Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays abstract

Global developmental delay and intellectual disability are relatively common pediatric conditions. This report describes the recommended clinical genetics diagnostic approach. The report is based on a review of published reports, most consisting of medium to large case series of diagnostic tests used, and the proportion of those that led to a diagnosis in such patients. Chromosome microarray is designated as a first-line test and replaces the standard karyotype and fluorescent in situ hybridization subtelomere tests for the child with intellectual disability of unknown etiology. Fragile X testing remains an important first-line test. The importance of considering testing for inborn errors of metabolism in this population is supported by a recent systematic review of the literature and several case series recently published. The role of brain MRI remains important in certain patients. There is also a discussion of the emerging literature on the use of whole-exome sequencing as a diagnostic test in this population. Finally, the importance of intentional comanagement among families, the medical home, and the clinical genetics specialty clinic is discussed. Pediatrics 2014;134:e903–e918 The purpose of this clinical report of the American Academy of Pediatrics (AAP) is to describe an optimal medical genetics evaluation of the child with intellectual disability (ID) or global developmental delays (GDDs). The intention is to assist the medical home in preparing families properly for the medical genetics evaluation process. This report addresses the advances in diagnosis and treatment of children with intellectual disabilities since the publication of the original AAP clinical report in 20061 and provides current guidance for the medical genetics evaluation. One intention is to inform primary care providers in the setting of the medical home so that they and families are knowledgeable about the purpose and process of the genetics evaluation. This report will emphasize advances in genetic diagnosis while updating information regarding the appropriate evaluation for inborn errors of metabolism and the role of imaging in this context. The reader is referred to the 2006 clinical report for background information that remains relevant, including the roles of the medical home or pediatric primary care provider. This clinical report will not address the importance of developmental screening in the medical home, nor will it address the diagnostic John B. Moeschler, MD, MS, FAAP, FACMG, Michael Shevell, MDCM, FRCP, and COMMITTEE ON GENETICS ABBREVIATIONS AAP—American Academy of Pediatrics CMA—chromosome microarray CNS—central nervous system CNV—copy number variant CT—computed tomography FISH—fluorescent in situ hybridization GAA—guanidinoacetate GDD—global developmental delay ID—intellectual disability XLID—X-linked intellectual disability This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. www.pediatrics.org/cgi/doi/10.1542/peds.2014-1839 doi:10.1542/peds.2014-1839 All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics PEDIATRICS Volume 134, Number 3, September 2014 e903 FROM THE AMERICAN ACADEMY OF PEDIATRICS Guidance for the Clinician in Rendering Pediatric Care by guest on October 23, 2017 http://pediatrics.aappublications.org/ Downloaded from evaluation of the child with an autism spectrum disorder who happens to have ID as a co-occurring disability. (For AAP guidance related to Autism Spectrum Disorders, see Johnson and Myers.2) For both pediatric primary care providers and families, there are specific benefits to establishing an etiologic diagnosis (Table 1): clarification of etiology; provision of prognosis or expected clinical course; discussion of genetic mechanism(s) and recurrence risks; refined treatment options; the avoidance of unnecessary and redundant diagnostic tests; information regarding treatment, symptom management, or surveillance for known complications; provision of conditionspecific family support; access to research treatment protocols; and the opportunity for comanagement of patients, as appropriate, in the context of a medical home to ensure the best health, social, and health care services satisfaction outcomes for the child and family. The presence of an accurate etiologic diagnosis along with a knowledgeable, experienced, expert clinician is one factor in improving the psychosocial outcomes for children and with intellectual disabilities and their families.3–5 Although perhaps difficult to measure, this “healing touch” contributes to the general well-being of the family. “As physicians we have experience with other children who have the same disorder, access to management programs, knowledge of the prognosis, awareness of research on understanding the disease and many other elements that when shared with the parents will give them a feeling that some control is possible.”5 Makela et al6 studied, in depth, 20 families of children with ID with and without an etiologic diagnosis and found that these families had specific stated needs and feelings about what a genetic diagnosis offers: 1. Validation: a diagnosis established that the problem (ID) was credible, which empowered them to advocate for their child. 2. Information: a diagnosis was felt to help guide expectations and management immediately and provide hope for treatment or cure in future. 3. Procuring services: the diagnosis assisted families in obtaining desired services, particularly in schools. 4. Support: families expressed the need for emotional companionship that a specific diagnosis (or “similar challenges”) assisted in accessing. 5. Need to know: families widely differed in their “need to know” a specific diagnosis, ranging from strong to indifferent. 6. Prenatal testing: families varied in their emotions, thoughts, and actions regarding prenatal genetic diagnosis. For some families in the Makela et al6 study, the clinical diagnosis of autism, for example, was sufficient and often more useful than “a rare but specific etiological diagnosis.” These authors report that “all of the families would have preferred to have an [etiologic] diagnosis, if given the option,” particularly early in the course of the symptoms. As was true of the 2006 clinical report, this clinical report will not address the etiologic evaluation of young children who are diagnosed with cerebral palsy, autism, or a single-domain developmental delay (gross motor delay or specific language impairment).1 Some children will present both with GDD and clinical features of autism. In such cases, the judgment of the clinical geneticist will be important in determining the evaluation of the child depending on the primary neurodevelopmental diagnosis. It is recognized that the determination that an infant or young child has a cognitive disability can be a matter of clinical judgment, and it is important for the pediatrician and consulting clinical geneticist to discuss this before deciding on the best approach to the diagnostic evaluation.”1 INTELLECTUAL DISABILITY ID is a developmental disability presenting in infancy or the early childhood years, although in some cases, it cannot be diagnosed until the child is older than ∼5 years of age, when standardized measures of developmental skills become more reliable and valid. The American Association on Intellectual and Developmental Disability defines ID by using measures of 3 domains: intelligence (IQ), adaptive behavior, and systems of supports afforded the individual.7 Thus, one cannot rely solely on the measure of IQ to define ID. More recently, the term ID has been suggested to replace “mental retardation.”7,8 For the purposes of this clinical report, the American Association on Intellectual and Developmental Disability definition is used: “Intellectual disability is a disability characterized by TABLE 1 The Purposes of the Comprehensive Medical Genetics Evaluation of the Young Child With GDD or ID 1. Clarification of etiology 2. Provision of prognosis or expected clinical course 3. Discussion of genetic mechanism(s) and recurrence risks 4. Refined treatment options 5. Avoidance of unnecessary or redundant diagnostic tests 6. Information regarding treatment, symptom management, or surveillance for known complications 7. Provision of condition-specific family support 8. Access to research treatment protocols 9. Opportunity for comanagement of appropriate patients in the context of a medical home to ensure the best health, social, and health care services satisfaction outcomes for the child and family e904 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on October 23, 2017 http://pediatrics.aappublications.org/ Downloaded from significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social and practical adaptive skills. The disability originates before age 18 years.”7 The prevalence of ID is estimated to be between 1% and 3%. Lifetime costs (direct and indirect) to support individuals with ID are large, estimated to be an average of approximately $1 million per person.9 Global Developmental Delay Identifying the type of developmental delay is an important preliminary step, because typing influences the path of investigation later undertaken. GDD is defined as a significant delay in 2 or more developmental domains, including gross or fine motor, speech/language, cognitive, social/personal, and activities of daily living and is thought to predict a future diagnosis of ID.10 Such delays require accurate documentation by using norm-referenced and ageappropriate standardized measures of development administered by experienced developmental specialists. The term GDD is reserved for younger children (ie, typically younger than 5 years), whereas the term ID is usually applied to older children for whom IQ testing is valid and reliable. Children with GDD are those who present with delays in the attainment of developmental milestones at the expected age; this implies deficits in learning and adaptation, which suggests that the delays are significant and predict later ID. However, delays in development, especially those that are mild, may be transient and lack predictive reliability for ID or other developmental disabilities. For the purposes of this report, children with delays in a single developmental domain (for example, isolated mild speech delay) should not be considered appropriate candidates for the comprehensive genetic evaluation process set forth here. The prevalence of GDD is estimated to be 1% to 3%, similar to that of ID.