A 4-year-old girl presents for a pre-school physical
examination. The child has a small head circumference, thin upper lip, and low-bridge nose. She shows evidence of mild mental retardation. Her parents state that she is often “emotional.” Which of the following maternal causes of birth defects most likely accounts for these clinicopathologic findings?
(A) Alcohol abuse
A 12-month-old boy is brought to the emergency room for examination of his right arm following a tumble at home. Radiologic examination of the limb reveals a recent fracture of the right ulna and evidence of additional healing fractures. The child is noted to have blue sclerae. This patient most likely carries a mutation in a gene that encodes which of the following proteins?
(C) Collagen
A 28-year-old woman gives birth to a stillborn neonate with a severe neural tube defect (shown). This birth defect was caused by an error of morphogenesis that occurred at which of the following stages of development after fertilization?
(A) 20–40 days
A 20-year-old man is examined by a new family physician who discovers numerous pigmented patches and pedunculated skin tumors on his back. Biopsy of a tumor discloses a benign neoplasm derived from Schwann cells. Neither the patient's father nor mother shows signs of this disease. This patient most likely carries a mutation in a gene that encodes which of the following proteins?
(A) GTPase activating protein
_____________________ is characterized by (1) disfiguring neurofibromas, (2) areas of dark pigmentation of the skin (café au lait spots), and (3) pigmented lesions of the iris (Lisch nodules).
Neurofibromatosis type 1 (NF1)
A 25-year-old pregnant woman, at 16 weeks of gestation, visits her obstetrician. A screening test suggests the possibility of a neural tube defect in her fetus. An ultrasound examination shows a 3-cm neural tube defect in the thoracic spine. The screening test that was administered to the mother measured serum levels of which of the following proteins?
(B) Alpha-fetoprotein
A 25-year-old man presents for a routine physical
examination. The patient is tall (6 feet, 5 inches) and has long fingers (shown). One year later, he suffers a dissecting aortic aneurysm. This patient most likely carries a mutation in a gene that encodes which of the following proteins?
(A) Fibrillin
The genetic disease known as Marfan syndrome follows which of the following patterns of inheritance?
(C) Autosomal dominant
A 12-month-old boy shows progressive weakness, mental deterioration, and loss of vision. Laboratory studies demonstrate decreased activity of hexosaminidase A. The child eventually becomes blind and dies at 3 years of age. Which of the following best describes the pathogenesis of neuronal degeneration in this patient?
(D) Accumulation of unmetabolized substrate
If the parents of a child with Tay-Sachs disease have a
total of four sons and two daughters, then, on average, how many of their children may be expected to be asymptomatic (i.e., silent) carriers of this
gene mutation?
(A) 3
A 4-year-old boy is admitted to the hospital with pneumonia and respiratory distress. The nurses report that the child's bowel movements are greasy and have a pungent odor. A sweat-chloride test is positive. Which of the following mechanisms of disease is the most likely cause of steatorrhea in this child?
(B) Lack of pancreatic enzyme secretion (Cystic fibrosis)
Cystic fibrosis is caused by a deficiency in what protein? What does this cause?
A patient with cystic fibrosis carries mutations in the gene that encodes which of the following types of protein?
(A) Membrane ion channel (Chloride ions)
A 10-year-old child presents with xanthomas on the extensor surfaces of his forearms. Laboratory studies demonstrate a total serum cholesterol of 820 mg/dL. The child's mother and maternal grandfather also have elevated serum cholesterol. This patient most likely has mutations in the gene that encodes which of the following proteins involved in lipid metabolism?
(E) Low-density lipoprotein (LDL) receptor
A 10-month-old boy who was adopted from an orphanage in Eastern Europe presents for a physical examination. His parents believe that he is failing to meet developmental milestones. The child is fair skinned and has blond hair. On physical examination, the patient is noted to have a “mousy” odor. Laboratory studies demonstrate an inborn error of amino acid metabolism. To prevent mental retardation, this patient should be placed on a special diet that lacks which of the following essential amino
acids?
(D) Phenylalanine
Which of the following best describes the pathogenesis of mental retardation in a patient with phenylketonuria?
(C) Accumulation of unmetabolized substrate
What autosomal dominant disorder is characterized by a lack of the enzyme lysol hydroxylase, extremely pliable skin, and hyperextendable joints?
Ehlers-Danlos syndrome
A 25-year-old woman complains of recurrent bone pain and increasing abdominal girth. Physical examination reveals massive hepatosplenomegaly. Radiologic studies reveal several radiolucent bone defects.A liver biopsy discloses sinusoids engorged with enlarged cells with a fibrillar appearance reminiscent of “wrinkled tissue paper.” This patient most likely carries mutations in the gene that encodes which of the following types of hydrolytic enzymes?
A neonate is born with severe motor dysfunction involving the lower extremities. Radiologic studies show that vertebral bodies in the lumbar region lack posterior arches. The vertebral defects are covered by a thin membrane. The space underneath the membrane contains a mass of tissue that is composed of meninges and spinal cord. The parents ask for information regarding risks for similar birth defects in their future offspring. You mention that dietary supplementation of the maternal diet has been shown to reduce the incidence of neural tube defects. What is this substance?
(D) Folic acid
A 30-year-old pregnant woman visits her obstetrician for prenatal care and eventual delivery. The patient volunteers that two of her three children had “yellow jaundice” at birth. Her youngest girl had been severely jaundiced and had been given two blood transfusions. Prenatal laboratory tests indicate that the mother is blood type O, Rh negative, whereas her husband is blood type A, Rh positive. The obstetrician samples amniotic fluid at 36 weeks of gestation and learns that the fetus is mature enough for pre-term delivery. Quantitative analysis of which of the following was most likely used as an indicator of fetal lung maturity?
(D) Lecithin
A 4-year-old boy is brought to the physician by his parents because he tires easily. Physical examination reveals weakness in the pelvic and shoulder girdles and enlargement of the child's calf muscle. Serum levels of creatine kinase are elevated. A biopsy of calf muscle shows marked variation in size and shape of muscle fibers. There are foci of muscle fiber necrosis, with myophagocytosis, regenerating fibers, and fibrosis. Molecular diagnostic assays would most likely show alterations in the length of the primary transcript for which of the following muscle-associated proteins?
(E) Dystrophin (Duchenne Muscular Dystrophy)
What will be the likely cause of death in a patient with Duchenne muscular dystrophy?
(E) Cardiomyopathy
A 22-year-old man complains about his inability to conceive a child. On physical examination, the patient is noted to be tall (6 ft, 5 inches) and exhibits gynecomastia and testicular atrophy. Laboratory studies demonstrate increased serum levels of follicle-stimulating hormone (FSH). Cytogenetic studies reveal a chromosomal abnormality. What is the most common cause of this patient's chromosomal abnormality?
(C) Meiotic nondisjunction
A 35-year-old pregnant woman delivers a baby prematurely at 28 weeks of gestation. Shortly after birth, the neonate becomes short of breath, with intercostal retraction and nasal flaring during respiration. The neonate is placed on a ventilator but dies of respiratory insufficiency and intraventricular hemorrhage. Histologic examination of the lungs at autopsy is shown. The eosinophilic material lining the air spaces represents an accumulation of which of the following proteins?
(D) Fibrin
If a neonate with infant respiratory distress syndrome survives, which of the following would be the most likely complication related to anoxia and acidosis?
A 16-year old girl complains that she has not started
menstruating like other girls her age. The patient is short (4 ft, 11 inches) and has a thick-webbed neck. Physical examination reveals widely spaced nipples and poor breast development. If this patient's genetic disease was caused by nondisjunction during mitosis of a somatic cell in the early stages of embryogenesis, which of the following is the patient's most likely karyotype?
(C) 45,X
A 34-year-old woman in her second pregnancy delivers a female neonate with severe generalized edema and jaundice. A CBC of the neonate shows hemolytic anemia. Subsequent work-up of the mother and the newborn reveal an Rh-incompatibility. Transplacental passage of which of the following proteins is the principal cause of anasarca and jaundice in this neonate?
(D) IgG
The parents of a child with cleft lip and cleft palate visit a genetic counselor to discuss the chances that a similar birth defect will occur in their future offspring. This birth defect shows which of the following patterns of inheritance?
(E) Multifactorial
A 42-year-old woman gives birth to a neonate with multiple congenital abnormalities. Physical findings included a flat facial profile, slanted eyes, epicanthal folds, Brushfield spots, short nose, short neck, dysplastic ears, clinodactyly, a large protruding tongue, and a pronounced heart murmur. What is the most common cause of this developmental birth disease?
(E) Nondisjunction
As an adult, the brain of a patient with Trisomy 21 (Down Syndrome) will show histopathologic changes that are seen in patients with which of the following neurologic diseases?
(B) Alzheimer disease
A 50-year-old man with a history of diabetes mellitus (type II) asks about the chances that his children will inherit his disorder. The patient is told that he has a genetic disease that shows which of the following
patterns of inheritance?
(A) Multifactorial
A 25-year-old man with a history of autism and mental retardation is seen by a genetic counselor. The man has coarse facial features, an increased head circumference, and macro-orchidism. His maternal uncle is similarly affected. After further evaluation, a diagnosis of fragile X syndrome is rendered. What is the most likely underlying cause of this patient's genetic disease?
(D) Expansion of trinucleotide repeat
A 28-year-old man presents to the emergency room 1 hour after experiencing crushing substernal chest pain. Laboratory studies and ECG confirm the diagnosis of acute myocardial infarction. The patient dies 24 hours later of cardiac arrhythmia. This patient most likely had which of the following genetic diseases?
(A) Familial hypercholesterolemia
A 5-year-old boy presents with a maculopapular rash. On physical examination, the rash affects the palms and soles. Cracks and fissures are noted around the mouth and anus. There is funduscopic evidence of
interstitial keratitis. Mild hepatosplenomegaly is present. The anterior tibial bones exhibit an outward curvature. What is the most likely etiology of these
clinicopathologic findings?
(A) Syphilis
A 3-year-old boy dies in an automobile accident. At autopsy, the right lung is markedly shrunken. Dissection shows that the right main stem bronchus ends blindly in nondescript tissue composed of rudimentary ducts and connective tissue. This finding represents an example of which of the following errors of morphogenesis?
(D) Aplasia
The mother of a newborn boy is alarmed that her baby regurgitates at every feeding. An endoscopic examination reveals that the child's esophagus is almost completely occluded. This finding represents an example of which of the following errors of morphogenesis?
An 87-year-old woman dies peacefully in her sleep. At autopsy, a rest of pancreatic tissue is identified in the wall of the lower esophagus. This finding represents an example of which of the following congenital tumor-like conditions?
(E) Choristoma
A 19-year-old college sophomore is referred by his ophthalmologist because of the finding of ectopia lentis (dislocation of the lens), which has resulted in visual difficulties that have interfered with his performance on the varsity basketball team. The patient is very tall, with long limbs and long, slender, spiderlike fingers. His chest has a "caved-in" appearance, and he also has a modest degree of scoliosis. A midsystolic "click" is heard, and an echocardiogram reveals mitral valve prolapse. The most likely diagnosis is...
(C) Marfan syndrome.
A 1-year-old female infant is hospitalized for pneumonia. Bacterial cultures of the sputum have grown Pseudomonas aeruginosa. She has had two prior hospitalizations for severe respiratory infections. Her mother has noted that when she kisses her child, the child tastes "salty." The child has had weight loss that the mother attributes to frequent vomiting and diarrhea with bulky, foul-smelling fatty stools. The child is small for her age. Which of the following critical proteins is altered in this condition?
A 2-year-old child has been followed
for mental retardation and slow development, as well as multiple birth defects.The child has a high-pitched catlike cry. On examination, microcephaly, hypertelorism, micrognathia, epicanthal folds, low-set ears, and hypotonia are noted. Karyotypic analysis would be expected to show
(C) 5p-.
The parents of a 17-year-old boy with Down syndrome seek counseling because they are concerned that their son may develop a life-threatening disorder known to be associated with his chromosomal abnormality. The physician should be prepared to discuss which ofthe following disorders in terms of its association with Down syndrome?
(C) Lymphoblastic leukemia
A 14-year-old girl with amenorrhea is concerned because of the delayed onset of menses. She has shortened stature and a wide, webbed neck; broad chest; and secondary sexual characteristics consistent with those of a much younger girl. Which of the following chromosomal changes is most consistent with these findings?
(E) 45,XO
A 50-year-old woman of Eastern European Jewish ancestry has a history of recurrent fractures and easy bruising and is found to have hepatosplenomegaly and mild anemia. Serum assays reveal elevations of chitotriosidase and angiotensin-converting enzyme. Assay of cultured leukocytes most likely reveals marked deficiency of which of the following enzymes?
A screening test for phenylketonuria (PKU) is performed on umbilical cord blood from a fair-skinned blond, blue-eyed infant born to dark-complexioned parents. The test is reported as negative, and no dietary restrictions are imposed. At 1 year of age, the child is seen again, this time with obvious signs of severe mental retardation, and a diagnosis of
PKU is made. The diagnosis was missed at birth because
(D) the test was performed too early.
An autosomal dominant, hereditary disturbance of epiphyseal chrondroblastic development that leads to inadequate enchondral bone formation.
Achondroplasia
Complete absence of an organ primordium.
Agenesis
A heterogeneous group of at least 10 inherited disorders of pigmentation characterized by absent or reduced
biosynthesis of melanin.
Albinism
A rare autosomal recessive disease characterized by excretion of homogentisic acid in the urine, generalized pigmentation, and arthritis. Due to deficiency in hepatic and renal homogentisic acid oxidase.
Alcaptonuria
Surgical transabdominal perforation of the uterus with a needle, to obtain amniotic fluid.
Amniocentesis
Synonomous with the "happy puppet" syndrome. May have microdeletion of 15q11-12. These children have severe mental retardation, seizures, no speech, paroxysms of laughter, microcephaly, prognathism, and ocular abnormalities. Important as an example the effects of genomic imprinting
Angelman Syndrome
Absence of an organ coupled with persistence of the organ anlage (primordium) or a rudiment that never develops completely.
Aplasia
Defects caused by the incomplete formation of a lumen.
Atresia
A subperiosteal hemorrhage confined to a single cranial bone which becomes apparent within the first few hours
after birth.
Cephal-hematoma
An example of multifactorial inheritance, it is caused by hereditary or environmental disturbance in gene expression in the genes involved in fusion of the frontal prominence with the maxillary process to form the upper lip.
Cleft lip/palate
An autosomal recessive disorder affecting children that is characterized by (1) chronic pulmonary disease; (2) deficient exocrine pancreatic function; and (3) other complications of inspissated mucus in a number of organs, including the small intestine, liver and reproductive tract.
Cystic Fibrosis
The most common variant of a number of devastating wasting muscle diseases, most of which are X-linked.
Duchenne muscular dystrophy
Defects caused by failure of apposed structures
to fuse.
Dystraphic
Retention of an organ at its developmental site. (The organ never moved to its mature location)
Dystopia
An anomaly in which an organ is located outside its normal anatomic site.
Ectopia
A group of rare, autosomal dominant inherited disorders of connective tissue that are characterized by remarkable hyper-elasticity and fragility of the skin, joint hyper-mobility, and often a bleeding diathesis.
Ehlers-Danlos syndromes
A hemolytic disease of the fetus or newborn caused by the transplacental passage of maternal antibodies against
fetal erythrocytes.
Erythroblastosis fetalis
A common autosomal dominant disorder characterized by striking acceleration of atherosclerosis and its complications.
Familial hypercholesterolemia
A common autosomal dominant disorder caused by a mutation in a gene that codes for low-density lipoprotein.
Familial Hypercholesteremia
The syndrome is a complex of abnormalities induced by the maternal consumption of alcoholic beverages thatincludes: 1) growth retardation; 2) dysfunction of the central nervous system; and 3) characteristic facial dysmorphology.
Fetal Alcohol Syndrome
A disorder associated with the expansion of a trinucleotide repeat on the X chromosome and is the most common form of inherited mental retardation.
Fragile X Syndrome
A lysosomal storage disease caused by a deficiency in glucocerebrosidase, characterized by accumulation of glucosylceramide, primarily in the lysosomes of macrophage.
Gaucher disease
A group of at least 10 distinct autosomal recessive disorders characterized by accumulation of glycogen, principally in the liver, skeletal muscle, and heart. Each type reflects a deficiency of one of the specific enzymes involved in metabolism of glycogen.
Glycogenoses
An X-linked recessive disorder of blood clotting that results in spontaneous bleeding, particularly in joints, muscles, and internal organs. The A subtype of this disorder is caused by a mutated gene coding for factor VIII. The B subtype is caused by a defect in the gene coding for factor IX.
Hemophilia
The most severe clinical form of mucopolysaccharidosis.
Hurler Syndrome
The most serious form of erythroblastosis fetalis in liveborn infants. Characterized by severe edema, secondary to congestive heart failure caused by severe anemia.
Hydrops fetalis
Also termed bilirubin encephalopathy, defined as a neurologic condition associated with severe jaundice and characterized by bile staining of the brain, particularly of the basal ganglia, pontine nuclei, and dentate nuclei in the cerebellum.
Kernicterus
Also called testicular dysgenesis, is the phenotype of the 47,XXY genotype and is characterized by male hypogonadism and infertility.
Klinefelter syndrome
Autosomal recessive disorders characterized by the accumulation of unmetabolized normal substrates in the lysosomes, owing to deficiencies of specific acid hydrolases.
Lysosomal storage disorders
An autosomal dominant, inherited disorder of connective tissue characterized by a variety of abnormalities in many organs, including the heart, aorta, skeleton, eyes, and skin.
Marfan syndrome
An assortment of lysosomal storage diseases characterized by accumulation of glycosaminoglycans (mucopolysaccharides) in many organs. All of these disorders are inherited as autosomal recessive traits, with the exception of hunter syndrome, which is x-linked recessive.
Mucopolysaccharidoses
A neural tube defect characterized by a hernial protrusion of the spinal cord and its meninges through a defect in
the vertebral column.
Myelomeningocele
A life-threatening disorder of the
lungs principally associated with prematurity and the lack of surfactant.
Neonatal respiratory distress syndrome
Two distinct autosomal dominant disorders characterized by development of multiple neurofibromas, which are benign tumors of peripheral nerves of Schwann cell origin.
Neurofibromatoses
A heterogenous group of disorders that are characterized by the lysosomal storage of sphingomyelin, cholesterol,
and other glycolipids in macrophages.
Niemann-Pick syndrome
Also called brittle bone disease, comprises a group of inherited disorders in which a generalized abnormality of connective tissue is expressed principally as fragility of bone. Most cases are inherited in an autosomal dominant pattern.
Osteogenesis Imperfecta
An autosomal recessive disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase and characterized by progressive mental deterioration in the first few years of life. The severe brain damage results from high levels of circulating phenylalanine.
Phenylketonuria
Clinical features are hypotonia and difficulty with feeding at birth, hyperphagia and excessive obesity in childhood. Hypoplasia of the external genitalia in boys, small hands and feet, psychomotor retardation, and seizures. About two-thirds of patients with Prader-Willi syndrome a have a detectable deletion of 15q11-12. Important as an example of the effects of genomic imprinting.
Prader-Willi syndrome
Defined by the World Health Organization as a newborn with a gestational age of less than 37 weeks from first day of the last menstrual period. Traditionally, the definition of prematurity was a birth weight of less than 2500 grams, regardless of gestational age.
Prematurity
The sudden death of an infant or young child which is unexpected by history and in which a thorough postmortem examination fails to demonstrate an adequate cause of death.
Sudden infant death syndrome (SIDS)
An autosomal recessive disorder that reflects the deposition of ganglioside GM2 in the neurons of the central nervous system, owing to failure of lysosomal degradation.
Tay-Sachs disease
Chemical, physical, and biologic agents that cause developmental anomalies.
Teratogen
What do each of the letters stand for in the ancronym TORCH? What do they refer to?
Toxoplasmosis, others, rubella, cytomegalovirus, herpes-simplex virus; Diseases that can be passed from mother to infant during parturition.
The spectrum of abnormalities that results from the presence of a complete or partial monosomy of the X chromosome in a phenotypic female.
