MCQs In Genetics And Dysmorphology And Inborn Errors Of Metabolism

Q 1: 

You are urgently called to the newborn nursery to evaluate a 3-day-old term male infant who is lethargic. The baby was taking formula well for the first 2 days but vomited after his last 2 feedings and has become increasingly difficult to arouse. A review of the record reveals that he was born at 36 weeks’ gestation to a 30-year-old gravida 2, now para 2 woman. The mother is Rh-negative and received Rh immune globulin during the pregnancy. Pregnancy, labor, and delivery were uneventful; Apgar scores were 8 and 9 at 1 and 5 minutes. Family history is noncontributory. On physical examination, the baby appears well developed, is very jaundiced,

and has hypotonia and tachypnea. He responds with a grimace to sternal rubbing but does not arouse to voice or to touch. Findings on abdominal examination are normal. You order a series

of laboratory tests, start intravenous fluids, and arrange for transfer to the neonatal intensive care unit. A laboratory technician subsequently notifies you of some critical laboratory values,

including a platelet count of 35x103/mcL (35x109/L), serum carbon dioxide of 4 mEq/L (4 mmol/L), anion gap of 28 mEq/L (28 mmol/L), serum ammonia of 250 mcmol/L, and total bilirubin

of 20 mg/dL (342 mcmol/L). There are large ketones in the urine.

Of the following, the MOST likely diagnosis is

A. bilirubin encephalopathy

B. citrullinemia

C. hypoxic-ischemic encephalopathy

D. propionic acidemia

E. transient hyperammonemia of the newborn

The Answer :

D

Comments :

Metabolic acidosis with an increased anion gap is suggestive of an organic acidemia.

Bone marrow suppression is seen in some organic acidemias, and the platelet count of 35x103/mcL (35x109/L) reported for the infant in the vignette also supports this possibility. Propionic acidemia is caused by defective activity of the enzyme propionyl CoA carboxylase that results in the inability to break down numerous amino and fatty acids and cholesterol, thereby compromising the citric acid cycle. Affected individuals have large ketones in the blood and urine, and the urea cycle also is affected negatively, resulting in hyperammonemia in some cases.

Hyperbilirubinemia of the newborn may be exacerbated by dehydration associated with vomiting.

Precise diagnosis of a suspected organic acid disorder is based on urine organic and amino acid and plasma amino acid test results.

Citrullinemia is an inborn error of urea cycle function caused by defective production or formation of the enzyme argininosuccinate synthetase that results in massive hyperammonemia, with concentrations often exceeding 560 mcg/dL (400 mcmol/L). Affected infants typically present in the first few days after birth with poor feeding, vomiting, lethargy, and coma. There may be hepatomegaly. In addition to elevated serum ammonia values, serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase concentrations often are elevated, and prothrombin time and partial thromboplastin time may be prolonged. 

Metabolic acidosis is not present; respiratory alkalosis is more typical. Precise diagnosis is based on the finding of very elevated citrulline values on plasma amino acid analysis.

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Q2 :

During a 2-week health supervision visit, a mother expresses concern about her son's poor feeding and small penis. On physical examination, you confirm micropenis and note hypotonia.

Of the following, the MOST likely diagnosis is:

A. Kallman syndrome

B. Klinefelter syndrome

C. Noonan syndrome

D. Prader-Willi syndrome

E. septo-optic dysplasia

Answer

D

The clinical presentation of hypotonia, poor feeding, and micropenis is most consistent with Prader-Willi syndrome (Figure 98A), which is associated with hypogonadotropic hypogonadism. Although affected infants are hypotonic and poor feeders, they develop morbid obesity during childhood. Short stature, small hands and feet, and hypogonadism are common. The diagnosis is confirmed by demonstration of a 15q11 deletion.

            A penile length of less than 2 standard deviations below the mean for age is considered micropenis. The mean penile length for a term infant is 3.5 cm.

Most newborns who have isolated micropenis have a hypothalamic-pituitary defect that results in hypogonadism. Many syndromes that present with micropenis can be difficult to diagnose in the neonate. They may present with hypoglycemia due to the associated deficiency of counterregulatory hormones or they may have a midline central nervous system defect (eg, Kallman syndrome, septo-optic dysplasia). Kallman syndrome is associated with anosmia, and septo-optic dysplasia is characterized by optic nerve hypoplasia and absence of the septum pellucidum. Abnormal hypothalamic-pituitary gonadal axis activity results in low luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in Kallman syndrome, in contrast to the typical neonatal elevation.

The infant described in the vignette has hypotonia and poor feeding, which are not features of Kallman syndrome or septo-optic dysplasia. Klinefelter syndrome rarely is diagnosed before puberty and is characterized by increased height, behavior problems (such as immaturity, poor judgement), and small testes and penis. Typical symptoms of Noonan syndromeinclude short stature, webbing of the neck, congenital heart disease, and cubitus valgus, but generally not micropenis.

            To measure penile length accurately, the clinician must press down firmly on the prepubertal fat pad to the pubic ramus, grasp the glans between the thumb and forefinger, and stretch the penis along the length of a ruler. The measurement should be from the base of the penis to the tip of the glans. If foreskin overlies the tip of the glans, it should not be included in the measurement. It is especially important to measure penile length in the obese child whenever micropenis is suspected because the prepubertal fat pad may obscure the penis, giving the false impression of micropenis.

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Q 3

A 7-year-old girl presents with hyposthenuria, growth retardation, and anemia. You diagnose medullary cystic disease.

When discussing the risks for having a similarly affected child in a future pregnancy with the parents, the MOST appropriate statement to include

is that:

A. because this is a multifactorial trait, the risk is approximately 2%

B. the risk can be assessed only after each parent has been evaluated for renal disease

C. the risk depends on whether the girl has any ocular manifestations of the disease

D. the risk is not increased over the general population

E.  there is a 25% risk for a similarly affected child in the next pregnancy

Answer

E

Juvenile-onset medullary cystic disease, which also is referred to as nephrophthisis, is inherited as an autosomal recessive trait. Therefore, the risk for a similarly affected child in a future pregnancy for the family described in the vignette is 25%. The disorder typically presents early in the second decade with polyuria, enuresis, and polydipsia. Short stature and ophthalmologic problems, such as retinitis pigmentosa and cataracts, also are evident at the time of diagnosis in many patients, but these symptoms are not related to inheritance risk. 

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Q3

On physical examination of a female infant, you note that she has a short neck, low hairline, limited movement of the head, and facial asymmetry. Neck radiographs reveal fusion of the cervical vertebrae.

Of the following, the MOST likely etiology of the infant's abnormalities is:

A.  CHARGE association

B.  Klippel-Feil sequence

C.  Noonan syndrome

D.  trisomy 13

E.   Turner syndrome

Answer

B

Klippel-Feil  is a malformation sequence characterized by fusion of cervical vertebrae that also may be accompanied by hemivertebrae. The vertebral fusion may result in webbed neck, torticollis, and facial asymmetry. In some instances, Klippel-Feil occurs as part of a more serious abnormality in neural tube development, such as cervical myelomeningocele. In these cases, associated neurologic deficits also will be evident, including paraplegia or hemiplegia and cranial or cerebral nerve palsies. The disorder occurs more commonly in females, but can affect both genders. Other associated abnormalities can include deafness in up to 30% of affected individuals, congenital heart defects, mental deficiency, cleft palate, posterior fossa dermoid cysts, scoliosis, and renal abnormalities. Therefore, affected infants must be evaluated carefully for these associated defects via audiologic evaluation, echocardiography, and renal ultrasonography. In addition, lateral flexion-extension radiographs must be obtained to identify patients who have hypermobility of the upper cervical segment and are at risk for developing neurologic impairment. If hypermobility is present, the child should be evaluated annually and avoid contact sports. Usually Klippel-Feil is a sporadic occurrence, although rare families have been described in which there was an autosomal dominant form with variable expression.

            CHARGE association is characterized by Coloboma, Heart defects, Atresia choanae, Retarded growth, central nervous system anomalies, Genital anomalies, and Ear abnormalities. Although features of both Noonan syndrome and Turner syndrome can include a low hairline and short neck, neither is associated with fused vertebrae or facial asymmetry. Infants who have trisomy 13 present in the newborn period with defects of the forebrain, which can include holoprosencephaly, microcephaly, polydactyly, and clefting.

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Q4 :

Of the following, the disorder associated with the GREATEST risk for a similarly affected child in a future pregnancy is:

. Aatrial septal defect

B.  hypothyroidism

C.  open neural tube defect

D.  phenylketonuria

E.   unilateral club foot

Answer

D

In general, single gene disorders, such as phenylketonuria (PKU), which are inherited as mendelian traits, have the highest recurrence for future pregnancies. The inheritance of PKU, which results from the deficiency of specific enzymatic activities, is autosomal recessive. Therefore, there is a 25% risk in each future pregnancy for a similarly affected child. 

Atrial septal defects, clubfoot, and open neural tube defects each are inherited as multifactorial traits in which a combination of genetic and environmental factors contribute to the development of the defect. In general, multifactorial traits have a recurrence risk of 2% to 4% in future children. The risk is greater if one of the parents also has the defect, but it usually does not approach the risk conferred by a single gene defect (ie, 25% for recessive traits and 50% for dominant traits).

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Q5:

A 13-year-old girl who has Down syndrome is experiencing deteriorating exercise tolerance. She has not seen a physician since early childhood. She has a loud single second heart sound. On pulse oximetry, oxygen saturation is 83% on room air.

Of the following, the MOST likely additional finding will be:

A. adenotonsillar hypertrophy

B.  bilateral wheezing

C.  digital clubbing

D.  marked thyroid enlargement

E.   murmur of a ventriculoseptal defect

Answer

C

. Increasing right-to-left shunting through an undiagnosed large ventricular septal defect results in a progressive and finally noticeable cyanosis accompanied by clubbing, the osteoarthropathy of chronic cyanosis, a clinical picture termed Eisenmenger syndrome or Eisenmenger complex.

            Pulmonary hypertension persisting from the neonatal period in children who have Down syndrome prevents the development of signs or symptoms of congestive heart failure. Equal ventricular pressures result in no discernible murmur. The hallmark physical signs of pulmonary hypertension, a loud single second heart sound and a right ventricular lift, often were missed in these children. Irreversible pulmonary hypertension causes a low-velocity right-to-left shunt across the ventricular septal defect, which produces no murmur.

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Q 6:

A 12-year-old boy who has Down syndrome exhibits increasing fatigue, somnolence, and apparent cognitive deterioration in school.

Of the following, the MOST likely explanation for these observations is:

A.  Addison disease

B.  airway obstruction

C.  Alzheimer-like brain changes

D.  Eisenmenger syndrome

E.  normal developmental changes


Answer:

B

Children and adolescents who have trisomy 21 (Down syndrome) are especially prone to airway obstruction during sleep (sleep apnea). Midfacial hypoplasia, hypopharyngeal collapse, and macroglossia all combine to create the risk for obstructive apnea during sleep. Adenotonsillary hypertrophy, if present, probably will produce significant obstruction, hypercarbia, and hypoxemia during sleep in affected individuals. Obesity also may be a significant contributing factor. Accordingly, questions designed to reveal the presence of obstructive sleep apnea should be a part of routine health screening in children who have Down syndrome. Daytime somnolence and cognitive deterioration are late sequelae of obstructive sleep apnea, which more commonly presents with snoring and difficulty breathing at night.

            Longstanding severe nighttime airway obstruction can produce pulmonary hypertension with secondary right heart failure. On physical examination, there may be a loud and narrowly split second heart sound, hepatomegaly, or dependent edema. When these changes are due to pulmonary hypertension, the condition is termed cor pulmonale, which can be fatal. 

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Q 7

You are discussing newborn screening with a group of first-year medical students. 

Of the following, the MOST appropriate statement to include in your discussion of PKU screening is that:

A.  affected infants cannot be breastfed

B.  dietary therapy should not be initiated until screening results are confirmed

C.  it relies on identification of a specific mutation in the phenylalanine hydroxylase gene

D.  there are no false-positive results

E.   to be most reliable, the specimen should be obtained after 24 hours of age

Answer

E

Newborn screening for phenylketonuria (PKU) relies on the detection of elevated levels of blood phenylalanine. Prenatally, fetal phenylalanine readily crosses the placenta and is metabolized by the mother. Accordingly, a newborn who has PKU will not have hyperphenylalaninemia. The phenylalanine level will begin to rise only after feeding has been established and may not be detectable in the first 24 hours of life. Therefore, it is important to obtain a specimen for newborn screening after the first day of life. If an infant is released from the hospital prior to this time, a return visit should be scheduled to obtain the appropriate specimen on day 2 or 3 of life.