What chromosomal metabolic disorders are associated with developmental delays in children?

Chromosomal Metabolic Disorders Associated with Developmental Delays in Children

The major chromosomal disorders causing developmental delays are the autosomal trisomies (13,18, and 21), with Down syndrome (trisomy 21) being the most common genetic cause, while inborn errors of metabolism affecting carbohydrate, amino acid, and nucleic acid metabolism also contribute significantly to developmental delays. 1

Primary Chromosomal Disorders

Autosomal Trisomies

• Trisomy 21 (Down syndrome) is the most common chromosomal cause of intellectual disability and developmental delay, presenting with characteristic dysmorphic features, hypotonia in infancy, and global developmental delays 1
• Trisomy 13 and Trisomy 18 are the other major autosomal trisomies associated with severe developmental delays and multiple congenital anomalies 1
• Chromosomal microarray testing is recommended as the first-line chromosome study, with a diagnostic yield averaging 7.8% in children with global developmental delay 1, 2, 3

Sex Chromosome Abnormalities

• Turner syndrome and Klinefelter syndrome present with neuromotor abnormalities, growth abnormalities, and developmental delays 1
• These conditions warrant routine chromosome testing when weakness is suspected alongside recognizable clinical features 1

Metabolic Disorders with Chromosomal/Genetic Basis

Fragile X Syndrome

• Fragile X syndrome is the most common inherited cause of cognitive impairment and developmental delay, resulting from a repeat variant in the FMR1 gene on the X chromosome 1
• Testing should be considered in both boys and girls, regardless of whether dysmorphic facial features or family history are present 1
• FMR1 testing shows full expansion in at least 2% of patients with mild to moderate global developmental delay 3
• Males are primarily affected, but females with FMR1 expansions may also exhibit developmental delays 1

Inborn Errors of Metabolism

• Inborn errors of metabolism result from disruption of individual genes encoding enzymes that metabolize carbohydrates, amino acids, or nucleic acids, as well as mitochondrial defects 1
• Tests for metabolic disorders have a diagnostic yield of up to 5% in children with developmental delays 3
• Congenital disorders of glycosylation and cerebral creatine disorders have yields of up to 2.8% 3
• Metabolic investigations should be performed if clinical features suggest an inherited metabolic disease, even while awaiting specialist consultation 2

Copy Number Variant Disorders

• Chromosomal or copy number variant disorders result from an extra or missing copy of an entire chromosome or chromosomal segment 1
• Subtelomeric fluorescence in situ hybridization is positive in 3.5% of cases with developmental delays 3
• G-banded karyotyping is abnormal in at least 4% of children with global developmental delay 3

Syndromic Chromosomal Conditions

Single-Gene Disorders with Metabolic Components

• Deletion 22q11 syndrome (DiGeorge/velocardiofacial syndrome) has high rates of congenital heart disease and developmental delays 1
• Prader-Willi syndrome, caused by loss of expression of paternal chromosome 15q11.2-q13, presents with hypotonia, feeding difficulties in infancy, and later developmental delays 1
• Tuberous sclerosis and neurofibromatosis are neurocutaneous syndromes causing developmental delays through brain malformations 1

Clinical Approach and Testing Strategy

First-Line Investigations

• Chromosomal microarray testing is the first-line test recommended by the American College of Medical Genetics and Genomics for children with neuromotor abnormalities, failure to thrive, growth abnormalities, or dysmorphic features 1, 2
• Fragile X testing should be done as first-tier when suggestive clinical features or family history are present 2
• All patients should have investigations for treatable metabolic conditions, as the yield is higher than previously recognized 4

Second-Line Testing

• Exome sequencing or comprehensive gene panels are recommended as second-tier tests for patients with global developmental delay or intellectual disability 2
• Testing for X-linked intellectual disability genes has a yield of up to 42% in males with appropriate family history 3
• MeCP2 testing is diagnostic in 1.5% of females with moderate to severe developmental delay 3

Critical Clinical Indicators

• Look for hypotonia, failure to thrive, growth abnormalities, dysmorphic facial features, or visceral anomalies as red flags requiring chromosomal evaluation 1
• Document any regression of motor skills, loss of strength, or concerns with respiration or swallowing, as these indicate progressive disorders requiring immediate attention 1
• Consider genetic syndromes when developmental delays occur alongside congenital heart disease, as up to 30% of pediatric patients with congenital heart disease have genetic disorders 1

Important Caveats

• Chromosome mosaicism can present with subtle dysmorphic features in infancy, making early recognition challenging 1
• Severe mental retardation is mostly due to genetic or acquired biological causes, while mild retardation more commonly has acquired causes with sociocultural factors playing a role 5
• Testing should be ordered by subspecialists familiar with interpretation, particularly for microarray testing, due to difficulty in result interpretation 1