Down Syndrome Care & Other Genetic Syndromes

Down syndrome: diagnosis and the newborn checklist

Genetics. About 95% of cases of trisomy 21 arise from maternal meiotic nondisjunction; the rest are Robertsonian translocations or mosaicism. Every affected newborn needs a karyotype, because a translocation may be carried by a parent and raises the recurrence risk.

Heart. About half of infants have congenital heart disease. Complete atrioventricular septal defect (AVSD) is the signature lesion; VSD, ASD, PDA, and tetralogy of Fallot also occur. An AVSD can be silent at birth while pulmonary vascular resistance is high, so every newborn gets an echocardiogram read by a pediatric cardiologist, even after a normal prenatal echo.

Blood. A newborn CBC screens for polycythemia, thrombocytopenia, and transient abnormal myelopoiesis (TAM). TAM affects about 10% of newborns with trisomy 21: GATA1-mutant blasts arise in the fetal liver, causing leukocytosis with circulating blasts and hepatosplenomegaly. It usually resolves by about 3 months, but about 20% later develop myeloid leukemia of Down syndrome (megakaryoblastic) before age 4, so parents learn leukemia warning signs. Overall risk of leukemia, both ALL and AML, is 10–20 times baseline.

Gut. Look for duodenal atresia (bilious vomiting, double-bubble sign), Hirschsprung disease (delayed passage of meconium), and imperforate anus. A newborn with both a double bubble and an AVSD is a classic trisomy 21 picture.

Development. Hypotonia and mild-to-moderate intellectual disability are expected; refer to early intervention (physical, occupational, and speech therapy) at diagnosis.

Down syndrome: ongoing surveillance

Sleep apnea. Midface hypoplasia, relative macroglossia, and hypotonia make obstructive sleep apnea common, and parental report is unreliable, so every child gets a sleep study by age 4.

Atlantoaxial instability. Routine screening radiographs are not recommended, because they do not predict who will be injured. Neck pain or torticollis, a change in gait, new weakness, bowel or bladder change, hyperreflexia, clonus, or a Babinski sign demands urgent cervical spine imaging and neurosurgical referral. Families are counseled about neck positioning during anesthesia and about contact sports.

Autoimmune disease. Celiac disease, type 1 diabetes, alopecia, and thyroid disease are all more frequent. Test for celiac disease when symptoms suggest it: poor growth, diarrhea, constipation, or anemia.

Aging. The extra copy of APP on chromosome 21 leads to amyloid plaques by about age 40 and early-onset Alzheimer dementia, often in the 50s. New functional decline in an adult should prompt evaluation for dementia and for treatable mimics such as hypothyroidism, depression, and hearing or vision loss.

Microdeletion and RASopathy syndromes

22q11.2 deletion. DiGeorge/velocardiofacial syndrome results from defective third and fourth pharyngeal pouches. It combines conotruncal heart defects (tetralogy, truncus arteriosus, interrupted aortic arch), hypoparathyroidism with neonatal hypocalcemic seizures, thymic hypoplasia with T-cell deficiency (absent thymic shadow), cleft palate or velopharyngeal insufficiency with hypernasal speech, learning problems, and later psychosis such as schizophrenia. The mnemonic CATCH-22 captures cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, and the chromosome 22 deletion. Chromosomal microarray or FISH confirms it; a routine karyotype usually misses it. Until T-cell function is known, give irradiated blood products to prevent transfusion-associated graft-versus-host disease, and assess immunity before live vaccines.

Williams syndrome. A 7q11.23 microdeletion that includes the elastin gene causes elfin facies (broad forehead, periorbital fullness, stellate iris, wide mouth), an overly friendly "cocktail party" personality with strong verbal but weak visuospatial skills, mild intellectual disability, supravalvular aortic stenosis with or without peripheral pulmonary stenosis, infantile hypercalcemia, and hypertension.

Noonan syndrome. An autosomal dominant RASopathy (PTPN11 in about half) affecting both sexes: webbed neck, low posterior hairline, hypertelorism, ptosis, short stature responsive to growth hormone, pectus deformity, cryptorchidism, and a bleeding tendency. The heart shows pulmonic stenosis with a dysplastic valve and hypertrophic cardiomyopathy. The karyotype is normal, unlike Turner syndrome (45,X), whose lesions are bicuspid aortic valve and coarctation.

Overgrowth and craniofacial disorders

Beckwith-Wiedemann syndrome. An imprinting disorder at 11p15.5 producing macrosomia, macroglossia, omphalocele, lateralized overgrowth (hemihypertrophy), ear creases or pits, and visceromegaly. Hyperinsulinism causes neonatal hypoglycemia, so glucose is checked early. Because of embryonal tumor risk, children get abdominal ultrasound every 3 months until about age 7 (Wilms tumor) and serum AFP every 3 months until about age 4 (hepatoblastoma).

CHARGE syndrome. Usually a de novo CHD7 variant: coloboma, heart defects, atresia of the choanae, restricted growth and development, genital hypoplasia, and ear anomalies with deafness. Newborns are obligate nasal breathers, so bilateral choanal atresia causes cyanosis that improves with crying, and a catheter will not pass through the nose; secure an oral airway, then repair surgically.

Pierre Robin sequence. A sequence is one primary anomaly that triggers a cascade: micrognathia displaces the tongue backward (glossoptosis), obstructing the upper airway, often with a U-shaped cleft palate. Start with prone or side-lying positioning, then a nasopharyngeal airway; severe obstruction needs mandibular distraction or tracheostomy. Monitor feeding and growth, and screen for Stickler syndrome (myopia, retinal detachment, hearing loss) and 22q11.2 deletion.

Choosing a genetic test

Microarray first. For unexplained global developmental delay, intellectual disability, autism, or multiple congenital anomalies, chromosomal microarray is a first-tier test, and exome sequencing is increasingly used first or next. Microarray detects copy-number changes but misses trinucleotide repeat expansions and balanced rearrangements.

Add-on tests. Order FMR1 CGG-repeat analysis for fragile X syndrome (long face, large ears, postpubertal macroorchidism, autistic features). Use a karyotype when aneuploidy or a translocation is suspected, as in Down syndrome, and methylation analysis for imprinting disorders.