12.2 Genetic and Congenital Disorders
Key Takeaways
- Most Down syndrome is maternal meiotic nondisjunction producing 47,XX or 47,XY,+21; atlantoaxial ligamentous laxity is a high-yield musculoskeletal association.
- Classic phenylketonuria is autosomal-recessive phenylalanine hydroxylase deficiency: untreated phenylalanine rises, tyrosine falls, and the treatment principle is restrict phenylalanine and supply tyrosine.
- Hurler syndrome is α-L-iduronidase deficiency (autosomal recessive, corneal clouding); Hunter syndrome is iduronate-2-sulfatase deficiency (X-linked, clear corneas).
- Malformations are intrinsic errors of organogenesis; deformations are extrinsic constraint on a formed part; disruptions destroy a previously normal structure (amniotic bands).
- Multifactorial traits such as neural-tube defects, cleft lip/palate, and pyloric stenosis follow a threshold-liability model: recurrence risk rises with more affected relatives and more severe phenotype.
Why genetic and congenital disease is a scored Pathology topic
Genetic and congenital disorders are 10% of the Pathology domain (Pathology is 16% of Part I, Session 2). Official bullets are chromosomal disorders, inborn errors of metabolism, and congenital disorders. The assignment for this section also requires the multifactorial threshold model, because that is how most common structural birth defects actually run in families. Chemistry chapters cover pathways (/study-guides/nbce-part1/chemistry-macromolecules/carbohydrates for glycogen; /study-guides/nbce-part1/chemistry-nucleic-energetics/nucleotides-nucleic-acids for DNA). This section is the phenotype and inheritance layer: which chromosome, which enzyme, which morphogenetic class.
Quick Answer: Aneuploidy is usually meiotic nondisjunction (trisomy 21/18/13; 45,X; 47,XXY). Inborn errors are almost all autosomal-recessive enzyme defects (PKU, glycogenoses, mucopolysaccharidoses) except X-linked Hunter disease. Malformation = intrinsic organogenesis failure; deformation = squeeze; disruption = destruction of a formed part. Clefts, neural-tube defects, and pyloric stenosis are multifactorial.
Chromosomal disorders: aneuploidy and deletions
Aneuploidy is a chromosome number that is not a multiple of 23. The usual mechanism is meiotic nondisjunction: homologs fail to separate in meiosis I, or sister chromatids fail in meiosis II. Maternal meiosis I errors rise with maternal age and explain most trisomy 21. Mitotic nondisjunction after fertilization produces mosaicism. Anaphase lag can lose a chromosome and contribute to monosomy. A Robertsonian translocation fuses long arms of acrocentric chromosomes (13, 14, 15, 21, 22); a balanced 14;21 carrier is phenotypically normal but can transmit an unbalanced gamete that causes translocation Down syndrome—the familial form you must separate from sporadic nondisjunction.
| Karyotype | Name | High-yield phenotype |
|---|---|---|
| 47,XX,+21 or 47,XY,+21 | Down syndrome (trisomy 21) | Hypotonia, epicanthal folds, single palmar crease, AV septal (endocardial cushion) defects, duodenal atresia, Hirschsprung disease, ALL and megakaryoblastic AML, early Alzheimer disease (APP on 21), atlantoaxial instability |
| 47,XX,+18 or 47,XY,+18 | Edwards syndrome | Clenched fists with overlapping fingers, rocker-bottom feet, omphalocele, horseshoe kidney, severe heart defects; usually lethal in infancy |
| 47,XX,+13 or 47,XY,+13 | Patau syndrome | Holoprosencephaly, cleft lip/palate, polydactyly, cutis aplasia, severe heart defects; usually lethal in infancy |
| 45,X | Turner syndrome | Cystic hygroma / webbed neck, coarctation of the aorta, bicuspid aortic valve, streak ovaries, horseshoe kidney, short stature (SHOX haploinsufficiency), no Barr body |
| 47,XXY | Klinefelter syndrome | Tall, hypogonadism, infertility, gynecomastia, Barr body present, increased breast-cancer risk relative to 46,XY |
Down syndrome is the chromosomal item you must know cold. About 95% are free trisomy 21 from nondisjunction; a minority are unbalanced Robertsonian translocations (risk of recurrence is high if a parent is a balanced carrier); mosaics are milder. The musculoskeletal fact that chiropractic candidates cannot drop: ligamentous laxity including the transverse atlantal ligament, so atlantoaxial instability is a recognized association. That is anatomy plus connective-tissue laxity, not a Part II adjustment lecture—know the lesion exists.
Sex-chromosome aneuploidy is more compatible with life than autosomal monosomy because of X inactivation. Turner patients are 45,X (or mosaic); they need estrogen for secondary sex characteristics and have specific left-heart lesions, not “just short.” Klinefelter is the most common cause of male hypogonadism with small firm testes and azoospermia.
Deletions and microdeletions remove contiguous genes.
| Locus | Name | Mechanism / clues |
|---|---|---|
| 5p− | Cri-du-chat | High-pitched cat-like cry, microcephaly, intellectual disability |
| 22q11.2 | DiGeorge / velocardiofacial (TBX1) | Failed 3rd/4th pharyngeal pouches: thymic hypoplasia (T-cell deficit), hypoparathyroidism (tetany), conotruncal heart defects (truncus, tetralogy); CATCH-22 mnemonic |
| 15q11–13 paternal deletion (or maternal uniparental disomy 15) | Prader–Willi | Imprinting: hypotonia, hyperphagia, obesity, hypogonadism |
| 15q11–13 maternal UBE3A loss (deletion or paternal uniparental disomy) | Angelman | Happy puppet gait, inappropriate laughter, seizures |
Imprinting is parent-of-origin silencing. The same 15q deletion causes Prader–Willi if the paternal copy is missing (paternal genes in that interval are the ones that should be expressed) and Angelman if the maternal UBE3A is missing. Uniparental disomy is the other route to the same syndromes. Fragile X is not a missing chromosome but a CGG expansion in FMR1 (Xq27.3) with a cytogenetic fragile site: X-linked intellectual disability, long face, large ears, macroorchidism, and anticipation (worse in later generations, especially through maternal transmission). It is the most common inherited cause of intellectual disability; Down syndrome is the most common genetic cause overall but is usually sporadic aneuploidy, not Mendelian.
A compact Mendelian table sits next to chromosomal disease because many “congenital” phenotypes are single-gene:
| Pattern | Rule | Examples |
|---|---|---|
| Autosomal dominant | One mutant allele; often structural proteins; variable expressivity | Marfan (FBN1), achondroplasia (FGFR3 gain-of-function), NF1, Huntington (CAG) |
| Autosomal recessive | Both alleles; often enzymes | PKU, glycogenoses, Hurler, cystic fibrosis, sickle cell |
| X-linked recessive | Males express; no male-to-male transmission | Hunter MPS II, Duchenne dystrophy, hemophilia A, Bruton agammaglobulinemia |
Achondroplasia is FGFR3 constitutive signaling that inhibits chondrocyte proliferation at growth plates: rhizomelic short stature, frontal bossing, lumbar stenosis risk, and a large head. Homozygosity is lethal. That is a receptor-tyrosine-kinase story, not a missing chromosome.
Inborn errors of metabolism
Most classic inborn errors are autosomal-recessive enzyme deficiencies. Substrate accumulates; downstream product is missing; a cofactor variant can mimic the enzyme defect (BH4 in a PKU-like picture). Newborn screening exists because early diet or enzyme replacement changes outcome; the exam still wants the enzyme and the toxic metabolite.
Phenylketonuria and amino-acid disorders
Classic phenylketonuria (PKU) is phenylalanine hydroxylase (PAH) deficiency on chromosome 12. PAH converts phenylalanine to tyrosine using tetrahydrobiopterin (BH4). Without PAH, phenylalanine and phenylketones accumulate; tyrosine becomes essential. Untreated infants are fair (less melanin from tyrosine), develop a musty odor, seizures, and severe intellectual disability. Treatment principle: restrict phenylalanine and supply tyrosine. Maternal PKU is a teratogen even if the fetus is genetically normal: microcephaly, heart defects, growth restriction from high maternal phenylalanine. A minority of hyperphenylalaninemia is BH4 synthesis or recycling failure—those children need cofactor, not only dietary restriction, because other BH4-dependent hydroxylases (tyrosine, tryptophan) fail too.
Nearby amino-acid items that show up as distractors: maple-syrup urine disease (branched-chain α-ketoacid dehydrogenase; leucine, isoleucine, valine); alkaptonuria (homogentisate oxidase; ochronosis, spine and large-joint arthropathy); homocystinuria (cystathionine β-synthase; Marfanoid habitus plus thrombosis and downward lens dislocation—contrast Marfan’s upward dislocation).
Glycogen storage diseases
Name the enzyme, the organ, and whether hypoglycemia or muscle cramps dominate.
| Type | Eponym | Enzyme | Clinical |
|---|---|---|---|
| I | von Gierke | Glucose-6-phosphatase | Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia (gout), doll-like facies |
| II | Pompe | Lysosomal acid α-glucosidase (acid maltase) | Cardiomegaly, hypotonia, macroglossia; a lysosomal storage disease that happens to store glycogen |
| III | Cori | Debranching enzyme | Milder hypoglycemia, limit-dextrin-like glycogen, hepatomegaly |
| IV | Andersen | Branching enzyme | Amylopectin-like polysaccharide, cirrhosis |
| V | McArdle | Muscle glycogen phosphorylase | Exercise cramps, myoglobinuria, second-wind; no hypoglycemia (liver enzyme intact) |
| VI | Hers | Liver glycogen phosphorylase | Hepatomegaly, mild hypoglycemia |
Von Gierke cannot export free glucose from glycogenolysis or gluconeogenesis—both pathways terminate at glucose-6-phosphate. McArdle cannot break muscle glycogen during anaerobic burst; lactate may fail to rise with ischemic exercise. Pompe is the one that looks like a cardiomyopathy, not a fasting-hypoglycemia clinic.
Mucopolysaccharidoses and sphingolipidoses
Mucopolysaccharidoses (MPS) fail to degrade glycosaminoglycans (dermatan, heparan, keratan sulfates). Coarse facies, hepatosplenomegaly, thickened meninges, and joint stiffness are shared. Discriminate by inheritance and corneas.
| Disease | Enzyme | Inheritance | Corneas | Stored GAG |
|---|---|---|---|---|
| Hurler (MPS IH) | α-L-iduronidase | AR | Cloudy | Dermatan + heparan sulfate |
| Hunter (MPS II) | Iduronate-2-sulfatase | X-linked | Clear | Dermatan + heparan sulfate |
| Morquio (MPS IV) | GALNS or β-galactosidase | AR | Variable | Keratan sulfate; odontoid hypoplasia and atlantoaxial instability; intellect often spared |
Hurler versus Hunter is the classic pair: Hunter is the X-linked “hunter needs to see” (no corneal clouding) mnemonic. Morquio is the chiropractic-relevant MPS: skeletal dysplasia with dens hypoplasia, so C1–C2 instability is a structural fact, not an adjustment cue.
High-yield sphingolipidoses (often sitting next to MPS on a lysosomal-storage stem):
| Disease | Enzyme | Stored lipid | Clue |
|---|---|---|---|
| Tay–Sachs | Hexosaminidase A | GM2 ganglioside | Cherry-red macula, no hepatosplenomegaly, onion-skin lysosomes |
| Niemann–Pick A/B | Sphingomyelinase | Sphingomyelin | Cherry-red macula plus hepatosplenomegaly, foam cells |
| Gaucher | Glucocerebrosidase | Glucocerebroside | Hepatosplenomegaly, bone crises, crumpled-paper macrophages |
| Fabry | α-galactosidase A | Ceramide trihexoside | X-linked, acroparesthesias, angiokeratomas, renal failure |
Galactosemia (GALT) is an inborn error of carbohydrate, not glycogen: reducing sugars in urine, E. coli sepsis, cataracts from galactitol, liver failure; remove lactose/galactose.
Congenital structural disorders: malformation, deformation, disruption
A congenital anomaly is present at birth; it may be genetic, environmental, or mixed. Robbins classifies the morphogenetic error, which is what the exam tests when a stem describes amniotic bands versus oligohydramnios versus an embryonic field defect.
| Class | Definition | Timing / mechanism | Examples |
|---|---|---|---|
| Malformation | Intrinsic abnormal development of a tissue or organ | Organogenesis, especially weeks 3–8 | Neural-tube defect, congenital heart defect, polydactyly, cleft lip from failed maxillary prominence fusion |
| Deformation | Extrinsic mechanical constraint on a normally formed part | Later fetal life, when the part already exists | Potter facies and clubfoot from oligohydramnios; breech developmental dysplasia of the hip |
| Disruption | Secondary destruction of a previously normal structure | Vascular accident or amniotic tear after formation | Amniotic-band amputations; some limb-reduction after chorionic-vessel thrombosis |
| Sequence | Cascade from one initial defect | Mechanical chain | Potter sequence: renal agenesis → oligohydramnios → pulmonary hypoplasia, flattened face, clubfeet; Pierre Robin sequence: micrognathia → glossoptosis → cleft palate |
| Syndrome | Multiple anomalies that are pathogenetically related | One cause, many fields | Down syndrome; fetal alcohol syndrome |
| Association | Anomalies that co-occur statistically without a proven single cause | Unknown shared field | VACTERL (vertebral, anal atresia, cardiac, TE fistula, renal, limb) |
Vocabulary of missing tissue: agenesis (never formed, no primordium), aplasia (primordium present but no development), hypoplasia (undergrowth), atresia (lumen failed to canalize). Heterotopia / ectopia is tissue in the wrong place (gastric mucosa in a Meckel diverticulum).
Teratogens produce malformations or disruptions depending on timing. Weeks 3–8 are the organogenetic window of maximum sensitivity. Named agents: alcohol (fetal alcohol spectrum: smooth philtrum, thin upper lip, microcephaly, ADHD-like cognition); isotretinoin (neural crest, ear and heart); valproate and folate antagonism (neural-tube defects); ACE inhibitors (fetal renal shutdown, oligohydramnios); thalidomide (limb reduction, historical); warfarin (nasal hypoplasia, stippled epiphyses). TORCH infections (toxoplasma, other, rubella, CMV, herpes) cause microcephaly, intracranial calcifications, cataracts, and heart defects depending on the organism—CMV is the most common congenital viral infection in many series; rubella is the classic PDA-plus-cataracts-plus-deafness triad.
Multifactorial inheritance
Most common congenital malformations are multifactorial: many loci plus environment, not a single Mendelian genotype. The threshold-liability model says everyone has a normally distributed liability; disease appears when liability crosses a threshold. Sex-specific thresholds explain why pyloric stenosis is more common in males (males have a lower threshold) yet an affected female (who had to cross a higher threshold) transmits a higher recurrence risk to offspring. Recurrence risk also rises when more relatives are affected and when the index case is more severe (bilateral cleft versus unilateral).
| Trait | Environmental / physiologic notes | Family pattern |
|---|---|---|
| Neural-tube defects | Folate deficiency, valproate, maternal diabetes | Empiric recurrence a few percent after one affected child; MZ concordance incomplete |
| Cleft lip ± palate | Distinct from isolated cleft palate embryologically | Recurrence rises with severity and number of affected relatives |
| Pyloric stenosis | First-born males classic | Higher recurrence through an affected mother |
| Congenital hip dysplasia | Breech, oligohydramnios, female, family history | Mechanical deformation plus genetic joint laxity |
| Isolated congenital heart defects | Rubella and diabetes are teratogenic overlays | Most are multifactorial, not 22q11 |
Concordance: monozygotic twins share nearly all alleles but not always the trait (proving environment and stochastic development). Dizygotic twins share about half. Multifactorial traits show MZ > DZ concordance that is still less than 100%. A fully penetrant chromosomal trisomy in both MZ twins would be nearly complete concordance for the karyotype, though expression can still vary.
When a stem gives an isolated clubfoot after oligohydramnios, call deformation. When a stem gives a missing finger with a fibrous amniotic remnant, call disruption. When a stem gives a ventricular septal defect in a child with no amniotic history, call malformation, then ask whether it is isolated multifactorial, 22q11, or trisomy. That classification—not a list of every named syndrome—is the 10% genetic-and-congenital block.
The most common chromosomal mechanism producing Down syndrome is which of the following?
Classic phenylketonuria is caused by deficiency of which enzyme, and what is the key dietary principle?
Amniotic-band constriction that amputates a previously formed digit is an example of which morphogenetic class?