18.1 Chromosomal Disorders & Dysmorphology
Key Takeaways
- Down syndrome (Trisomy 21) has a maternal-age-related incidence rising from about 1 in 1,500 at age 20 to about 1 in 100 at age 40, but 95% of cases are non-disjunction and 75-80% of affected infants are still born to mothers under 35 because of higher fertility rates in that group.
- Atrioventricular (AV) canal defect is the single most characteristic congenital heart lesion of Down syndrome and should be actively screened for with echocardiography in every newborn, even without a murmur.
- A Robertsonian translocation carrier parent — especially the mother — carries a materially higher recurrence risk (about 10-15% if mother, 2.5-5% if father) than the roughly 1% recurrence risk after standard non-disjunction trisomy 21.
- Turner syndrome (45,X) presents with short stature and streak gonads/ovarian failure in a phenotypic female; look for lymphedema of the hands/feet in the newborn and webbed neck, wide-spaced nipples, and coarctation of the aorta or bicuspid aortic valve later.
- 22q11.2 deletion (DiGeorge/velocardiofacial syndrome) causes conotruncal cardiac defects, hypocalcemia from hypoparathyroidism, and T-cell immunodeficiency from thymic hypoplasia; a normal standard karyotype does not exclude it because this is a submicroscopic deletion detected by FISH or chromosomal microarray.
Why Chromosomal Disorders Matter on This Exam
Genetics and dysmorphology is a smaller blueprint slice than neonatology or infectious disease, but chromosomal syndromes are high-frequency topics within that domain — especially Down syndrome, which examiners return to for cardiac screening, recurrence-risk counseling, and association-pattern questions. Turner, Edwards, and Patau syndromes appear as shorter "match the phenotype to the karyotype" vignettes, and 22q11.2 deletion (DiGeorge syndrome) is the critical microdeletion tested through its cardiac, calcium, and immune triad.
Down Syndrome (Trisomy 21)
Down syndrome is the most common autosomal chromosomal disorder compatible with survival to adulthood and the single most heavily tested dysmorphology topic on this exam. It results from an extra copy of chromosome 21, most often (about 95% of cases) from meiotic non-disjunction, giving a full trisomy 21 karyotype (47,XX or XY,+21). The remainder are due to Robertsonian translocation (about 3-4%, most often t(14;21)) or mosaicism (about 1-2%, with a milder, more variable phenotype because some cell lines are normal).
The overriding risk factor for non-disjunction trisomy 21 is advanced maternal age: incidence rises from roughly 1 in 1,500 live births at maternal age 20 to about 1 in 100 by age 40 and higher still beyond 45. A key exam trap: because younger women have far more pregnancies overall, the majority of Down syndrome infants are still born to mothers under 35 — maternal age raises the per-pregnancy risk, not the population share.
Clinical Features
| System | Finding |
|---|---|
| Craniofacial | Flat facial profile, upslanting palpebral fissures, epicanthal folds, small ears, flat nasal bridge, protruding tongue (relative macroglossia) |
| Hands/feet | Single transverse palmar (simian) crease, short/broad hands, clinodactyly of the fifth finger, wide gap between first and second toes ("sandal gap") |
| Neurodevelopmental | Hypotonia at birth (often the presenting sign in the newborn nursery), intellectual disability of variable severity |
| Growth | Postnatal growth deceleration; Down-syndrome-specific growth charts should be used, not standard population charts |
Associated Conditions — High-Yield for the Exam
- Congenital heart disease occurs in roughly 40-50% of infants. The single most characteristic lesion is the atrioventricular (AV) canal defect (endocardial cushion defect), followed by ventricular septal defect (VSD), atrial septal defect (ASD), and tetralogy of Fallot. Because AV canal defects can be clinically silent early on, every newborn with Down syndrome should get a screening echocardiogram, regardless of auscultation findings.
- Gastrointestinal anomalies: duodenal atresia is the classic association, producing the "double-bubble" sign on abdominal X-ray with bilious vomiting in the first days of life. Also watch for Hirschsprung disease, tracheoesophageal fistula, and imperforate anus.
- Hematologic/oncologic risk: infants with Down syndrome have a markedly increased risk of leukemia, both acute myeloid leukemia (particularly the megakaryoblastic subtype, AML-M7) and acute lymphoblastic leukemia — overall leukemia risk is roughly 10-20 times that of the general pediatric population. A distinct entity, transient abnormal myelopoiesis (transient leukemia), occurs in the neonatal period, usually resolves spontaneously by 3 months of age, but carries its own later risk of progressing to true AML in early childhood and mandates close blood-count follow-up.
- Other associations to recognize: hypothyroidism (screen annually), atlantoaxial instability (caution with neck hyperextension, e.g., during intubation or sports clearance), obstructive sleep apnea, hearing loss, cataracts/refractive errors, and celiac disease.
Screening and Diagnosis
Prenatal screening combines maternal serum markers (in the first-trimester combined test: low pregnancy-associated plasma protein-A [PAPP-A] and high free beta-human chorionic gonadotropin [beta-hCG], plus increased nuchal translucency on ultrasound) with cell-free fetal DNA (cfDNA) non-invasive prenatal testing, which has high sensitivity and specificity for trisomy 21. A positive screen is not diagnostic — definitive diagnosis requires a karyotype from chorionic villus sampling, amniocentesis, or postnatal peripheral blood, which also distinguishes non-disjunction from translocation (critical for counseling).
Recurrence Risk — A Frequent Exam Discriminator
| Mechanism | Recurrence risk in a future pregnancy |
|---|---|
| Standard non-disjunction trisomy 21 | About 1% (or maternal-age-related risk, whichever is higher) |
| Robertsonian translocation, mother is carrier | About 10-15% |
| Robertsonian translocation, father is carrier | About 2.5-5% |
| t(21;21) translocation, either parent is carrier | 100% (every liveborn pregnancy will be trisomy 21) |
Worked example: A 26-year-old mother has an infant with Down syndrome. Karyotype shows a translocation, and parental karyotyping identifies the mother as a balanced 14;21 Robertsonian translocation carrier. Because her age alone would predict a low background risk, the translocation — not maternal age — is the operative recurrence-risk driver, and she should be counseled toward the 10-15% figure, not the roughly 1% figure quoted for standard trisomy 21.
Other Chromosomal Syndromes (Briefly)
These are tested as short vignettes keyed to one or two pathognomonic features — do not over-invest time beyond the table below.
| Syndrome | Karyotype | Key distinguishing features |
|---|---|---|
| Turner syndrome | 45,X (or mosaic 45,X/46,XX) | Phenotypic female; short stature; streak gonads with ovarian failure/primary amenorrhea; neonatal lymphedema of the hands and feet; webbed neck, low posterior hairline, wide-spaced nipples/shield chest; coarctation of the aorta and bicuspid aortic valve; horseshoe kidney; normal intelligence in most |
| Edwards syndrome (Trisomy 18) | 47,XX or XY,+18 | Second most common autosomal trisomy; clenched fists with overlapping ("index over third") fingers, rocker-bottom feet, micrognathia, low-set ears, prominent occiput, severe intrauterine growth restriction, congenital heart disease (VSD common); prognosis is poor — most series report median survival well under a month without intensive intervention |
| Patau syndrome (Trisomy 13) | 47,XX or XY,+13 | Midline defects: cleft lip/palate, holoprosencephaly, microphthalmia/coloboma, cutis aplasia of the scalp, postaxial polydactyly; also poor prognosis |
| 22q11.2 deletion (DiGeorge / velocardiofacial syndrome) | Normal karyotype; deletion detected by FISH or chromosomal microarray | Conotruncal cardiac defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch), hypocalcemia from hypoparathyroidism (neonatal or late-onset seizures), T-cell immunodeficiency from thymic hypoplasia (recurrent infections, absent thymic shadow on chest X-ray); characteristic facies with hooded eyelids, bulbous nasal tip, and small ears; cleft palate; learning difficulties |
| Klinefelter syndrome | 47,XXY | Phenotypic male; usually unrecognized until puberty; tall stature with disproportionately long legs, small firm testes, gynecomastia, infertility/azoospermia, mildly reduced verbal IQ/learning difficulties; incidence roughly 1 in 500-1,000 male births, making it the most common sex-chromosome aneuploidy |
Microdeletion Syndromes
Unlike full trisomies, microdeletions remove a small segment of a chromosome and may not be visible on a standard karyotype. 22q11.2 deletion is the most important example on this exam — always suspect it when a neonate or infant has a conotruncal heart defect together with hypocalcemia and/or recurrent infections. Diagnosis is confirmed with FISH or chromosomal microarray, not a routine karyotype alone.
Exam trap to remember: hand/foot findings are a fast discriminator — simian crease and sandal gap point to Trisomy 21, rocker-bottom feet and overlapping fingers point to Trisomy 18, and congenital lymphedema of the hands/feet in a female newborn points to Turner syndrome.
A newborn has hypotonia, upslanting palpebral fissures, and a single transverse palmar crease. Karyotype confirms trisomy 21 from standard non-disjunction. Which additional evaluation is most important to perform before discharge, regardless of physical exam findings?
Parents of a child with Down syndrome undergo karyotyping after the child's karyotype shows a Robertsonian translocation. The mother is found to be a balanced 14;21 translocation carrier. For their next pregnancy, which recurrence risk estimate should they be counseled on?
A term newborn girl has congenital lymphedema of the hands and feet, a webbed neck, and a systolic murmur. Which chromosomal diagnosis is most likely, and which cardiac lesion should be specifically evaluated for?
A dysmorphic newborn has micrognathia, low-set ears, a prominent occiput, and clenched fists with the index finger overlapping the third finger. Rocker-bottom feet are also noted. This presentation is most consistent with which condition, and what is the expected prognosis?
A newborn with tetralogy of Fallot develops seizures on day 3 of life. Serum calcium is low, and recurrent infections have been noted. Standard karyotype is normal. Which test best confirms the underlying diagnosis?