Common Genetic & Chromosomal Syndromes
A board-focused tour of the classic genetic and chromosomal syndromes — autosomal trisomies, sex-chromosome aneuploidies, microdeletions, imprinting disorders, and Fragile X — organized around buzzword recognition, the associated cardiac lesion, and the confirmatory next-best test.
How the boards test genetic syndromes
Genetic and chromosomal syndromes are among the highest-yield Step 1 pediatrics topics, and the boards reward pattern recognition: a cluster of dysmorphic buzzwords names the syndrome, then the question pivots to mechanism or the single most dangerous complication. Organize them by mechanism:
- Autosomal trisomies (meiotic nondisjunction, risk rises with maternal age): Down (21), Edwards (18), Patau (13).
- Sex-chromosome aneuploidies: Turner (45,X), Klinefelter (47,XXY).
- Microdeletions: DiGeorge (22q11), Williams (7q11), Cri-du-chat (5p−).
- Imprinting disorders on 15q: Prader-Willi and Angelman.
- Trinucleotide repeat: Fragile X (CGG in FMR1).
Nondisjunction recurrence rises with maternal age, whereas an unbalanced Robertsonian translocation gives maternal-age-independent recurrence. For each syndrome, anchor three facts: the cardinal facies, the associated cardiac lesion, and the confirmatory test — karyotype, FISH, or methylation studies.
- Down (trisomy 21) — 1/700, most common viable trisomy. Flat facies, upslanting palpebral fissures, epicanthal folds, single palmar (simian) crease, Brushfield spots, protruding tongue, brachycephaly.
- Cardiac: complete atrioventricular septal defect (endocardial cushion) is most characteristic.
- GI: duodenal atresia ('double bubble'), annular pancreas, Hirschsprung disease.
- Increased risk of ALL and AML (esp. acute megakaryoblastic, M7) and early-onset Alzheimer disease (APP on chr 21); also hypothyroidism and atlantoaxial instability.
- Screening — quad: ↓AFP, ↓estriol, ↑hCG, ↑inhibin A; first-trimester ↑nuchal translucency, ↓PAPP-A, ↑β-hCG.
- Edwards (18) — clenched fists with overlapping fingers, rocker-bottom feet, micrognathia, prominent occiput, low-set ears, VSD; death usually <1 year.
- Patau (13) — holoprosencephaly, cleft lip/palate, polydactyly, microphthalmia, cutis aplasia, omphalocele; death usually <1 year.
Trisomy 21 vs 18 vs 13
| Feature | Trisomy 21 (Down) | Trisomy 18 (Edwards) | Trisomy 13 (Patau) |
|---|---|---|---|
| Incidence | 1/700 (most common) | 1/8000 | 1/15,000 |
| Facies | Flat face, epicanthal folds, Brushfield spots | Micrognathia, prominent occiput, low-set ears | Holoprosencephaly, cleft lip/palate, microphthalmia |
| Hands/feet | Single palmar crease | Overlapping fingers, rocker-bottom feet | Polydactyly, rocker-bottom feet |
| Cardiac | Complete AV septal defect | VSD | VSD |
| Quad screen | ↓AFP, ↓estriol, ↑hCG, ↑inhibin A | ↓AFP, ↓estriol, ↓hCG, ↓/normal inhibin | Often normal; ↓PAPP-A on 1st-tri screen |
| Survival | Into adulthood | <1 year | <1 year |
- Turner (45,X) — short stature, streak ovaries → primary amenorrhea (most common cause) and infertility; webbed neck (residual cystic hygroma), newborn lymphedema of hands/feet, shield chest with widely spaced nipples, low posterior hairline.
- Cardiac: bicuspid aortic valve (most common) and coarctation of the aorta — brachial > femoral pulses / arm BP > leg BP; also horseshoe kidney.
- Labs: ↑FSH, ↑LH, ↓estrogen (hypergonadotropic hypogonadism); no Barr body. The retained X is usually maternal — the paternal sex chromosome is the one lost. Rx: growth hormone + estrogen.
- Klinefelter (47,XXY) — tall with long extremities, small firm testes, gynecomastia, azoospermia/infertility, learning difficulties. ↑FSH, ↑LH, ↑estrogen, ↓testosterone; Barr body present; biopsy shows seminiferous tubule hyalinization. Rx testosterone.
- Fragile X — CGG repeat expansion silencing FMR1; most common inherited cause of intellectual disability. Long face, large everted ears, macroorchidism, mitral valve prolapse, autism; shows anticipation.
Vignette: A 15-year-old girl is evaluated for short stature and never having had a menstrual period. She has no breast development, a low posterior hairline, a broad chest with widely spaced nipples, and mild neck webbing. Blood pressure is higher in the arms than the legs, and femoral pulses are diminished.
Diagnosis: Turner syndrome (45,X) — short stature + primary amenorrhea + webbed neck + coarctation physiology.
Best initial labs: ↑FSH and ↑LH with low estradiol (ovarian dysgenesis / hypergonadotropic hypogonadism).
Next best step / confirmation: Karyotype (peripheral blood) confirms 45,X. Then screen for complications: echocardiogram for bicuspid aortic valve and coarctation, and renal ultrasound for horseshoe kidney. Treat short stature with growth hormone and induce puberty with estrogen.
Vignette A: A floppy newborn has poor suck and feeding difficulty; by age 2–3 he develops insatiable hyperphagia, obesity, small genitalia, almond-shaped eyes, and mild intellectual disability. → Prader-Willi syndrome (loss of the paternal 15q11-13 — paternal deletion or maternal uniparental disomy).
Vignette B: A child has severe intellectual disability, minimal speech, inappropriate laughter, hand-flapping, an ataxic 'puppet-like' gait, and seizures. → Angelman syndrome (loss of the maternal 15q / UBE3A — maternal deletion or paternal UPD).
Next best step: DNA methylation analysis of the 15q11-13 region is the single best initial test for both — it detects deletion, uniparental disomy, and imprinting defects. Same locus, opposite parent of origin: the classic imprinting board question.
Imprinting & microdeletion syndromes
| Syndrome | Locus / mechanism | Buzzwords | Board pearl |
|---|---|---|---|
| Prader-Willi | Loss of paternal 15q11-13 (or maternal UPD) | Hyperphagia, obesity, hypotonia, hypogonadism, almond eyes | 'Paternal'; methylation test |
| Angelman | Loss of maternal 15q / UBE3A (or paternal UPD) | Happy 'puppet,' laughter, ataxia, seizures | 'mAternal = from Mom' |
| DiGeorge | 22q11 deletion; 3rd/4th pharyngeal pouch failure | Conotruncal defect (TOF, truncus, interrupted arch), cleft palate | Hypocalcemic tetany + T-cell deficiency |
| Williams | 7q11 deletion (elastin) | Elfin facies, 'cocktail-party' friendliness, supravalvular aortic stenosis | Hypercalcemia |
| Cri-du-chat | 5p deletion | High-pitched cat-like cry, microcephaly, VSD | Severe intellectual disability |
Trisomy age-of-milestone (also the incidence rank):
- Patau = Puberty ≈ 13
- Edwards = Election age = 18
- Down = Drinking age = 21
DiGeorge — CATCH-22 (chromosome 22):
- Cardiac (conotruncal) defects
- Abnormal facies
- Thymic aplasia (T-cell deficiency)
- Cleft palate
- Hypocalcemia (parathyroid aplasia)
Imprinting parent-of-origin: Prader-Willi = Paternal deletion; Angelman = mAternal deletion (UBE3A). Same 15q locus, opposite parent — the tested distinction.
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