Developmental Delay: A Pediatric Neurologist's Perspective

Educational Objectives

The goal of this program is to improve assessment of global developmental delay (GDD). After hearing and assimilating this program, the clinician will be better able to:

1. Differentiate among features associated with GDD or intellectual disability.
2. Evaluate the clinical utility of various tests used to help diagnose causes of GDD.

Summary

Global developmental delay (GDD): to encourage earlier referral, the Centers for Disease Control and Prevention (CDC) updated its checklist of milestones that 75% of children should reach by a given age; a developmental pediatrician (among others) can confirm the extent and severity of delay; neurologic evaluation for GDD is recommended for children >2 standard deviations below their peers in ≥2 aspects of development (including, eg, gross and fine motor, speech and language, cognition, social and personal, activities of daily living); the term GDD is used for children <5 yr of age; neuropsychological testing is conducted in children ≥5 yr old to diagnose intellectual disability (ID; ie, intelligence quotient <70 and significant adaptive behavior limitations); GDD or ID is present in 1% to 3% of the population

Distinguishing between disorders: in ID, motor skills may be normal, but language and problem-solving skills are decreased; in communication disorders, expressive language may be delayed, without impact to problem-solving skills; cerebral palsy impacts motor skills without affecting language or problem-solving skills; Riou et al (2009) — demonstrated that a child with GDD does not necessarily also have ID; expressive language scores most strongly correlate with a diagnosis of ID

Evaluation: start with medical and developmental evaluation; obtain a thorough history, including information about gestation and delivery; older parental (especially paternal) age is associated with increased risk for single-gene changes; ask about miscarriages, prenatal screening (including noninvasive prenatal testing), concern for exposures during pregnancy, the course of delivery, and neonatal events; assess the child's overall health for any medical considerations; create a 3-generation pedigree to identify siblings and other family members who may be similarly affected; review the child's head circumference to understand changes over time; conversion of head circumference into Z-scores helps determine deviation from the mean; if a concern exists, measure the parents’ head circumferences; consider any dysmorphic features or neurocutaneous stigmata; assess for any features of neurodevelopmental genetic syndromes; conduct a developmental assessment and neurologic examination

Magnetic resonance imaging (MRI): demonstrates minor differences in the brains of ≈15% of individuals without any neurologic symptoms and in ≥30% of children with developmental delays; meaningful findings include, eg, malformations of cortical development, atrophy, white-matter abnormalities, delayed myelination, postischemic lesions, phakomatoses, ventricular abnormalities; because MRI requires anesthesia, clinicians must assess the anticipated yield; Engbers et al (2010) found that MRI demonstrated abnormalities in ≈33% of children but supported a diagnosis in only ≈5% of children; the diagnostic yield of MRI was ≈13% in children with neurologic symptoms vs≈2% in children without neurologic symptoms; prioritize MRI with presence of microcephaly, macrocephaly, significant central hypotonia, motor asymmetries, spasticity, or epilepsy; otherwise, defer unless initial genetic testing is normal

Chromosomal microarray analysis (CMA): used to identify copy-number variations (CNVs) too small for microscopic visibility; the diagnostic yield is 11% to 15% for individuals with developmental delays or ID and may be even higher in patients with syndromic features, including multiple congenital anomalies; microarray types include array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array; CMA identifies deletions, duplications, unbalanced rearrangements, genomic region gain or loss, uniparental disomy (a region on both chromosome copies inherited from the same parent), and loss of heterozygosity (may indicate consanguinity); neither aCGH nor SNP array can detect balanced rearrangements or point mutations, and low-frequency mosaicism may be missed; pretest counseling — normal CMA results do not rule out a genetic etiology; rather, a CNV may be responsible for the phenotype, or a significant CNV may be present that is unrelated to the patient’s issues; a variant of uncertain significance (VUS) may also be present; CMA may reveal whether the parents share common relatives; CMA will not reveal paternity (revealed by whole-exome sequencing)

Causality of CNVs: consider whether the CNV was inherited from a healthy parent, was reported in healthy individuals, overlaps with a known genomic imbalance syndrome, and whether the interval contains genes associated with human disease; CNVs may contribute to ID

Karyotyping: not routinely sent unless an obvious chromosomal syndrome, family history of chromosomal rearrangements, or maternal history of multiple miscarriages exists

Genetic sequencing: whole-exome sequencing (WES) — Srivastava et al (2019) support use of WES as a first-tier test for diagnosing neurodevelopmental disorders; WES only examines exons; a diagnosis is found in ≈33% of patients, a VUS is found in ≈33%, and a negative result occurs in ≈33%; the overall yield is typically ≈40%; limitations include incomplete coverage of some genes, the possibility of missing deletions and duplications (a negative result reflexes to CMA), and inability to detect expansion repeats (seen with fragile X syndrome; requires separate testing) and epigenetic changes (seen with Prader-Willi syndrome and Angelman syndrome; methylation testing is needed); whole-genome sequencing — eliminates the need for CMA and improves detection of expansion repeats

Recommendations: genetic testing — in the past, the standard evaluation of GDD involved CMA and testing for fragile X and Rett syndromes (which accounted for 1%-2% of causes of GDD); however, certain commonly-seen genes now account for a small percentage of diagnoses of neurodevelopmental syndromes; therefore, order a broad neurodevelopmental panel or WES; metabolic testing — was more commonly used in the past; with the current high yield of genetic testing from a buccal swab, metabolic testing is no longer needed for every patient; however, metabolic testing or imaging can clarify a VUS, and thorough metabolic testing is used for children with developmental regression

Coffin-Siris syndrome: most commonly associated with a pathogenic variant in the ARID1B gene; characterized by fifth-digit nail hypoplasia or aplasia and variable cognitive and developmental delays; individuals tend to have distinctive facial features (may suggest coarseness), central hypotonia, hirsutism, and sparse scalp hair; echocardiography and renal ultrasonography are recommended for children with Coffin-Siris syndrome and ARID1B-related disorders

Readings

Belanger SA, Caron J. Evaluation of the child with global developmental delay and intellectual disability. Paediatr Child Health. 2018;23(6):403–410. doi:10.1093/pch/pxy093; Donato ND, Timms AE, Aldinger KA, et al. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genet Med. 2018;20(11):1354–1364. doi:10.1038/gim.2018.8; Engbers H, Nievelstein R, Gooskens R, et al. The clinical utility of MRI in patients with neurodevelopmental disorders of unknown origin. Eur J Neurol. 2010;17(6):815-822. doi:10.1111/j.1468-1331.2009.02927.x; Miller DT, Adam MP, Aradhya S, 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. doi:10.1016/j.ajhg.2010.04.006; Mithyantha R, Kneen R, McCann E, Gladstone M. Current evidence-based recommendations on investigating children with global developmental delay. Arch Dis Child. 2017;102:1071-1076. doi:10.1136/archdischild-2016-311271; Purugganan O. Intellectual disabilities. Pediatr Rev. 2018;39(6):299–309. doi:10.1542/pir.2016-0116; Riou EM, Ghosh S, Francoeur E, Shevell MI. Global developmental delay and its relationship to cognitive skills. Dev Med Child Neurol. 2009;51(8);600-606. doi:10.1111/j.1469-8749.2008.03197; Srivastava S, Love-Nichols JA, Dies KA, 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 Nov;21(11):2413-2421. doi: 10.1038/s41436-019-0554-6. Epub 2019 Jun 11. Erratum in: Genet Med. 2020 Oct;22(10):1731-1732. doi: 10.1038/s41436-020-0913-3; Taylor JL, Debost JCPG, Morton SU, et al. Paternal-age-related de novo mutations and risk for five disorders. Nat Commun. 2019;10:3043. doi:10.1038/s41467-019-11039-6; Toriello HV, Meck JM; Professional Practice and Guidelines Committee. Statement on guidance for genetic counseling in advanced paternal age. Genet Med. 2008;10(6):457-60. doi:10.1097/GIM.0b013e318176fabb; Vergano SS, Deardorff MA. Clinical features, diagnostic criteria, and management of Coffin–Siris syndrome. Am J Med Genet C Semin Med Genet. 2014;166(3):252-256. doi:10.1002/ajmg.c.31411.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Barañano was recorded at the 50th Annual Pediatric Trends, held virtually May 14-17, 2024, and presented by the Johns Hopkins University School of Medicine, Baltimore, MD; and Johns Hopkins Children’s Center, Baltimore. For information on upcoming CME activities from this presenter, please visit https://hopkinscme.cloud-cme.com. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

PD704101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.