McGraw-Hill Specialty Board Review Pediatrics, 2nd Edition

Chapter 10. GENETICS


A newborn is evaluated in the regular nursery. The child was born full term to a 39-year-old mother by a normal spontaneous vaginal delivery. A prenatal ultrasound showed the presence of a congenital heart defect, most likely an atrioventricular (AV) canal defect. The family elected not to have prenatal testing. The family history is otherwise negative.

On physical examination the vital signs are within normal limits. Brachycephaly, up-slanted palpebral fissures, epicanthal folds, protruding tongue, and generalized hypotonia with an otherwise normal neurologic examination are noted.


1. The most likely diagnosis for this child is

(A) Down syndrome

(B) Edward syndrome

(C) Holt-Oram syndrome

(D) Patau syndrome

(E) Treacher Collins syndrome

2. Which of the following is not a common feature of Down syndrome in the newborn infant?

(A) small, low-set ears with an overfolded upper helix

(B) transverse palmar (simian) crease

(C) increased gap between toes 1 and 2

(D) rocker bottom feet

(E) excess nuchal skin fold

3. In a newborn suspected of having Down syndrome, which of the following investigations are routinely indicated in all patients regardless of symptoms?

(A) chest radiograph

(B) echocardiogram

(C) head ultrasound

(D) renal ultrasound

(E) upper gastrointestinal (GI) series

4. A karyotype to determine the chromosomal basis of Down syndrome is essential for which of the following reasons?

(A) confirming the diagnosis because the clinical features of Down syndrome can be difficult to recognize in some newborns and can overlap with other conditions

(B) allows appropriate counseling regarding recurrence risks for the parents

(C) helpful in assigning gender in a child with Down syndrome

(D) A and C

(E) none of the above; karyotype is not essential in the evaluation for a child with Down syndrome

5. Results of chromosome analysis show an unbalanced Robertsonian translocation between the long arm of chromosome 14 and 21: 46, XY, der,(14;21) (q10;q10). Part of the family counseling should include which of the following with regard to this chromosomal rearrangement?

(A) parents should be offered chromosome analysis to see if they are carriers of a balanced Robertsonian translocation

(B) advice not to have any more children

(C) counseling that this is not really Down syndrome because that only applies to trisomy 21

(D) prognostic information that children with unbalanced Robertsonian translocations as the cause of Down syndrome are less severely affected

(E) none of the above

6. All of the following are associated medical problems in children with Down syndrome except

(A) atlantoaxial instability

(B) hearing loss

(C) polycystic kidneys

(D) sleep apnea

(E) strabismus

7. Which of the following best describes the expected intelligence and personality of a child with Down syndrome?

(A) all have severe mental retardation with an IQ in the range of 30-40

(B) IQ range of 35-65 with a mean of 54, and occasionally higher

(C) aggressive and violent; prefers to be alone and has little social interaction

(D) affectionate and docile, tends toward mimicry, enjoys music, and has a good sense of rhythm but poor coordination

(E) B and D

8. The most common cause of trisomy 21 is

(A) maternal nondisjunction at meiosis I with increasing risk associated with advanced maternal age

(B) nondisjunction associated with advanced paternal age

(C) mosaicism

(D) sporadic events unrelated to maternal age

(E) environmental exposure

9. What is the overall recurrence risk for Down syndrome because of trisomy 21 (as opposed to an unbalanced translocation)?

(A) 1% in women younger than 40 years of age and age-related risk for women older than 40 years of age

(B) age-related risk

(C) 10% in women younger than 35 and agerelated risk in women older than 35

(D) the same as the population risk

(E) none of the above

10. Which of the following are features of trisomy 13?

(A) micro-ophthalmia, cleft lip and palate, polydactyly, holoprosencephaly

(B) up-slanting palpebral fissures, epicanthal folds, clinodactyly

(C) hypotonia, rocker bottom feet, clenched hand, low-set malformed ears

(D) obesity, hypogenitalism, almond-shaped eyes, small hands and feet

(E) supravalvular aortic stenosis, hypercalcemia, short stature

11. All of the following are features of trisomy 18 except

(A) cardiac defect

(B) clenched hand

(C) hypoplastic nails

(D) protruding tongue, large cheeks

(E) small palpebral fissures

12. Which of the following modalities can be used for screening/testing for Down syndrome?

(A) amniocentesis

(B) chorionic villus sampling (CVS)

(C) maternal serum screening

(D) prenatal ultrasonography

(E) all of the above

13. A newborn is evaluated in the nursery. Pregnancy was complicated by a prenatal ultrasound that showed coarctation of the aorta. This female infant was delivered at term by normal spontaneous vaginal delivery. On physical examination the baby is noted to have lymphedema of the feet and hands, webbed neck, and shield chest. The most likely diagnosis to explain the features is

(A) DiGeorge syndrome

(B) Down syndrome

(C) Klinefelter syndrome

(D) Turner syndrome

(E) Williams syndrome

14. Which of the following medical problems are not associated with Turner syndrome?

(A) agenesis of the corpus callosum

(B) coarctation of the aorta

(C) horseshoe kidney

(D) hypothyroidism

(E) premature gonadal failure

15. Standard treatment of growth failure in Turner syndrome includes

(A) estrogen replacement

(B) leg-lengthening procedures

(C) maximizing caloric intake

(D) recombinant human growth hormone

(E) none of the above

16. Which of the following is true regarding Noonan syndrome?

(A) Noonan affects only males

(B) Noonan syndrome is the result of a sex chromosome abnormality

(C) the clinical features of Noonan syndrome have significant overlap with those of Turner syndrome

(D) Noonan syndrome is not a genetic condition

(E) none of the above

17. An 8-year-old boy is noted to be tall, to have gynecomastia, underdeveloped secondary sexual characteristics, and small testes. The most likely diagnosis is

(A) Noonan syndrome

(B) Marfan syndrome

(C) Klinefelter syndrome (47,XXY)

(D) 47,XYY

(E) mosaic trisomy 8

18. A newborn with tetralogy of Fallot (TOF) with pulmonary atresia has a normal karyotype by chromosome analysis. Additional genetic testing should include

(A) fluorescent in situ hybridization (FISH) for DiGeorge syndrome

(B) FISH for Down syndrome

(C) FISH for Williams syndrome

(D) high-resolution karyotype

(E) microarray analysis


1. (A) The features described are most consistent with Down syndrome or trisomy 21. Edward syndrome or trisomy 13 is characterized by polydactyly, holoprosencephaly, and cleft lip and palate in addition to many other congenital birth defects. Holt-Oram is associated with congenital heart defect, most often atrial septal defect (ASD) or ventricular septal defect (VSD), and upper limb abnormalities. Patau syndrome or trisomy 18 is associated with clenched hands, feeble activity, weak cry, rocker bottom feet, and many other congenital birth defects. Treacher Collins syndrome, also known as mandibulofacial dysostosis, is associated with defects of the lower eyelids, mandibular and malar hypoplasia, microtia and dysplastic ears, and hearing loss.

2. (D) Common newborn features of Down syndrome include those in the answer to question 1 and mild microcephaly, flat occiput, brachycephaly, upslanting palpebral fissures, epicanthal folds, Brushfield spots, protruding tongue, low flat nasal bridge, clinodactyly of the 5th digit, transverse palmar crease, and short stature. Rocker bottom feet are common features of trisomy 18.

3. (B) The only investigation listed that should be done in all individuals with Down syndrome is an echocardiogram. Congenital heart defects are present in 40-45% and not all are recognizable by physical examination (thus the need for an echocardiogram). Additional problems that should be remembered in the newborn period but do not necessarily require screening if there are no associated symptoms including intestinal abnormalities such as esophageal or duodenal atresia, or Hirschsprung disease. The incidence of renal malformations in Down syndrome is not significantly higher than the general population risk. Brain malformations such as holoprosencephaly and vertebral anomalies are common in trisomy 13 and 18 but not in Down syndrome.

4. (D) Karyotype is helpful in confirming the clinical suspicion especially in premature newborns. The most important reason, however, is for counseling regarding recurrence risks. Trisomy 21 has a low recurrence risk (either based on maternal age or 1%, whichever is higher), whereas an unbalanced translocation may be inherited from a balanced translocation carrier parent and the recurrence risk may be as high as 100% depending on the translocation.

5. (A) Robertsonian translocations involve acrocentric chromosomes (the acrocentric chromosomes are 13, 14, 15, 21, 22). Unbalanced rearrangements that include chromosome 21 account for 3.3% of all cases of Down syndrome. One-third of these cases are inherited from a parent with a balanced translocation and two-thirds are de novo events in the infant. The term Down syndrome applies to individuals with the recognizable clinical phenotype described and does not imply a specific genetic mechanism. There is no clinical distinction between patients with trisomy 21 (3 full copies of chromosome 21) and translocation cases.

6. (C) About 60-80% of children with Down syndrome have hearing deficits. Eye problems may include cataracts, strabismus, myopia, and so on. Fifteen percent will have atlantoaxial instability; although most are asymptomatic, 1-2% will require surgical correction. Other skeletal problems include patella and hip dislocation. Other medical problems in addition to those listed in the answer to question 3 include nutrition (failure to thrive in infancy and obesity in older children and adults), leukemia, seizure disorders, sleep apnea, delayed eruption of teeth, and Alzheimer disease.

7. (E) Intelligence is variable and cannot be readily predicted by any reliable factor. Research has shown that early intervention, environmental enrichment, and assistance to the families will result in progress that is usually not achieved by those children who have not had such educational and stimulating experiences. Intelligence deteriorates in adulthood, with clinical and pathologic findings consistent with advanced Alzheimer disease. Although most children and adults have the friendly, docile personality described, 13% have serious emotional problems including depression.

8. (A) Most cases of Down syndrome involve nondisjunction of maternal meiosis I, which may be related to the time from meiotic arrest between oocyte development in the fetus and ovulation. There is an increased risk for nondisjunction associated with advancing maternal age (maternal age 30: 1:1000 risk of Down syndrome; age 35: 1:365 risk; age 40: 1:100 risk; age 45: 1:50 risk). The risk is for nondisjunction of any chromosome, but trisomy 13, 21, and 18 are the only trisomies that can result in live born children; the rest tend to result in miscarriage. There is no association between Down syndrome and environmental exposures in the mother. There is no proven increased risk for trisomy with advanced paternal age, but there is an increased risk of new mutation in advanced paternal age. Mosaicism refers to the finding of two different cell lines in an individual. There are individuals with mosaic Down syndrome, meaning they have some cells with trisomy 21 and some cell lines with normal chromosome number. Mosaicism may be associated with a milder phenotype.

9. (A) The incidence of Down syndrome is approximately 1.0-1.2 in 1000 live births. The recurrence risk in chromosomally normal parents is 1% until the agerelated risk becomes higher than 1% (older than 40 years of age). Although the individual risk for Down syndrome is higher in older women, only 20% of all babies with Down syndrome are born to women older than the age of 35 because they account for only about 5% of all pregnancies. If the mother carries a balanced translocation, the recurrence risk is 10%; if the father is the carrier, the recurrence risk is 3-5%.

10. (A) See Table 83-1. The features described in answer B are most consistent with Down syndrome, those in C with trisomy 18, those in D with Prader-Willi syndrome, and those in E with Williams syndrome.

TABLE 83-1 Clinical Features of Common Autosomal Trisomies










Head shape

Microcephaly, brachycephaly, 3 fontanels


Microcephaly, cutis aplasia, sloping forehead


Up-slanting palpebral fissures, epicanthal folds, Brushfield spots

Short palpebral fissures, corneal opacity

Micro-ophthalmia, hypotelorism, coloboma


Small, low set

Low set, dysplastic

Low set, dysplastic

Facial dysmorphic features

Protruding tongue, low flat nasal bridge

Small oral opening, micrognathia

Cleft lip and palate (60-80%)


Clinodactyly of 5th finger, simian crease, short metacarpals, wide gap between 1st and 2nd toe

Overlapping clenched fingers, hypoplastic nails, rocker bottom feet

Postaxial polydactyly hands and/or feet, hypoconvex nails

Cardiac defect

40% (AV canal most common)



Kidney malformations


Polycystic kidney, horseshoe kidney

Polycystic kidney, duplicated ureters


Small penis, hypogonadism

Cryptorchidism, hypoplasia labia majora, prominent clitoris

Cryptorchidism, bicornuate uterus

Neurological findings

Hypotonia, mild to moderate mental retardation

Feeble fetal activity, weak cry, postneonatal hypertonia, severe mental defect

Hypo- or hypertonia, holoprosencephaly, seizures, apnea, severe mental defect


Delayed eruption of teeth


11. (D) See Table 83-1. Protruding tongue and large cheeks are seen in Down syndrome.

12. (E) Amniocentesis and CVS can both be used to obtain a prenatal karyotype to determine the presence of a trisomy or other chromosomal abnormality. CVS is done at 10-12 weeks of gestation and has a 1:100 risk of miscarriage; amniocentesis is done at 16 weeks of gestation and has a 1:200 risk of miscarriage. Maternal serum screening results of low levels of α-fetoprotein and unconjugated estriol, and elevated levels of human chorionic gonadotropin are associated with an increased risk of Down syndrome. Ultrasound can detect major fetal anomalies as early as 16 weeks of gestation, and those associated with increased risk for the presence of Down syndrome include increased nuchal thickening, congenital heart defects, duodenal atresia, and echogenic bowel.

13. (D) Turner syndrome has the karyotype 45,X and occurs in 1 in 8000 live births. Commonly associated features include short stature, webbed neck, low posterior hairline, shield chest, lymphedema of the extremities, cubitus valgus of elbow, and short fourth metacarpal and/or metatarsal. The physical phenotype is highly variable and often normal with the exception of short stature, which is typically not present at birth with a mean length of 146 cm (5th percentile). Approximately onethird of girls with Turner syndrome are diagnosed at birth because of lymphedema, one-third are diagnosed at ages 5-10 years because of short stature, and one-third are diagnosed secondary to delay or absence of puberty.

14. (A) The medical complications are highly variable with respect to severity and frequency and do not correlate with karyotype findings. Clinical manifestations include feeding problems in the newborn period, short stature, coarctation of the aorta, and/or bicuspid aortic valve (present in 17-45%), hypertension, mitral valve prolapse, hypothyroidism (occurring in 15-30% of adults), gonadal dysgenesis (90% require estrogen to initiate puberty and complete growth and estrogen and progesterone to maintain menses), ocular problems (strabismus), recurrent otitis media, and structural renal malformations in 40% (renal agenesis, horseshoe kidney, duplication of the collecting system, ureteropelvic and uretero vesicular obstruction). Cerebral findings include arteriovenous malformations but not agenesis of the corpus callosum or other structural brain malformations.

15. (D) Treatment with recombinant human growth hormone (GH) is effective in increasing height velocity. Many girls achieve heights of 150 cm or more with early initiation of treatment. Girls should be followed closely by an endocrinologist to track growth velocity and determine the optimal time to initiate GH. Children with Turner syndrome may have excessive weight gain, and careful monitoring of nutrition is essential to prevent obesity.

16. (C) Noonan syndrome is an autosomal dominant condition with 50% of patients having a mutation in the PTPN11 gene on chromosome 12q24.1. Noonan syndrome occurs in boys and girls with equal frequency. It is often mistakenly referred to as male Turner syndrome because of the overlapping features. In both Noonan and Turner syndromes, patients have short stature, webbed neck, cardiac defects (coarctation of the aorta in Turner and pulmonary stenosis in Noonan), low posterior hairline, shield chest, wide-spaced nipples, and edema of the hands and feet (see Figure 83-1).


FIGURE 83-1. Noonan syndrome: ptosis, hypertelorism, and low-set ears associated with valvular pulmonic stenosis. (Reproduced, with permission, from Fuster V, O'Rourke RA, Walsh RA, et al. Hurst’s the Heart. 12th ed. New York: McGraw-Hill; 2008: Fig. 12-17.)

17. (C) Klinefelter is caused by a sex chromosome abnormality, 47,XXY, and occurs with a frequency of 1:600 male live births. Common clinical features include tall stature that becomes evident by 5 years of age (newborns have normal growth parameters), eunuchoid habitus, slightly delayed motor and language milestones with IQ of 80-100, delayed sexual development, and infertility. The most frequently observed personality characteristics are shyness, nonassertiveness, immaturity, and a lack of confidence. Noonan syndrome has features that overlap with Turner syndrome and can occur in both boys and girls. Marfan syndrome is characterized by aortic root dilation, subluxed lens of the eye, and marfanoid body habitus. The 47,XYY pattern is characterized by tall stature, severe acne, and normal IQ with more aggressive behavior and behavioral problems. The testes are of normal size and function.

18. (A) Microdeletions such as DiGeorge syndrome are large deletions of chromosomal material but too small to be seen by routine karyotype. The resolution of karyotype is about 5-7 million base pairs (Mb) of genetic material. Microdeletions are often in the range of 3 Mb so are missed by routine karyotype and can only be detected by testing such as FISH. In the past, high-resolution karyotype was available as an independent test but is now considered standard for all karyotypes. Any karyotype would reliably pick up Down syndrome and would not need additional testing. Microarray technology now allows scanning the entire human genome for deletions and duplications as small as 100,000 bp. It would detect a deletion of the DiGeorge region, but in the case of a child with this specific heart defect, the likelihood of DiGeorge is high enough that focused testing with cheaper FISH technology is indicated. DiGeorge syndrome is characterized by heart defects, hypocalcemia, and immune function abnormalities. Approximately 40% of patients with TOF harbor this deletion. Williams syndrome is characterized by supravalvular aortic stenosis.


Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 3rd ed. New York, NY: Wiley-Liss; 2010.

Cohen WI, ed. Health Care Guidelines for Individuals with Down Syndrome: 1999 revision. Down Syndrome Research Foundation Web site. Accessed June 5, 2006.


A 7-month-old girl presents with lethargy, diaphoresis, pallor, and tachycardia. The mom states the child had a viral infection during the last few days with emesis one time, and she did not eat very well. The girl went to bed without eating dinner. This morning, the family had a difficult time arousing her and brought her straight to the office. She has no history of other health problems in the past. The family history is significant for two healthy siblings and one sibling who died at 4 months of sudden infant death syndrome (SIDS).

On examination, the vital signs show a respiratory rate of 60, heart rate of 160 bpm, and a blood pressure of 90/50 mm Hg. You note diaphoresis and pallor. The child is lethargic and difficult to arouse.


1. Immediate investigations should include a

(A) blood culture

(B) chest radiograph

(C) complete blood count

(D) computed tomography (CT) brain scan

(E) glucose measurement by glucose oxidase reagent strip

2. The glucose oxidase reagent strip reveals a glucose of 30. The next most appropriate step in management is

(A) consult an endocrinologist for advice on how to evaluate the hypoglycemia

(B) intravenous dextrose 25% at a dose of 2-4 ml/kg

(C) oral glucose replacement with orange juice

(D) immediate intubation and mechanical ventilation

(E) call for newborn screen results

3. When starting the intravenous (IV) for glucose replacement, which of the following laboratory investigations are important in determining the underlying etiology of the hypoglycemia?

(A) electrolytes, blood urea nitrogen (BUN), creatinine, plasma glucose, liver profile, complete blood count

(B) urine and/or serum ketones

(C) endocrinology labs including cortisol, insulin, C-peptide, growth hormone

(D) carnitine levels, acylcarnitine profile, urine organic acids, serum amino acids, and lactate level

(E) all of the above

4. The initial results of the laboratory testing are as follows: sodium 139 mEq/L, potassium 4.5 mEq/L, chloride 107 mEq/L, bicarbonate 17 mEq/L, glucose 32 mg/dL, urine ketones negative, serum ketones negative, aspartate aminotransferase (AST) 257 U/L, alanine aminotransferase (ALT) 205 U/L. The remaining labs are unremarkable. The most likely diagnosis given this information is

(A) galactosemia

(B) hyperinsulinism

(C) medium chain acyl-CoA dehydrogenase (MCAD)

(D) physiologic ketotic hypoglycemia

(E) salicylate poisoning

5. What other additional history or physical findings in this case are consistent with MCAD?

(A) prolonged period of poor appetite

(B) diaphoresis and lethargy

(C) family history of SIDS

(D) history of vomiting

(E) A and C

6. How would you counsel the family about other siblings and the risk of MCAD for future children?

(A) siblings and future children are at 5% risk for MCAD

(B) siblings and future children are at 25% risk for MCAD

(C) siblings and future children are at 50% risk for MCAD

(D) siblings and future children are at less than 1% risk for MCAD

(E) only girls are at 50% risk; boys are not affected

7. If this patient had hepatomegaly without splenomegaly, retarded growth, poorly developed musculature, hyperlipidemia, and hypercholesterolemia, the most likely diagnosis would be

(A) fatty acid oxidation defect

(B) glycogen storage disorder

(C) growth hormone deficiency

(D) insulin-induced hypoglycemia

(E) none of the above

8. Which of the following symptoms would be suspicious for galactosemia as a cause of the hypoglycemia?

(A) vomiting and jaundice

(B) Escherichia coli sepsis

(C) hepatomegaly with elevated transaminases

(D) renal Fanconi syndrome

(E) all of the above

9. All of the following regarding the long-term sequelae of galactosemia are true except

(A) patients may have deficits in speech and language

(B) sequelae may be present even if appropriate treatment is initiated early

(C) pseudotumor cerebri is a possible sequela

(D) liver failure is a possible sequela

(E) possible sequelae include hypergonadotropic hypogonadism in females

10. The diagnosis of galactosemia is confirmed. You check the newborn screen results from the patient and find they were reported as normal. What are the possible explanations for why the newborn screen did not detect the galactosemia?

(A) the state where the child was born does not screen for galactosemia

(B) the child was placed on lactose-free milk (Isomil) immediately after birth

(C) the child had the newborn screen sent before receiving any formula, and the requested repeat testing was never performed

(D) all of the above

(E) none of the above

11. Results of the laboratory screening of the child in case 83 show sodium 139 mEq/L, potassium 4.5 mEq/L, chloride 107 mEq/L, bicarbonate 7 mEq/ L, glucose 32 mg/dL, urine and serum ketones markedly positive, lactate of 7.2 mEq/L, ammonia level of 550 μmol/L, white blood cell (WBC) of 4.2, and platelet count of 75,000. The most likely diagnosis would be

(A) fatty acid oxidation defect

(B) glycogen storage disorder

(C) organic acidemia

(D) urea cycle defect

(E) none of the above

12. Which of the following would be suspicious of a urea cycle defect?

(A) synthetic liver dysfunction with normal liver transaminases

(B) vomiting, lethargy, and tachypnea

(C) respiratory alkalosis, with an ammonia level of 1500 μmol/L

(D) hepatosplenomegaly, hypercholesterolemia, and hypoglycemia

(E) no clinical features differentiate organic acidemias from urea cycle defects

13. If a urea cycle defect is suspected, appropriate treatments would include all of the following except

(A) removal of protein source

(B) IV glucose

(C) carnitine supplementation

(D) hemodialysis

(E) suspicion and possible treatment for cerebral edema

14. Jaundice and liver dysfunction may be the presenting symptoms of which of the following inherited metabolic disorders?

(A) α1-antitrypsin deficiency

(B) galactosemia

(C) neonatal hemochromatosis

(D) tyrosinemia

(E) all of the above

15. Which of the following is not true regarding phenylketonuria (PKU)?

(A) PKU is an autosomal dominant disorder.

(B) PKU is a disorder of phenylalanine metabolism.

(C) untreated PKU leads to severe mental retardation (IQ 50) and seizures

(D) PKU is not easily recognized in a newborn infant

(E) mental retardation because PKU is rare because of newborn screening

16. The newborn screening test (NBS) is positive for PKU in a premature baby born at 30 weeks of gestation who had multiple complications and was on total parenteral nutrition (TPN) at the time of the NBS. What is the most likely explanation?

(A) the child has PKU

(B) the child is a carrier for PKU

(C) the positive NBS is related to prematurity. The child probably does not have PKU and no further testing is indicated

(D) the positive NBS is related to prematurity. The child probably does not have PKU but repeat or confirmatory testing is indicated

(E) none of the above

17. The treatment of PKU is characterized by

(A) restriction of dietary phenylalanine

(B) avoidance of fruits and vegetables that have high phenylalanine content

(C) careful monitoring of phenylalanine and tyrosine metabolism

(D) use of phenylalanine-free formulas but only during the first year of life

(E) A and C

18. Which of the following is/are true regarding the long-term management of PKU?

(A) dietary restriction of phenylalanine may be discontinued after 8 years of age

(B) there is no further loss of IQ in untreated PKU after 6-10 years of age

(C) the outcome of pregnancy in untreated mothers with PKU leads to severe mental retardation, microcephaly, and birth defects in offspring

(D) dietary treatment during pregnancy eliminates the risks associated with maternal PKU

(E) all of the above


1. (E) The clinical features of hypoglycemia include irritability, pallor, cyanosis, tachycardia, tremors, lethargy, apnea, seizures, diaphoresis, anxiety, headache, tachypnea, weakness, confusion, stupor, ataxia, and coma. When a patient presents with these features, a glucose determination by an oxidase reagent strip is indicated while the child is being stabilized and other investigations (such as the other options listed) are being considered and organized.

2. (B) Determining the underlying etiology of the hypoglycemia is of utmost importance but should not interfere with the primary goal of treatment with glucose. Prolonged exposure to hypoglycemia may result in irreversible brain damage and eventual death. Patients with symptoms and a glucose concentration less than 45 mg/dL and/or a glucose concentration of 25-35 mg/dL irrespective of symptoms require treatment. IV glucose is the first line of therapy. Glucose is administered in a dose of 0.5 g/kg. Dextrose 25% at a dose 2-4 mL/kg is also appropriate. In neonates and preterm infants, dextrose 10% at a dose of 5-10 mL/kg is used to avoid sudden hyperosmolarity. In older children and adolescents, dextrose 50% at a dose of 1-2 mL/kg is used. Patients with mild hypoglycemia who are capable of eating or drinking are treated with orange juice or some other age-appropriate source of oral glucose.

3. (E) The differential diagnosis of hypoglycemia includes metabolic diseases, endocrine disorders, poisoning, liver disease, and systemic disorders. It is often difficult to obtain all of the laboratory data needed in the diagnostic approach to hypoglycemia, but the initial laboratory data are crucial in refining the diagnostic possibilities. The endocrine causes of hypoglycemia can be determined by the tests mentioned and are maximally useful when obtained at the time of the hypoglycemia. The metabolic diagnosis leading to hypoglycemia can be categorized based on hepatomegaly, presence or absence of ketones, and studies that reflect fat, protein, and carbohydrate metabolism. The metabolic laboratory tests are still useful even if obtained within the first few hours after the hypoglycemia. They can be misleading, however, if done days after recovery; in some diseases, the metabolic abnormalities will normalize with time.

TABLE 84-1 Inborn Errors of Metabolism and Characteristic Laboratory Findings





Fatty acid oxidation defects (includes MCAD, LCHAD, VLCAD)

Metabolic acidosis; elevated liver transaminases; hyperammonemia; nonketotic hypoglycemia; carnitine deficiency, abnormal urine organic acids


Positive urine-reducing substances; conjugated hyperbilirubinemia; liver dysfunction with elevated transaminases; hypoglycemia

Glycogen storage disorders

Hypercholesterolemia, hyperlipidemia, lactic acidosis, elevated uric acid, hypoglycemia

Organic acidemias (includes MMA, PA, IVA, MCD)

Metabolic acidosis with increased anion gap; elevated plasma and urine ketones; variably elevated plasma ammonia and lactate; abnormal urine organic acids

Urea cycle defects

Variable respiratory alkalosis; no metabolic acidosis; markedly elevated plasma ammonia; elevated orotic acid in OTC; abnormal plasma amino acids

Maple syrup urine disease

Metabolic acidosis with increased anion gap; elevated plasma and urine ketones; abnormal plasma amino acids


Synthetic dysfunction of the liver with normal transaminases; succinylacetone in urine, abnormal urinary organic acids; abnormal plasma amino acids; generalized aminoaciduria


Abbreviations: IVA, isovaleric acidemia; LCHAD, long chain hydroxyacyl CoA dehydrogenase; MCAD, medium chain acyl CoA dehydrogenase; MCD, multiple carboxylase deficiency; MMA, methylmalonic acidemia; OTC, ornithine transcarbamylase deficiency; PA, propionic acidemia; VLCAD, very long chain acyl CoA dehydrogenase.

4. (C) MCAD is the most common of the fatty acid oxidation disorders, which are characterized by nonketotic hypoglycemia, with mild acidosis. Other findings may include elevated liver transaminases, mild elevation of lactate, hepatomegaly, elevated creatine phosphokinase (CPK), carnitine deficiency, and evidence of medium chain dicarboxylic aciduria on urine organic acid or acylcarnitine analysis (Table 84-1). Hyperinsulinism typically presents at an earlier age with nonketotic hypoglycemia, no acidosis or liver abnormalities, and hypoglycemia that occurs after a short fast. Salicylate poisoning is characterized by an elevated anion gap acidosis. Galactosemia typically has more abnormal liver function tests with conjugated hyperbilirubinemia. Physiologic ketotic hypoglycemia is accompanied by significant ketosis.

5. (E) The risk for hypoglycemia in fatty acid oxidation disorders is highest after a prolonged fast, especially during times of intercurrent viral illness. The symptoms of diaphoresis, lethargy, vomiting, and signs of hypoglycemia are nonspecific and not specific for an underlying disease. A family history of SIDS should raise the suspicion for an inherited inborn error of metabolism. Many metabolic conditions go unrecognized at the time of presentation and are diagnosed as SIDS or Reye syndrome.

6. (B) With few exceptions, inborn errors of metabolism, including fatty acid oxidation defects, are inherited in an autosomal recessive pattern. Therefore, the parents of the affected child should be counseled that there is a 25% risk of recurrence for the condition with each additional pregnancy, and unaffected children are at two-thirds risk of being carriers. There are several conditions (Hunter syndrome, ornithine transcarbamylase deficiency, and Lesch-Nyhan syndrome) associated with Xlinked inheritance patterns, where boys are typically affected and females may be asymptomatic carriers, but because of X-inactivation patterns, girls may be mildly to severely affected as well.

7. (B) There are several types of glycogen storage disorders, and they can present with different clinical features. It is difficult to differentiate among them on a purely clinical basis. These disorders result in hypoglycemia because of the inability to break down stored glycogen, with the resulting medical problems listed in the question. Insulin-induced hypoglycemia would not result in lipid abnormalities or hepatomegaly, it and would give nonketotic hypoglycemia. GH deficiency will have growth retardation and hypoglycemia but may be associated with micropenis and does not have the lipid abnormalities or hepatomegaly. Fatty acid oxidation defects were discussed above.

8. (E) Galactosemia is an inborn error of carbohydrate metabolism that results from deficiency of galactose-1-phosphate uridyl transferase and is part of most newborn screening programs. Manifestations (Table 84-1) usually appear within days of the initiation of milk feedings and may have onset before newborn screen results. Any newborn patient with liver dysfunction including cirrhosis, hepatomegaly, cataracts, renal Fanconi syndrome (renal tubular glycosuria, generalized aminoaciduria, proteinuria), presence of urine reducing substance, and especially E coli sepsis should be considered for possible galactosemia.

9. (D) Treatment of galactosemia involves restriction of galactose in the diet, mostly by exclusion of milk and its products. The earlier the treatment is initiated, the better the long-term prognosis. Despite treatment, milder manifestations may be present, especially problems in school even with normal IQ levels. Close follow-up of growth and development is indicated. Liver failure may be present in the initial presentation of galactosemia but typically resolves with treatment and is not a long-term sequela.

10. (D) It is important to understand the NBS in your state. At the present time there is not a standard set of diseases for which all states screen. All of the states in the continental United States screen for galactosemia. It is also important to understand how the state-specific screening test works to interpret the result correctly. If a child is not given lactose-containing milk before the screen, there may not be a buildup of galactose and galactose-1-phosphate so the NBS will not be abnormal.

11. (C) The characteristic findings of an organic acidemia (Table 84-1) include significant anion gap acidosis, ketosis, variable elevations in lactate and ammonia, neutropenia, and thrombocytopenia. Urine organic acid analysis typically reveals the main anion contributing to the acidosis and the diagnosis. All protein feeds should be stopped and the child should be given liberal amounts of IV glucose while the results of the laboratory tests are pending. IV bicarbonate should be administered and, because of the ongoing organic acid production, the child may require large amounts. Dialysis should be considered for severely acidotic neonates.

12. (C) Hyperammonemia is a common finding in many inborn errors of metabolism including organic acidemias and urea cycle defects. Urea cycle defects are characterized by significant hyperammonemia (typically >1000 μmol/L) and respiratory alkalosis in the early presentation, whereas organic acidemias usually have severe metabolic acidosis (Table 84-1). Plasma amino acid analysis and urine orotic acid measurement are useful tests in the differentiation of the types of urea cycle defects, which is important to determine therapy. Synthetic liver dysfunction with normal transaminases suggests tyrosinemia. Vomiting, lethargy, and tachypnea, which are nonspecific features, and hepatosplenomegaly with hypercholesterolemia and hypoglycemia are suggestive of a glycogen storage disorder.

13. (C) Immediate treatment should include removal of all sources of protein, and in cases of severe hyperammonemia, hemodialysis (as opposed to peritoneal dialysis, continuous arteriovenous hemoperfusion, or exchange transfusion) is the most efficient way to remove the ammonia. Cerebral edema is common in urea cycle defects and should be treated aggressively. Carnitine is useful in the treatment of fatty acid oxidation defects but not in urea cycle defects.

14. (E) Tyrosinemia should be considered in any child who presents with liver disease in early infancy and is characterized by elevations of tyrosine and methionine with generalized aminoaciduria (Table 84-1). α1-antitrypsin deficiency may present with clinical manifestations similar to neonatal or giant cell hepatitis. Neonatal hemochromatosis is a poorly understood disorder with an associated fulminating course and hepatic and extrahepatic parenchymal iron deposition.

15. (A) PKU is an inborn error of phenylalanine (phe) metabolism most often caused by a deficiency of the enzyme phenylalanine hydroxylase, which converts phe into tyrosine. Newborns with PKU have a normal examination, and the diagnosis is not evident until 6-12 months of age when the symptoms of mental retardation, seizures, spasticity, and hypopigmentation are evident. Screening for PKU is a part of all newborn screening programs and has been successful in early disease identification and treatment. This program has virtually eliminated the severe clinical manifestations. PKU is inherited in an autosomal recessive fashion with 25% risk of recurrence for siblings of an affected individual.

16. (D) It is common for premature babies who are on TPN at the time of the NBS to have false elevations of some amino acids including phenylalanine. These cases are typically false positives and the child does not have PKU, but additional testing is mandatory for confirmation.

17. (E) Treatment of PKU involves dietary restriction of phe and careful monitoring of phe and tyrosine levels. Fruits and vegetables are low in phe; high protein content foods are rich in phe. The use of phe-free formulas is needed throughout life to provide adequate calories and other nutrition.

18. (C) Previous treatment recommendations suggested that the PKU diet can be safely discontinued at 5 or 6 years of age. Recent studies have shown there is a uniform and progressive loss of IQ after stopping the diet leading to the current recommendations to continue the diet throughout life. The successful treatment of PKU has allowed affected individuals to become normal functioning adults. Women with PKU are at risk during pregnancy of having children with severe mental retardation as a result of fetal exposure to high phenylalanine levels throughout pregnancy, even though the children do not typically have PKU themselves. Initiation of the diet before conception and continuing throughout pregnancy decreases, but does not eliminate, the potential for retardation, microcephaly, and birth defects.


Burton B. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998;102:e69.

Nyhan WL, Ozand PT. Atlas of Metabolic Diseases. 2nd ed. London, United Kingdom: Chapman & Hall Medical; 2005.


A newborn is evaluated for a heart murmur and found to have a VSD. History is notable for a lack of prenatal care. At the time of delivery, ultrasound evaluation showed intrauterine growth retardation (IUGR).

On examination, the child is noted to have symmetric growth retardation, small palpebral fissures, thin upper lip, and underdeveloped philtrum.


1. The most likely diagnosis to explain these features is

(A) chromosome anomaly

(B) diabetic embryopathy

(C) fetal alcohol syndrome

(D) maternal smoking

(E) sporadic heart defects with familial features

2. Which of the following are common features of fetal alcohol syndrome?

(A) hypoplastic philtrum with thin upper lip

(B) microcephaly and midface hypoplasia

(C) mild to moderate mental retardation

(D) short palpebral fissures, epicanthal folds, ptosis, strabismus

(E) all of the above

3. A child has a VSD, sacral agenesis, rib and vertebral anomalies, femoral hypoplasia, and a renal malformation. Which of the following diagnoses best explains these clinical features?

(A) chromosome abnormality

(B) diabetic embryopathy

(C) fetal alcohol syndrome

(D) folic acid deficiency

(E) warfarin embryopathy

4. Which of the following are features of the fetal phenytoin sodium syndrome?

(A) caudal regression, sacral agenesis, renal defects, cardiac defects

(B) spina bifida, craniofacial abnormalities

(C) hypoplasia of midface, low nasal bridge, ocular hypertelorism, cleft lip and palate, and hypoplasia of distal phalanges with small nails

(D) IUGR, microcephaly, mental retardation, birth defects such as congenital heart defects, and vertebral anomalies

5. Severe nasal hypoplasia, choanal atresia, microcephaly, optic atrophy, lag in skeletal maturation, and stippling of epiphyseal growth centers is characteristic of prenatal exposure to

(A) antihistamine

(B) heparin

(C) hydantoins (eg, phenytoin)

(D) isotretinoin

(E) warfarin

6. A newborn is treated for a myelomeningocele. Counseling of the family regarding neural tube defects should include which of the following statements and recommendations?

(A) there is no increased risk of recurrence for future children

(B) mom should use prenatal vitamins during all subsequent pregnancies

(C) there is a 25% risk of recurrence for future children. Additionally, you recommend use of prenatal thiamine

(D) 3-4% risk of recurrence for future children and use of 4 mg folate per day starting before conception

(E) 50% recurrence risk and use of 0.4 mg folate per day during pregnancy

7. Strands of amniotic membrane (amniotic bands) may become dislodged and cause which of the following birth defects?

(A) amputations of digits

(B) cleft lip and/or palate

(C) clefts of the face and eye

(D) ring-like constriction of the limbs

(E) all of the above

8. Which of the following definitions is incorrect?

(A) association: relationship between a birth defect and a prenatal infection

(B) malformation: morphologic defect of an organ from an intrinsically abnormal developmental process (eg, congenital heart defect)

(C) disruption: extrinsic destructive process that interferes with previously normal development (eg, amniotic bands that cause amputation of a finger)

(D) deformation: extrinsic mechanical force that causes asymmetric abnormalities (eg, breech position causing tibial bowing and club foot)

(E) dysplasia: abnormal cellular organization or function that generally affects only a single tissue type (eg, a cartilage abnormality that results in achondroplasia)

9. A newborn is noted to have frontal bossing, midfacial hypoplasia, and ptosis suggestive of craniosynostosis. The child also has fusion (syndactyly) of all of the digits on each hand. The most likely diagnosis is

(A) Apert syndrome

(B) Crouzon syndrome

(C) Pfeiffer syndrome

(D) Saethre-Chotzen syndrome

(E) none of the above: sporadic craniosynostosis

10. A newborn with vertebral anomalies, anal atresia, tracheoesophageal fistula, radioulnar synostosis, and horseshoe kidney most likely has

(A) CHARGE association

(B) DiGeorge syndrome

(C) MURCS association

(D) Poland anomaly

(E) VATER association

11. A newborn with coloboma of the eye, heart defect, choanal atresia, and ambiguous genitalia most likely has

(A) CHARGE association

(B) DiGeorge syndrome

(C) MURCS association

(D) Poland anomaly

(E) VATER association

12. A newborn with evidence of fetal compression leading to a squashed, flat face, clubbing of the feet, pulmonary hypoplasia, and breech presentation should have a detailed evaluation of which of the following organ systems?

(A) cardiovascular

(B) central nervous system (CNS)

(C) dermatologic

(D) genitourinary system

(E) peripheral nervous system

13. Long-term management of a patient with the Beckwith-Wiedemann syndrome includes

(A) calcium monitoring and replacement

(B) routine serial renal ultrasounds and α-fetoprotein (AFP) measurements

(C) growth hormone replacement

(D) seizure precautions

(E) monitoring for development of cardiomyopathy

14. The most likely diagnosis in a child with hyperphagia resulting in morbid obesity, micropenis, short stature, small hands and feet, and hypotonia is

(A) Angelman syndrome

(B) Bardet-Biedl syndrome

(C) Beckwith-Wiedemann syndrome

(D) Prader-Willi syndrome

(E) Sotos syndrome

15. The clinical features suggestive of a 22q11 deletion (velocardiofacial, DiGeorge syndrome) include all of the following except

(A) conotruncal heart defects

(B) hypoparathyroidism

(C) immune dysfunction

(D) transverse palmar crease

(E) velopharyngeal insufficiency

16. The best way to diagnose a microdeletion syndrome (eg, Prader-Willi, Williams, or DiGeorge syndrome) is

(A) routine karyotype


(C) sequencing

(D) PCR (polymerase chain reaction)

(E) none of the above


1. (C) Most teratogenic drugs exert a deleterious effect in a minority of exposed fetuses. The features described are most consistent with fetal alcohol exposure (see Figure 85-1). Diabetic embryopathy can cause heart defects but do not lead to the dysmorphic features described or IUGR. Sporadic heart defects do not typically have IUGR. All infants with dysmorphic features and a heart defect without a specific diagnosis should have a chromosome analysis and FISH studies for 22q deletion. But the features noted in this case point toward alcohol exposure. Maternal smoking is associated with IUGR but not with specific heart defects or dysmorphism.

2. (E) All of the features listed are frequent in the fetal alcohol syndrome. Additional features include prominent lateral palatine ridges, micrognathia, flat nasal bridge, short and upturned nose, VSD, ASD, pectus excavatum, altered palmar creases, small fifth fingernails, hemangiomas, poor coordination, fine motor impairment, hypotonia, irritability in infancy, and hyperactivity in childhood.


FIGURE 85-1. Fetal alcohol syndrome: midface hypoplasia, absent philtrum, and microcephaly associated with a ventricular septal defect. (Reproduced, with permission, from Fuster V, O’Rourke RA, Walsh RA, et al. Hurst’s the Heart. 12th ed. New York: McGraw-Hill; 2008: Fig. 12-15.)

3. (B) Congenital malformations occur more frequently in infants of diabetic mothers than in the general population, and multiple anomalies may be present. These anomalies include those mentioned and also coarctation, complete transposition, macrosomia, brain malformations (including holoprosencephaly, agenesis of the corpus callosum, and others), and renal malformations.

4. (C) The features of the fetal hydantoin (eg, phenytoin) syndrome are seen in approximately 7-10% of exposed infants, and an additional 30% may show lesser effects. In addition to the features listed, the syndrome is characterized by prenatal onset growth failure for weight, length, and head circumference; mental retardation; craniofacial features of wide anterior fontanel; metopic ridging; ocular hypertelorism; broad depressed nasal ridge; short nose with bowed upper lip; major malformations including clefts of the lip and palate; cardiovascular anomalies; and minor limb reduction malformations. The features in answer A are characteristic of maternal diabetes, those in answer B characteristic for valproic acid exposure, and in answer D characteristic for maternal PKU.

5. (E) Prenatal exposure to warfarin leads to an increase in abortion, stillbirth, and prenatal growth deficiency. The period of greatest risk is 6-9 weeks postconception. Developmental delay, mental deficiency, hypotonia, and seizures may occur. After 9 weeks, ocular defects and midline CNS malformations may occur. Antihistamine exposure is not known to lead to increased risk of birth defects. Isotretinoin exposure occurs by treatment of acne or other skin disorders, and it leads to features reminiscent of the DiGeorge sequence. Heparin exposure leads to 10-15% risk of stillbirth and a 20% risk for premature birth, but a specific malformation syndrome has not been described. Fetal hydantoin syndrome is reviewed in question 4.

6. (D) Neural tube defects occur with an incidence of about 1 in 1000 live births. Most cases are inherited in a polygenic or multifactorial pattern with both genetic and environmental factors contributing to the increased recurrence risk. The risk of recurrence after one affected child rises to 3-4% and increases to approximately 10% with two previous abnormal pregnancies. Periconceptional use of folic acid supplementation has been shown to decrease the risk of neural tube defects. Folic acid should be started 1 month before conception and continued until at least 12 weeks of gestation. All women considering pregnancy should take 0.4 mg folic acid daily, and women who have previously had a pregnancy with a neural tube defect should take 4 mg folic acid daily.

7. (E) All can be seen with amniotic bands. The bands can become adherent to any part of the fetal body and impair vascular supply or interfere with normal tissue growth leading to a variety of malformations. The bands can be swallowed and lead to major disruption of normal tissue growth and clefts of the face.

8. (A) All definitions are correct except for “association.” See answer 10 for definition of association.

9. (A) Several craniosynostosis syndromes are characterized by the facial findings described and occur secondary to bilateral coronal synostosis. In addition to craniosynostosis, there can be other findings such as syndactyly of digits as seen in Apert syndrome, large thumbs and first toes seen in Pfeiffer syndrome, proptosis seen in Crouzon syndrome, and ear malformations seen in Saethre-Chotzen syndrome. Craniosynostosis can be isolated and sporadic, but a careful examination must be done to look for the other associated malformations.

10. (E) An association is the nonrandom occurrence of multiple anomalies without a known developmental field defect, sequence initiator, or causal relationship. The clustering occurs at such a frequency that the malformations have a statistically significant rate of simultaneous connection. VATER association: Vertebral anomalies, Anal anomalies, Tracheoesophageal fistula, Renal or Radial anomalies.

11. (A) CHARGE association: Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital anomalies, Ear anomalies. DiGeorge syndrome is characterized by conotruncal heart defects, immune deficiency, and hypoparathyroidism. MURCS association: llerian duct aplasia, Renal aplasia, Cervicothoracic Somite dysplasia. Poland anomaly is characterized by unilateral defect of the pectoralis muscle and syndactyly of the hand.

12. (D) The features listed are those associated with severe oligohydramnios and are commonly referred to as the Potter facies or syndrome. Normal fetal lung development depends on the normal production and inhalation of amniotic fluid, and in the absence of amniotic fluid, significant pulmonary hypoplasia occurs. This is the cause of death in many affected individuals. The underlying mechanism can be renal agenesis or renal dysplasia, and these complications should be investigated in any child with the Potter facies. Additional causes include bladder outlet obstruction or prolonged premature rupture of the membranes.

13. (B) Beckwith-Wiedemann syndrome is an overgrowth condition that is a complex multigenic disorder caused by alterations in growth regulatory genes on chromosome 11p15. Clinical features include macrosomia, hemihyperplasia, macroglossia, abdominal wall defects, embryonal tumors, adrenocortical cytomegaly, ear anomalies, visceromegaly, renal abnormalities, and neonatal hypoglycemia. Children with Beckwith-Wiedemann have an increased risk for cancer (estimated to be 7.5%). The 2 most common tumors are Wilms’ tumor and hepatoblastoma. Screening includes abdominal ultrasounds every 3 months until 8 years of age for Wilms’ tumor and AFP for the first few years as a marker for hepatoblastoma. AFP levels tend to be higher in children with Beckwith-Wiedemann in the first year of life. Calcium levels are typically normal in Beckwith-Wiedemann syndrome but may be abnormal in Williams syndrome and 22q deletion. GH is not appropriate because this is an overgrowth condition, and there is not an increased incidence of seizures. Structural cardiac abnormalities occur in 9-34%. Cardiomyopathy has been rarely reported, and cardiomegaly of early infancy usually resolves spontaneously.

14. (D) Prader-Willi syndrome is a result of genetic abnormalities involving an imprinting region on the long arm of chromosome 15. In addition to the features listed, affected individuals typically have infantile central hypotonia and feeding difficulties with failure to thrive, rapid weight gain between 1 and 6 years, developmental delays and mental retardation, hypopigmentation, thick viscous saliva, skin picking, and a high pain threshold. Angelman syndrome is characterized by microcephaly, seizures, ataxia, and severe mental retardation. Beckwith-Wiedemann was discussed in question 13; Bardet-Biedl and Sotos syndromes are both overgrowth syndromes. Bardet-Biedl is characterized by polydactyly, retinitis pigmentosa, hypertension, truncal obesity, and developmental delay. Sotos syndrome is characterized by growth greater than the 97th centile, significant macrocephaly, developmental delay, and characteristic facial features.

15. (D) Velocardiofacial syndrome and DiGeorge syndrome were thought to be clinically distinct syndromes that are now both known to be a result of a microdeletion of 22q11. The common clinical features of this microdeletion include conotruncal heart defects in 70% of patients (TOF, interrupted aortic arch, VSD, truncus arteriosus, vascular ring, ASD, aortic arch anomaly); feeding difficulties in 30%; immune dysfunction in 70% (impaired T-cell production and function, immunoglobulin [Ig]A deficiency); hypoparathyroidism leading to hypocalcemia in 50%; palate abnormalities in 70% (velopharyngeal incompetence [VPI], submucosal or overt cleft palate, bifid uvula, cleft lip/palate); developmental delays and psychiatric abnormalities; growth failure. A transverse palmar crease is a sign of Down syndrome.

16. (B) Microdeletion syndromes are caused by deletions of relatively large segments of the genome, 1-3 megabases (Mb) of DNA, which affect multiple genes. The resolution of routine cytogenetics is 3-5 Mb of DNA so these microdeletions are not readily detected by routine methods. FISH is a molecular cytogenetic method that combines DNA probes and fluorescence methods to identify specific regions of chromosomes. Each microdeletion syndrome always involves the same region of a specific chromosome, and probes directed at these regions can be used to detect the deletions. The syndromes are suspected based on specific clinical features, and then FISH with a probe specific for that syndrome can be ordered/done. Sequencing is used to determine the exact sequence of DNA and to detect single base pair mutations. PCR is a molecular technique that allows amplification of discrete fragments of DNA and is used in many diagnostic tests.


Aase JM. Diagnostic Dysmorphology. New York, NY: Plenum Medical; 1990.

Jones KL. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Philadelphia, PA: WB Saunders; 2005.


A 6-month-old boy comes for evaluation of short stature. The history shows that the child was born after an uncomplicated pregnancy and delivery. He has been well with no medical complications or hospitalizations. The parents do not remember that anyone was concerned about his size at birth, but they noted shortly thereafter that he was not growing as they expected and they felt that he has short extremities. They also report that recently he has been snoring more at night and has loud breathing during the daytime.

On physical examination, growth parameters show height 60 cm (<5th percentile), head circumference 46 cm (>95th percentile). You note macrocephaly, frontal bossing, flat nasal bridge, hypoplasia of the maxilla, rhizomelic shortening of the extremities, lumbar lordosis, and short hands and feet.


1. Based on the clinical features the most likely diagnosis is

(A) achondroplasia

(B) growth hormone deficiency

(C) hypochondroplasia

(D) osteogenesis imperfecta (OI)

(E) Turner syndrome

2. Evaluations that could be helpful in establishing the diagnosis might include

(A) bone age

(B) CT scan of brain

(C) renal ultrasound

(D) skeletal survey

(E) vertebral radiographs

3. The child is confirmed to have achondroplasia. What are potential medical complications that need to be addressed in this child?

(A) congenital heart defects

(B) diabetes mellitus

(C) fatty liver

(D) obstructive or central sleep apnea

(E) renal malformations

4. In regard to the history of the snoring and breathing issues reported, what evaluations should be considered?

(A) counseling regarding weight control

(B) evaluation for possible tonsillectomy

(C) magnetic resonance imaging (MRI) scan of the brainstem

(D) sleep study

(E) all of the above

5. How should a person who has achondroplasia be counseled about the chance of having an affected child?

(A) achondroplasia is an autosomal dominant condition with 50% chance of an affected offspring

(B) achondroplasia is an autosomal recessive condition with 25% chance of an affected offspring

(C) achondroplasia is an X-linked condition and only affects females

(D) there is no chance for a second affected offspring

(E) the chance of another affected offspring is very low

6. Multiple genetic conditions are associated with short stature and growth failure. Which of the following syndromes does not have short stature as a major feature?

(A) Cornelia de Lange syndrome

(B) Marfan syndrome

(C) Russell Silver syndrome

(D) Turner syndrome

(E) Williams syndrome

7. The skeletal survey on a child with short stature shows microcephaly, oval-shaped and hook-shaped vertebral bodies on the lateral view of the spine, wide iliac flare, irregular diaphyseal modeling, metaphyseal widening, all features of dysostosis multiplex. The most likely diagnosis is

(A) Down syndrome

(B) growth hormone deficiency

(C) a mucopolysaccharidosis (MPS)

(D) nutritional rickets

(E) warfarin embryopathy

8. Clinical features of MPS include all of the following except

(A) coarse facial features

(B) developmental delay and/or mental retardation

(C) hepatomegaly or splenomegaly

(D) structural heart defects associated with hypoxia

(E) restricted joint mobility

9. If an MPS disease is suspected, which of the following investigations should be considered in pursuing the diagnosis?

(A) enzyme analysis

(B) skeletal survey

(C) urine screening for glycosaminoglycan excretion

(D) A, B, and C

(E) none of the above

10. MPS occurs by which of the following inheritance patterns?

(A) autosomal dominant inheritance

(B) autosomal recessive inheritance

(C) X-linked inheritance

(D) A and B

(E) B and C

11. A newborn is noted to have a short forearm or radial ray defect. Further investigations for associated anomalies might include all of the following except

(A) echocardiogram

(B) MRI of the brain

(C) renal ultrasound

(D) upper GI series

(E) vertebral radiographs

12. The differential diagnosis for the child in question 11 would include

(A) Fanconi syndrome

(B) Holt-Orom syndrome

(C) VATER association

(D) A and C

(E) A, B, and C

13. What are the recommendations regarding evaluation of an individual with Down syndrome with respect to participation in sports?

(A) no specific precautions are needed

(B) individuals with Down syndrome should be restricted from all sports activities

(C) lateral cervical radiographs in the neutral, flexed, and extended position in children 3-5 years of age

(D) routine blood counts

(E) none of the above

14. A child presents with blue sclera, multiple fractures from minimal trauma, bowing of the lower limbs, and opalescent dentin (dentinogenesis imperfecta). The most likely diagnosis is

(A) achondroplasia

(B) Ellis-van Creveld syndrome


(D) OI

(E) none of the above

15. Which of the following do not correctly describe the clinical features associated with the specific subtype of OI?

(A) OI type I: Few fractures at birth, deformities of the limbs, mild short stature, dentinogenesis imperfecta, and generalized osteopenia

(B) OI type II: Low birthweight and length, crumpled long bones, beaded ribs, soft skull, extremely short, bent, deformed long bones, and early lethality

(C) OI type III: Newborn or young infant with mild bowing of extremities, mild scoliosis, and no effect on final height

(D) A, B, and C

(E) none are correct

16. Which of the following medical complications is common in OI type I?

(A) cleft lip and palate

(B) congenital heart defect

(C) duodenal atresia

(D) hearing loss

(E) renal abnormality


1. (A) Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head, and characteristic facial features. The clinical features include short stature, rhizomelic (proximal) shortening of the arms and legs with redundant skin folds on limbs, limitation of elbow extension, trident configuration of the hands, genu varum (bow legs), thoracolumbar gibbus in infancy, exaggerated lumbar lordosis, which develops when walking begins, large head with frontal bossing, and midface hypoplasia. Turner syndrome is characterized by short stature but not by macrocephaly or the other clinical features noted. Hypochondroplasia is very similar to achondroplasia but is typically less severe and does not have the facial features listed. OI is a disease characterized by bone fractures.

2. (D) A skeletal survey may show findings characteristic of achondroplasia including narrowing of the interpediculate distance of the caudal spine, notchlike sacroiliac groove, and circumflex or chevron seat on the metaphysis. Achondroplasia is a result of mutations in the FGFR3 gene on chromosome 4p. The common mutation, Gly380Arg, accounts for 98% of all cases. There may be hydrocephalus detected by a CT scan, but that finding would be nonspecific and not lead to the final diagnosis. Similarly findings of vertebral anomalies alone would not be enough to make the correct diagnosis. There is no increased risk of renal malformations in achondroplasia.

3. (D) Sleep apnea may be obstructive or central secondary to craniocervical junction cord compression. The other choices are not common problems in achondroplasia. The best predictors of the need for suboccipital decompression include lower-limb hyperreflexia or clonus, central hypopnea demonstrated by polysomnography, and decreased foramen magnum size, determined by CT examination of the craniocervical junction. Additional problems include spinal stenosis and obesity.

4. (E) As many as 7.5% of infants with achondroplasia die in the first year of life from obstructive or central apnea. Obstructive apnea may result from midface hypoplasia. Brainstem compression is common and may cause abnormal respiratory function, including central apnea. In one study, 10% of infants had craniocervical junction compression with abnormality of the cervical spinal cord. All children undergoing surgical decompression of the craniocervical junction show marked improvement of neurologic function.

5. (A) Achondroplasia is an autosomal dominant disease with only one copy of the FGFR3 allele being mutated. Thus there is a 50% chance of passing on the mutated allele.

6. (B) Marfan syndrome occurs in individuals who are taller than expected for their family. Cornelia de Lange is a relatively common syndrome with growth failure, feeding problems, limb defects, and characteristic facial features including round face and synophrys. Russell Silver syndrome is characterized by proportional short statue with preserved head circumference. Turner syndrome is a chromosome anomaly among girls that causes ovarian failure in addition to short stature. Williams syndrome is associated with supravalvular aortic stenosis, hypercalcemia, and friendly personality.

7. (C) The term dysostosis multiplex refers to the specific skeletal findings mentioned, and they are specific in the sense that their presence indicates an abnormality of complex carbohydrate degradation or lysosomal transport. The intralysosomal accumulation of partially degraded complex carbohydrates results in a variety of disorders, which, depending on the type of stored material, have been classified as mucopolysaccharidoses, oligosaccharidoses, and glycoproteinosis. The finding of dysostosis multiplex is specific for one of these classes of disorders but not diagnostic of a specific one.

8. (D) The clinical features of MPS have significant overlap, although there are distinct variations within the different subtypes. The general features that should raise suspicion about MPS include those listed as well as microcephaly, corneal opacities, and mental retardation. The age of onset of developmental issues including neurodegeneration varies from the newborn period to several years of age. There can also be short stature, progressive joint contractures, and heart disease (valvular disease and cardiomyopathy but not structural lesions causing hypoxia).

9. (D) When MPS is suspected on a clinical basis, a skeletal survey to look for the presence of dysostosis can be helpful. Dysostosis is specific for MPS as a class of disease but is not specific for a particular subtype. Urine screening tests to look for excretion of glycosaminoglycans can be helpful but are not always diagnostic and can sometimes be normal even though the patient has a form of MPS. Finally, specific enzyme analysis is available for the different subtypes of MPS and can be tested on blood and/or skin fibroblasts depending on the specific subtype in question.

10. (E) Like most metabolic diseases, the vast majority of cases of MPS are inherited in an autosomal recessive fashion. When a child is newly diagnosed, the family should be counseled that the parents are carriers of a gene mutation, and their chance of recurrence for future offspring is 25% for each pregnancy. An exception with regard to MPS is type II (Hunter syndrome), which is X-linked and mostly affects boys; females may be asymptomatic carriers.

11. (B) Limb malformations including radial ray anomalies and short limbs can be associated with vertebral anomalies, imperforate anus, cardiac defects, tracheoesophageal fistula (T-E fistula), and renal malformations. Brain malformations are less common and should only be looked for if there is a specific indication to do so based on clinical findings.

12. (E) The VATER association is an acronym for vertebral anomalies, anal anomalies, T-E fistula, and renal anomalies. Affected individuals may also have cardiac defects and limb anomalies. Fanconi pancytopenia syndrome should be considered in any patient where VATER is being entertained. Holt-Orom syndrome is characterized by ASD and limb defects but could be distinguished from the other choices if any other complex birth defects were found.

13. (C) The current recommendations include screening as indicated in answer C. Children with borderline findings or abnormal films should be evaluated with a careful neurologic examination to rule out spinal cord compression. Neuroimaging (CT or MRI) is probably indicated. Significant changes in a child’s neurologic status would necessitate evaluation and possible treatment. Asymptomatic children with instability (5-7 mm) should be managed conservatively, with restriction only in those activities that pose a risk for cervical spine injury. Contact sports, such as football, wrestling, rugby, boxing, and recreational activities such as trampolining, gymnastics (tumbling), and diving, which require significant flexion of the neck, would best be avoided. It is unnecessary to restrict all activities.

14. (D) OI is a result of a disorder of collagen synthesis and is the most prevalent of the osteoporosis syndromes in childhood. OI is characterized by fractures and skeletal deformities. Some affected patients die in the newborn period with extreme fragility of bone and numerous fractures. Others manifest bone fragility later in life and live a normal lifespan. Ellis-Van Creveld syndrome is characterized by polydactyly, short distal extremities, and nail hypoplasia.

15. (C) There is great overlap in the clinical subtypes; all are a result of mutations in collagen. The different clinical severity is a result of different genetic mutations, their severity, and their effect on collagen synthesis and function. The clinical features of each subtype are all described correctly except for type III. OI type III has severe bone fragility and multiple fractures, which lead to progressive skeletal deformity, and severe short stature.

16. (D) In OI type I, hearing loss is rare before the end of the first decade but affects most patients by the fifth decade. Type II is typically lethal so there is little associated hearing loss described. Hearing impairment is not a common feature in OI type III.


Spranger JW, Brill PW, Poznanski A. Bone Dysplasias.New York, NY: Oxford University Press; 2002.