Clinical features and initial targeted diagnostic tests for specific causes of ID in children

Disorder	Clinical features	Targeted tests
Down syndrome	Characteristic dysmorphic features Wide range of cognitive impairment Cardiac defects and multiple congenital anomalies	G-banded karyotype analysis
Fragile X	Males with moderate to severe ID, macrocephaly, large ears, enlarged testes after puberty, perseverative speech, and poor eye contact Males and females with family history of ID	FMR1 DNA analysis
Rett syndrome	Females with normal early development followed by regression to moderate or severe ID Stereotypic hand movements	MECP2 testing
Klinefelter syndrome	Males with mild ID, hypogonadism, tall stature, gynecomastia, reduced body hair	G-banded karyotype analysis
Prader-Willi syndrome	Mild to moderate ID, behavior difficulties, food-seeking behavior and obesity, hypogonadism, neonatal hypotonia, delayed motor milestones	Methylation analysis to detect abnormal parent-specific methylation on chromosome 15q11.2-13
DiGeorge (22q11.2 deletion) syndrome	Mild to moderate ID, multiple congenital anomalies (including cardiac defects, hypoplastic thymus, palatal abnormalities), immunodeficiency	FISH for 22q11.2 deletion
Metabolic disorders	Severity of ID varies Episodic decompensation (eg, with febrile illnesses or periods of starvation) Family history of metabolic disorders or parental consanguinity Seizures, developmental regression, failure to thrive	Metabolic screening (typically this includes measurement of plasma amino acids, urine organic acids, serum ammonia, and lactate; more selective testing can be performed based on the patient's specific characteristics). Further metabolic testing is guided by a specialist.
Muscular dystrophy	Mild ID Proximal muscle weakness	Measure serum creatinine kinase as initial screen; if elevated, perform additional evaluation (refer to UpToDate topics on muscular dystrophy for details).
Congenital hypothyroidism*	Decelerating growth velocity/short stature, cold intolerance, feeding problems, puffy facies, macroglossia, large fontanels, hypotonia, dry skin, prolonged jaundice	Thyroid function tests (serum TSH free T4)
Lead poisoning^¶	Mild to moderate ID, language delay, and behavior problems Vomiting, colicky abdominal pain, fatigue, renal insufficiency Exposure history (eg, persistent mouthing behavior, living in a house or child care facility built before 1950, recent immigration or home renovation, folk remedies, and some parental occupations [smelting, soldering, and auto body repair])	Blood lead level

This table summarizes the clinical features and approach to targeted testing for some common specific causes of ID. This list is not comprehensive as there are many other causes of ID in children. Targeted testing is generally warranted when there are dysmorphic features or other characteristics that suggest a particular syndrome or disorder. If no specific disorder is clinically suspected, then initial testing usually involves a broader genetic evaluation (eg, CMA or next generation genetic sequencing panels). For more details, refer to UpToDate's topics on ID in children and topics on the specific diseases and conditions listed.

CMA: chromosomal microarray analysis; CT: computed tomography; DNA: deoxyribonucleic acid; FISH: fluorescence in situ hybridization; FMR1: fragile X mental retardation 1 gene; GDD: global developmental delay; ID: intellectual disability; MECP2: methyl-CpG-binding protein 2 gene; MRI: magnetic resonance imaging; TSH: thyroid stimulating hormone; T4: thyroxine.

* Thyroid testing is recommended routinely for infants and children presenting with ID in countries without newborn screening programs for congenital hypothyroidism. In these areas, unrecognized congenital hypothyroidism is a more common cause of ID. In countries where newborn screening for hypothyroidism is routinely performed, congenital hypothyroidism is an uncommon cause of ID and therefore routine thyroid testing is not necessary for children with ID who lack associated signs and symptoms of hypothyroidism.

¶ Blood lead testing should also be performed if the child has not had prior lead screening. While lead toxicity is an uncommon cause of ID in the United States, children with ID are at increased risk for lead exposure. Case identification is essential to allow for treatment and for evaluation of other children who may have been similarly exposed. Refer to UpToDate content on screening for lead poisoning for further information.

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Clinical features and initial targeted diagnostic tests for specific causes of ID in children