5 Genetic Disorders
1 A clinical study is undertaken with subjects from families in which complications of atherosclerotic cardiovascular disease and tendinous xanthomas occurred before age 30. Some of the children in these families are observed to have early atheroma formation. It is observed that affected individuals benefit from treatment with pharmacologic agents that inhibit HMG-CoA reductase. These affected individuals are most likely to have a mutation in a gene encoding a cell surface receptor for which of the following?
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(B) 
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(D) 
(E) 2 A 27-year-old man comes to the physician for an infertility work-up. He and his wife have been trying to conceive a child for 6 years. Physical examination shows bilateral gynecomastia, reduced testicular size, reduced body hair, and increased length between the soles of his feet and the pubic bone. A semen analysis indicates oligospermia. Laboratory studies show increased follicle-stimulating hormone level and slightly decreased testosterone level. Which of the following karyotypes is most likely to be present in this man?
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(B) 
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(D) 
(E) 3 The parents of a male infant come to the physician because of their concern that male children over several generations in the mother’s family have been affected by a progressive disorder involving multiple organ systems. These children have had coarse facial features, corneal clouding, joint stiffness, hepatosplenomegaly, and mental retardation, and many died in childhood. At autopsy, some of the children had subendothelial coronary arterial deposits that caused myocardial infarction. Laboratory testing of the infant shows increased urinary excretion of mucopolysaccharides. Bone marrow biopsy is performed, and the accumulated mucopolysaccharides are found in macrophages (“balloon cells” filled with minute vacuoles). Which of the following enzyme deficiencies is most likely to be seen in this infant?
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(D) 
(E) 
(F) 
(G) 4 A 25-year-old woman stops going to her aerobic exercise class because of severe muscle cramps that have occurred during every session for the past 2 months. Several hours after each session, she notices that her urine is a brown color. On physical examination, she has normal muscle development and strength. An inherited defect in which of the following substances is most likely to explain these findings?
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(B) 
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(D) 
(E) 
(F) 
(G) 5 A female infant shows failure to thrive and failure to achieve developmental milestones. A pedigree reveals only this child is affected out of four generations on both sides of the family. Tissue fibroblasts obtained from this child shows a 46,XX karyotype. Cultured fibroblasts have increased amounts of an intermediate product in a multiple enzymic metabolic pathway from substrate to end product. What is the most likely recurrence risk for this condition in siblings of this infant?
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(F) 6 A 19-year-old woman, G3, P2, gives birth after an uncomplicated pregnancy to a term male infant. On physical examination soon after birth, the infant is recorded at the 60th percentile for height and weight. The only abnormal finding is a cleft lip. There is no family history of birth defects, and the mother’s other two children are healthy with no apparent abnormalities. Which of the following factors is most likely to influence the appearance of this infant?
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(E) 
(F) 7 A 25-year-old woman with amenorrhea has never had menarche. On physical examination, she is 145 cm (4 ft 9 in) tall. She has a webbed neck, a broad chest, and widely spaced nipples. Strong pulses are palpable in the upper extremities, but there are only weak pulses in the lower extremities. On abdominal MR imaging, the ovaries are small, elongated, and tubular. Which of the following karyotypes is most likely to be present in this patient?
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(B) 
(C) 
(D) 
(E) 
8 A 37-year-old woman gives birth at 35 weeks’ gestation to a female infant. Physical examination of the infant soon after delivery shows rocker-bottom feet, a small face and mouth, and low-set ears. On auscultation of the chest, a heart murmur is detected. The appearance of the infant’s hands is shown in the figure. The infant dies at 4 months of age. Which of the following karyotypes was most likely present in this infant?
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(B) 
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(D) 
(E) 9 A 10-year-old boy who is mentally retarded is able to carry out activities of daily living, including feeding and dressing himself. On physical examination, he has brachycephaly and oblique palpebral fissures with prominent epicanthal folds. A transverse crease is seen on the palm of each hand. On auscultation of the chest, there is a grade III/VI systolic murmur. Which of the following diseases is he most likely to develop by age 20?
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(E) 
10 The left hand of an infant born at 38 weeks’ gestation to a 25-year-old woman, G2, P1, has the appearance shown in the figure. The infant is small for gestational age. Which of the following chromosomal abnormalities is most likely to be present?
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(E) 11 A 19-year-old man is referred to a neurologist because of failing eyesight and progressive muscle weakness. The neurologist takes a history and finds that several of the patient’s male and female relatives have similar symptoms. His mother, her brother and sister, and two of the aunt’s children are affected, but the uncle’s children are not. Which of the following types of genetic disorders is most likely to be present in this patient?
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(E) 12 A healthy 20-year-old woman, G3, P2, Ab1, comes to the physician for a prenatal visit. She has previously given birth to a liveborn infant and a stillborn infant, both with the same karyotypic abnormality. On physical examination, she is at the 50th percentile for height and weight. She has no physical abnormalities noted. Which of the following karyotypic abnormalities is most likely to be present in this patient?
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(E) 13 A 36-year-old woman gives birth at 34 weeks’ gestation to a male infant who lives for only 1 hour after delivery. On physical examination, the infant is at the 30th percentile for height and weight. Anomalies include microcephaly, a cleft lip and palate, and postaxial polydactyly, with six digits on each hand and foot. Which of the following karyotypes is most likely to be present in this infant?
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(B) 
(C) 
(D) 
(E) 
(F) 
14 A 6-month-old male infant is brought to the physician because of failure to thrive and abdominal enlargement. His parents are concerned that he has shown minimal movement since birth. On physical examination, the infant has marked muscle weakness and hepatosplenomegaly. A chest radiograph shows marked cardiomegaly. He dies of congestive heart failure at age 19 months. The microscopic appearance of myocardial fibers at autopsy is shown in the figure. A deficiency of which of the following enzymes is most likely to be present in this infant?
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(F) 
(G) 
15 A 10-year-old child has had recurrent otitis media for the past 8 years. On physical examination, there is hepatosplenomegaly. No external anomalies are present. Laboratory findings include anemia and leukopenia. A bone marrow biopsy is performed, and high magnification of the sample shows the findings depicted in the figure. An inherited deficiency of which of the following enzymes is most likely to produce these findings?
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(E) 16 Mental retardation has affected several generations of a family, and most of the affected individuals have been males. The severity of mental retardation has increased with each passing generation. Genetic testing is performed, and about 20% of the males who have the genetic abnormality are unaffected. Which of the following mechanisms is most likely to produce this genetic condition?
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(E) 17 A 15-year-old girl is brought to the physician by her parents, who are concerned because she has developed multiple nodules on her skin. On physical examination, there are 20 scattered, 0.3- to 1-cm, firm nodules on the patient’s trunk and extremities. There are 12 light brown macules averaging 2 to 5 cm in diameter on the skin of the trunk. Slit-lamp examination shows pigmented nodules in the iris. These findings are most likely to be associated with which of the following types of neoplasm?
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(E) 18 A 39-year-old woman gives birth to a term infant with a right transverse palmar crease, low-set ears, oblique palpebral fissures, and a heart murmur. The infant survives to childhood and exhibits only mild mental retardation. Which of the following chromosomal abnormalities is most likely to be present in the somatic cells of this child?
(A) 
(B) 
(C) 
(D) 
(E) 19 A 23-year-old woman gives birth to a term infant after an uncomplicated pregnancy. On physical examination, the infant has ambiguous external genitalia. The parents want to know the infant’s sex, but the physician is hesitant to assign a sex without further information. A chromosomal analysis indicates a karyotype of 46,XX. An abdominal CT scan shows bilaterally enlarged adrenal glands, and the internal genitalia appear to consist of uterus, fallopian tubes, and ovaries. This infant is most likely to have which of the following abnormalities?
(A) 
(B) 
(C) 
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