Intellectual disability and global developmental delay

Global developmental delay (GDD) is delay in two or more developmental domains (gross motor, fine motor, language, cognition, social) in a child younger than 5, and is a clinical proxy for future intellectual disability. Intellectual disability (ID) is the formal diagnosis after age 5, defined by IQ < 70 plus deficits in adaptive functioning, with onset before 18. This leaf is the general approach to a child with GDD or ID without a diagnosis. Regression (loss of skills) is its own presentation; see developmental regression. Specific syndromes (Down, Williams, etc.) have their own leaves.

Three principles structure the workup:

1. Yield-driven, not exhaustive. Modern genetic testing has a defined diagnostic hierarchy: chromosomal microarray first (~15% yield in unselected GDD/ID), fragile X testing in parallel for any boy and most girls (~2% yield), then exome sequencing (~30-40% incremental yield), then targeted assays for clinically recognizable syndromes. A diagnosis matters: it ends the diagnostic odyssey, anchors prognosis, drives surveillance (e.g., Wilms in Beckwith-Wiedemann), reframes recurrence risk, and unlocks family planning options.
2. Look at the child first; gestalt narrows the panel. If you recognize Down syndrome, Williams syndrome, Angelman syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, or Rett syndrome on inspection, do the targeted test (karyotype + FISH, FISH for 7q11.23, methylation, MECP2) before broad-spectrum testing. CMA still picks most of these up, but turnaround is faster with the targeted assay when the phenotype is clear.
3. Always think comorbidity and treatability. Hearing loss and vision impairment masquerade as cognitive delay; rule them out at every visit. Treatable inborn errors of metabolism are rare in the NBS era but should be reconsidered in any unscreened immigrant child or regressive course.

Chromosomal and copy-number variants (CMA territory)

• Down syndrome (trisomy 21): most common chromosomal cause of ID; usually recognized on exam.
• Williams syndrome (7q11.23 deletion): hypercalcemia, supravalvular aortic stenosis, "cocktail party" personality, stellate iris.
• Smith-Magenis syndrome (17p11.2 deletion): sleep dysregulation (inverted melatonin), self-hugging, brachycephaly.
• 22q11.2 deletion syndrome: cardiac, hypocalcemia, immune, palatal, ID.
• Cri-du-chat (5p−), Wolf-Hirschhorn (4p−), and many other microdeletion / microduplication syndromes pick up on CMA.

Imprinting and methylation disorders

• Angelman syndrome (15q11-q13 maternal loss): happy demeanor, ataxic gait, seizures, severe language delay.
• Prader-Willi syndrome (15q11-q13 paternal loss): neonatal hypotonia, later hyperphagia and obesity, hypogonadism, ID.
• Beckwith-Wiedemann syndrome (11p15.5 imprinting): overgrowth, macroglossia, omphalocele, hypoglycemia, Wilms risk. ID is uncommon; the syndrome belongs in the broader pediatric workup more than the pure ID workup.

Single-gene ID disorders (exome / panel territory)

• Fragile X syndrome (FMR1 CGG expansion > 200): the most common single-gene cause of inherited ID. Long face, large ears, macroorchidism postpubertally, hand-flapping, social anxiety. Always test boys with unexplained ID; test girls too (skewed X-inactivation can produce a phenotype). Repeat sizing is a separate assay from sequencing panels.
• Rett syndrome (MECP2): girls, regression-pattern. MECP2 duplication (MECP2 duplication syndrome) affects boys with ID, recurrent infections, spasticity.
• PTEN hamartoma tumor syndrome: macrocephaly + ID / autism is a high-yield combination for PTEN testing.
• Tuberous sclerosis complex (TSC1, TSC2): ID, autism, seizures (often infantile spasms), hypopigmented macules.
• Cornelia de Lange syndrome (NIPBL and others): synophrys, long philtrum, limb anomalies, ID.
• Rubinstein-Taybi syndrome (CREBBP, EP300): broad thumbs/halluces, distinctive face, ID.
• Kabuki syndrome (KMT2D, KDM6A): elongated palpebral fissures with everted lower lid, ID, immune, cardiac.
• Coffin-Siris syndrome (BAF-complex genes including ARID1B): hypoplastic fifth nails / phalanges, coarse face, ID.

ID with autism

Macrocephaly + autism is the classic PTEN combination. Additional ID + ASD genes to keep in mind: CHD8, SCN2A, SHANK3 (Phelan-McDermid), ADNP, DYRK1A, SYNGAP1, ARID1B, GRIN2B, MECP2, UBE3A.

ID with epilepsy / epileptic encephalopathy

• STXBP1-related disorders: early infantile epileptic encephalopathy, Ohtahara, later Lennox-Gastaut-like phenotypes.
• CDKL5-related disorders: female-predominant; intractable seizures, hand stereotypies similar to Rett.
• KCNQ2-related disorders: neonatal epileptic encephalopathy; some respond to sodium channel blockers.
• SCN1A / Dravet syndrome: SCN1A seizure disorders; fever-sensitive seizures, hemiclonic, status; avoid sodium channel blockers.
• SCN2A, SCN8A, GRIN2A, GNAO1, KCNT1: other epileptic encephalopathy genes.
• Tuberous sclerosis complex: infantile spasms; vigabatrin is first-line.

ID with metabolic features

Metabolic causes of isolated, non-regressive ID are rare in NBS-era populations but increase in importance for unscreened children. Consider testing in: regression, consanguinity, coarse features, organomegaly, parental concern about decline, episodic encephalopathy, dysmorphism unexplained by CMA / exome.

• Untreated phenylketonuria: severe ID, fair skin/hair, eczema, musty odor. Preventable with newborn screening + diet.
• Smith-Lemli-Opitz syndrome (DHCR7): 2-3 toe syndactyly, microcephaly, ID, cholesterol biosynthesis defect.
• Homocystinuria (CBS): marfanoid habitus, lens dislocation (downward), thromboembolism, ID.
• Lesch-Nyhan syndrome (HPRT1, X-linked): ID, self-injurious behavior, hyperuricemia, dystonia.
• Cerebral creatine deficiency syndromes (GAMT, AGAT, SLC6A8): treatable with creatine and supplementation when caught early; CSF/MRS shows absent creatine peak.
• Untreated congenital hypothyroidism: ID prevented by newborn screening.

The American College of Medical Genetics tiered workup:

1. Chromosomal microarray (CMA): first-tier in any unexplained GDD/ID. Yield ~15% in unselected populations, higher with dysmorphism or congenital anomalies.
2. Fragile X (FMR1 CGG repeat sizing): in parallel with CMA for boys, and most girls. Repeat sizing is not covered by sequencing panels or CMA.
3. Targeted testing if recognizable syndrome:
   • Karyotype if Down or aneuploidy suspected (CMA misses balanced rearrangements)
   • Methylation studies for Angelman / Prader-Willi / Beckwith-Wiedemann
   • MECP2 sequencing and deletion/duplication for Rett (girls) and MECP2 duplication (boys)
   • FISH or CMA for 7q11.23 (Williams), 17p11.2 (Smith-Magenis), 22q11.2 (DiGeorge / VCFS)
4. Exome sequencing: if CMA and fragile X are negative. ACMG guidelines now support exome as a first- or second-tier test in unexplained ID; yield 30-40%. Reanalysis at 18-24 months is recommended in undiagnosed cases.
5. Targeted metabolic workup (when indicated): plasma amino acids, urine organic acids, lactate, ammonia, total homocysteine, copper / ceruloplasmin, acylcarnitines, creatine / GAA, lysosomal enzymes, VLCFAs, urine GAGs. Routine on every child is low yield; targeted to phenotype.
6. EEG and MRI: EEG if seizures or staring spells. MRI if focal exam, microcephaly, macrocephaly, regression, or unexplained ID after first-pass genetic testing.
7. Hearing and vision screen. Always. Sensory impairment masquerades as cognitive delay.