PEDS GENETICS and METABOLICS

PAS 5420 Clinical Pediatrics — Genetics & Metabolic Disorders

36-Question PANCE-Style Clinical Vignette Practice Exam

South College Atlanta · ATL-2026 · Based on work of Tricia Callaghan Mullins MD FAAP

Topics: Genetic Testing · Teratogens (TORCH/FAS) · Inheritance Patterns · Achondroplasia · OI · Fragile X · Trisomy 21/18 · Klinefelter · Turner · 22q11 · Prader-Willi · Angelman · PKU · Galactosemia

PART I — QUESTIONS

Question 1

A PA student is reviewing the types of genetic testing available. A patient has a suspected microdeletion syndrome but the specific chromosomal region is not known. Which test is BEST suited to detect small chromosomal deletions and duplications across the entire genome without requiring prior knowledge of the specific abnormality?

A. Karyotype — gross examination of chromosomes

B. FISH — uses fluorescently labeled probe but requires knowing the specific genetic change in advance

C. Cytogenetic microarray analysis — can analyze 3 billion base pairs and detect chromosomal microdeletions without prior knowledge of the specific change

D. Whole exome sequencing — looks at exonic regions (~1–2% of genome)

Question 2

A couple presents for preconception counseling. The woman is of Ashkenazi Jewish descent. Which conditions should she specifically be screened for prior to conception?

A. Sickle cell disease and thalassemia

B. Tay-Sachs, Niemann-Pick, Gaucher, Bloom syndrome, Canavan disease, Fanconi anemia, and familial dysautonomia

C. Cystic fibrosis and PKU only

D. Turner syndrome and Klinefelter syndrome

Question 3

A 16-week pregnant woman undergoes a quad screen. Her alpha-fetoprotein (AFP) level is significantly elevated. Which fetal conditions are associated with elevated AFP?

A. Trisomy 21, 18, and 13 — chromosomal abnormalities elevate AFP

B. Neural tube defects, gastroschisis, and omphalocele — open fetal defects allow AFP to leak into maternal serum

C. Only Down syndrome is associated with elevated AFP

D. Elevated AFP only occurs in chromosomally normal fetuses

Question 4

A newborn is noted to have sensorineural deafness, cataracts, PDA, and a blueberry muffin rash. The mother reports having a maculopapular rash with postauricular lymphadenopathy in the first trimester. What teratogen is responsible?

A. Cytomegalovirus; mother is typically asymptomatic

B. Toxoplasmosis; associated with cat litter exposure and chorioretinitis

C. Congenital rubella syndrome; maternal maculopapular rash + postauricular lymphadenopathy; deafness, cataracts, blueberry muffin rash, intellectual disability, heart defects (PDA)

D. Herpes simplex; vesicular rash and meningoencephalitis

Question 5

A newborn boy has microcephaly, low birth weight, and a periventricular calcification pattern on head CT. His mother was asymptomatic during pregnancy. Which TORCH infection is most likely?

A. Rubella; maternal rash and postauricular lymphadenopathy

B. Toxoplasmosis; intracranial calcifications + hydrocephalus + chorioretinitis

C. Cytomegalovirus (CMV); LOW BIRTH WEIGHT, progressive/permanent deafness, chorioretinitis, seizures, MICROCEPHALY, mother ASYMPTOMATIC

D. Herpes simplex; vesicular rash on baby

Question 6

A newborn presents with chorioretinitis, hydrocephalus, and diffuse intracranial calcifications. The mother has cats at home. What is the diagnosis?

A. CMV; periventricular calcifications, microcephaly

B. Congenital toxoplasmosis; cat litter exposure, chorioretinitis + hydrocephalus (macrocephaly) + intracranial calcifications, mother rarely symptomatic

C. Congenital rubella; deafness and cataracts

D. Herpes simplex; vesicular rash and meningoencephalitis

Question 7

A 4-year-old boy has microcephaly, a flat midface, short palpebral fissures, a flattened and elongated philtrum, thin vermilion border of the upper lip, sensorineural hearing loss, and behavioral/learning deficits. His mother admits to heavy alcohol use during pregnancy. What is the diagnosis?

A. Angelman syndrome; chromosome 15 deletion

B. Fetal alcohol syndrome; facial features + CNS issues + growth restriction from maternal alcohol use

C. Fragile X syndrome; macroorchidism and large jaw

D. Trisomy 21; upslanting palpebral fissures and single palmar crease

Question 8

A couple has four children. Their first child has cystic fibrosis. Both parents are unaffected carriers. What is the probability that their NEXT child will have cystic fibrosis?

A. 100% — once one child is affected, all subsequent children will be affected

B. 50% — autosomal dominant inheritance

C. 25% — autosomal recessive; both parents are carriers (Aa × Aa)

D. 0% — parents are unaffected so subsequent children cannot be affected

Question 9

A family has multiple members with Marfan syndrome across three consecutive generations. Each affected person has an affected parent. Males and females are equally affected. Which inheritance pattern does this represent?

A. Autosomal recessive; 25% risk per pregnancy

B. X-linked recessive; only affects males

C. Autosomal dominant; ONE COPY of mutant gene is sufficient; phenotype in EVERY GENERATION; each affected person has an affected parent; 50% risk per pregnancy

D. Mitochondrial inheritance; passed through all mothers to all children

Question 10

A couple is concerned because the wife is a carrier for hemophilia (X-linked recessive). What is the risk that their SON will be affected with hemophilia?

A. 0% — X-linked conditions never affect males

B. 25% — same as autosomal recessive

C. 50% — each SON of a female carrier has a 50% CHANCE of being affected

D. 100% — all sons of carrier females are affected

Question 11

A newborn male has macrocephaly with frontal bossing, a depressed nasal bridge, short and stubby digits, and limbs that appear short relative to trunk length. His father has similar features. What is the diagnosis, inheritance pattern, and associated gene?

A. Osteogenesis imperfecta; autosomal dominant; COL1A1/COL1A2 gene; blue sclera

B. Achondroplasia; autosomal dominant; FGFR3 gene on chromosome 4; disorder of cartilage calcification; associated with ADVANCED PATERNAL AGE; can arise as new mutation

C. Turner syndrome; 45,XO; congenital heart disease

D. Prader-Willi syndrome; chromosome 15q11 deletion; hypotonia and hyperphagia

Question 12

A 3-year-old girl with achondroplasia develops nocturnal breathing pauses noted by her parents. Her neurosurgeon explains that her foramen magnum is narrowed. What complication is this causing?

A. Obstructive sleep apnea from adenotonsillar hypertrophy — unrelated to achondroplasia

B. CENTRAL APNEA due to NARROWING OF FORAMEN MAGNUM causing compression on the BRAINSTEM — a medical complication of achondroplasia

C. Cheyne-Stokes breathing from pulmonary hypertension

D. Laryngomalacia causing stridor

Question 13

A 2-year-old girl presents after her third fracture this year, each with minimal trauma. On exam she has blue sclera, mild short stature, and bowed extremities. Her mother also has blue sclera. What is the diagnosis and treatment?

A. Child abuse; complete skeletal survey and report to CPS

B. Osteogenesis imperfecta ('brittle bone disease'); autosomal dominant; ABNORMAL SYNTHESIS OF TYPE 1 COLLAGEN; blue sclera + frequent fractures with minimal trauma + short stature; treatment = fracture care + bracing + bisphosphonates

C. Achondroplasia; FGFR3 mutation; macrocephaly

D. Legg-Calvé-Perthes; avascular necrosis of femoral head

Question 14

A 10-year-old boy is referred for intellectual disability. On exam he has a large jaw, large prominent ears, and macroorchidism. His mother has a lower than average IQ. Genetic testing shows a triplet repeat expansion on the X chromosome. What is the diagnosis?

A. Klinefelter syndrome; XXY; delayed puberty and gynecomastia

B. Fragile X syndrome; X-LINKED; expansion of terminal triplet repeat (CGG) on FRAX gene; macrosomia, macroorchidism, large jaw, large ears, cognitive impairment; female carriers have below average IQ

C. Trisomy 21; Down syndrome; upslanting palpebral fissures

D. Prader-Willi syndrome; chromosome 15 deletion; hyperphagia and obesity

Question 15

A newborn girl is noted to have hypotonia, upslanting palpebral fissures, epicanthal folds, a large protruding tongue, a flat nasal bridge, brachycephaly, single transverse palmar crease, and wide gap between the 1st and 2nd toes. Echocardiography shows an ASD. What is the diagnosis and most common chromosomal abnormality in live births?

A. Trisomy 18; clenched hands, rocker-bottom feet, poor prognosis

B. Trisomy 21 (Down syndrome); most common chromosomal abnormality (1 in 700 live births); hypotonia, upslanting palpebral fissures, epicanthal folds, single palmar crease, ASD/VSD cardiac defects

C. Turner syndrome; 45,XO; webbed neck and lymphedema

D. Klinefelter syndrome; XXY; not apparent at birth

Question 16

A 5-year-old with Down syndrome is cleared for a recreational soccer program. The physician explains that a specific screening is required before athletic participation. What condition must be screened for and what is the risk?

A. Hypothyroidism — thyroid screening before all sports

B. Leukemia — CBC before athletic participation

C. ATLANTOAXIAL INSTABILITY — screen before school entry or athletics; Down syndrome causes laxity at C1-C2 from hypotonia and joint laxity; can cause spinal cord compression with neck hyperextension

D. Congenital heart disease — echo required before all athletic activities

Question 17

A newborn with Down syndrome has bilious vomiting and abdominal distension. X-ray shows a 'double bubble' sign with no gas in the distal bowel. What GI anomaly is this, and which other GI anomalies are associated with Trisomy 21?

A. Pyloric stenosis; associated with SCFE in Down syndrome

B. Duodenal atresia (double bubble sign); associated GI anomalies in Trisomy 21 include duodenal atresia, annular pancreas, and imperforate anus

C. Jejunal atresia; no association with chromosomal abnormalities

D. Hirschsprung disease only — not associated with duodenal atresia

Question 18

A severely premature-appearing newborn is born with clenched hands with overlapping fingers, rocker-bottom feet, micrognathia, prominent occiput, hypertonia, low-set malformed ears, and a VSD. What is the most likely diagnosis and prognosis?

A. Trisomy 21; hypotonia and upslanting palpebral fissures; good prognosis

B. Trisomy 18 (Edwards syndrome); clenched overlapping hands, rocker-bottom feet, hypertonia, prominent occiput, VSD; 30% die before 1 month; 90% die before 1 year

C. Klinefelter syndrome; XXY; not apparent at birth

D. Prader-Willi syndrome; severe hypotonia and failure to thrive

Question 19

A 16-year-old male is evaluated for delayed puberty. He is taller than his peers, has gynecomastia, sparse body and facial hair, small testes, and an arm span greater than his height. His testosterone is low and he is found to be azoospermic. Karyotype shows 47,XXY. What is the treatment?

A. Growth hormone therapy — primary concern is short stature

B. TESTOSTERONE THERAPY during puberty to induce and maintain secondary sexual characteristics; Klinefelter is the most common genetic cause of hypogonadism and infertility in men (1 in 1,000 males); accounts for 20% of aspermic adult men

C. Estrogen therapy — to reverse gynecomastia

D. No treatment needed — Klinefelter syndrome resolves spontaneously at adulthood

Question 20

A newborn girl has lymphedema of the hands and feet, a webbed neck, and a shield-shaped chest with widely spaced nipples. Echocardiography shows coarctation of the aorta. Karyotype shows 45,XO. What is the diagnosis and what proportion survive to birth?

A. Noonan syndrome; autosomal dominant, affects both sexes

B. Turner syndrome (45,XO); 95% RATE OF FETAL DEMISE; 1 in 2,500 live births; lymphedema at birth, webbed neck, shield chest, coarctation of aorta, gonadal dysgenesis, short stature

C. Trisomy 18; clenched hands and rocker-bottom feet

D. Down syndrome; hypotonia and upslanting palpebral fissures

Question 21

A 14-year-old girl has not yet begun menstruating and has short stature. She has a broad chest and cubitus valgus (wide carrying angle of the arms). FSH and LH are markedly elevated. Which additional finding should be specifically screened for?

A. Testicular cancer — elevated gonadotropins indicate testicular pathology

B. Coarctation of the aorta, renal anomalies, and autoimmune thyroiditis — Turner syndrome (45,XO) is associated with congenital heart disease (coarctation most common), renal anomalies, and autoimmune thyroiditis

C. Fragile X — elevated FSH indicates FMRP deficiency

D. Trisomy 21 — cardiac screening is required

Question 22

A newborn boy has a cleft palate, micrognathia, hypertelorism, and cardiac defects (truncus arteriosus). On labs, his calcium is critically low. Thymic shadow is absent on chest X-ray. He develops recurrent otitis media, sinusitis, and pneumonia in his first year. What is the diagnosis?

A. Down syndrome; hypothyroidism and ASD/VSD

B. 22q11 deletion syndrome (DiGeorge syndrome); absent thymus → T-cell immune deficiency; hypocalcemic hypoparathyroidism; cardiac anomalies; cleft palate; recurrent infections

C. Turner syndrome; webbed neck and coarctation

D. Prader-Willi syndrome; severe hypotonia and hyperphagia

Question 23

A 6-month-old boy has profound hypotonia and failure to thrive — he cannot suck adequately and requires tube feeding. His parents note he has small hands and feet, a narrow forehead, and a down-turned mouth. Chromosome 15q11 deletion is found with PATERNAL origin. What is the diagnosis and what happens to his appetite as he grows?

A. Angelman syndrome; maternally derived deletion; happy demeanor and seizures

B. Prader-Willi syndrome; PATERNAL deletion at 15q11; severe neonatal hypotonia → FTT in infancy; later develops UNCONTROLLABLE APPETITE leading to obesity

C. Trisomy 21; hypotonia and feeding difficulties; later tendency toward obesity

D. Fragile X syndrome; macroorchidism and large jaw

Question 24

A 3-year-old girl has severe intellectual disability (non-verbal), seizures, ataxia, spasticity, and microcephaly. Her family notes she has a happy, cheerful demeanor with frequent unprovoked laughing and emotional lability. Genetic testing shows a deletion at chromosome 15q11 with MATERNAL origin. What is the diagnosis?

A. Prader-Willi syndrome; paternal deletion at 15q11; hypotonia and hyperphagia

B. Angelman syndrome; MATERNALLY DERIVED deletion (or point mutation in UBE3A gene or paternal UPD); happy demeanor + severe intellectual disability + seizures + ataxia + microcephaly

C. Rett syndrome; X-linked; loss of purposeful hand movements

D. Trisomy 21; hypotonia and upslanting palpebral fissures

Question 25

A 2-week-old female begins refusing feeds and develops jaundice, vomiting, and hepatomegaly after starting breast milk feedings. Labs show direct hyperbilirubinemia, elevated liver enzymes, and hypoglycemia. She subsequently develops E. coli sepsis. Newborn screen was sent but results are pending. What is the most likely diagnosis and immediate treatment?

A. Biliary atresia; hepatoportoenterostomy (Kasai procedure)

B. Galactosemia; deficiency of galactose-1-phosphate uridyltransferase; eliminate dietary GALACTOSE and LACTOSE immediately — NO breast milk

C. Phenylketonuria; restrict phenylalanine; normal diet is acceptable initially

D. Glycogen storage disease; avoid fasting

Question 26

A 7-month-old white female presents with severe developmental delay, episodes of vomiting, blue eyes, light skin with an eczematoid rash, hypertonia, hyperactive DTRs, failure to thrive, and microcephaly. Urine has a 'mousy' odor. This is the lecture's own clinical vignette. What is the diagnosis?

A. Angelman syndrome; maternally derived chromosome 15 deletion; happy demeanor

B. Trisomy 21; hypotonia and upslanting palpebral fissures

C. Fragile X; macroorchidism and large jaw in boys

D. Phenylketonuria (PKU); deficiency of phenylalanine hydroxylase; LIGHT COMPLEXION, blue eyes, eczematous rash, hypertonia, intellectual disability, MOUSY ODOR IN URINE from phenylacetic acid accumulation

Question 27

A mother with PKU is planning her first pregnancy. She asks if she needs to maintain her low-phenylalanine diet during pregnancy since she feels well without it. What is the correct advice?

A. Dietary restriction is not needed during pregnancy if the mother has mild PKU

B. STRICT RESTRICTION OF PHENYLALANINE DURING PREGNANCY is essential to prevent MICROCEPHALY, INTELLECTUAL DISABILITY, and CONGENITAL HEART DISEASE in the fetus — maternal hyperphenylalaninemia is teratogenic even in a heterozygous fetus

C. Only restrict during the first trimester

D. The fetus is protected by the placenta from maternal phenylalanine levels

Question 28

A genetics fellow is teaching PA students about the difference between galactosemia and PKU. Which of the following correctly compares the two inborn errors of metabolism?

A. Both are X-linked; galactosemia affects carbohydrate metabolism; PKU affects protein metabolism

B. GALACTOSEMIA = most common CARBOHYDRATE metabolism error; AR; deficiency of galactose-1-phosphate uridyltransferase; no breast milk; E. coli sepsis risk; cataracts. PKU = most common AMINO ACID (protein) disorder; AR; deficiency of phenylalanine hydroxylase; light complexion + mousy odor; restrict phenylalanine; normal intelligence if treated within first 10 days

C. PKU causes cataracts and E. coli sepsis; galactosemia causes mousy urine odor

D. Both are treated by eliminating all protein from the diet

Question 29

A PA student is making a study chart comparing chromosomal syndromes. Which statement CORRECTLY matches a syndrome with its karyotype, key features, and primary concern?

A. Turner syndrome = 47,XXY; webbed neck; fertility is preserved

B. Klinefelter = 45,XO; lymphedema at birth; coarctation of aorta

C. Trisomy 21 = extra chromosome 21; hypotonia + upslanting palpebral fissures + ASD/VSD + atlantoaxial instability; most common chromosomal abnormality (1/700 live births). Trisomy 18 = extra chromosome 18; clenched overlapping hands + rocker-bottom feet + HYPERTONIA; 90% die before age 1

D. Klinefelter = 45,XO; Turner = 47,XXY; same cardiac complications

Question 30

A newborn screening result returns positive for PKU. The baby currently appears healthy and is feeding normally on breast milk. What must happen within the FIRST 10 DAYS of life to preserve normal intelligence?

A. Start phenylalanine supplements immediately

B. RESTRICTION OF PHENYLALANINE WITHIN FIRST 10 DAYS OF LIFE = NORMAL INTELLIGENCE; immediately switch to low-phenylalanine formula; lifelong dietary restriction required

C. PKU babies always have intellectual disability — dietary restriction is only for symptom management

D. Restriction is needed only if symptoms appear — wait and see

Question 31

A PA student is reviewing the CATCH-22 mnemonic for 22q11 deletion syndrome. Which of the following lists all five components correctly?

A. Coarctation, Autism, Thymus (absent), Cleft palate, Hypocalcemia

B. Cardiac defects + Abnormal facies + Thymic hypoplasia → T-cell deficiency + Cleft palate + Hypocalcemia (hypoparathyroidism) = 22q11 deletion syndrome (DiGeorge)

C. Chromosomal abnormality, Autism, Tracheoesophageal fistula, Collagen defect, Hypertelorism

D. Cleft palate, Arrhythmia, Turner overlap, Chorioretinitis, Hydrocephalus

Question 32

A genetic counselor explains to a couple that their child's condition results from a deletion at chromosome 15q11 that is on the MATERNAL chromosome. The child has severe intellectual disability, is non-verbal, has seizures, and an unusually happy demeanor. Which syndrome is this and what is the genetic mechanism?

A. Prader-Willi syndrome; maternal deletion at 15q11; hypotonia and hyperphagia

B. Angelman syndrome; MATERNAL deletion at 15q11 (or UBE3A point mutation or PATERNAL UPD); genomic imprinting causes different syndromes from same chromosomal region depending on parent of origin

C. Trisomy 21; extra chromosome 21

D. Fragile X; triplet repeat on X chromosome

Question 33

A 3-year-old boy with Trisomy 21 is brought for a routine well visit. His mother asks what screenings are needed. Which of the following best describes the comprehensive monitoring needed in a child with Down syndrome?

A. Only cardiac evaluation is needed in Down syndrome — other systems are not affected

B. Comprehensive screening: THYROID (hypothyroidism), VISION and HEARING, ATLANTOAXIAL INSTABILITY (before school/athletics), CARDIAC DEFECTS (ASD/VSD/valvular), GI anomalies, LEUKEMIA risk monitoring, DENTAL CARE, HIP DYSPLASIA, GROWTH MONITORING

C. Only growth monitoring and cognitive testing are needed

D. Newborn screening is sufficient — no additional monitoring required after the neonatal period

Question 34

A PA student compares Prader-Willi and Angelman syndromes for an exam. Which statement MOST clearly distinguishes the two?

A. Prader-Willi: maternal deletion at 15q11; Angelman: paternal deletion at 15q11

B. Both affect boys only — girls are not affected by either syndrome

C. Prader-Willi: PATERNAL deletion at 15q11; neonatal hypotonia + FTT → HYPERPHAGIA + OBESITY; hypogonadism. Angelman: MATERNAL deletion (or UBE3A mutation) at 15q11; HAPPY DEMEANOR + SEVERE ID + SEIZURES + ATAXIA — same chromosomal region, OPPOSITE parent of origin

D. Prader-Willi causes microcephaly; Angelman causes macrocephaly

Question 35

A newborn is found to have cataracts during routine newborn exam. Her galactosemia screen is positive. The parents ask why cataracts develop in galactosemia. What is the mechanism?

A. Phenylalanine accumulation deposits in the lens

B. GALACTOSE-1-PHOSPHATE and GALACTITOL (a byproduct of galactose metabolism) accumulate in the lens → osmotic damage → CATARACTS

C. Cataracts in galactosemia are caused by hypoglycemia damaging the lens

D. Cataracts are from vitamin A deficiency secondary to liver failure

Question 36

A PA student is asked to identify which genetic syndrome is associated with each cardiac defect. Which of the following CORRECTLY matches the syndrome to its cardiac defect?

A. Turner syndrome = ASD; Trisomy 21 = coarctation of aorta; 22q11 = PDA

B. Turner syndrome = COARCTATION OF AORTA (+ aortic stenosis + bicuspid aortic valve); Trisomy 21 = ASD/VSD/valvular disease; 22q11 deletion = CONOTRUNCAL DEFECTS (truncus arteriosus, tetralogy of Fallot, interrupted aortic arch); Trisomy 18 = VSD/ASD/PDA

C. All genetic syndromes cause the same cardiac defects — only the severity differs

D. Only Trisomy 21 has cardiac defects — other chromosomal syndromes do not affect the heart

PART II — ANSWER KEY WITH CLINICAL RATIONALES

Q1.  Answer: C

GENETIC TESTING OPTIONS: KARYOTYPE = gross chromosome examination (identifies large structural changes). FISH = uses fluorescently labeled probe — REQUIRES KNOWING the specific genetic change in advance. CYTOGENETIC MICROARRAY ANALYSIS = detects much smaller deletions and duplications; can analyze 3 BILLION BASE PAIRS and detect CHROMOSOMAL MICRODELETIONS without needing to know the specific change in advance — best for unknown microdeletion syndromes. WHOLE EXOME SEQUENCING = detects even smaller abnormalities down to single nucleotide variants; looks at exonic regions (~1–2% of genome). WHOLE GENOME SEQUENCING = most comprehensive. Microarray is ideal when karyotype is normal but microdeletion syndrome is suspected.

Q2.  Answer: B

POPULATION-SPECIFIC PRECONCEPTION SCREENING: ASHKENAZI JEWISH ancestry: screen for Tay-Sachs, Niemann-Pick, Gaucher, Bloom Syndrome, Canavan Disease, Fanconi anemia, familial dysautonomia. AFRICAN ANCESTRY: screen for SICKLE CELL DISEASE. MEDITERRANEAN BASIN ancestry: screen for THALASSEMIA. These population-specific screens allow identification of carrier couples at risk for having affected children. Newborn screening is performed on all newborns within 24–48 hours of life (unless parents opt out) for conditions where suitable screening/diagnostic tests are available and acceptable, effective treatment exists, and it is cost-effective.

Q3.  Answer: B

QUAD SCREEN (performed in 2nd trimester): measures AFP, unconjugated estriol, inhibin A, and human chorionic gonadotropin. AFP INTERPRETATION: ELEVATED AFP = neural tube defects (spina bifida, anencephaly), GASTROSCHISIS, OMPHALOCELE — open fetal defects allow AFP to leak into maternal serum. DECREASED AFP = Trisomy 21, 18, 13. The quad screen is non-invasive. Invasive prenatal testing includes AMNIOCENTESIS and CHORIONIC VILLUS SAMPLING (CVS). AFP at 16–18 weeks gestational age is the screening window. Ultrasound can also visualize neural tube defects and abdominal wall defects.

Q4.  Answer: C

CONGENITAL RUBELLA SYNDROME: maternal presentation = maculopapular rash + POSTAURICULAR LYMPHADENOPATHY. Fetal effects: DEAFNESS, CATARACTS, BLUEBERRY MUFFIN RASH (dermal erythropoiesis), intellectual disability, HEART DEFECTS (PDA most classic). TORCH comparison: TOXOPLASMOSIS = cat litter exposure, chorioretinitis + hydrocephalus + intracranial calcifications, mom rarely symptomatic. CMV = low birth weight, progressive/permanent deafness, chorioretinitis, seizures, MICROCEPHALY, mom asymptomatic. HERPES SIMPLEX = vesicular rash, lethargy, seizures, meningoencephalitis — transmitted to baby DURING CHILDBIRTH. All have chorioretinitis and CNS involvement; the specific pattern distinguishes them.

Q5.  Answer: C

CONGENITAL CMV: MOTHER IS ASYMPTOMATIC (key distinguishing feature — CMV-infected mothers typically have no symptoms). Fetal effects: LOW BIRTH WEIGHT, PROGRESSIVE/PERMANENT DEAFNESS (most common cause of non-hereditary congenital sensorineural hearing loss), CHORIORETINITIS, SEIZURES, MICROCEPHALY. Periventricular calcifications are characteristic of CMV (distinguishes from toxoplasmosis which causes diffuse intracranial calcifications). TOXOPLASMOSIS = cat litter, chorioretinitis + hydrocephalus (MACROCEPHALY) + intracranial calcifications + mom rarely symptomatic. The microcephaly + asymptomatic mother combination points to CMV.

Q6.  Answer: B

CONGENITAL TOXOPLASMOSIS: exposure via CAT LITTER (or undercooked meat). MOTHER RARELY SYMPTOMATIC. Classic triad: CHORIORETINITIS + HYDROCEPHALUS (MACROCEPHALY from obstructive hydrocephalus) + INTRACRANIAL CALCIFICATIONS. Note: CMV causes MICRO-cephaly; toxoplasmosis causes MACRO-cephaly (hydrocephalus). The diffuse intracranial calcification pattern in toxoplasmosis differs from the periventricular pattern of CMV. HERPES SIMPLEX: transmitted to baby DURING CHILDBIRTH; presents with vesicular rash, lethargy, irritability, seizures, meningoencephalitis — NOT a transplacental infection in the same way.

Q7.  Answer: B

FETAL ALCOHOL SYNDROME: caused by maternal alcohol use during pregnancy. Facial features: SHORT PALPEBRAL FISSURES, FLAT MIDFACE, LONG AND FLATTENED PHILTRUM, THIN VERMILION BORDER OF UPPER LIP. CNS issues: MICROCEPHALY, SENSORINEURAL HEARING LOSS, structural brain anomalies. GROWTH RESTRICTION. BEHAVIORAL/LEARNING DEFECTS. These features together with maternal alcohol history = FAS. The palpebral fissures are SHORT (vs. trisomy 21 which has upslanting fissures). The flat philtrum and thin upper lip vermilion border are pathognomonic for FAS. No safe amount of alcohol during pregnancy has been established.

Q8.  Answer: C

AUTOSOMAL RECESSIVE INHERITANCE: manifests when BOTH COPIES of the gene have mutations. Phenotype SKIPS GENERATIONS. AFFECTED children usually born to UNAFFECTED PARENTS (carriers). Males and females EQUALLY affected. With two carriers (Aa × Aa): 25% AA (unaffected, non-carrier), 50% Aa (carrier, unaffected), 25% aa (AFFECTED). RISK = 25% PER PREGNANCY — this does NOT change based on previous children (each pregnancy is independent). Examples: Cystic fibrosis, Sickle cell disease, PKU, Galactosemia, adrenal hyperplasia. CONTRAST with autosomal dominant: one copy sufficient, 50% risk per pregnancy, phenotype in every generation.

Q9.  Answer: C

AUTOSOMAL DOMINANT INHERITANCE: a SINGLE COPY of a gene bearing mutation is sufficient to cause disease (gene is NOT on sex chromosomes). KEY FEATURES: (1) phenotype appears in EVERY GENERATION; (2) each affected person has an AFFECTED PARENT; (3) males and females are EQUALLY affected; (4) 50% RISK of inheriting trait per pregnancy. Examples: Achondroplasia, Osteogenesis imperfecta, Marfan syndrome, Huntington disease, Neurofibromatosis type 1, Familial hypercholesterolemia. Contrast with autosomal recessive (phenotype SKIPS generations, 25% risk) and X-linked (higher incidence in males, can skip generations through carrier females).

Q10.  Answer: C

X-LINKED RECESSIVE INHERITANCE: TRAIT is passed from CARRIER FEMALES (may show mild expression) to SONS who are MORE SEVERELY AFFECTED. Each SON of a female carrier has a 50% CHANCE of being affected (50% chance of inheriting the X chromosome with the mutation). Incidence is HIGHER IN MALES than females. CAN SKIP GENERATIONS as it is passed through carrier females. Examples: Fragile X, Duchenne muscular dystrophy, Hemophilia, G6PD deficiency, color blindness, Rett syndrome. DAUGHTERS of a carrier female: 50% chance of being a carrier (usually unaffected), 50% chance of being non-carrier. DAUGHTERS of an affected FATHER: all are carriers.

Q11.  Answer: B

ACHONDROPLASIA ('dwarfism'): AUTOSOMAL DOMINANT; FGFR3 (fibroblast growth factor receptor 3) gene on CHROMOSOME 4. Incidence: 1 in 12,000–15,000 births. DISORDER OF CARTILAGE CALCIFICATION — skeletal dysplasia. ASSOCIATED WITH ADVANCED PATERNAL AGE. CAN ARISE AS A NEW MUTATION (30% new mutations — explains cases without family history). Physical features: SHORT STATURE, MACROCEPHALY, prominent forehead with FRONTAL BOSSING and DEPRESSED NASAL BRIDGE, SHORT STUBBY DIGITS, long bones wide + short + curved. NORMAL INTELLIGENCE, NORMAL SEXUAL FUNCTION, NORMAL LIFE EXPECTANCY. Medical issues: hydrocephalus + central apnea (narrowing of foramen magnum), bowing of legs, dental malocclusion, hearing loss, nerve root compression.

Q12.  Answer: B

ACHONDROPLASIA MEDICAL COMPLICATIONS: (1) HYDROCEPHALUS and CENTRAL APNEA — due to NARROWING OF FORAMEN MAGNUM and compression on the BRAINSTEM. Central apnea is a critical complication that can cause sudden death in infancy and requires monitoring. (2) BOWING OF LEGS — due to unequal growth of tibia and fibula. (3) DENTAL MALOCCLUSION. (4) HEARING LOSS. (5) COMPRESSION OF NERVE ROOTS causing sciatica. Treatment: adaptive modifications; conjugated C-type natriuretic peptide (vosoritide — promotes growth, currently/recently in clinical trials). The brainstem compression from narrow foramen magnum is the most dangerous complication.

Q13.  Answer: B

OSTEOGENESIS IMPERFECTA ('brittle bone disease'): 4 types; MOST ARE AUTOSOMAL DOMINANT. ABNORMAL SYNTHESIS OF TYPE 1 COLLAGEN → bones not formed normally; can range from mild to severe. Clinical features: BLUE SCLERA (thin sclera allows uveal pigment to show through), SHORT STATURE, FREQUENT FRACTURES WITH MINIMAL TRAUMA, BOWED EXTREMITIES, SCOLIOSIS. TREATMENT: fracture care, bracing, BISPHOSPHONATES (increase bone density, reduce fracture frequency). Mother with blue sclera confirms autosomal dominant transmission. This is different from child abuse: OI has positive family history, blue sclera, diffuse bone fragility, and no bruising/retinal hemorrhages. The combination of minimal trauma + blue sclera + family history = OI until proven otherwise.

Q14.  Answer: B

FRAGILE X SYNDROME: X-LINKED inheritance. EXPANSION OF TERMINAL TRIPLET REPEAT (CGG) at end of X chromosome — FRAX gene. AFFECTS 1 IN 4,000 MALES. FEMALE CARRIERS have BELOW AVERAGE IQ (mild expression due to X-inactivation). Clinical features: MACROSOMIA, MACROORCHIDISM with testicular edema, DYSMORPHIC FACIAL FEATURES (large jaw, large ears), PRESERVATIVE SPEECH, COGNITIVE IMPAIRMENT, AUTISM in 20%, behavioral issues (anxiety, hyperactivity). Note: Macroorchidism often not apparent until puberty. The combination of intellectual disability + large jaw + large ears + macroorchidism + carrier mother with low IQ = Fragile X.

Q15.  Answer: B

TRISOMY 21 (DOWN SYNDROME): THREE complete or partial copies of chromosome 21. MOST COMMON CHROMOSOMAL ABNORMALITY — 1 IN 700 LIVE BIRTHS. Diagnosed during newborn period. Physical features: normal birthweight, HYPOTONIA, BRACHYCEPHALY, flattened occiput, hypoplastic midface, FLAT NASAL BRIDGE, UPSLANTING PALPEBRAL FISSURES, EPICANTHAL FOLDS, large PROTRUDING TONGUE, SHORT BROAD HANDS, SINGLE TRANSVERSE PALMAR CREASE, WIDE GAP between 1st and 2nd toes. MEDICAL ISSUES: feeding issues (hypotonia → poor weight gain → later obesity), hip dysplasia, reduced cell-mediated immunity, HYPOTHYROIDISM, GI anomalies (duodenal atresia, annular pancreas, imperforate anus), increased leukemia risk, ATLANTOAXIAL INSTABILITY (screen before school/athletics), CARDIAC DEFECTS (ASD, VSD, valvular disease), intellectual disability.

Q16.  Answer: C

ATLANTOAXIAL INSTABILITY in Trisomy 21: Down syndrome patients have HYPOTONIA and JOINT LAXITY that can cause instability at the C1-C2 (atlantoaxial) joint. Screen BEFORE SCHOOL ENTRY OR ATHLETICS (cervical spine X-rays in flexion, neutral, and extension). Risk: subluxation or dislocation of C1 on C2 → spinal cord compression → paralysis, especially with neck hyperextension (certain sports activities). Other Down syndrome medical issues requiring ongoing monitoring: THYROID DYSFUNCTION (hypothyroidism — screen regularly), VISION AND HEARING screening regularly, CARDIAC DEFECTS (ASD, VSD, valvular disease), GI anomalies (duodenal atresia), increased risk of LEUKEMIA, dental care (small/misshapen teeth), hip dysplasia.

Q17.  Answer: B

TRISOMY 21 GI ANOMALIES: GI anomalies include DUODENAL ATRESIA (classic 'double bubble' sign on X-ray — stomach + dilated proximal duodenum; requires surgical repair), ANNULAR PANCREAS (ring of pancreatic tissue encircles the duodenum → obstruction), and IMPERFORATE ANUS. Duodenal atresia presents with BILIOUS VOMITING in newborn period. The double bubble sign on X-ray (two air-fluid levels: stomach and dilated proximal duodenum with no distal gas) is pathognomonic. Any newborn with Down syndrome presenting with bilious vomiting needs immediate evaluation. Treatment: surgical repair (duodenoduodenostomy). Duodenal atresia in the absence of Down syndrome may also occur sporadically.

Q18.  Answer: B

TRISOMY 18 (EDWARDS SYNDROME): three copies of chromosome 18. Incidence: 1 in 3,500 live births; associated with ADVANCED MATERNAL AGE; >95% of conceptuses ABORT spontaneously. PROGNOSIS: 30% die before age 1 MONTH; 90% die before age 1 YEAR. Clinical features: small premature appearance, CLEFT LIP OR PALATE, PROMINENT OCCIPUT, NARROW BIFRONTAL DIAMETER, LOW-SET MALFORMED EARS, MICROGNATHIA, CONGENITAL HEART DISEASE (VSD, ASD, PDA), short sternum, HYPERTONIA (in contrast to Trisomy 21 which has HYPOtonia), CLENCHED HANDS WITH OVERLAPPING FINGERS, ROCKER-BOTTOM FEET, horseshoe kidney, lack of subcutaneous fat, hypoplastic nails. The clenched overlapping fingers and rocker-bottom feet are pathognomonic for Trisomy 18.

Q19.  Answer: B

KLINEFELTER SYNDROME (47,XXY): extra X chromosome; may have mosaicism. Incidence: 1 IN 1,000 MALES. Physical characteristics NOT present until PUBERTY. MOST COMMON GENETIC CAUSE OF HYPOGONADISM AND INFERTILITY IN MEN. Accounts for 20% of ASPERMIC adult men. Clinical features: FEMALE BODY HABITUS, GYNECOMASTIA, decreased body hair, SMALL PHALLUS AND TESTES, ARM SPAN > HEIGHT, LEARNING DISABILITIES/LOWER IQ, TALLER THAN AVERAGE for family. TESTOSTERONE LEVELS LOW → delayed/absent/incomplete puberty, AZOOSPERMIA, infertility. TREATMENT: TESTOSTERONE THERAPY DURING PUBERTY to induce and maintain secondary sexual characteristics. Does not restore fertility. Diagnosis often made during puberty evaluation or infertility workup.

Q20.  Answer: B

TURNER SYNDROME (45,XO): single X chromosome; other mosaic variants exist. Incidence: 1 IN 2,500 LIVE BIRTHS; 95% RATE OF FETAL DEMISE (most pregnancies with 45,XO spontaneously abort). SUSCEPTIBILITY TO X-LINKED DISORDERS. Diagnosis: 33% at birth, 33% shortly after birth, 33% in adolescence. Clinical features: LYMPHEDEMA of hands and feet at birth (first presenting sign in newborns), SHIELD-SHAPED CHEST with widely spaced nipples, WEBBED NECK, CUBITUS VALGUS, SHORT STATURE, GONADAL DYSGENESIS (primary amenorrhea, infertility), RENAL ANOMALIES, CONGENITAL HEART DISEASE (COARCTATION, aortic stenosis, bicuspid aortic valve), AUTOIMMUNE THYROIDITIS, learning disabilities. TREATMENT: GROWTH HORMONE, ESTROGEN AND PROGESTERONE REPLACEMENT.

Q21.  Answer: B

TURNER SYNDROME medical surveillance: CONGENITAL HEART DISEASE — COARCTATION OF AORTA (most common), aortic stenosis, BICUSPID AORTIC VALVE (requires cardiac MRI/echo); RENAL ANOMALIES (horseshoe kidney, duplicated collecting system — renal ultrasound); AUTOIMMUNE THYROIDITIS (hypothyroidism — screen regularly); LEARNING DISABILITIES (particularly visuospatial difficulties); gonadal dysgenesis → primary amenorrhea + infertility. The markedly elevated FSH and LH indicate the pituitary is trying to stimulate absent/streak gonads (hypergonadotropic hypogonadism). TREATMENT: growth hormone for stature; estrogen and progesterone replacement for puberty induction and bone health; fertility treatment if desired.

Q22.  Answer: B

22Q11 DELETION SYNDROME (DIGEORGE SYNDROME): 1 IN 4,000; sporadic (some autosomal dominant evidence). Clinical features: ABSENT THYMUS → T-CELL MEDIATED IMMUNE DEFICIENCY (recurrent infections: OM, sinusitis, tonsillitis, pneumonia), HYPOCALCEMIC HYPOPARATHYROIDISM (critical hypocalcemia presenting as seizures or tetany in newborn period), CARDIAC ANOMALIES (conotruncal defects: truncus arteriosus, tetralogy of Fallot, interrupted aortic arch), CLEFT PALATE/FEEDING DIFFICULTIES, behavioral and speech disorders, cognitive disabilities, MICROGNATHIA, HYPERTELORISM. Mnemonic: CATCH-22 — Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, 22q11 deletion.

Q23.  Answer: B

PRADER-WILLI SYNDROME: 1 IN 10,000; DELETION ON CHROMOSOME 15Q11 (60–70% PATERNALLY DERIVED deletion; 20–30% maternal uniparental disomy). CRITICAL CONCEPT: the SAME region (15q11) is affected in BOTH Prader-Willi AND Angelman syndrome — the PARENT OF ORIGIN determines which syndrome results (genomic imprinting). Clinical features: SEVERE HYPOTONIA AFTER BIRTH → FAILURE TO THRIVE (poor feeding, tube feeding in infancy), NARROW BIFRONTAL DIAMETER, DOWN-TURNED MOUTH, SMALL HANDS AND FEET, SHORT STATURE, HYPOGONADISM, then later: UNCONTROLLABLE APPETITE = OBESITY (hyperphagia develops in childhood), OSA, INTELLECTUAL DISABILITY. Recurrence risk in parents: 1 in 100.

Q24.  Answer: B

ANGELMAN SYNDROME: 1 IN 12,000; DELETION ON CHROMOSOME 15Q11 — 70% MATERNALLY DERIVED deletion (vs. Prader-Willi = PATERNALLY derived). 20% due to point mutation in maternally inherited UBE3A gene; 5–7% have paternal UPD. HIGH-YIELD GENOMIC IMPRINTING: Same 15q11 region — MATERNAL deletion = ANGELMAN; PATERNAL deletion = PRADER-WILLI. Clinical features: dysmorphic characteristics, MICROCEPHALY, SHORT STATURE, SEVERE INTELLECTUAL DISABILITY (NON-VERBAL), HAPPY DEMEANOR WITH EMOTIONAL LABILITY (inappropriate laughing), SEIZURES, SPASTICITY, ATAXIA. Sometimes called 'happy puppet syndrome' for the characteristic ataxic gait and happy demeanor.

Q25.  Answer: B

GALACTOSEMIA: MOST COMMON ERROR OF CARBOHYDRATE METABOLISM. 1 IN 40,000 live births. AUTOSOMAL RECESSIVE. DEFICIENCY OF GALACTOSE-1-PHOSPHATE URIDYLTRANSFERASE → galactose-1-phosphate accumulates in LIVER, KIDNEY, and BRAIN. Clinical features: LIVER FAILURE (hepatomegaly, direct hyperbilirubinemia, coagulopathy), RENAL DYSFUNCTION (acidosis, glycosuria, aminoaciduria), SEVERE LEARNING DISABILITIES, POOR GROWTH, CATARACTS, INCREASED RISK OF E. COLI SEPSIS (high-yield association), PREMATURE OVARIAN FAILURE. DIAGNOSIS: must be made in first week; extreme reduction of erythrocyte galactose-1-phosphate uridyltransferase is diagnostic. TREATMENT: ELIMINATION OF DIETARY GALACTOSE/LACTOSE — NO BREAST MILK (breast milk contains lactose → galactose).

Q26.  Answer: D

This is the LECTURE'S OWN CLINICAL VIGNETTE (Slide 59). PHENYLKETONURIA (PKU): MOST COMMON AMINO ACID DISORDER. 1 IN 10,000. DEFICIENCY OF PHENYLALANINE HYDROXYLASE → phenylalanine not converted to tyrosine → toxic metabolites (phenylacetic acid) accumulate. Clinical features: MODERATE TO SEVERE INTELLECTUAL DISABILITY (IQ ~30 within first year), HYPERTONIA, TREMORS, behavioral problems, LIGHT COMPLEXION/HYPOPIGMENTATION (blond hair, blue eyes) — because tyrosine is a melanin precursor, its deficiency causes hypopigmentation, ATOPIC DERMATITIS/ECZEMATOUS RASH, MOUSY ODOR IN URINE (phenylacetic acid). TREATMENT: EARLY DETECTION (newborn screen); LIFELONG RESTRICTION OF PHENYLALANINE; restriction within FIRST 10 DAYS of life = normal intelligence. Also: restrict phenylalanine in PREGNANT women with PKU to prevent microcephaly, intellectual disability, and congenital heart disease in the fetus.

Q27.  Answer: B

MATERNAL PKU SYNDROME: women with PKU who have elevated phenylalanine during pregnancy cause TERATOGENIC EFFECTS on the fetus even if the fetus itself is not PKU-affected. Maternal hyperphenylalaninemia causes: MICROCEPHALY, INTELLECTUAL DISABILITY, and CONGENITAL HEART DISEASE in the offspring. This is because the fetal brain is highly susceptible to elevated phenylalanine levels crossing the placenta. TREATMENT: STRICT RESTRICTION OF PHENYLALANINE THROUGHOUT THE ENTIRE PREGNANCY (ideally starting before conception) to maintain near-normal phenylalanine levels. Restriction within the FIRST 10 DAYS of life for the BABY = normal intelligence. PKU is identified on newborn screening — early detection is the key.

Q28.  Answer: B

GALACTOSEMIA vs PKU COMPARISON: GALACTOSEMIA = most common error of CARBOHYDRATE metabolism; AR; deficiency of GALACTOSE-1-PHOSPHATE URIDYLTRANSFERASE; accumulates in liver/kidney/brain; CATARACTS, liver failure, renal dysfunction, INCREASED E. COLI SEPSIS RISK, premature ovarian failure; ELIMINATE DIETARY GALACTOSE/LACTOSE (no breast milk). PKU = most common AMINO ACID DISORDER; AR; deficiency of PHENYLALANINE HYDROXYLASE; phenylalanine not converted to tyrosine; LIGHT COMPLEXION (hypopigmentation), ECZEMATOUS RASH, MOUSY ODOR (phenylacetic acid), intellectual disability, hypertonia; RESTRICT PHENYLALANINE; normal intelligence if treated within FIRST 10 DAYS. Both identified on newborn screen. Both autosomal recessive.

Q29.  Answer: C

CHROMOSOMAL SYNDROME COMPARISON: TRISOMY 21 (Down) = extra chromosome 21; 1/700 live births; MOST COMMON; HYPOTONIA; upslanting palpebral fissures; single palmar crease; ASD/VSD; ATLANTOAXIAL INSTABILITY; hypothyroidism; intellectual disability. TRISOMY 18 (Edwards) = extra chromosome 18; 1/3,500; 90% die before age 1; HYPERTONIA (opposite of Trisomy 21); CLENCHED OVERLAPPING HANDS; ROCKER-BOTTOM FEET; prominent occiput; congenital heart disease; micrognathia. KLINEFELTER = 47,XXY (extra X in male); 1/1,000 males; gynecomastia; azoospermia; tall; testosterone replacement. TURNER = 45,XO; 1/2,500 females; 95% fetal demise; lymphedema at birth; webbed neck; coarctation; gonadal dysgenesis; growth hormone treatment.

Q30.  Answer: B

PKU CRITICAL TREATMENT WINDOW: RESTRICTION OF PHENYLALANINE WITHIN THE FIRST 10 DAYS OF LIFE results in NORMAL INTELLIGENCE. This is why newborn screening (performed within 24–48 hours of life) is so critical — it identifies PKU before irreversible brain damage occurs. After 10 days, neurological damage begins accumulating. Treatment: LIFELONG RESTRICTION OF PHENYLALANINE (phenylalanine-free formula + restricted protein diet). The baby should be switched from breast milk immediately since breast milk contains phenylalanine. Symptoms DEVELOP IN INFANCY but not necessarily in the NEWBORN PERIOD — this is why newborn screening is essential (the baby appears healthy at birth). CONTRAST with galactosemia which causes symptoms within the first 1–2 weeks of lactose/galactose exposure.

Q31.  Answer: B

CATCH-22 MNEMONIC for 22q11 DELETION SYNDROME (DiGeorge): C = CARDIAC DEFECTS (conotruncal: truncus arteriosus, tetralogy of Fallot, interrupted aortic arch, VSD); A = ABNORMAL FACIES (micrognathia, hypertelorism); T = THYMIC HYPOPLASIA → T-CELL MEDIATED IMMUNE DEFICIENCY → recurrent infections (OM, sinusitis, tonsillitis, pneumonia); C = CLEFT PALATE + feeding difficulties, behavioral and speech disorders; H = HYPOCALCEMIA from HYPOPARATHYROIDISM (hypoparathyroid → low PTH → low calcium → seizures in newborn period); 22 = chromosome 22q11 deletion. Incidence: 1 in 4,000. Mostly sporadic. Cognitive disabilities also present. This is a critical syndrome to recognize due to the combined immunodeficiency, hypocalcemia, and cardiac defects.

Q32.  Answer: B

GENOMIC IMPRINTING — 15Q11 REGION: this is the classic imprinting example. SAME CHROMOSOMAL REGION → TWO DIFFERENT SYNDROMES depending on PARENT OF ORIGIN: MATERNAL DELETION at 15q11 = ANGELMAN SYNDROME (happy demeanor, severe ID, non-verbal, seizures, ataxia, microcephaly). PATERNAL DELETION at 15q11 = PRADER-WILLI SYNDROME (neonatal hypotonia + FTT → later hyperphagia + obesity, small hands/feet, hypogonadism). ANGELMAN causes: 70% maternally derived deletion; 20% UBE3A point mutation; 5–7% paternal UPD (paternal UPD for Angelman = both chromosomes from father, neither from mother → maternal gene is absent). This parent-of-origin dependent expression is genomic imprinting — only the maternal or paternal copy of a gene is expressed.

Q33.  Answer: B

TRISOMY 21 COMPREHENSIVE MANAGEMENT: (1) THYROID DYSFUNCTION — hypothyroidism very common; screen regularly; (2) VISION AND HEARING — screen regularly (strabismus, cataracts, otitis media are common); (3) ATLANTOAXIAL INSTABILITY — screen BEFORE SCHOOL ENTRY OR ATHLETICS (C-spine X-rays); (4) CARDIAC — ASD, VSD, valvular disease; echo; (5) GI ANOMALIES — duodenal atresia, annular pancreas, imperforate anus; (6) HEMATOLOGIC — increased incidence of LEUKEMIAS; (7) DENTAL CARE — small/misshapen teeth; (8) HIP DYSPLASIA — low tone + joint laxity; (9) FEEDING ISSUES — hypotonia → poor weight gain → later obesity; (10) REDUCED CELL-MEDIATED IMMUNITY — more infections. All of these require proactive monitoring — Down syndrome affects virtually every organ system.

Q34.  Answer: C

PRADER-WILLI vs ANGELMAN — the ultimate genomic imprinting distinction: PRADER-WILLI = PATERNAL deletion (or MATERNAL UPD) at 15q11 → NEONATAL HYPOTONIA + FTT → later HYPERPHAGIA + OBESITY; NARROW BIFRONTAL DIAMETER; DOWN-TURNED MOUTH; SMALL HANDS AND FEET; SHORT STATURE; HYPOGONADISM; OSA; intellectual disability. ANGELMAN = MATERNAL deletion (or UBE3A mutation) at 15q11 → HAPPY DEMEANOR (unprovoked laughing, apparent happiness); SEVERE INTELLECTUAL DISABILITY (NON-VERBAL); SEIZURES; ATAXIA; SPASTICITY; MICROCEPHALY. Memory aid: 'HAPPY' = 'ANGELman' (angels are happy); 'HUNGRY' = 'PRADER-WILLI' (always hungry). The critical distinction: SAME REGION (15q11), DIFFERENT PARENT OF ORIGIN → DIFFERENT SYNDROME.

Q35.  Answer: B

GALACTOSEMIA CATARACTS: when galactose-1-phosphate uridyltransferase is deficient, galactose accumulates and is converted to GALACTITOL (a sugar alcohol) via aldose reductase. Galactitol accumulates in the LENS → OSMOTIC DAMAGE → CATARACTS. This can occur within weeks of lactose/galactose exposure. Treatment: ELIMINATION OF DIETARY GALACTOSE/LACTOSE (no breast milk — breast milk contains lactose → galactose). Cataracts may be reversible if treatment is begun early enough. OTHER galactosemia features: liver failure (hepatomegaly, direct hyperbilirubinemia, coagulopathy), renal dysfunction, E. COLI SEPSIS (high-yield), severe learning disabilities, poor growth, premature ovarian failure. Diagnosis confirmed by: extreme reduction of erythrocyte galactose-1-phosphate uridyltransferase.

Q36.  Answer: B

GENETICS-CARDIAC DEFECT ASSOCIATIONS: TURNER SYNDROME (45,XO) = COARCTATION OF AORTA (most classic), aortic stenosis, BICUSPID AORTIC VALVE. TRISOMY 21 = ASD, VSD, VALVULAR DISEASE (atrioventricular septal defect most common in Down syndrome). TRISOMY 18 = VSD, ASD, PDA. 22Q11 DELETION (DiGeorge) = CONOTRUNCAL DEFECTS: truncus arteriosus, TETRALOGY OF FALLOT, interrupted aortic arch, VSD. CONGENITAL RUBELLA = PDA (classic). ACHONDROPLASIA = not typically cardiac. These cardiac-syndrome pairings are extremely hig