Congenital & Genetic Disorders (Clinical)

The autosomal trisomies and prenatal screening

Down syndrome genetics. Trisomy 21 is the most common trisomy and the most common genetic cause of intellectual disability. Risk rises with maternal age; most cases result from meiotic nondisjunction and a minority from a Robertsonian translocation, which can recur in families and prompts parental karyotyping.

Prenatal pathway. Cell-free fetal DNA screens for aneuploidy. The first-trimester combined test (nuchal translucency, PAPP-A, hCG) and the second-trimester quad screen adjust risk; a high AFP instead suggests a neural tube or abdominal wall defect (or incorrect dating). Screening never diagnoses: confirm with chorionic villus sampling (first trimester) or amniocentesis (second trimester) for karyotype or microarray.

Congenital heart disease clusters in syndromes, so evaluate the heart (echocardiogram) in any dysmorphic infant.

Sex chromosome disorders, fragile X, and 22q11 deletion

Turner syndrome (45,X). Short stature, webbed neck (from a fetal cystic hygroma), shield chest with widely spaced nipples, lymphedema of the hands and feet, coarctation of the aorta and bicuspid aortic valve, and horseshoe kidney. Streak ovaries cause primary amenorrhea with high FSH and LH; Turner is the most common cause of primary amenorrhea. There is no Barr body. Treat with growth hormone and estrogen replacement; if a mosaic karyotype contains Y material, the gonads are removed because of gonadoblastoma risk.

Klinefelter syndrome (47,XXY). Tall stature, gynecomastia, small firm testes, infertility, and learning difficulties. Labs show low testosterone with high LH and FSH (primary hypogonadism), and a Barr body is present. Testosterone replacement treats the hypogonadism.

Fragile X syndrome. A CGG trinucleotide repeat expansion in FMR1 on the X chromosome makes it the most common inherited cause of intellectual disability. Features are a long face, large ears, macroorchidism (large testes after puberty), autism features, and mitral valve prolapse. Down syndrome is usually sporadic, which is why fragile X, not Down, is the answer for "inherited".

22q11.2 deletion (DiGeorge), CATCH-22:

• Cardiac defects: truncus arteriosus, tetralogy of Fallot
• Abnormal facies
• Thymic aplasia: T-cell deficiency and recurrent infections
• Cleft palate
• Hypocalcemia from absent parathyroids: neonatal tetany and seizures

Congenital heart disease

Tetralogy physiology. Tetralogy combines pulmonary (right ventricular outflow) stenosis, right ventricular hypertrophy, an overriding aorta, and a VSD. Squatting raises systemic vascular resistance, which reduces right-to-left shunting across the VSD and relieves a tet spell; the same logic underlies knee-chest positioning, oxygen, and phenylephrine in the hospital.

Long-standing left-to-right shunts cause pulmonary hypertension that can reverse the shunt (Eisenmenger syndrome), producing late cyanosis and clubbing; at that point the defect can no longer be closed.

Cystic fibrosis and the newborn screen

Cystic fibrosis is autosomal recessive, caused by CFTR mutations (most commonly Phe508del, also written ΔF508, on chromosome 7). Thick secretions produce meconium ileus, recurrent lung infections (S. aureus early, then Pseudomonas), pancreatic insufficiency with steatorrhea and deficiency of fat-soluble vitamins (A, D, E, K), nasal polyps, clubbing, and infertility: congenital bilateral absence of the vas deferens makes almost all affected males infertile.

Diagnosis. The newborn screen measures immunoreactive trypsinogen; an elevated result is confirmed with a sweat chloride test. CFTR modulator drugs now target specific mutations, alongside airway clearance, antibiotics, and pancreatic enzymes.

The heel-stick screen at 24–48 hours of life detects treatable conditions before irreversible harm:

• Phenylketonuria: musty odor, intellectual disability if untreated; restrict phenylalanine and aspartame.
• Congenital hypothyroidism: start levothyroxine promptly to protect cognition.
• Galactosemia: jaundice, hepatomegaly, cataracts, E. coli sepsis after milk feeds; remove galactose.
• MCAD deficiency: hypoketotic hypoglycemia with fasting; avoid fasting.
• Congenital adrenal hyperplasia, sickle cell disease, and cystic fibrosis.

TORCH infections