical Genetics Professional Practice and Guidelines Committee . American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation . Genet Med 2005 ; 7 ( 9 ): 650 – 4 .

Tirosh E , Jaffe M . Global developmental delay and mental retardation–A pediatric perspective . Dev Disabil Res Rev 2011 ; 17 ( 2 ): 85 – 92 .

Wong VC , Chung B . Value of clinical assessment in the diagnostic evaluation of global developmental delay (GDD) using a likelihood ratio model . Brain Dev 2011 ; 33 ( 7 ): 548 – 57 .

Silove N , Collins F , Ellaway C . Update on the investigation of children with delayed development . J Paediatr Child Health 2013 ; 49 ( 7 ): 519 – 25 .

Manning M , Hudgins L ; Professional Practice and Guidelines Committee, American College of Medical Genetics . Array-based Technology and Recommendations for Utilization in Medical Genetics Practice for Detection of Chromosomal Abnormalities . 2010 . www.acmg.net/StaticContent/PPG/Array_based_technology_and_recommendations_for.13.pdf (Accessed March 17, 2017 ).

Sherr EH , Michelson DJ , Shevell MI , Moeschler JB , Gropman AL , Ashwal S . Neurodevelopmental disorders and genetic testing: current approaches and future advances . Ann Neurol 2013 ; 74 ( 2 ): 164 – 70 .

Flore LA , Milunsky JM . Updates in the genetic evaluation of the child with global developmental delay or intellectual disability . Semin Pediatr Neurol 2012 ; 19 ( 4 ): 173 – 80 .

Hersh JH , Saul RA ; Committee on Genetics . Health supervision for children with Fragile X syndrome . Pediatrics 2011 ; 127 ( 5 ): 994 – 1006 .

Wright CF , McRae JF , Clayton S , et al.  Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders . Genet Med 2018 .

Boycott K , Hartley T , Adam S , et al.  ; Canadian College of Medical Geneticists . The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position statement of the Canadian College of Medical Geneticists . J Med Genet 2015 ; 52 ( 7 ): 431 – 7 .

van Karnebeek CD , Stockler S . Treatable inborn errors of metabolism causing intellectual disability: A systematic literature review . Mol Genet Metab 2012 ; 105 ( 3 ): 368 – 81 .

van Karnebeek CD , Shevell M , Zschocke J , Moeschler JB , Stockler S . The metabolic evaluation of the child with an intellectual developmental disorder: Diagnostic algorithm for identification of treatable causes and new digital resource . Mol Genet Metab 2014 ; 111 ( 4 ): 428 – 38 .

Lowry JA . Childhood Lead Poisoning: Clinical Manifestations and Diagnosis . 2016 . www.uptodate.com/contents/childhood-lead-poisoning-clinical-manifestations- and-diagnosis?source=search_result&search=Childhood+lead+poisoning&selectedTitle=1%7E150 (Accessed March 17, 2017 ).

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Diagnosis and Management of Global Development Delay: Consensus Guidelines of Growth, Development and Behavioral Pediatrics Chapter, Neurology Chapter and Neurodevelopment Pediatrics Chapter of the Indian Academy of Pediatrics

Affiliations.

• 1 Department of Pediatrics, Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi. Correspondence to: Dr Monica Juneja, Director-Professor and Head, Department of Pediatrics, Maulana Azad Medical College, New Delhi. [email protected].
• 2 Department of Pediatrics, Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi.
• 3 Department of Pediatrics, Christian Medical College, Ludhiana.
• 4 Niramaya Hospital and Guidance Clinic, Chembur, Mumbai, Maharashtra.
• 5 Ummeed Child Development Centre, Mumbai, Maharashtra.
• 6 Rainbow Children's Hospital, Hyderabad.
• 7 Indian Academy of Pediatrics, Neurodevelopment Chapter.
• 8 Department of Pediatrics, MP Shah Government Medical College, Jamnagar, Gujarat.
• 9 Department of Pediatrics, MGM Medical College, Kolkata, West Bengal.
• 10 New Horizons Child Development Centre, Mumbai, Maharashtra.
• 11 Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi.
• 12 GCS Medical College, Hospital and Research Centre, Ahmedabad, Gujarat.
• 13 Department of Medical Genetics, Kasturba Medical College, Manipal, Karnataka.
• 14 Mumbai Port Trust Hospital, Mumbai, Maharashtra.
• 15 Department of Pediatric Neurology, Medical College Thiruvananthapuram, Kerala.
• 16 Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh.
• 17 Ummeid Group of Child Development Centers, Bhopal, Madhya Pradesh.
• 18 Center for Child Development and Disabilities (CCDD) Bengaluru, Karnataka.
• 19 NIMS-SPECTRUM-Child Development Research Centre (CDRC) NIMS Medicity, Thiruvananthapuram, Kerala.
• 20 Christian Medical College, Vellore, Tamil Nadu.
• 21 ASHA, Centre for Autism and Intellectual Developmental Disorders, Chandigarh.
• 22 All India Institute of Medical Sciences, Jodhpur, Rajasthan.
• 23 Bharati Vidyapeeth Medical College and Hospital, Pune, Maharashtra.
• 24 Child Development Centre, Sir Gangaram Hospital, New Delhi.
• 25 The Children's Neurodevelopmental Centre, Patna, Bihar.
• PMID: 35188106

Justification: Global developmental delay (GDD) is a relatively common neurodevelopmental disorder; however, paucity of published literature and absence of uniform guidelines increases the complexity of clinical management of this condition. Hence, there is a need of practical guidelines for the pediatrician on the diagnosis and management of GDD, summarizing the available evidence, and filling in the gaps in existing knowledge and practices.

Process: Seven subcommittees of subject experts comprising of writing and expert group from among members of Indian Academy of Pediatrics (IAP) and its chapters of Neurology, Neurodevelopment Pediatrics and Growth Development and Behavioral Pediatrics were constituted, who reviewed literature, developed key questions and prepared the first draft on guidelines after multiple rounds of discussion. The guidelines were then discussed by the whole group in an online meeting. The points of contention were discussed and a general consensus was arrived at, after which final guidelines were drafted by the writing group and approved by all contributors. The guidelines were then approved by the Executive Board of IAP.

Guidelines: GDD is defined as significant delay (at least 2 standard deviations below the mean with standardized developmental tests) in at least two developmental domains in children under 5 years of age; however, children whose delay can be explained primarily by motor issues or severe uncorrected visual/hearing impairment are excluded. Severity of GDD can be classified as mild, moderate, severe and profound on adaptive functioning. For all children, in addition to routine surveillance, developmental screening using standardized tools should be done at 9-12 months,18-24 months, and at school entry; whereas, for high risk infants, it should be done 6-monthly till 24 months and yearly till 5 years of age; in addition to once at school entry. All children, especially those diagnosed with GDD, should be screened for ASD at 18-24 months, and if screen negative, again at 3 years of age. It is recommended that investigations should always follow a careful history and examination to plan targeted testing and, vision and hearing screening should be done in all cases prior to standardized tests of development. Neuro-imaging, preferably magnetic resonance imaging of the brain, should be obtained when specific clinical indicators are present. Biochemical and metabolic investigations should be targeted towards identifying treatable conditions and genetic tests are recommended in presence of clinical suspicion of a genetic syndrome and/or in the absence of a clear etiology. Multidisciplinary intervention should be initiated soon after the delay is recognized even before a formal diagnosis is made, and early intervention for high risk infants should start in the nursery with developmentally supportive care. Detailed structured counselling of family regarding the diagnosis, etiology, comorbidities, investigations, management, prognosis and follow-up is recommended. Regular targeted follow-up should be done, preferably in consultation with a team of experts led by a developmental pediatrician/ pediatric neurologist.

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ORIGINAL RESEARCH article

A multicenter clinical study on parent-implemented early intervention for children with global developmental delay.

• 1 Department of Child Healthcare, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
• 2 Department of Child Healthcare, Chengdu Women’s and Children’s Central Hospital, Chengdu, China
• 3 Department of Rehabilitation, Children’s Hospital of Zhejiang University School of Medicine, Hangzhou, China
• 4 Department of Developmental-Behavioral Pediatrics, The First Hospital of Jilin University, Changchun, China
• 5 Department of Child Healthcare, Children’s Hospital of Fudan University at Xiamen, Xiamen, China
• 6 Department of Child Healthcare, Shanghai Maternal and Child Health Hospital of Changning District, Shanghai, China

Objective: Early identification and intervention for children with global developmental delay (GDD) can significantly improve their prognosis and reduce the possibility of developing intellectual disability in the future. This study aimed to explore the clinical effectiveness of a parent-implemented early intervention program (PIEIP) for GDD, providing a research basis for the extended application of this intervention strategy in the future.

Methods: During the period between September 2019 and August 2020, children aged 3 to 6 months diagnosed with GDD were selected from each research center as the experimental group and the control group. For the experimental group, the PIEIP intervention was conducted for the parent-child pair. Mid-term and end-stage assessments were performed, respectively, at 12 and 24 months of age, and parenting stress surveys were completed.

Results: The average age of the enrolled children was 4.56 ± 1.08 months for the experimental group ( n  = 153) and 4.50 ± 1.04 months for the control group ( n  = 153). The comparative analysis of the variation in the progress between the two groups by independent t -test showed that, after the experimental intervention, the developmental quotient (DQ) of locomotor, personal-social, and language, as well as the general quotient (GQ) of the Griffiths Mental Development Scale-Chinese (GDS-C), the children in the experimental group demonstrated higher progress than those in the control group ( P  < 0.05). Furthermore, there was a significant decrease in the mean standard score of dysfunctional interaction, difficult children and the total level of parental stress in the term test for the experimental groups ( P  < 0.001 for all).

Conclusions: PIEIP intervention can significantly improve the developmental outcome and prognosis of children with GDD, especially in the areas of locomotor, personal-social, and language.

Introduction

Global developmental delay (GDD) refers to a delay in two or more domains of development in children under the age of five years, including activities of daily living, personal social skills, motor skills, and cognitive and language/speech development ( 1 ). The developmental outcome of GDD has many possibilities. Timeous treatment and intervention for GDD can restore some of the children's measured intelligence quotient (IQ) when they reach the age of the feasible intelligence test and mitigate the onset of severe intellectual disability (ID). And those who do not intervene in a timely manner or are seriously retarded may develop into ID. The global prevalence of GDD is approximately between 1% and 3% ( 2 , 3 ). Furthermore, GDD is often caused by genetic factors (i.e., chromosomes, genes, metabolic diseases, etc.), perinatal factors (i.e., congenital infection, toxic exposure, birth injury, asphyxia, premature delivery, intracranial hemorrhage, etc.), social and cultural factors (i.e., isolation, lack of stimulation, and loss of learning opportunities), and early diseases (i.e., severe concussion, traumatic brain injury, malnutrition, poisoning, and endocrine diseases). Thus, GDD has a complex etiology and a high disability rate. Moreover, no effective cure has been discovered, which exacerbates the mental and economic burden imposed on the family and society, severely affecting the quality of the population.

The first three years of life are considered a critical period for infant brain development. During this period, neurogenesis, myelination, and synaptogenesis interact. Repeated exposure of infants to multiple types of stimulation during early growth enhances the activation of the underlying circuits in the brain and forms new neural connections. Therefore, this period is also considered important for developing the sensitivity of the infant's brain to stimulation. Scientific interventions that target this critical period of brain development are crucial for improving neural development and reducing disabilities.

Several studies have shown that parental or caregiver involvement in interventions has a positive effect on functional improvement in children with neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) ( 4 – 9 ). Furthermore, a few studies have examined family interventions for cerebral palsy ( 10 – 12 ), impaired vision ( 13 ), and school-age ID ( 14 ). But so far, including very young children in the first two years of life is relatively few, and the most commonly reported disability of child participants included was ASD ( 15 ). To date, only a few studies have investigated family interventions for children with GDD in the early postnatal period (i.e., the first three years). A previous clinical study showed that early intervention and the addition of a structured home activity program (HAP) demonstrated a positive effect on brain development in children with GDD ( 16 ). Furthermore, in 2018, several scholars published an article on the influence of parental involvement on the occupational treatment of children with GDD ( 17 ). Overall, the sample size of the two studies was small, and the initial age of intervention was relatively older (i.e., the average age of these participants at enrollment was 20.7 and 46.8 months, respectively).

Currently, there is increasing advocacy for interventions aimed at children with various types of NDDs in natural scenes ( 18 ). Particularly, families comprise the natural scenes within which children are most exposed. Hence, the active participation of parents in early intervention activities is crucial. Moreover, they play the dual roles of parents and educational trainers in the intervention of children with GDD during the first three years after birth when the brain plasticity is most strong. Thus, we designed and developed a parent-implemented early intervention program (PIEIP). Providing training for caregivers of children with GDD to accurately understand and implement family-appropriate interventions is a key feature of the PIEIP.

In addition, parents with various NDDs experience increased parenting stress in contrast to parents with children with typical development (TD) ( 19 ). However, limited studies underscore psychosocial mediators that influence parental intervention on child development outcomes. Family interventions are associated not only with parenting stress but also with developmental outcomes in children with GDD. Therefore, parenting stress is considered one of the mediators of both family interventions and developmental outcomes in children with GDD.

By conducting this multicenter pretest-posttest experimental study, we aimed to assess the effect of the PIEIP intervention for children with GDD compared to the control group based on child outcomes at 24 months. Furthermore, the target group that is likely to gain the most from early intervention needs to be chosen considering the extensive amount of time and money required for early intervention. Thus, the second aim of this study was to investigate the possible predictors of PIEIP efficacy. Possible predictors included paternal variables (i.e., parents' age, educational level, parenting stress, and family income) and child variables (i.e., age of children at enrollment, sex, gestational age, birth weight, and developmental level at baseline).

Participants and methods

Ethical approval.

This study was approved by the Ethics Committee of the Children's Hospital of Fudan University [Children's Hospital of Fudan University Ethics Protocol (2016) no.131]. This study follows the Declaration of Helsinki and informed consent was obtained from the guardian of the child with GDD.

Participants

The inclusion criteria of children with GDD were based on: (1) a chronological age ranging from 3 to 6 months (corrected age for use in premature infants); (2) the assessment of a physician and therapists where children with significant delays in two or more areas of development were diagnosed with GDD (Griffiths Mental Development Scale-Chinese (GDS-C) assessed developmental quotient (DQ) < 70); and (3) the knowledge and consent of the guardians.

The exclusion criteria comprised: (1) children diagnosed with a genetic disorder, congenital deformity, physical disability, audiovisual disability, traumatic brain injury, neurodegenerative diseases, or neuro-musculoskeletal disorders; and (2) children with other severe chronic diseases.

According to the voluntary principle of parents, children with GDD were assigned to the experimental group or the control group. For the experimental group, at least one parent was willing to attend the course and complete family training. The recruitment and follow-up flowchart is shown in Figure 1 .

Figure 1 . Recruitment and follow-up flow chart. GD, global developmental delay; PIEIP, parent-implemented early intervention program; GDS-C, Griffiths Mental Development Scale-Chinese; PSI/SF, parental stress index-short form.

Research design and process

The research design for the experimental (PIEIP intervention) group involved: (1) a baseline assessment based on basic demographic data, medical history, GDS-C and parental stress index-short form (PSI/SF); (2) Several processes followed after enrollment including (1) performing a baseline ability assessment and drafting the first family intervention training plan; (2) participation of parents in the parent class at the hospital corresponding with the current development level of children; (3) begin training in the family environment; (4) return of parents to the hospital for parent intervention skill evaluation after two weeks of parent class; (5) return home and continue training; (6) regularly (i.e., once every two months for children aged 3–6 months old and once every three months for 7–24 month-year-olds) come back to the hospital to reassess the ability of children and write the next stage of the family training plan. Furthermore, parents were required to participate in the subsequent stages of the parent class and continue family training repeatedly until the child reached 24 months of age. We summarize the process framework of PIEIP intervention with Figure 2 . All the children could be enrolled in any additional institutional therapy.

Figure 2 . The process framework of parent-implemented early intervention program (PIEIP) intervention.

Furthermore, with regard to our PIEIP: (1) Family intervention training plan formulation: we used our specific assessment scales and tools to assess the current ability of children to write 8–12-week family intervention training programs. The evaluation scale included seven aspects, namely, understanding communication, expressive communication, social interaction, play skills, fine motor skills, gross motor skills, and self-care ability. Each developmental domain had to write 3–4 training plans, namely, (1) to align development with children's current skills, (2) each training objective ought to be specific and measurable, and (3) deliverables expected to be achieved within subsequent 8–12 weeks. (2) Parent classes comprised: (1) one general course introducing the basic law of neuromotor development in children and some basic intervention-related technologies such as applied behavior analysis (ABA), types and utilization of assistance, establishing the training environment, maintaining the face-to-face position, and managing children's problematic behavior during training; (2) eight parent courses for different age stages (i.e., 3–4 months, 5–6 months, 7–9 months, 10–12 months, 13–15 months, 16–18 months, 19–21 months and 22–24 months) to introduce the developmental level of each developmental domain at this age stage. Furthermore, the parents are coached on how to encourage the development of children's corresponding skills through a variety of item games or sensory social games in the family environment. Moreover, this course includes other suggestions about integrating training goals into daily care. The teaching form first constituted theoretical teaching before transforming into a demonstration and discussion, comprising a total of 90 min. (3) Parent intervention skill evaluation: parents were required to submit two 10 to 15-minute home training videos two weeks after the parent class and rate the video clips according to a fidelity table and the guidance feedback for parents.

The control group: (1) Baseline assessment: basic demographic data, medical history, GDS-C; and PSI/SF; (2) After enrollment: parents were free to participate in any institutional-based rehabilitation, telephone follow-up occurred every three months, where parents were asked about the basic milestone level of children and providing child health care guidance until 24 months of age.

Outcome measurement

Mid-term and final assessments were conducted in the two groups at the ages of 12 months and 24 months. The content included the GDS-C and PSI/SF.

1. GDS-C: Child cognitive development before and after the intervention was evaluated ( 20 , 21 ). The Griffiths Mental Development Scale (GMDS) was originally developed by Ruth Griffiths in the United Kingdom in 1954, which is a widely used diagnostic measure in many countries and has good psychometric properties ( 22 ). And the Chinese version of the GMDS, namely GDS-C, which was used in our current study has been adapted to assess the development of Chinese children after completing the revision of China norm research in seven cities between 2009 and 2013. It displays good reliability and validity ( 21 ). To manage children in a laboratory setting, physicians assessed different aspects of mental development in infants and children through semi-structured activities. The five subscales that were administered and scored for children under two ages included locomotor [A] (assessing a child's gross motor skills including his or her balance and ability to coordinate movements), personal-social [B] (assessing a child's self-care ability and the ability of interact with other children, language [C] (assessing a child's receptive language and expressive language ability), eye-hand coordination [D] (assessing a child's fine motor skills, finger dexterity, and visual tracking, and performance [E] (assessing a child's visual spatial ability, including processing speed and accuracy). According to the Chinese norm, the raw sub-scale scores were converted into percentiles and developmental age equivalents. The DQ = developmental age/chronological age × 100. The general quotient (GQ) was derived by calculating the average of the raw scores of the five subscales. All scores were standardized (M = 100, SD = 15).

2. PSI/SF: PSI/SF is widely used clinically as a standardized tool to identify stress early in parent-child relationships ( 23 ). The PSI/SF contains 36 terms rated on a five-point Likert scale. Based on the three scales (Parental Distress (PD), Parent-Child Dysfunctional Interaction (P-CDI), and Difficult Child (DC)), the PSI/SF yielded a total stress score. Considering only the individual factors of parents as caregivers, PD was used to define caregiver stress levels. During their interactions with their children, parents perceived P-CDI as a difficult and problematic situation. Specifically, the feeling of rejection by their children comprised a form of P-CDI. Moreover, DC examined parents' perceptions of a grumpy child in the household and the child's behavioral characteristics.

Statistical analysis

SPSS software [version 26; SPSS, Inc., Chicago, IL, United States] was used to perform statistical analyses. Descriptive analysis, independent t -test, χ 2 test, paired-sample t -test, and multivariate linear regression analysis were used in this study. The significance level for all statistical methods was set at P  < 0.05.

Children's demographic characteristics and baseline development level

A total of 306 children were recruited for this study according to the criteria. The participants' characteristics are shown in Table 1 . There were no significant differences in chronological age ( t  = 0.535, P  = 0.593), sex ( χ 2  = 1.096, P  = 0.295), birth weight (Z = −0.685, P  = 0.493), delivery mode ( χ 2  = 0.511, P  = 0.475), parents' education level ( χ 2  = 0.052, P  = 0.819), family income ( χ 2  = 0.327, P  = 0.567), and parents' age ( χ 2  = 0.678, P  = 0.410) between the experimental and control groups. Table 1 shows a significant difference in gestational age (Z = −2.143, P  = 0.032).

Table 1 . Baseline characteristics of infants with GDD.

During the initial assessment, the average age of the enrolled children was 4.53 ± 1.06 [standard deviation (SD)] months. Based on the GDS-C, the pretest developmental age was 2.09 ± 1.04 months for locomotor, 2.28 ± 1.12 months for personal-social, 2.30 ± 1.13 months for language, 2.52 ± 1.29 months for eye-hand coordination and 2.72 ± 1.30 months for performance. The mean deferred times for these children were 2.44 months for locomotor, 2.25 months for personal-social, 2.23 months for language, 2.01 months for eye-hand coordination, and 1.81 months for performance. Furthermore, there was no difference in the pretest developmental age-equivalent between groups in each development domain ( P  > 0.05, for all analyses) ( Table 2 ).

Table 2 . The developmental age-equivalent at baseline of GDD children (GDS-C).

Developmental differences between the two groups before and after the intervention

During the follow-up period, the participation of 89 children was withdrawn. Consequently, a total of 217 24-month-year old children with GDD (i.e., 101 and 116 children in the experimental and control group, respectively) completed the assessment. Children with GDD showed significant improvements in development, as assessed by the GDS-C. The results of paired t -test showed that the DQ of locomotor, personal-social, language, eye-hand coordination, and performance, as well as the total GQ score in the experimental group, changed significantly after the PIEIP intervention ( P  < 0.001 for all) ( Table 3 ). Moreover, significant differences were also found in the mean DQ of the above GDS-C subscales as well as the total GQ score in the control group ( P  < 0.001 for all).

Table 3 . Comparison of pretest and posttest of the developmental quotient between two groups (GDS-C).

In the control group, locomotor ability exhibited the most significant progress, achieving an average improvement of 29.97, followed by personal-social with 25.61. However, the performance ability yielded the lowest progress, achieving an average improvement of 19.79.

After the PIEIP intervention, the language DQ score demonstrated the most progress, achieving an average improvement of 40.44 in the experimental group, followed by locomotor, with 39.60. However, the performance ability exhibited the least progress, with an average improvement of 27.42.

After continuous intervention until GDD child reached 2 years of age, an independent t -test was used to make a comparison of the progress between two groups to confirm the effectiveness of the PIEIP. The total GQ score of the experimental group made an increase of 33.49, and that of the control group made an increase of 24.32. This development progress before and after the intervention of two groups had a statistically significant difference ( P  = 0.019). It indicates that the overall progress of development in the experimental group is more than that in the control group. The comparative analysis on the differences in the progress between two groups by independent t -test also shows that, after experimental intervention, for DQ of locomotor ( P  = 0.044), personal-social ( P  = 0.033) and language ( P  = 0.002), but not eye-hand coordination ( P  = 0.113) and performance ( P  = 0.165), the children in experimental group made more progress than those in the control group ( Table 3 ). From the above results, it can be inferred that PIEIP has significant positive effects on the development of children with GDD, particularly in the locomotor, personal-social and language domains.

Comparison of the differences in pretest and posttest parenting stress standard scores between the two groups

The results of paired t -test showed that, after PIEIP interference, the children with GDD in the experimental group exhibited a significant decrease in the total level of parental stress, mean standard score of dysfunctional interaction, and difficult children ( P  < 0.001 for all) ( Table 4 ). Similarly, the mean standard score for dysfunctional interaction and the total standard scores significantly decreased in the control group ( P  < 0.001 for both). However, the mean standard score of children with difficulties showed no significant change between the pretest and posttest. An independent t -test was used to make a comparison of the parenting stress changes between two groups. The analysis result shows that, no significant difference was observed for the change in each sub-scale and the total score between the two groups ( P  > 0.05) ( Table 4 ). This indicates that the addition of PIEIP intervention has no significant effect on further reducing each subscale scores and total scores of parenting stress.

Table 4 . Comparison of pretest and posttest parenting stress standard scores between two groups (PSI/SF).

Prediction of improvement based on characteristics of parents and children

A multivariate linear regression analysis was performed and the relationships between the factors and their improvement among children and parents are shown in Table 5 . For child gender, family income, developmental age-equivalent at baseline, parents' educational level, birth weight, parents' age, and the age of children when recruited didn't have statistical difference between groups, these factors were implemented as covariates into a regression model. And the independent variables included the pretest and posttest parenting stress standard score changes and gestational age. Specifically, 0.05 and 0.1 were set as the entry and removal levels, respectively (model: stepwise). Furthermore, the significant factors ( P  < 0.05) are shown in Table 5 . The group factor was significant for most of the test items. Moreover, a decrease in parenting distress contributed significantly to the improvement in locomotor, language, eye-hand coordination, and performance domains (change in DQ score) among children with GDD.

Table 5 . Prediction of improvement by pre-intervention scores and subject characteristics.

It is widely accepted that a life routine plays the most significant role in the relationship between parental psychology and parenting. The more normal the children's daily life is, the more regularly the intervention can be implemented to yield more of an obvious effect ( 24 ). Numerous studies have shown that the cognitive, social, and emotional development of children with TD improves in the context of good interaction between caregivers and children ( 25 , 26 ). Functional and effective interactions positively influence children's cognitive abilities and overall development. However, experimental studies on the effect of parental participation on the developmental outcomes of children with GDD are limited ( 16 , 17 , 27 ).

In 2018, a study investigated the effect of parental involvement in occupational therapy on treatment outcomes in children with GDD. The study included 30 pairs of children with developmental delay (average age 46.8 ± 16.0 months) and their parents. The cognitive, social, motor, language, and self-care abilities of the children with GDD improved with increased parental involvement in treatment. This intervention is conducted primarily in a medical setting (i.e., a therapeutic room), in which parents watch or act as collaborative therapy personnel ( 17 ). Some researchers have used HAP in children with GDD. Therapists have designed the HAP to help children achieve specific goals in their daily lives. HAP is often used to supplement traditional rehabilitation training in hospitals or as an alternative intervention particularly when parents cannot bring their children to hospitals regularly. Tétreault et al. ( 27 ) found that families comprising children with GDD showed good adherence to the HAP program. Tang et al. ( 16 ) found that children who participated in HAP demonstrated more advanced progress in language, social, cognitive, and motor domains, except for self-help as compared to children who only participated in the weekly interviews. However, the duration of the treatment period was only 12 weeks. Furthermore, the overall sample size was relatively small ( n  = 70 in total) comprising participants of older age at enrollment (average age 20.7 ± 10.0 months).

There were obvious differences between our PIEIP intervention and the above-mentioned studies which also included parents in the early intervention. The PIEIP carried out closed-loop and progressive family intervention from early life (i.e., 3–6 months) until the age of two years through several processes. Namely, evaluating the current development level of children, formulating a family training plan for the subsequent 8–12 weeks, parent class correspondence with the current development level of children, family intervention implementation and parents' intervention technical feedback, regular follow-up, and the following round of parent class and family intervention implementation. Thus, in PIEIP, family members are the main body of intervention, and professionals serve as training, supervision and evaluation, forming an intervention mode of long-term cooperation and joint implementation. Through PIEIP, children with GDD can receive early and higher-frequency intervention in the family environment.

Here, compared with baseline scores, all developmental scores were improved at 2 years of age. Children who received further PIEIP demonstrated significant improvements in locomotor, personal-social, language, and general development, but not eye-hand coordination and performance, as compared to the control group. Thus, the addition of FECIP has a positive effect on the improvement of GDD children’s outcomes, especially in the field of locomotor, personal-social and language. PIEIP intervention is a naturalistic developmental–behavioral intervention. This is a class of interventions for young children with GDD that has been informed by the fields of developmental and communication sciences and applied behavior analysis. It uses a unique blend of developmental and behavioral intervention techniques. They are designed to increase the parent's responsiveness to the child's behavior and teach the child to use new communication, imitation, and play skills within ongoing interactions in daily routines. This may be the main reason for the rapid improvement of children’s personal-social and language ability after PIEIP intervention. As for the promotion of locomotor, it may be related to the fact that PIEIP intervention also introduced many parent-child sports games which are suitable for family and community environments to parents.

Parenting stress can destroy family resources and parenting efficacy, which in turn, negatively impacts the development of the child ( 28 ). Parents of children with GDD showed higher levels of stress than parents of children with TD, further affecting parent-child interaction ( 19 ). Behavioral problems among children are influenced by their parents’ negative emotions such as stress-induced restlessness. Parental involvement in early interventions for children with NDDs, such as ASD, ADHD, and GDD can increase parental pressure. However, the current study observed a significant decrease in the total level of parental stress and several subdomains at two years of age in both the experimental and control groups. And the variation in the changes between the two groups showed no statistical differences for each sub-scale or the total score. We speculated that the decrease in parenting stress from applying the PIEIP intervention may be because of established positive relationships between parents and doctors. Furthermore, by using the PIEIP, doctors can help children more effectively as it is recognized by the majority of parents. In addition, our multiple regression analysis indicated that the change in the parental stress score might be associated with the outcome of the child. These findings are consistent with previous studies on intervention models for children with NDDs, in which parental stress, especially mothers' stress, emerged as a predictor ( 18 , 29 – 31 ). Thus, we conclude that parental stress affects parents' ability to complete home training.

This study was advantageous because it comprised a multicenter intervention across multiple geographic locations in China. However, this study had some limitations. First, this study was not a randomized controlled trial (RCT) but allowed parents to voluntarily choose whether to participate in the PIEIP intervention, which may lead to inherent bias on parental variables. There are many structural barriers that can affect a parent's ability to access and participate in parent-mediated intervention, including child care, work schedule, transportation, and other family responsibilities or life stressors ( 32 ). On the other hand, some parents of newly diagnosed children may not yet be emotionally ready to process information and apply it to their children ( 33 ). These parents may need a period of grieving before they can fully benefit from a parent-mediated intervention program. Instead, parents who participated in the PIEIP may be those who have more flexibility to participate in these sorts of parent-mediated interventions, and those who have strong intrinsic motivation and believe that their own efforts can improve the development of their children ( 34 , 35 ). Therefore, we cannot totally attribute the effects to the intervention itself. In addition to parental stress, other psychological factors such as executive function and self-efficacy should also be considered important parental variables for family interventions. Moreover, these should be added to the regression model for further analysis. Furthermore, in the future, we can try to balance these factors by conducting a rigorously designed RCT study to explore the role of PIEIP itself in the developmental outcome of GDD children. Second, we did not collect and compare data based on the content, frequency, and intensity of other institution-based interventions in which the individuals might have participated. Thus, this variable could potentially affect the development outcomes of the two groups of children. Third, the current study conducted interventions targeting individuals from 3 to 6 months after birth until 2 years of age. Although parents regularly brought their children to the hospital for assessment, attended parental classes, and periodically delivered family training videos, their detailed training time and quality of intervention at home were not monitored in this study. Fourth, the rate of lost to follow-up in this study was relatively high, especially in the intervention group. In the future, we will choose a more stable population in the research and design stage, arrange the time of follow-up and parent class in the evening or weekend, carry out distance learning, establish better interpersonal communication with the parents, clarify the meaning of the project more clearly to parents and the importance of follow-up, provide additional consultation and referral services, and continue to provide follow-up services for the lost population to maximize follow-up and compliance.

Conclusions

We found that the PIEIP is effective as an intervention to improve the development of children with GDD. Using the PIEIP as a supplement to traditional interventions in hospitals or communities can improve the developmental outcomes of children with GDD at the age of two years. Particularly, parental involvement and expansion of capacity acquisition in the natural environment are important throughout the process. In the future, more extensive intervention and follow-up studies are required that include measures such as executive function, parent-child interaction factors, self-efficacy, and other physiological risk factors to better elucidate the underlying pathways linking parent-based early intervention with child outcomes.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material , further inquiries can be directed to the corresponding author/s.

Ethics statement

The studies involving human participants were reviewed and approved by Children's Hospital of Fudan University Ethics Protocol (2016) no.131. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Author contributions

XX, HPL, PD conceived the study; PD, QX, YZ, DYL, BRZ, CCH, CXL, LZ, HFL, FYJ, XBT, JW, HPL, XX identified and recruited the patients; PD, LZ, HFL, FYJ, XBT, JW conducted the intervention of the patients; PD, XRT, SYF carried out the developmental assessment of the patients; PD, XX, HPL wrote the manuscript; All authors contributed to the article and approved the submitted version.

The authors would like to acknowledge the National Key Research and Development Program of China (No. 2016YFC1306205) and Key Subject Construction Project of Shanghai Municipal Health Commission (No. shslczdzk02903) for their contributions.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2023.1052665/full#supplementary-material .

1. Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the quality standards subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology . (2003) 60(3):367–80. doi: 10.1212/01.WNL.0000031431.81555.16

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Jimenez-Gomez A, Standridge SM. A refined approach to evaluating global developmental delay for the international medical community. Pediatr Neurol . (2014) 51(2):198–206. doi: 10.1016/j.pediatrneurol.2013.12.018

3. Mithyantha R, Kneen R, McCann E, Gladstone M. Current evidence-based recommendations on investigating children with global developmental delay. Arch Dis Child . (2017) 102(11):1071–6. doi: 10.1136/archdischild-2016-311271

4. Dunn W, Cox J, Foster L, Mische-Lawson L, Tanquary J. Impact of a contextual intervention on child participation and parent competence among children with autism spectrum disorders: a pretest-posttest repeated-measures design. Am J Occup Ther . (2012) 66(5):520–8. doi: 10.5014/ajot.2012.004119

5. Smith T, Buch GA, Gamby TE. Parent-directed, intensive early intervention for children with pervasive developmental disorder. Res Dev Disabil . (2000) 21(4):297–309. doi: 10.1016/S0891-4222(00)00043-3

6. Zhou B, Xu Q, Li H, Zhang Y, Wang Y, Rogers SJ, et al. Effects of parent-implemented early start denver model intervention on Chinese toddlers with autism spectrum disorder: a non-randomized controlled trial. Autism Res . (2018) 11(4):654–66. doi: 10.1002/aur.1917

7. Frolli A, Bosco A, Di Carmine F, Cavallaro A, Lombardi A, Sergi L, et al. Parent training and therapy in children with autism. Pediatr Rep . (2021) 13(2):216–26. doi: 10.3390/pediatric13020030

8. Perzolli S, Bertamini G, de Falco S, Venuti P, Bentenuto A. Emotional availability and play in mother-child dyads with ASD: changes during a parental based intervention. Brain Sci . (2020) 10(12):904. doi: 10.3390/brainsci10120904

CrossRef Full Text | Google Scholar

9. Muldoon D, Cosbey J. A family-centered feeding intervention to promote food acceptance and decrease challenging behaviors in children with ASD: report of follow-up data on a train-the-trainer model using eat-up. Am J Speech Lang Pathol . (2018) 27(1):278–87. doi: 10.1044/2017_AJSLP-17-0105

10. Case-Smith J, Nastro MA. The effect of occupational therapy intervention on mothers of children with cerebral palsy. Am J Occup Ther . (1993) 47(9):811–7. doi: 10.5014/ajot.47.9.811

11. Chiarello LA, Palisano RJ, Maggs JM, Orlin MN, Almasri N, Kang LJ, et al. Family priorities for activity and participation of children and youth with cerebral palsy. Phys Ther . (2010) 90(9):1254–64. doi: 10.2522/ptj.20090388

12. Whittingham K, Sheffield J, Mak C, Wright A, Boyd RN. Parenting acceptance and commitment therapy: an RCT of an online course with families of children with CP. Behav Res Ther . (2022) 155:104129. doi: 10.1016/j.brat.2022.104129

13. Dale NJ, Sakkalou E, O’Reilly MA, Springall C, Sakki H, Glew S, et al. Home-based early intervention in infants and young children with visual impairment using the Developmental Journal: longitudinal cohort study. Dev Med Child Neurol . (2019) 61(6):697–709. doi: 10.1111/dmcn.14081

14. Almalki S, Alqabbani A, Alnahdi G. Challenges to parental involvement in transition planning for children with intellectual disabilities: the perspective of special education teachers in Saudi Arabia. Res Dev Disabil . (2021) 111:103872. doi: 10.1016/j.ridd.2021.103872

15. Acar S, Chen CI, Xie H. Parental involvement in developmental disabilities across three cultures: a systematic review. Res Dev Disabil . (2021) 110:103861. doi: 10.1016/j.ridd.2021.103861

16. Tang MH, Lin CK, Lin WH, Chen CH, Tsai SW, Chang YY. The effect of adding a home program to weekly institutional-based therapy for children with undefined developmental delay: a pilot randomized clinical trial. J Chin Med Assoc . (2011) 74(6):259–66. doi: 10.1016/j.jcma.2011.04.005

17. Lin CL, Lin CK, Yu JJ. The effectiveness of parent participation in occupational therapy for children with developmental delay. Neuropsychiatr Dis Treat . (2018) 14:623–30. doi: 10.2147/NDT.S158688

18. Strauss K, Vicari S, Valeri G, D’Elia L, Arima S, Fava L. Parent inclusion in Early Intensive Behavioral Intervention: the influence of parental stress, parent treatment fidelity and parent-mediated generalization of behavior targets on child outcomes. Res Dev Disabil . (2012) 33(2):688–703. doi: 10.1016/j.ridd.2011.11.008

19. Barroso NE, Mendez L, Graziano PA, Bagner DM. Parenting stress through the lens of different clinical groups: a systematic review & meta-analysis. J Abnorm Child Psychol . (2018) 46(3):449–61. doi: 10.1007/s10802-017-0313-6

20. Wang H, Du Y, Mao Z, Che Y, Li H, Ding L, et al. Use of the Griffiths mental development scale-Chinese in the assessment of children with autism spectrum disorder and global developmental delay/intellectual disability. Medicine (Baltimore) . (2021) 100(13):e25407. doi: 10.1097/MD.0000000000025407

21. Tso WWY, Wong VCN, Xia X, Faragher B, Li M, Xu X, et al. The Griffiths Development Scales-Chinese (GDS-C): a cross-cultural comparison of developmental trajectories between Chinese and British children. Child Care Health Dev . (2018) 44(3):378–83. doi: 10.1111/cch.12548

22. Griffiths R. The griffiths mental development scales from birth to 2 years, manual, the 1996 revision . Henley: Association for Research in Infant and Child Development, Test agency (1996).

23. Abidin R, Flens JR, Austin WG. The parenting stress index. In: Archer RP, editor. Forensic uses of clinical assessment instruments . Mahwah, NJ, United States: Lawrence Erlbaum Associates Publishers (2006). p. 297–328.

24. May-Benson TA. Best practice occupational therapy for children and families in community settingsbest practice occupational therapy for children and families in community settings. Occup Ther Health Care . (2012) 26(4):318–20. doi: 10.3109/07380577.2012.717734

25. Gartstein MA, Crawford J, Robertson CD. Early markers of language and attention: mutual contributions and the impact of parent-infant interactions. Child Psychiatry Hum Dev . (2008) 39(1):9–26. doi: 10.1007/s10578-007-0067-4

26. Rattaz V, Puglisi N, Tissot H, Favez N. Associations between parent-infant interactions, cortisol and vagal regulation in infants, and socioemotional outcomes: a systematic review. Infant Behav Dev . (2022) 67:101687. doi: 10.1016/j.infbeh.2022.101687

27. Tetreault S, Parrot A, Trahan J. Home activity programs in families with children presenting with global developmental delays: evaluation and parental perceptions. Int J Rehabil Res . (2003) 26(3):165–73. doi: 10.1097/01.mrr.0000088441.78481.56

28. Han KS, Yang Y, Hong YS. A structural model of family empowerment for families of children with special needs. J Clin Nurs . (2018) 27(5-6):e833–e44. doi: 10.1111/jocn.14195

29. Rollins PR, John S, Jones A, De Froy A. Pathways early ASD intervention as a moderator of parenting stress on parenting behaviors: a randomized control trial. J Autism Dev Disord . (2019) 49(10):4280–93. doi: 10.1007/s10803-019-04144-4

30. Ozturk Y, Vivanti G, Uljarevic M, Dissanayake C, Victorian AT. Treatment-related changes in children’s communication impact on maternal satisfaction and psychological distress. Res Dev Disabil . (2016) 56:128–38. doi: 10.1016/j.ridd.2016.05.021

31. Fu L, Weng J, Feng M, Xiao X, Xiao T, Fu J, et al. Predictors of change in play-based communication and behavior intervention for high-risk ASD: the role of mother-child dyadic synchrony. Front Pediatr . (2020) 8::581893. doi: 10.3389/fped.2020.581893

32. Harachi TW, Catalano RF, Hawkins JD. Effective recruitment for parenting programs within ethnic minority communities. Child Adolesc Soc Work J . (1997) 14:23–39. doi: 10.1023/A:1024540829739

33. Whitaker P. Supporting families of preschool children with autism: what parents want and what helps. Autism . (2002) 6(4):411–26. doi: 10.1177/1362361302006004007

34. Ingersoll B, Wainer A. Initial efficacy of project ImPACT: a parent-mediated social communication intervention for young children with ASD. J Autism Dev Disord . (2013) 43(12):2943–52. doi: 10.1007/s10803-013-1840-9

35. Hurtubise K, Carpenter C. Learning experiences and strategies of parents of young children with developmental disabilities: implications for rehabilitation professionals. Phys Occup Ther Pediatr . (2017) 37(5):471–84. doi: 10.1080/01942638.2017.1280872

Keywords: global developmental delay, children, parent-implemented early intervention program, parenting stress, multicenter study

Citation: Dong P, Xu Q, Zhang Y, Li D-y, Zhou B-r, Hu C-c, Liu C-x, Tang X-r, Fu S-y, Zhang L, Li H-f, Jia F-y, Tong X-b, Wang J, Li H-p and Xu X (2023) A multicenter clinical study on parent-implemented early intervention for children with global developmental delay. Front. Pediatr. 11:1052665. doi: 10.3389/fped.2023.1052665

Received: 24 September 2022; Accepted: 26 January 2023; Published: 15 February 2023.

Reviewed by:

© 2023 Dong, Xu, Zhang, Li, Zhou, Hu, Liu, Tang, Fu, Zhang, Li, Jia, Tong, Wang, Li and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Hui-ping Li [email protected] Xiu Xu [email protected]

Specialty Section: This article was submitted to Children and Health, a section of the journal Frontiers in Pediatrics

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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• Current evidence-based recommendations on investigating children with global developmental delay
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• Renuka Mithyantha 1 ,
• Rachel Kneen 2 , 3 ,
• Emma McCann 4 ,
• http://orcid.org/0000-0002-2579-9301 Melissa Gladstone 1 , 5
• 1 Department of Developmental Paediatrics , Alder Hey Children’s NHS Foundation Trust , Liverpool , UK
• 2 Department of Paediatric Neurology , Alder Hey Children’s NHS Foundation Trust , Liverpool , UK
• 3 Institute of Infection and Global Health, University of Liverpool , Liverpool , UK
• 4 Department of Clinical Genetics , Liverpool Women’s Hospital , Liverpool , UK
• 5 Department of Women and Children’s Health , Institute of Translational Medicine, University of Liverpool, Alder Hey Children’s NHS Foundation Trust , Liverpool , UK
• Correspondence to Dr Melissa Gladstone, Department of Women and Children’s Health, Institute of Translational Medicine, University of Liverpool, Alder Hey Children’s NHS Foundation Trust, Liverpool, L14 5AB, UK; M.J.Gladstone{at}liverpool.ac.uk

Introduction Global developmental delay (GDD) affects 1%–3% of the population of children under 5 years of age, making it one of the most common conditions presenting in paediatric clinics; causes are exogenous, genetic (non-metabolic) or genetic (metabolic). Recent advances in biotechnology and genetic testing mean that the investigations available to perform for children under 5 years are increasing and are more sensitive than previously. This change in availability and type of testing necessitates an update in the recommendations for investigating GDD.

Methods We conducted a review of the literature from 2006 to 2016 to identify articles with evidence relating to the investigation of developmental delay in children under the age of 5 years. We collated the evidence into first-line and second-line investigations and, where available, on their yield and cost implications.

Results We have provided up-to-date guidance for first-line and second-line investigations for children with GDD under the age of 5 years. Recent evidence demonstrates that genetic testing for all children with unexplained GDD should be first line, if an exogenous cause is not already established. Our review of the literature demonstrates that all patients, irrespective of severity of GDD, should have investigations for treatable conditions. Evidence demonstrates that the yield for treatable conditions is higher than previously thought and that investigations for these metabolic conditions should be considered as first line. Additional second-line investigations can be led by history, examination and developmental trajectories.

Discussion We may need to update present recommendations in the UK for investigation of developmental delay. This would include microarray testing as first line and a more thorough approach to investigations for metabolic disorders that can be treated. Clinical assessment remains vital for guiding investigations.

• neurodevelopment
• neurodisability

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Introduction

Global developmental delay (GDD) is defined as a delay in two or more developmental domains of gross/fine motor, speech/language, cognition, social/personal and activities of daily living, affecting children under the age of 5 years. 1 2 The degree of developmental delay is further subclassified as: mild (functional age <33% below chronological age), moderate (functional age 34%–66% of chronological age) and severe (functional age <66% of chronological age). 1 GDD is considered significant when there is a deficit in performance of at least 2 SD below the age appropriate mean on accepted standardised assessment tests. 3 With a prevalence of 1%–3%, GDD is one of the the most common conditions encountered in paediatrics with genetic and structural brain abnormalities being the most frequent causes. 1 Establishing a diagnosis enables clinicians to define treatment options and conduct surveillance for known complications as well as provide prognosis and condition-specific family support (including family planning choices). This ensures the best overall outcomes for the child and their families/carers. 4 A diagnosis may also provide an explanation, a source of closure or acceptance to parents and stops clinicians advancing to potentially more expensive and invasive tests 5–7

Previous estimates for the yield of investigations for GDD are broad (10%–81%). 2 The variability may be due to differences in patient populations, clinical settings where tests are performed and the range of tests undertaken. 2 The last evidence-based UK guideline for investigation of developmental delay was published 10 years ago. 8 With the advent of more recent techniques in genetics and a recent burgeoning of guidelines in other countries, 4 9 10 there is a need to review our practice in the UK.

The primary objective of this paper is to provide (1) an update of the latest evidence for investigation of GDD, (2) recommendations for investigations and (3) evidence relating to yield and cost from literature presently available.

We conducted a systematic review of the literature relating to the investigation of GDD published in the last 10 years (since the McDonald review in 2006). We searched Pubmed, Google Scholar and Embase using the MESH terms: ‘developmental delay’, ‘developmental disorders’, ‘mental retardation’, ‘intellectual disability’, ‘learning disorders’ AND ‘guidelines’ AND ‘investigations’. ‘Cost’ and ‘yield’ were included along with the MESH terms. Papers included were reviews, consensus recommendations, retrospective or prospective studies. Relevant articles from reference lists were also included. We included papers published in English that were relevant to children that included investigations for GDD. We excluded papers that targeted specific metabolic, genetic or neurological conditions. We used the term GDD as meaning: delayed developmental domains in children under the age of 5 years and intellectual disability (ID) as the term used after this age when IQ can be reliably tested. 11

For this review, we discuss and categorise investigations into first-line and second-line tests and subcategorised them to genetics, metabolic and imaging. See table 1 for recommended first-line investigations to be considered prior to referral to specialist services. We show a flowchart and decision-making tree for investigations in figure 1 .

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Flow chart for decision making for investigations for global developmental delay in young children.

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Table demonstrating recommendations for first-line investigations for global developmental delay from four guidelines and our proposed recommendations

First-line assessment and investigations

History and examination.

Comprehensive clinical assessment remains the core to planning investigations in young children presenting with GDD. 4 8–10 Aetiology can be categorised into exogenous, genetic (non-metabolic) and genetic (metabolic). 11 The diagnosis of exogenous causes includes teratogenic agents (alcohol and drugs); prenatal, perinatal causes (prematurity, infections); and social causes often best assessed by history but must not be assumed.

Investigations following a thorough clinical history (including a family pedigree, pregnancy and birth history) and a detailed physical examination by a trained specialist lead to a higher diagnostic yield. 3 12 Identification and correction of sensory deficits are essential, while evaluating these children and may provide pointers to the underlying aetiology. 2 6

An examination of the child’s developmental status in all domains (gross motor, fine motor, language, socioemotional and cognitive skills) using a recognised tool to provide a normative comparison should also be conducted. Repeated clinical/dysmorphology and developmental assessments over time are more informative than one-off assessments in planning investigations and management.

It is important that the clinician consider investigations in all levels of developmental delay including those with persistent mild GDD, given the variable phenotypic presentations of genetic and metabolic conditions. Some studies, although from tertiary centres, have found that severity did not impact on the diagnostic rate of investigations, 12 while others report higher yield in patients with moderate-to-severe GDD. 13 Serial assessment enables clinicians to identify changing phenotypes over time. When metabolic conditions are clinically suspected, annual evaluation after the first year of life until school age is recommended. 14

Some studies have demonstrated that we can identify the cause of developmental or cognitive delay in a one-third of cases by history and examination alone. With clinical evaluation prompting investigations, we can identify another one-third. It is only the latter one-third that are identified by investigations only. 12 The presence of abnormal neurology, microcephaly, female gender, dysmorphism, abnormal prenatal or perinatal history and absence of autistic features are linked with higher aetiological yield of investigations. 15 Investigations following comprehensive clinical evaluation are also cost effective. 16

Genetic testing

First-line tests .

Genetic investigation by means of standard karyotyping was recommended as a first-line investigation in the UK guidance from 2006. 8 The implementation of ‘molecular karyotyping’ or chromosome microarray (array-based comparative genomic hybridisation (aCGH)) has changed the state of play. Recent evidence-based international guidelines promote the use of aCGH as a first-tier investigation for GDD if no aetiological indicators from history and examination are found. 4 9 10 The higher sensitivity that it has for identifying submicroscopic deletions and duplications (than standard karyotyping methods) and better definition of the breakpoints and size of imbalances all make microarray a suitable first-line test. 4 17 18

Chromosome microarray has been described to be the ‘single most efficient diagnostic test’ for GDD after history and examination. 4 A literature search of 33 studies that used this technique in nearly 22 000 patients has demonstrated that the diagnostic yield of aCGH is between 15% and 20%, while karyotyping is 3%. 18 The diagnostic yield of microarray is supported by a health economics report, which showed cost saving when comparing a National Health Service (NHS) clinical genetics service use of aCGH as a first-tier test while evaluating learning disability, compared with CGH as second line after negative karyotyping. 19

Molecular karyotyping will not detect conditions where structural changes in the chromosomes result in no loss or gain of genetic material such as balanced translocations or inversions, ring chromosomes and low-level mosaicism. 18 20 A standard karyotype is still required if such a disorder is suspected (eg, refractory epilepsy, if a family is known to have a balanced translocation associated with a phenotype, a history of multiple miscarriages or clinical features to suggest mosaicism). Syndromes caused by methylation defects (eg, Beckwith-Wiedemann, Angelman syndrome) or mutations in single genes will also go undetected unless specifically tested.

Fragile X syndrome affects approximately 1/5000 births, typically causing moderate ID in boys and a variable phenotype in girls (unaffected to significant). Phenotypic features evolve and are not as apparent in younger children. 9 The UK genetic testing network and international guidelines therefore do promote testing for fragile X for children with moderate-to-severe GDD, without profound physical disability, as an additional first-tier genetic investigation. 4 9 10 21 Testing criteria are available to help aid clinical decisions in older children. 21

Second-line tests

Clinical syndromes can present with variable phenotypes, and children who have a normal aCGH and FMR1 may be best assessed by a clinical geneticist to ensure that the most appropriate and cost-effective additional tests are undertaken. 22 Use of specific gene tests such as those for Rett syndrome (or its variants) or gene panels for ID has been proposed as second-line tests. 4 There is an increasing number of panels and exome sequencing tests available for ID (UK Genetic Testing Network; http://www.ukgtn.nhs.uk ) or private providers, but specialist services (clinical genetics or paediatric neurology) do most requests for these tests, although this is likely to change as mainstreaming of these investigations advances.

Metabolic and biochemical investigations

There is limited good quality evidence for first-line metabolic investigations. Recommendations from Ireland are based on evidence review by expert committee, 10 while those from Australia are based on a literature review, quoting grade III–IV evidence. 9

Inborn errors of metabolism (IEMs) are rare, their prevalence likely to vary in different populations. There is limited UK data on detecting metabolic disorders in patients with GDD. 14 IEMs are usually associated with systemic features, and previous guidelines recommend selective metabolic investigations. 2 8 Some IEMs are now (partially) treatable, and for others, treatment is in the research stages. Treatment includes dietary supplements (folinic acid for cerebral folate deficiency, pyridoxine or pyridoxal phosphate for B6-responsive epilepsy, creatine in creatine transporter deficiency, uridine in pyrimidine 5-nucleotidase super activity), dietary restriction (homocystinuria, glutaricacidaemia) and ketogenic diet (pyruvate dehydrogenase deficiency, Glut1 transporter deficiency). Other treatments include: haematopoietic stem cell transplantation (mucopolysaccharidoses, metachromatic leucodystrophy), enzyme replacement (Fabry’s disease, Gaucher’s disease, neuronal ceroid lipofuscinosis) or gene therapy (adrenoleucodystophy, lysosomal storage disorders). 23–25

A systematic review of literature by van Karnebeek et al identified 89 conditions presenting with ID as a major feature, which are susceptible to treatment. Of these, 60% could be identified by non-targeted urine and blood tests. Some of these conditions (eg, creatine transporter defects, mild homocystinuria, female ornithine transcarbamylase deficiency) can initially present as GDD alone. 25 26 While individual treatable IEMs are extremely rare in the general population, the prevalence will be higher in the at-risk population. Hence, though small in number, these treatable causes of GDD have been the focus of the more recent US guidance, with recommendations that screening for IEM should be used in all patients with GDD of unknown aetiology. 4 24 A list of tests with treatable conditions they identify is shown in table 2 .

Table demonstrating IEM tested for by first-line metabolic investigations 25

The neonatal screening programme in the UK (Guthrie test) currently includes six IEMs (phenyketonuria, medium-chain acyl-CoA dehydrogenase deficiency, maple syrup urine disease, isovaleric acidaemia, glutaricaciduria type 1, homocystinuria (pyridoxine unresponsive)) and congenital hypothyroidism. It is restricted when compared with other countries (eg, Canada, the USA, The Netherlands), which offer a wider range including urea cycle disorders, organic and some amino acid disorders. Testing for these is, therefore, more relevant in UK patients with GDD, and IEMs should be considered in symptomatic children. 14

There are also some conditions where early diagnosis can be made from simple and cheap biochemical screening tests. This includes creatine kinase and thyroid function tests as well as ferritin, vitamin B12 and lead on a selective basis when Pica, dietary restrictions (vegan diet in child/mother) or environmental exposure risk is possible. 9 While these tests seldom lead to a diagnosis, they also may add to a diagnosis (eg, macrocytic anaemia in organic acidaemias, abnormal triiodothyronine in Allan-Herdon-Dudley syndrome). 10 27

There is limited research on comprehensive metabolic evaluation in larger groups of individuals with GDD. It is, therefore, difficult to estimate the yield of many of the proposed first-line metabolic tests. A recent systematic review conducted for the American Academy of Neurology found that yield of metabolic investigations varied between 0.2% and 4.6%, based on clinical signs and range of tests undertaken in the studies (grade III evidence). 28 Second-line individually tailored testing in a tertiary setting in the Netherlands produced an overall yield of 2.8% for metabolic investigations. 11

Individually tailored second-line testing 4 14 26 and referral to a specialist service is recommended, 4 9 when clinical suspicion remains. An evidence-based, free web-based application ( http://www.treatable-id.org ) may be useful to tailor investigations for treatable IEMs not covered by first-line tests. 29

Neuroimaging

MRI of the brain has been used selectively and non-selectively in evaluating patients with GDD. The diagnostic yield of MRI is higher when used in patients where GDD is associated with clinical signs such as abnormal head circumference (microcephaly, non-familial macrocephaly, rapid change in head circumference), focal neurological signs or epilepsy. Targeted imaging was hence advocated by previous guidelines. 2 8 Previous studies have demonstrated abnormal results in targeted imaging in about 41% compared with 14% with non-selective screening. 3 Recent studies continue to demonstrate higher abnormality detection rates when MRI is performed in patients with GDD with additional clinical/neurological signs. 30 31 More complex MRI protocols (eg, proton magnetic resonance spectroscopy) are promising tools to investigate GDD and enable a non-invasive measure of brain metabolites such as lactate or white matter choline, 32 but studies have so far failed to show an increased diagnostic yield, 31 33 and hence these are best used as second line in selected patients.

MRI is a more sensitive test and has no radiation exposure, making it a preferred choice over CT. However, all children under 5 years will need sedation or a general anaesthetic, which has a slim risk attached, and some children will need further investigations including a lumbar puncture. There is an argument, therefore, that children requiring brain imaging should see a specialist prior to imaging, if an anaesthetic is required.

Special considerations

Ten most common causes of progressive intellectual and neurological deterioration.

10 most common causes of PIND reported in the PIND study in the UK ( www.rcpch.ac.uk/pind ) 34

NCL late infantile

Mucopolysaccharidosis IIIA (San Filippo)

Rett syndrome

Metachromatic leucodystrophy

Adrenoleucodystrophy

NCL juvenile

GM2 gangliosidosis type 1 (Tay-Sachs)

Niemann-Pick type C

GM2 gangliosidosis type 2 (Sandhoff)

NCL, neuronal ceroid lipofuscinosis; PIND, progressive intellectual and neurological deterioration.

Children that should be referred to a specialist in neurodisability or neurology are shown on table 3 . Investigations should be individualised and targeted as they can be invasive (eg, LP, muscle/skin biopsy) or painful (eg, nerve conduction studies and electromyography) and are expensive and time consuming for medical staff and families. Children with regression may also be referred to the clinical genetics team where specific next-generation sequencing panels can be undertaken and, at present, considered for the 100 000 Genome Project ( www.genomicsengland.co.uk/the-100000-genomes-project ).

Clinical pointers to consider referral to a specialist in neurodisability or neurology

Immigrant children

Immigrant children are exposed to a combination of biological, socioeconomical, emotional and environmental adverse events placing them at higher risk of developmental problems. This includes malnutrition and disability from trauma, overcrowding and toxin exposure and loss of parents or trauma from lack of stability. 35 Furthermore, children may have missed new-born screens and vaccinations and been exposed to infectious diseases. In these children, comprehensive clinical assessments should consider all these factors while planning individual investigations.

Despite new advances in technology, particularly in the realm of genetic investigation, clinical assessment continues to be vital in guiding investigation. Clues to investigation may lie in the history and examination with clinical judgement being essential to enabling the right pathways to be taken in making a diagnosis. A good history can help direct which route to take in terms of investigation, particularly when exogenous causes are identified. Assessment over a period will provide clarity as to whether a condition is resolving, static or deteriorating. Assessment over time enables the phenotype to evolve and more appropriate targeting of investigations.

It is clear that establishing a diagnosis enables us to answer questions on: why it has happened (aetiology), what does it mean for our child (prognosis), what treatments might be available (precision medicine) and whether it can be prevented in the future (prenatal testing and preimplantation genetic diagnosis).

In these recommendations, we have also highlighted the recent evidence that promotes metabolic screening tests to detect treatable conditions. This is a move away from older guidance where metabolic investigations were not recommended for children with no features/risk factors other than GDD. 2 Though rare, the possibility of presentation as stable developmental delay and potential for treatment merits their inclusion as first-line tests. Treatment outcomes vary but can potentially improve cognitive development, slow deterioration, prevent metabolic decompensation and improve seizure control and systemic manifestations. 25 26

GDD and ID affect 2%–3% of the worldwide population with a lifetime cost of up to US$1 million. 36 First-line metabolic investigations to identify treatable IEMs cost approximately $C568, 26 with costs in Ireland for all first-line tests at €1335. 10 Costs in the UK NHS laboratory for aCGH are not astronomical (£338–£350), 37 38 with the majority of combined metabolic tests costing under £1000. 38 Not all children will get a diagnosis and cost per diagnosis may be high, but there are obvious long-term cost savings if early diagnosis and treatment are possible. The options of genetic counselling and support for young families also make diagnosis invaluable.

Recent advances in genomic medicine are transforming the investigation of children with significant developmental delay and are likely to transform the way we assess and investigate children. Traditional models of care have relied on history and examination with broad and then specific investigations to funnel down to specific diagnoses. The advent of rapid genetic testing and ‘omic’ medicine is likely to turn this paradigm on its head with whole genome/exome sequencing identifying genes, which may be causing the phenotype in an individual. The clinician will then use knowledge of their patient to make a judgement about whether this is the cause for their patient—‘reverse dysmorphology’.

These advances in genomic medicine will lead to an increase in diagnoses that will modify how the individual is clinically cared for (precision medicine). The Deciphering Developmental Disorders study and the 100 000 Genome Project will both aid our understanding of disorders. We predict that, with time, whole genome sequencing/exome sequencing may become the first-line investigation of choice for all children with unexplained GDD and that other investigations will be secondary to this and used primarily for phenotyping. These will provide answers for families about the underlying cause of their child’s condition and will prevent further costly and potentially distressing investigations taking place.

Conclusions

In this paper, we have outlined the present evidence and recommendations for both first-line and second-line investigations for GDD in children in the UK. We have provided new evidence relating to the use of genetic testing techniques and have demonstrated that this should be a first-line investigation for all children with GDD. Second to this, any treatable metabolic conditions should be always considered. With time, it is likely that the investigation of children with developmental delay will be turned on its head and we will be going from genetic diagnosis to phenotypic diagnosis. Despite this, history and examination will always be crucial for defining the condition and the change over time.

• Majnemer A ,
• Shevell M ,
• Donley D , et al
• Shevell MI ,
• Rosenbaum P , et al
• Moeschler JB ,
• Shonkoff JP ,
• Hauser-Cram P
• McConachie H ,
• Hayeems RZ ,
• Babul-Hirji R ,
• Hoang N , et al
• McDonald L ,
• Tolmie J , et al
• Collins F ,
• O’Byrne JJ ,
• Treacy EP , et al
• Engbers HM ,
• van Hasselt P , et al
• van Karnebeek CD ,
• Scheper FY ,
• Abeling NG , et al
• Cleary MA ,
• Thomas RL , et al
• Miller DT ,
• Aradhya S , et al
• Kharbanda M ,
• Milunsky JM
• Corbella M ,
• Fons C , et al
• Stockler IS
• Zschocke J , et al
• Michelson DJ ,
• Sherr EH , et al
• Popurs MA ,
• Lafek M , et al
• Griffiths PD ,
• Warren D , et al
• Verbruggen KT ,
• Meiners LC ,
• Sijens PE , et al
• Maurits NM ,
• Meiners LC , et al
• Ritter S , et al
• Winstone AM ,
• Stellitano L , et al
• Davidson N ,
• Chaney G , et al
• ↵ Centers for Disease Control and Prevention (CDC) . Economic costs associated with mental retardation, cerebral palsy, hearing loss, and vision impairment--United States, 2003 . MMWR Morb Mortal Wkly Rep 2004 ; 53 : 57 – 9 . OpenUrl PubMed
• ↵ Great Ormond Street Hospial for Children NHS Foundation Trust,North East Thames Regional Genetics Service . Pricing , 2014 .
• ↵ Community Children’s Health Partnership . Investigations for developmental delay: blood tests costs (2014) and what results could indicate? 2014 .

Contributors RM, RK, EM and MG contributed to the initial idea for the paper, wrote and reviewed sections of the paper and approved the final version. RM conducted the literature review with the support of MG and wrote the first draft of the paper.

Funding None declared.

Competing interests None declared.

Provenance and peer review Commissioned; externally peer reviewed.

Linked Articles

• Original article Aetiological investigations in early developmental impairment: are they worth it? Anthony Richard Hart Ruchi Sharma Mark Atherton Samer Alabed Sally Simpson Stuart Barfield Judith Cohen Nicholas McGlashan Asha Ravi Michael James Parker Daniel JA Connolly Archives of Disease in Childhood 2017; 102 1004-1013 Published Online First: 22 Jul 2017. doi: 10.1136/archdischild-2017-312843

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Case 2: Developmental delay, especially language, in a toddler

An 18-month-old girl was first referred at eight months of age to a developmental centre because of general developmental delay. She was born after a normal pregnancy and delivery. Her birth weight was 3.7 kg, with Apgar scores of 9 and 10 at 1 min and 5 min, respectively. The neonatal period was uneventful. Her parents are non-consanguineous and have two older healthy sons. There are no known individuals with developmental delay or mental retardation in the enlarged families of both parents.

Beginning at four months of age, the infant suffered recurrent episodes of otitis media, and was hospitalized twice with pneumonia and purulent otitis media. A hearing test performed at seven months of age revealed profound hearing loss mainly in her right ear (70 dB), and a brainstem auditory evoked response test confirmed the hearing loss; ventilatory tubes were inserted. Her physical examination when she was first seen in the developmental centre was normal, with no dysmorphic features or abnormal neurological signs. Repeated developmental examinations and follow-up at 18 months of age confirmed a general developmental delay corresponding to motor developmental skills of a 12-month level and language skills at a nine-month level. The neurological examination showed mild hypotonia. Laboratory tests including a complete blood count, chemistry, thyroid function and urinalysis were normal. Toxoplasma, rubella, cytomegalovirus and herpes simplex virus titres were negative. Metabolic work-up including lactate, ammonia, amino acids and biotinidase in the blood, and organic and amino acids in the urine were normal. At this point, a blood test was ordered, which confirmed the suspected diagnosis.

CASE 2 DIAGNOSIS: FEMALE FRAGILE X SYNDROME

The developmental delay and recurrent episodes of otitis media, with hearing loss that persisted after the ventilatory tubes were inserted, led us to think of a syndromic cause for the patient’s symptoms. Chromosomal analysis revealed a normal female 46,XX karyotype, and molecular studies found a full mutation in the FMR1 gene (more than 200 copies of the CGG trinucleotide repeat sequence at the fragile X locus on the X chromosome), thus establishing the diagnosis of fragile X syndrome (FXS).

In 1991, the gene for FXS, designated FMR1 , which codes for the fragile X MR protein (FMRP) was discovered. The lack of FMRP production causes the syndrome. The DNA sequence at the FMR1 gene is a CGG trinucleotide repeat sequence. Normal individuals have between six and 55 CGG repeats, and carriers of the ‘premutation’ have 56 to 199 repeats, in which FMRP production still occurs. Those who have 200 CGG repeats or more have the ‘full mutation’, and in this situation, the DNA nucleotides are methylated, resulting in the absence of the FMRP. Forty per cent of patients with the full mutation are mosaics with cells containing variable length of full or premutation alleles.

FXS is the most common inherited cause of intellectual disability affecting males and females, with a prevalence of 1:3500 to 1:4000 in males, and 1:8000 to 1:9000 in females who show the full mutation. The overall prevalence may be as high as 1:2000 to 1:3000 because many prevalence studies have not screened children with milder cognitive deficits. The syndrome is characterized by certain physical features and impaired cognition, with language and behavioural problems. Approximately 80% of males have a dysmorphic appearance in contrast with most females who are not dysmorphic. Physical features may not be apparent at an early age. The characteristic facies are usually apparent by eight to 10 years of age, and may consist of macrocephaly, long face, prominent forehead, epicanthal folds, prognathism, dental crowding and large protruding ears. Entering puberty at approximately nine years of age, macroorchidism may become evident, increasing until a mean testicular volume of 50 mL in adulthood. Other features that may be seen in FXS include strabismus, mitral valve prolapse, high arched palate, soft velvety skin over the dorsum of the hands, hyperextensible joints, flat feet, scoliosis and simian creases of the palms. Recurrent otitis media (in 60% to 80% of individuals) and sinusitis (in 23% of individuals) are common in infancy and childhood.

Neurological abnormalities such as seizures (25%), hypotonia and motor dyspraxia may occur. The seizures appear mainly in boys. Partial seizures have been described in two girls who are fragile X carriers. In girls with the pre-mutation, the typical physical characteristics are more subtle, and they may exhibit premature ovarian insufficiency later in life. Approximately 30% of males who carry a pre-mutation allele will develop fragile X-associated tremor and ataxia syndrome after 50 years of age. Cognitive function in boys is more severely impaired, and most of them have moderate to severe intellectual disability with an average IQ of 30, whereas girls are borderline to mild, and 35% to 50% of those with the full mutation may have IQ scores of less than 85. With regard to language skills, boys may show greater delays in gaining expressive language skills compared with receptive language. Their speech may be rapid; dysfluent; characterized by repetitions of sounds, words and phrases; and they occasionally may have garbled, slurred and disorganized speech. Language impairment is also noted in affected girls.

Behavioural problems in boys are manifested by social avoidance, and deficits in attention and hyperactivity. Nearly 25% of boys meet the criteria for autism. Girls express social anxiety, social avoidance, withdrawal and depression. Shyness and social discomfort appear more in those with the premutation. Selective mutism has also been described in girls with the full mutation. Girls express more attentional difficulties, without the hyperactivity and impulsivity of attention-deficit hyperactivity disorder. Autistic behaviours may be reported in girls by six to 16 years of age, but unlike boys with the syndrome, they are usually not severly affected.

There are still reports in the literature of delayed diagnosis of the syndrome because of nonspecific features, unremarkable physical examination, noncontributory family history and delayed molecular testing. The case presented is one of the earliest ages of diagnosis in a female described in the literature.

There is no specific treatment for the syndrome. However, affected children do benefit from early developmental treatments in physical, speech and occupational therapy. More specific therapy includes psychopharmacological treatments for those with attention-deficit hyperactivity disorder symptoms; selective serotonin reuptake inhibitors for those with anxiety, perseveration, compulsive and depressive symptoms; and risperidone for aggressive behaviours.

CLINICAL PEARLS

• Consider FXS in any child, boy or girl, with a delay in language, social anxiety, hyperactivity or hand flapping.
• Girls generally have a milder presentation than boys because they have two X chromosomes and the normal X produces variable amounts of FMRP, depending on the amount of X inactivation. The level of FMRP correlates with the degree of cognitive involvement in both males and females.
• Early diagnosis is important for genetic counselling, particularly in young couples, and it is also useful for early intervention for those children who have special educational and psychosocial needs.
• In girls presenting with partial seizures of unknown cause, consider the possibility that they may be fragile X carriers.

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