Chromosomal Syndromes — Down, Edwards, Patau, Turner and Klinefelter Compared

A chromosomal syndrome is a recognisable pattern of malformations caused by a change in the number or structure of chromosomes. The exam favourites are numerical (aneuploidy) disorders: a trisomy (2n + 1) such as Down syndrome, or a monosomy (2n − 1) such as Turner syndrome (45,X). Within three years of 1959, numerical abnormalities had been identified in Turner, Down and Klinefelter syndromes.

The usual mechanism is nondisjunction — replicated chromosomes fail to separate in one of the two meiotic divisions. For autosomal trisomies this happens predominantly in meiosis I of oocyte formation, which is why risk climbs with advanced maternal age: StatPearls notes that trisomy 21 rates increase nearly exponentially after a maternal age of 35. Sex chromosome aneuploidies behave differently — paternal nondisjunction accounts for at least half of them.

• Nondisjunction (meiotic) — full trisomy in every cell; the commonest route for trisomies 21, 18 and 13.
• Robertsonian translocation — two acrocentric chromosomes fuse at their centromeres, losing both short arms. A balanced carrier is healthy but can produce an unbalanced (trisomic) child; carrier frequency is about 1 in 1000.
• Mosaicism — a post-zygotic error leaves two cell lines (normal and abnormal); the phenotype is usually milder and more variable.

Down syndrome (trisomy 21) is the most common viable autosomal trisomy and the leading genetic cause of intellectual disability. Live-birth incidence is roughly 1 in 700 to 1 in 800 (StatPearls range: 1 in 319 to 1 in 1000 across populations). About 50% to 75% of affected fetuses are lost through miscarriage. Chromosome 21 is the smallest and least gene-dense autosome — one reason trisomy 21 survives better than other trisomies.

Features: flat facies, prominent epicanthic folds, flat occiput, Brushfield spots in the iris, single transverse palmar crease, clinodactyly and hypotonia — present in nearly all infants and the cause of delayed motor milestones. Nearly all have mild to moderate intellectual disability.

The American Academy of Pediatrics' 2022 health-supervision guidance (summarised in StatPearls) sets out a schedule that is commonly paraphrased in questions:

• Echocardiogram for every newborn with Down syndrome, regardless of prenatal imaging.
• Thyroid: review newborn screen, then TSH at 6 and 12 months and yearly thereafter (every 6 months if antithyroid antibodies are present).
• Hearing: ear-specific testing in the first month, repeated at 6 months, then yearly.
• Eyes: ophthalmology review within the first 6 months (strabismus, cataract, nasolacrimal duct obstruction, refractive error).
• Blood: CBC with differential and iron studies from age 1, yearly.
• Atlantoaxial instability: history and examination for myelopathy at each visit; the AAP no longer recommends routine neck X-rays in asymptomatic children.

Edwards syndrome (trisomy 18) is the second most common autosomal trisomy, first reported by Edwards in 1960. Complete trisomy accounts for about 94% of cases, usually from maternal nondisjunction, mostly in meiosis II; mosaic (under 5%) and partial (2%) forms make up the rest. Live-birth prevalence ranges from 1 in 3600 to 1 in 10,000, with a female-to-male ratio of 3:2 because male fetuses are lost more often.

• Hands: clenched fists with overriding (overlapping) fingers with hypoplastic nails.
• Feet: rocker-bottom feet with prominent calcanei.
• Head and face: microcephaly, prominent occiput, micrognathia, low-set malformed ears.
• Chest: short sternum.
• Heart: defects in about 90% — VSD, ASD, PDA, polyvalvular disease.
• Other: omphalocele, horseshoe kidney, severe growth restriction and profound developmental delay; increased risk of Wilms tumour and hepatoblastoma.
• Antenatal clues: growth restriction, polyhydramnios, choroid plexus cysts, clenched hands, omphalocele, single umbilical artery.

Survival: among live-born infants, 60–75% survive the first week, 20–40% the first month and 10–19% the first year; intensive care including cardiac surgery can raise 1-year survival to 30–50%. Current neonatal resuscitation guidance no longer advocates automatically withholding active management.

Patau syndrome (trisomy 13) is the third most common autosomal trisomy, about 1 in 10,000 to 20,000 live births, with antenatal mortality above 95%. Complete trisomy is commonest (about 80%); maternal meiotic nondisjunction accounts for about 91% of cases. Partial trisomy usually comes from a Robertsonian translocation, typically t(13;14). The defects reflect failed prechordal mesoderm fusion, so they cluster in the midline.

• Holoprosencephaly spectrum (about 74%) — the forebrain fails to divide into two hemispheres. Trisomy 13 is the most common cause of holoprosencephaly.
• Midline face: cleft lip and/or palate (about 45%), hypotelorism, microphthalmia or anophthalmia, cyclopia in severe forms.
• Postaxial polydactyly (about 63–67%).
• Cutis aplasia (punched-out scalp defect).
• Heart: congenital heart disease in most (ASD, VSD, PDA, hypoplastic left heart).
• Other: omphalocele, renal anomalies, cryptorchidism; postnatal mortality about 50% in the first month and up to 90% in the first year.

Turner syndrome is a phenotypic female with one intact X and complete or partial loss of the second sex chromosome. It occurs in about 1 in 2000 to 2500 live female births, is the most common sex chromosome abnormality in females and the most common genetic cause of primary amenorrhoea. More than 99% of 45,X fetuses miscarry, usually before 28 weeks. Pure 45,X accounts for about 45% of cases; the rest are mosaics (45,X/46,XX; 45,X/46,XY) or structural changes such as isochromosome Xq or ring X.

• Ovaries: replaced by fibrous tissue — streak gonads with few or no follicles.
• Heart: congenital heart disease in about 50% — bicuspid aortic valve and coarctation of the aorta; lifelong risk of aortic dilatation and dissection.
• Kidney: horseshoe kidney, collecting-system malformations, malrotation.
• Brain: intelligence usually normal, with visuospatial and executive weaknesses.
• Autoimmune: hypothyroidism, celiac disease, inflammatory bowel disease.
• Y material (in 45,X/46,XY mosaics) → risk of gonadoblastoma; prophylactic gonadectomy is decided individually.

Treatment: growth hormone improves final height even though GH deficiency is not the cause; estrogen replacement begins if breast development has not started by 11–12 years, starting low and titrating, preferably with 17β-estradiol, then cyclic estrogen–progesterone until about the age of natural menopause.

Klinefelter syndrome is a phenotypic male with two or more X chromosomes; 47,XXY accounts for more than 90%, with mosaic 46,XY/47,XXY and 48,XXXY or 49,XXXXY variants making up the rest. It affects 1 in 500 to 1 in 1000 males, yet up to two-thirds are never diagnosed — the average age at diagnosis is about 30 years, often during an infertility work-up (about 3% of men evaluated for infertility have it).

• Tall stature with long limbs and a low upper-to-lower segment ratio (extra SHOX dosage).
• Small, firm testes — rarely above 4 mL — from hyalinisation and fibrosis of the seminiferous tubules; azoospermia and infertility.
• Gynaecomastia, sparse facial and body hair, incomplete puberty.
• Mean full-scale IQ about 85–90 with language and expressive speech difficulties.
• Risks: male breast cancer, extragonadal germ cell tumours, non-Hodgkin lymphoma, osteoporosis, type 2 diabetes and venous thromboembolism.

Prenatal screening combines ultrasound with maternal serum analytes. First-trimester screening (11–14 weeks) uses nuchal translucency plus PAPP-A and free β-hCG; a nuchal translucency above 3 mm is abnormal. The second-trimester triple screen measures β-hCG, maternal serum AFP and unconjugated estriol; the quadruple screen adds inhibin A. Cell-free DNA (cfDNA/NIPT) gives the highest detection rate, and the American College of Medical Genetics and Genomics recommends it as the preferred first-line screen for trisomies 13, 18 and 21 in singleton pregnancies.

• Ultrasound soft markers for Down syndrome (11–24 weeks): increased nuchal fold, small or absent nasal bone, large ventricles.
• Increased nuchal translucency is not specific — it also occurs in trisomies 13 and 18 and in Turner syndrome; cystic hygroma points strongly to Turner.
• Diagnostic tests: chorionic villus sampling (typically 11–13 weeks) or amniocentesis (typically 15–18 weeks) with karyotype or chromosomal microarray. Screening results alone never confirm a diagnosis.

• Image of a newborn's hand or foot — clenched fist with overlapping fingers or rocker-bottom foot → trisomy 18.
• Midline facial cleft + polydactyly + holoprosencephaly on scan → trisomy 13.
• Most common heart defect in Down syndrome → AVSD (endocardial cushion defect).
• Quadruple test pattern — high hCG and inhibin A with low AFP and estriol → Down syndrome.
• Girl with short stature, webbed neck and primary amenorrhoea → Turner; heart lesion → bicuspid aortic valve / coarctation; ovary → streak gonad.
• Tall man with small firm testes, gynaecomastia and azoospermia → Klinefelter; hormones → high FSH and LH, low testosterone.
• Translocation Down syndrome → next step is parental karyotyping.