Chromosomal Disorders

Chromosomal (cytogenetic) disorders result from numerical or structural alterations of chromosomes and are among the most heavily tested topics in NEET PG Paediatrics and Genetics. Mastering karyotypes, signature dysmorphic features, the single best clinical clue, and prenatal screening cut-offs reliably fetches 2-4 marks every cycle.

Definition & Classification

A chromosomal disorder is any clinical syndrome caused by a change in chromosome number (aneuploidy/polyploidy) or structure (deletion, duplication, translocation, inversion, ring, isochromosome). The normal human karyotype is 46,XX (female) or 46,XY (male).

Broad classification:

Category	Mechanism	Examples
Autosomal trisomy	Extra autosome (usually meiotic non-disjunction)	Down (21), Edwards (18), Patau (13)
Sex-chromosome aneuploidy	Extra/missing X or Y	Turner (45,X), Klinefelter (47,XXY)
Microdeletion	Loss of contiguous genes	DiGeorge (22q11), Cri-du-chat (5p−), Williams (7q11), Prader-Willi/Angelman (15q11-13)
Structural	Translocation, ring, isochromosome	Robertsonian Down, ring 13/18
Triploidy/Tetraploidy	Whole extra haploid set	69,XXX – usually lethal, partial mole

High-yield: Non-disjunction during maternal meiosis I is the commonest mechanism of autosomal trisomy, and its frequency rises sharply with advanced maternal age (≥35 years). Structural rearrangements (translocations) are independent of maternal age and are the ones that can recur in families.

Etiology & Pathophysiology

• Non-disjunction: failure of homologous chromosomes (meiosis I) or sister chromatids (meiosis II) to separate → gametes with 24 or 22 chromosomes → trisomic/monosomic zygote.
• Robertsonian translocation: fusion of two acrocentric chromosomes (13, 14, 15, 21, 22) at the centromere. A carrier parent is phenotypically normal (45 chromosomes) but produces unbalanced gametes. t(14;21) is the classic translocation Down syndrome.
• Mosaicism: post-zygotic mitotic non-disjunction → two cell lines (e.g., 46,XX/47,XX,+21). Generally a milder phenotype.
• Anaphase lag: loss of a chromosome → monosomy, the basis of most 45,X Turner (paternal sex chromosome usually lost).

Down Syndrome (Trisomy 21)

The commonest autosomal trisomy compatible with survival; incidence ~1 in 700-800 live births.

Cytogenetics (must memorise the proportions):

Type	Karyotype	Frequency	Maternal age link	Recurrence
Free trisomy 21 (non-disjunction)	47,XX/XY,+21	~94-95%	Strong	~1%
Translocation	46,XX,t(14;21) etc.	~4%	None	High (up to 100% if parent carries 21;21)
Mosaic	46/47,+21	~1-2%	Weak	Low; mildest features

Clinical features — head to toe:

• Craniofacial: brachycephaly, flat occiput, upslanting palpebral fissures, epicanthal folds, Brushfield spots (speckled iris), flat nasal bridge, protruding tongue (relative macroglossia), small low-set ears.
• Hands: single transverse palmar (simian) crease, clinodactyly of 5th finger, wide sandal gap between 1st-2nd toes.
• Hypotonia ("floppy infant"), short stature, intellectual disability (mean IQ ~50).
• Atlantoaxial instability — screen before sports/anaesthesia.

Associated systemic problems (exam favourites):

• Cardiac: endocardial cushion / AV canal (AVSD) defect is the MOST characteristic; VSD is the most common overall. → Leading cause of early mortality.
• GI: duodenal atresia ("double-bubble" on X-ray, bilious vomiting), Hirschsprung disease, annular pancreas, imperforate anus, TEF.
• Endocrine: hypothyroidism (acquired autoimmune common; screen periodically), type 1 diabetes.
• Haematology: transient myeloproliferative disorder (TMD) in neonates; markedly increased risk of AML (esp. AMKL/M7) and ALL.
• Alzheimer-type dementia by 4th decade (APP gene on chr 21).

High-yield: Down baby with bilious vomiting + double-bubble sign = duodenal atresia. Down baby with a murmur → think AV septal (endocardial cushion) defect. Both are repeatedly asked image/clinical-vignette questions.

Mnemonic — "DOWN": Duodenal atresia, Occipital flattening/upslant eyes, Wide simian crease, Neck (atlantoaxial, redundant nuchal skin).

Edwards Syndrome (Trisomy 18)

Second commonest autosomal trisomy; female predominance; most die in infancy.

• Karyotype 47,XX/XY,+18.
• Clenched fist with overlapping fingers (index over 3rd, 5th over 4th) — the single most pathognomonic sign.
• Rocker-bottom feet, prominent occiput, micrognathia, low-set ears, short sternum.
• Severe IUGR, congenital heart disease (VSD), horseshoe kidney.

High-yield: Clenched fist with overlapping fingers + rocker-bottom feet + micrognathia = Edwards (18). "Edwards = Election age 18" memory hook.

Patau Syndrome (Trisomy 13)

• Karyotype 47,XX/XY,+13; very high early mortality.
• Midline defects: holoprosencephaly, cleft lip/palate, microphthalmia/cyclopia.
• Polydactyly (postaxial), cutis aplasia (scalp defects), rocker-bottom feet, omphalocele, polycystic kidneys, cardiac defects.

High-yield: Patau = "P" for Polydactyly, holoProsencephaly, cleft Palate/liP, microPhthalmia. Midline + scalp defects distinguish it from Edwards.

Trisomy comparison (very frequently asked side-by-side):

Feature	Down (21)	Edwards (18)	Patau (13)
Incidence	1/700	1/6000	1/10,000
Hands/feet	Simian crease, sandal gap	Overlapping fingers, rocker-bottom feet	Polydactyly, rocker-bottom feet
Face	Upslant eyes, macroglossia	Micrognathia, prominent occiput	Cleft lip/palate, microphthalmia
CNS	Mild-moderate ID	Severe ID	Holoprosencephaly
Renal	–	Horseshoe kidney	Polycystic kidneys
Survival	Years-decades	Weeks-months	Days-weeks
Cardiac	AVSD	VSD	VSD

Turner Syndrome (45,X)

The only viable monosomy in humans; phenotypically female.

• Karyotype 45,X (~50%); rest are mosaics (45,X/46,XX) or structural (isochromosome Xq, ring X). Often the paternal X is lost.
• Short stature (SHOX gene haploinsufficiency) — hallmark; gonadal dysgenesis → streak ovaries → primary amenorrhoea & infertility.
• Webbed neck (cystic hygroma in utero), low posterior hairline, shield chest with widely spaced nipples, cubitus valgus, short 4th metacarpal, multiple pigmented naevi.
• Lymphoedema of hands/feet in the newborn.
• Cardiac: bicuspid aortic valve (commonest) and coarctation of aorta → risk of aortic dissection.
• Renal: horseshoe kidney. Also: hypothyroidism (Hashimoto), normal intelligence (may have poor visuospatial skills).

High-yield: Short adolescent girl + primary amenorrhoea + no/incomplete secondary sexual characteristics + webbed neck = Turner. Investigation of choice = karyotype; hormones show high FSH/LH (hypergonadotropic hypogonadism).

Management: Growth hormone for short stature; oestrogen replacement (started ~11-12 yr) to induce puberty, then cyclical oestrogen-progesterone.

Klinefelter Syndrome (47,XXY)

Commonest cause of primary male hypogonadism / non-obstructive azoospermia.

• Karyotype 47,XXY (extra X from either parent).
• Tall stature with long limbs (eunuchoid), small firm testes, gynaecomastia, sparse body hair, infertility.
• Mild learning/behavioural issues; increased risk of breast cancer and extragonadal germ cell tumours.
• Hormones: low testosterone, high FSH & LH (hypergonadotropic hypogonadism); raised oestradiol.

High-yield: Tall + gynaecomastia + small testes + azoospermia = Klinefelter (47,XXY). Contrast: Turner = short; Klinefelter = tall. The extra X (Barr body) makes Klinefelter chromatin-positive despite being male.

Barr bodies = (number of X) − 1. Normal female = 1; Turner = 0; Klinefelter = 1; 47,XXX = 2.

Sex-chromosome & monosomy comparison

Feature	Turner (45,X)	Klinefelter (47,XXY)
Phenotype	Female	Male
Stature	Short	Tall
Gonad	Streak ovary	Small firm testis
Fertility	Infertile (amenorrhoea)	Infertile (azoospermia)
Hormones	↑FSH/LH, ↓oestrogen	↑FSH/LH, ↓testosterone
Barr body	0	1
Classic extra	Coarctation, webbed neck, lymphoedema	Gynaecomastia, learning issues

Diagnosis & Investigation of Choice

Stepwise diagnostic flow: Clinical/dysmorphic suspicion → Karyotype (GTG banding) [gold standard / confirmatory] → FISH for rapid aneuploidy or microdeletion → Chromosomal microarray (CMA) for submicroscopic CNVs.

• Karyotype is the definitive/confirmatory test for numerical and large structural anomalies and is essential to distinguish free trisomy from translocation (vital for recurrence counselling).
• FISH: rapid (24-48 h) detection of specific aneuploidies (13, 18, 21, X, Y) and microdeletions (22q11).
• Chromosomal microarray (CMA): first-line for a child with unexplained intellectual disability / multiple congenital anomalies (detects copy-number variants karyotype misses); cannot detect balanced translocations.
• QF-PCR / MLPA: rapid prenatal aneuploidy detection.

Prenatal Screening (very high-yield numbers)

First trimester combined test (11-13⁺⁶ weeks):

• Nuchal translucency (NT) ↑ + PAPP-A ↓ + free β-hCG ↑ in Down syndrome.

Second trimester — Quadruple (Quad) marker test (15-20 weeks):

Marker	Down (21)	Edwards (18)	Open NTD
AFP	↓	↓	↑
hCG	↑	↓	normal
Unconjugated oestriol (uE3)	↓	↓	normal
Inhibin A	↑	normal/↓	normal

High-yield: Down syndrome triple/quad pattern = ↓AFP, ↓uE3, ↑hCG, ↑Inhibin A. Edwards = all three (AFP, hCG, uE3) low. Memorise the arrows — directly examinable.

• NIPT (cell-free fetal DNA): highest sensitivity/specificity screening test (esp. trisomy 21), done from 10 weeks; a screen, not diagnostic.
• Definitive prenatal diagnosis: chorionic villus sampling (CVS, 10-13 wk) or amniocentesis (15-18 wk) with fetal karyotype/CMA. Amniocentesis is the most widely used confirmatory procedure.

High-yield: A positive NIPT or abnormal quad screen must be confirmed by amniocentesis/CVS karyotype before any irreversible decision. NIPT can give false positives from confined placental mosaicism.

Management / Drug of Choice principles

• No cure for the aneuploidy; management is multidisciplinary and supportive.
• Down: surgical repair of cardiac/GI defects, periodic thyroid screening (TSH), audiology/ophthalmology, cervical spine imaging before sports, developmental therapy.
• Turner: recombinant growth hormone + oestrogen replacement; cardiology surveillance.
• Klinefelter: testosterone replacement from puberty; assisted reproduction (TESE-ICSI) for fertility.
• Genetic counselling for all — translocation Down mandates parental karyotyping because recurrence is high.

Complications

• Down: congenital heart disease (commonest cause of death in infancy), leukaemia (AML/ALL), hypothyroidism, recurrent infections, OSA, early Alzheimer dementia, atlantoaxial subluxation.
• Edwards/Patau: high perinatal mortality; severe cardiac and CNS malformations.
• Turner: aortic dissection/rupture (esp. in pregnancy), osteoporosis, infertility, autoimmune disease.
• Klinefelter: osteoporosis, metabolic syndrome, breast carcinoma, venous thromboembolism, psychosocial issues.

Key Differentials

• Hypotonic floppy infant: Down vs Prader-Willi vs spinal muscular atrophy vs congenital hypothyroidism.
• Short girl + amenorrhoea: Turner vs constitutional delay vs Noonan syndrome ("male Turner": normal karyotype 46,XY/XX, PTPN11 mutation, pulmonary stenosis, normal/variable intellect).
• Tall boy + gynaecomastia: Klinefelter vs Marfan vs familial tall stature.
• Microdeletion mimics: Cri-du-chat (5p−, cat-like cry, microcephaly), DiGeorge (22q11 — CATCH-22: Cardiac, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcaemia), Williams (7q — elfin face, supravalvular AS, friendly personality, hypercalcaemia), Prader-Willi (paternal 15q deletion — hypotonia then hyperphagia/obesity) vs Angelman (maternal 15q — "happy puppet").

High-yield: Noonan = "Turner-like" but with normal karyotype and pulmonary (not aortic) lesion. This contrast is a classic single-best-answer trap.

Recently asked / exam angle

• Image of a neonatal abdominal X-ray "double bubble" → diagnosis and the underlying syndrome (Down + duodenal atresia).
• Single transverse palmar crease + AVSD → karyotype expected = 47,XX,+21.
• "Most common cardiac defect characteristic of Down" → endocardial cushion/AV canal (AVSD) (most characteristic), VSD most common overall — read the stem carefully.
• Quad-marker arrow patterns matched to Down vs Edwards vs NTD.
• Barr body count for given karyotypes (47,XXX → 2; 45,X → 0).
• Mechanism question: trisomy 21 most often due to maternal meiosis I non-disjunction.
• Noonan vs Turner differentiation by karyotype and cardiac lesion.
• Investigation of choice for a dysmorphic child with ID → chromosomal microarray; confirmatory for aneuploidy → karyotype.

Rapid revision

1. Commonest viable autosomal trisomy = Down (21); commonest mechanism = maternal meiosis I non-disjunction, rises with maternal age.
2. Translocation Down (t14;21) is maternal-age independent and has high recurrence → always karyotype parents.
3. Down: simian crease, Brushfield spots, AVSD, duodenal atresia (double bubble), hypothyroidism, ↑AML/ALL.
4. Edwards (18): overlapping clenched fingers + rocker-bottom feet + micrognathia; female predominant.
5. Patau (13): holoprosencephaly, cleft lip/palate, polydactyly, cutis aplasia, microphthalmia.
6. Turner (45,X): short female, streak ovaries, primary amenorrhoea, webbed neck, coarctation + bicuspid aortic valve, Barr body = 0.
7. Klinefelter (47,XXY): tall male, small firm testes, gynaecomastia, azoospermia, Barr body = 1.
8. Hypergonadotropic hypogonadism (↑FSH/LH) in BOTH Turner and Klinefelter.
9. Down quad screen = ↓AFP, ↓uE3, ↑hCG, ↑Inhibin A; Edwards = AFP/hCG/uE3 all low; open NTD = ↑AFP.
10. First-trimester Down screen: ↑NT, ↑free β-hCG, ↓PAPP-A.
11. Karyotype = confirmatory; CMA = first-line for ID/multiple anomalies; NIPT = best screen but needs amnio/CVS confirmation.
12. Noonan = normal karyotype, PTPN11, pulmonary stenosis — the "male Turner" mimic.