PEDS · EP 08 · GENETICS
Before You Listen
Episode Setup
- Topic in one line: the high-yield chromosomal aneuploidies (Down, Edwards, Patau, Turner, Klinefelter), the imprinting paradigm of Prader-Willi and Angelman at 15q11-q13, the X-linked dominant Rett syndrome, the elastin-deletion Williams syndrome at 7q11.23, the trinucleotide-repeat Fragile X (FMR1), the TORCH infections with periventricular versus diffuse calcifications, the VACTERL association, fetal alcohol spectrum disorders, and the ACMG genetic testing hierarchy of karyotype → chromosomal microarray → whole exome sequencing → whole genome sequencing.
- Prerequisites: basic Mendelian inheritance (autosomal dominant, autosomal recessive, X-linked), the concept of chromosomal aneuploidy and translocation, and the developmental milestones framework (covered in PEDS-01).
- Runtime: 68 minutes.
Vignette. A 4-year-old boy with global developmental delay is referred for evaluation. He has central hypotonia in infancy that improved with growth hormone (GH) therapy. Beginning around age 3 he developed insatiable hyperphagia, food-seeking behavior, and progressive obesity despite caloric restriction. His parents describe high pain threshold and temperature instability. Examination shows small hands and feet, almond-shaped eyes, downturned corners of the mouth, cryptorchidism, and skin picking. Cognitive testing is in the mild intellectual disability range. The geneticist has not yet performed confirmatory testing.
What is the diagnosis, what genetic mechanism is most likely, what is the gold-standard diagnostic test that detects more than 99 percent of cases regardless of mechanism, and what genetic principle distinguishes this condition from the syndrome at the same chromosomal locus that produces a “happy puppet” phenotype?
(Answer at the end of this chapter)
Section 1: Down Syndrome (Trisomy 21)
Bottom line: Down syndrome is the most common chromosomal cause of intellectual disability (1:700), with 95 percent from nondisjunction trisomy 21, 3-4 percent from Robertsonian translocation, and 1-2 percent mosaic; congenital heart disease in 40-50 percent (atrioventricular septal defect (AVSD) is the most common); the AAP 2022 health-supervision schedule mandates echocardiogram in all newborns, thyroid screening, hearing/vision evaluations, lateral cervical radiographs at ages 3-5 years for atlantoaxial instability, and a 10-30x increased risk of leukemia.
Down syndrome is the most common chromosomal cause of intellectual disability, occurring in approximately 1 in 700 live births. Approximately 95 percent result from nondisjunction producing full trisomy 21, 3-4 percent involve Robertsonian translocation (most commonly between chromosomes 14 and 21), and 1-2 percent are mosaic. The risk increases with maternal age: approximately 1 in 1,500 at age 20, 1 in 350 at age 35, 1 in 100 at age 40, and 1 in 25 at age 45. Life expectancy has improved dramatically, from approximately 25 years in 1983 to approximately 60 years currently.
Cardinal features. Newborns demonstrate central hypotonia in nearly 100 percent, upslanting palpebral fissures, epicanthal folds, flat nasal bridge, small ears, protruding tongue, Brushfield spots (white speckles on the iris periphery, 38-60 percent), single palmar crease (“simian crease,” approximately 45 percent), sandal gap (wide space between first and second toes), and intellectual disability with average IQ 40-55 (moderate range; DSM-5 emphasizes adaptive functioning over IQ scores).
Source: Vanellus Foto (Wikimedia Commons), “Boy with Down Syndrome.” CC BY-SA 3.0 / GFDL.
Cardiac disease affects 40-50 percent. The distribution among Down syndrome with congenital heart disease is AVSD 40-45 percent (most common — the classic board association), ventricular septal defect (VSD) ~35 percent, atrial septal defect (ASD) ~8 percent, patent ductus arteriosus (PDA) ~7 percent, and tetralogy of Fallot ~4 percent. Echocardiography is recommended in all newborns regardless of murmur.
AAP 2022 health supervision schedule:
| Screening | Schedule |
|---|---|
| Cardiac | Echocardiogram in all newborns |
| Thyroid | Thyroid stimulating hormone (TSH) at birth, 6 months, 12 months, then annually |
| Hearing | Auditory brainstem response (ABR) at birth or by 1 month; audiology every 6 months until age 3, then annually |
| Vision | Ophthalmologic evaluation by 6 months, then annually (refractive errors in 50-70%) |
| Cervical spine | Lateral cervical radiographs (flexion/extension + neutral) between ages 3-5 |
| Hematology | Complete blood count (CBC) at birth (polycythemia, transient myeloproliferative disorder ~10%) |
| Celiac | Tissue transglutaminase IgA antibody starting at age 2 |
| Sleep | Polysomnography by age 4 (obstructive sleep apnea (OSA) in 50-75%) |
| Growth | Down-syndrome-specific growth charts |
| Mental health | Screening in adolescents and adults (2022 emphasis) |
| Bone density | DEXA screening (2022 addition) |
Associated medical conditions include hearing loss 75 percent (conductive, sensorineural, or mixed), OSA 50-75 percent, hypothyroidism 15-20 percent, radiographic atlantoaxial instability 10-30 percent (symptomatic 1-2 percent), leukemia risk 10-30x increased (acute lymphoblastic leukemia (ALL) and acute megakaryoblastic leukemia (AMKL)), transient myeloproliferative disorder ~10 percent in neonates, celiac disease 5-16 percent, duodenal atresia ~5 percent (and 30 percent of all duodenal atresia has Down syndrome — the “double bubble sign” on abdominal radiograph), Hirschsprung disease 2-15x increased risk, and Alzheimer disease in 50-70 percent by age 60.
Clinical Pearl — AAI in Down syndrome
Radiographic atlantoaxial instability occurs in 10-30 percent of individuals with Down syndrome, but symptomatic cord compression occurs in only 1-2 percent. The American Academy of Pediatrics recommends lateral cervical radiographs (flexion/extension/neutral) between ages 3 and 5 years. Special Olympics requires screening cervical spine films before participation in designated high-risk sports. Clinical signs of myelopathy — neck pain, torticollis, gait deterioration, hyperreflexia, clonus, bowel/bladder change — drive management more than radiographic measurements alone. (Reviewed in detail in PEDS-07.)
High Yield — Down syndrome
- Most common chromosomal cause of intellectual disability (1:700).
- 95% nondisjunction trisomy 21; 3-4% translocation; 1-2% mosaic.
- AVSD = most common cardiac defect (40-45%).
- Cervical spine films at ages 3-5 for AAI screening; Special Olympics requires for high-risk sports.
- Leukemia risk 10-30x (ALL and AMKL).
- 30% of all duodenal atresia has Down (“double bubble” sign).
- Alzheimer disease in 50-70% by age 60.
- AAP 2022: echo at birth, TSH at birth/6/12 months/annual, ABR at 1 month, ophtho by 6 months, polysomnography by age 4.