American Academy of Pediatrics Metabolic Disorders 2014 Practice Test

American Academy of Pediatrics PREP 2014
Item 86
A child in your practice was identified with phenylketonuria (PKU) on routine newborn
screening, and the diagnosis was confirmed on follow-up testing. She was started on a
low-phenylalanine diet and has been followed regularly by the metabolic specialist. She
is doing quite well and shown excellent weight gain and normal developmental
milestones for age. Her parents have gone online and read about potential problems with
growth and cognitive development and risks to a developing fetus for adult women with
PKU who have been maintained on the PKU diet. They are uncertain about the sources of
this information and wish to know which, if any, of these issues are still a concern with
optimal dietary management.
Of the following, you are MOST likely to tell the parents that with proper treatment their
child will have
A. normal bone mineral densities in adulthood if maintained on the PKU diet

B. normal cognitive development if the diet is well managed until 10 years of age
C. normal height and head circumference measurements if maintained on the
PKU diet
D. no teratogenic effects in her offspring if phenylalanine levels are well-
controlled
E. some neurocognitive or psychosocial deficits in childhood despite good
dietary management
American academy of pediatrics 1

Item 86 Preferred Response: E
The child described in this vignette was identified shortly after birth to have
phenylketonuria (PKU), and dietary management was promptly initiated. However,
despite early introduction of dietary therapy, long-term studies suggest that growth,
neurocognitive outcomes, and bone health are still suboptimal in treated patients.
Untreated PKU is associated with severe neurocognitive deficits; however, the

combination of newborn screening and maintenance of a therapeutic, phenylalanine-
restricted diet has ameliorated but not eliminated the most serious clinical consequences.
While some children on phenylalanine restricted diets were in the past permitted to go off
diet after 10 years of age, studies have clearly demonstrated significant neurocognitive
consequences of relaxing dietary intake, even for older children and adults. Therefore,
lifelong dietary adherence is now recommended for all persons with PKU. In addition to
a phenylalanine-restricted diet, use of oral sapropterin dihydrochloride as an adjuvant
therapy has further helped to control blood phenylalanine levels in some patients.
Many children and young adults who had early dietary restriction and continued
management still exhibit higher rates of executive functioning deficits and attention
problems as well as reduced processing speed when compared to age-matched controls.
Treated adults also may have decreased verbal memory, expressive naming, and verbal
fluency despite optimal management. These individuals are also at greater risk for social
and emotional difficulties, including low self-esteem, depression, generalized anxiety,
phobias, and social isolation. Brain imaging of patients who have diet-treated PKU
demonstrates a higher incidence of white matter abnormalities, decreased cerebral protein
synthesis, altered L-DOPA uptake, volumetric changes in grey matter and altered
cerebral metabolism.
Studies of diet-treated children and adolescents who have PKU have demonstrated
reduced height and head circumference measurements, presumably due to the low dietary
content of natural proteins. These patients are also subject to micronutrient deficiencies
of zinc, copper, and selenium as well as deficient intake of calcium, cholesterol, and
preformed long-chain polyunsaturated fatty acids (PLC-PUFAs). PLCPUFAs are critical
to normal brain and retinal development; deficiencies of these fatty acids can lead to
cognitive and visual dysfunction.
Bone metabolism is also disrupted in children and teens on the PKU diet, with evidence
of slower bone formation and resorption in these individuals. This likely accounts for the
higher incidence of osteopenia and osteoporosis in adults with PKU who have endured
years of dietary deficiencies of protein, calcium, vitamin D, and trace elements.
Maternal PKU effects continue to be a significant concern for adult women with PKU
who are pregnant or contemplating a pregnancy. Optimally, women with PKU should
begin to lower their blood phenylalanine levels with dietary changes and medical input 3
months before conception. The goal is to reduce the maternal blood phenylalanine level
to between 2.0 and 6.0 mg/dL (120 and 360 µmol/L) before the 8th to 10th week of
gestation and to maintain this level throughout pregnancy. Failure to achieve this

metabolic tar-get by this point in gestation significantly increases the risks for congenital
cardiac defects, microcephaly, cognitive deficits, and behavioral problems in offspring.
However, because of daily blood phenylalanine fluctuations in even the most adherent
mother-to-be, one cannot guarantee that optimal dietary management will completely
negate potential teratogenic effects.
PREP Pearls
• Children and adults who have PKU are still at increased risk for cognitive,
growth, and behavioral problems despite optimal dietary management.
• Adults who have PKU are at increased risk for osteopenia and osteoporosis.
• Women who have PKU and are of childbearing age should be cautioned about
the need for additional preconceptional and prenatal dietary restrictions to
minimize potential teratogenic influences of high levels of circulating
maternal blood phenylalanine.
American Board of Pediatrics Content Specification(s):

• Know the natural history of treated and untreated phenylketonuria
Suggested Reading:
• Enns G, Koch R, Brumm V, Blakely E, Suter R, Jurecki E. Suboptimal
outcomes in patients with PKU treated early with diet alone: revisiting the
evidence. Mol Genet Metab. 2010;101(2-3):99-109. doi:10.1016/j.
ymgme.2010.05.017
• Kaye CI, Committee on Genetics. Newborn screening fact sheets. Pediatrics.
2006;118(3):e934-e963 doi: 10.1542/peds.2006-1783
• Levy HL. Historical background for the maternal PKU syndrome. Pediatrics.
2003;112:1516-1518
• Widaman KF, Azen C. Relation of prenatal phenylalanine exposure to infant
and childhood cognitive outcomes: results from the international maternal
PKU collaborative study. Pediatrics. 2003;112:1537-1543

Item 174
A 13-month-old boy is seen in the emergency department (ED) for the third time with a
history of decreased oral intake, lethargy, and irritability. Symptoms have been present
for 4 hours since awakening at 6:00 AM; his last formula feed prior to this morning was
at 11:00 PM last night. His first visit to the ED at 5 months of age resulted in admission
to the hospital with concurrent symptoms of an upper respiratory infection without fever;
he also had hypoglycemia that resolved spontaneously. The result of a sepsis workup was
negative (normal complete blood cell count as well as negative blood, cerebral spinal
fluid, and urine cultures), and he received 3 days of antibiotics until the cultures were
negative. His second visit to the ED took place at 8 months of age, when he had a mild
bout of acute gastroenteritis. He was also hypoglycemic at that time but responded well
to intravenous glucose, a single bolus of normal saline, and oral rehydration; he was
discharged after 6 hours of observation in the ED, during which time he had frequent
fingerstick glucose levels that were within normal limits.
Results of a basic chemistry panel are within normal limits except for a glucose level of
27 mg/dL (1.5 mmol/L). There is moderate elevation in his transaminases, a mildly
elevated ammonia level, and negative urinary ketones. His examination is significant for
mild hepatomegaly with no fever or other systemic symptoms.
Of the following, the study MOST likely to be helpful in identifying a cause for this
child's symptoms is
A. a cortisol level
B. a liver biopsy
C. plasma carnitine levels
D. serum immunoglobulins
E. urine organic acids

Item 174 Preferred Response: C
The child described in the vignette has some of the typical presenting signs of systemic
primary carnitine deficiency (PCD). Children with PCD generally present between the
ages of 3 months and 2 years with hypoketotic hypoglycemia characterized by poor oral
intake, lethargy, and irritability. Primary carnitine deficiency results in defective long-
chain fatty acid transport into the mitochondria, which leads to decreased energy
production. Symptoms are often triggered by an intercurrent illness such as an upper
respiratory infection or acute gastroenteritis. Symptoms are also often apparent after
longer than usual periods of fasting. In addition to low carnitine levels, other laboratory
findings may include mildly elevated transaminases and mildly elevated ammonia levels.
Hepatomegaly may also be noted on examination in some patients. Primary carnitine
deficiency is inherited as an autosomal recessive condition and may be detected in some
infants on expanded newborn screening. Diagnostic testing for PCD includes a skin
biopsy for a fibroblast assay that assesses carnitine transport or a molecular genetic study
on a DNA sample that looks for mutations in SLC22A5 on chromosome 5. Untreated,
PCD can result in symptomatic hypoglycemia and heart and skeletal muscle dysfunction.
Supplementation with levocarnitine can restore plasma carnitine levels and prevent long-
term, life-threatening sequelae.
Although this is a boy, he is rather old to present with con-genital adrenal hyperplasia
(CAH) with a secondary cortisol deficiency. Classic CAH due to 21-hydroxylase
deficiency would generally present with hyponatremia secondary to a salt-losing crisis
with or without hypotension and elevations in 17-hydroxyprogesterone but would not
present with hypoglycemia. A liver biopsy might be indicated if a glycogen storage
disease or tyrosinemia was suspected. However, glycogen storage disease type 1 (Von
Gierke disease) would typically present much earlier with persistent and intractable
hypoglycemia, significant hepatomegaly and renomegaly, and secondary lactic acidosis,
hyperlipidemia, and hyperuricemia. A normal blood chemistry panel is inconsistent with
this diagnosis. Tyrosinemia type 1 (T1) would also present in the first few months of life
with failure to thrive, jaundice, Fanconi syndrome, and signs of liver failure but would
not present with hypoglycemia. Plasma amino acids would demonstrate elevations in
tyrosine and methionine, with excretion of succinylacetone in the urine being
pathognomonic for T1. Liver findings might include nodular cirrhosis, but early
identification of T1 through newborn screening and prompt treatment with a metabolic
pathway blocker known as NTBC has shown promise in slowing down or preventing
liver failure in patients with T1.
The 2 previous infections seen in the child in the vignette are not unusual for a child his
age and would not raise suspicions about an immunodeficiency. Therefore, immuno-
globulins would not be indicated. A child with an organic acidemia may also have a
mildly elevated ammonia level but should also have evidence of a metabolic acidosis
with a significant anion gap on blood chemistries. While the history is certainly
consistent with an inborn error of metabolism and a metabolic workup, including urine
organic acids, is in order, his history and presentation are most consistent with PCD.
Other metabolic tests to consider while awaiting the carnitine levels should include
plasma amino acids, lactate, pyruvate, and urinary reducing substances.

PREP Pearls
• Recurrent hypoglycemia associated with intercurrent illness in the absence of
metabolic acidosis or other electrolyte imbalances is suggestive of carnitine
deficiency.
• Untreated carnitine deficiency can result in irreversible cardiomyopathy and
skeletal muscle dysfunction.

• Recognize the laboratory findings in a patient who has a disorder of carnitine
metabolism
Suggested Reading:
• El-Hattah AW. Systemic primary carnitine deficiency. In: Pagon RA, Bird TD,
Dolan CR, eds. GeneReviews. Seattle, Washington: University of Washington;
2013
• Ficicioglu C, an Haack K. Failure to thrive: when to suspect inborn errors of
metabolism. Pediatrics. 2009;124(3):972-979
• Gessner BD, Gillingham MB, Birch S, Wood T, Koeller DM.
• Evidence for an association between infant mortality and a carnitine
palmitoyltransferase 1A genetic variant. Pediatrics. 2010;126(6):945-951.
doi:10.1542/peds.2010-0687
• Helton E, Darragh R, Francis P, et al. Metabolic aspects of myocardial disease
and a role for L-carnitine in the treatment of childhood cardiomyopathy.
Pediatrics. 2000;105(6):1260-1270

Item 242
A 4-month-old girl is brought in by her mother with the complaint of progressive
weakness and poor head control. She has also noted that her daughter appears less
attentive and has an exaggerated startle response. Results of examination are
unremarkable except for diffuse hypotonia. She has a good suck and swallow, and she
fixes and follows intermittently. As part of a comprehensive evaluation, she is seen by a
pediatric ophthalmologist who notes slightly impaired visual acuity as well as cherry-red
spots (Item Q242).
ITEM Q242: Macular spot, as described for the patient in the vignette.
Of the following, the MOST likely diagnosis for this child is
A. infantile Gaucher disease

B. Krabbe disease
C. neuronal ceroid lipofuscinosis
D. Niemann-Pick type A
E. Tay-Sachs disease

Item 242 Preferred Response: E
The infant described in this vignette has typical clinical features of infantile Tay-Sachs
disease (TSD), including hypotonia, inattentiveness, an exaggerated startle response,
evidence of visual dysfunction, and cherry-red spots on retinal examination.
Whereas babies with infantile TSD appear normal at birth, progressive weakness may be
noted between 3 and 6 months of age. Simultaneously, myoclonic jerks and an
exaggerated startle reaction to sound may be seen. Between 6 and 10 months of age, there
is plateauing of motor skill acquisition and even some loss of milestones. Following this
period, the neurologic progression of infantile TSD is fairly rapid, with blindness,
decrease in purposeful movements, and seizures noted prior to death. Macrocephaly often
appears by 18 months of age but is not secondary to hydrocephalus. The so-called cherry-
red macular spots result from diffuse retinal pallor secondary to accumulation of
metabolic storage products in ganglion cells. The red color represents the normal foveal
cells, which appear redder because of the retinal pallor in an area (ie, the fovea) that has
no ganglion cells. In addition to infantile TSD, cherry-red spots are seen in many lipid
storage disorders, including GM1 gangliosidosis, Sandhoff disease, some of the
mucopolysaccharidoses, Niemann-Pick disease, and mucolipidoses.
The diagnosis of TSD is made by hexosaminidase A assay. Molecular genetic testing

may also uncover disease-causing mutations but is not essential for making an accurate
diagnosis. Three common disease-causing mutations account for more than 90% of
mutations in the Ashkenazi Jewish population, but the mutations cannot be used for
identification of affected individuals or carrier detection in other ethnic groups. Although
TSD is found in about 1 in 3,600 individuals of Ashkenazi Jewish ancestry, it is also seen
with increased frequency in individuals of French Canadian ancestry, Cajuns from
Louisiana, and the Old Order Amish in Pennsylvania. Infantile TSD can actually be seen
in any population, but with a frequency about 100 times less than in individuals of
Ashkenazi Jewish ancestry. At present, there is no cure or enzyme replacement therapy
for infantile TSD. Therefore, management is symptomatic and supportive for progressive
complications as they occur.
Although cherry-red spots may also be seen in some infants with infantile Gaucher
disease and Niemann-Pick type A, a child with infantile Gaucher disease or Niemann-
Pick type A would typically exhibit hepatosplenomegaly. Infantile Gaucher disease is
also frequently associated with pancytopenia, cranial nerve palsies, hyperreflexia, and
spasticity. While neurologic regression is consistent with Krabbe disease and neuronal
ceroid lipofuscinosis, in addition to infantile Gaucher disease and Niemann-Pick type A,
infants with Krabbe disease often have very early onset of seizures and irritability, as
well as unexplained fevers and vomiting. An infant with neuronal ceroid lipofuscinosis
would typically develop microcephaly and myoclonus as well as visual failure due to
retinitis pigmentosa (without cherry-red spots).

PREP Pearls
• Infants with Tay-Sachs disease appear normal at birth, but progressive
weakness and an exaggerated startle response are typically noted by 4 to 6
months of age followed by a progressive deterioration.
• Tay-Sachs disease is most often seen in the Ashkenazi Jewish population, but
it can and does occur in any ethnic group. Screening for Tay-Sachs carrier
status in individuals who are not of Ashkenazi Jewish descent is best done
through enzyme assay.

• Recognize the signs and symptoms of Tay-Sachs disease
Suggested Reading:
• Bley AE, Giannikopoulos OA, Hayden D, Kubilus K, Tifft CJ, Eichler FS.
Natural history of infantile GM2 gangliosides. Pediatrics. 2011;128(5):e1233-
e1241. doi:10.1542/peds.2011-0078
• Kaback MM, Desnick RJ. Hexosaminidase A deficiency. In: Pagon RA, Bird
TD, Dolan CR, eds. GeneReviews. Seattle, Washington: University of
Washington; 2013

American Academy of Pediatrics 2013 PREP SA on CD-ROM
Question: 28
A 4-year-old girl enters your practice for the first time. Her mother reports that her birth history was
unremarkable and early developmental milestones were within normal limits. However, over the past
year her development has seemed to plateau. Her medical history is significant for recurrent ear
infections and, more recently, rather loud snoring. On physical examination, you note slightly coarse
facial features, a protuberant abdomen with a small reducible umbilical hernia, enlarged liver, and mild
contractures of the fingers (Item Q28).
Of the following, according to these findings, the test that would be MOST diagnostically helpful is
A. a lipid profile
B. plasma amino acids
C. a sleep study
D. urine glycosaminoglycans
E. urine organic acids
Copyright 2013 © American Academy of Pediatrics 1

Critique: 28 Preferred Response: D
The clinical findings described in this vignette are typical for a child with a form of
mucopolysaccharidosis (MPS) disorder. Development for many children with an MPS disorder is initially
normal, subsequently plateaus, and then regresses because of accumulation of metabolic by-products
(glycosaminoglycans). This is typical of some MPS subtypes, including Hurler, Hunter, and Sanfilippo
syndromes. Diagnostic screening includes urine testing for glycosaminoglycans and definitive testing for
specific enzymes, depending on the findings on the urine test. Recurrent otitis media and snoring
secondary to tonsillar and adenoidal hypertrophy are also quite common early features. Later findings
include bony changes (dysostosis multiplex), joint contractures (especially in the fingers),
hepatosplenomegaly, and secondary umbilical hernias. The child in this case is most likely affected with
Hurler syndrome or a slightly milder variant known as Hurler-Scheie syndrome, both of which are
associated with deficiency of the enzyme a-L-iduronidase and are inherited in an autosomal recessive
manner. Hunter syndrome primarily affects boys because it is inherited as an X-linked recessive
condition. Sanfilippo syndrome is a clinically distinct condition associated with a later onset of
organomegaly. Classic phenotypic findings, such as the coarsening of facial features and hirsutism seen
earlier with Hurler and Hunter syndromes, occur later in Sanfilippo syndrome. Enzyme replacement
therapy has been developed for some forms of MPS, including Hurler and Hurler-Scheie, and results in
decreased organomegaly, improvement in respiratory function, and resolution of other somatic features.
Current enzyme therapy is ineffective in improving cognitive function because these intravenously
infused enzymes do not cross the blood-brain barrier.
A lipid profile would not be helpful in determining a diagnosis in this child. A sleep study may
demonstrate or uncover obstructive sleep apnea but would not explain the other clinical findings that
point to an MPS disorder. Plasma amino acids and urine organic acids are studies used to diagnose
other types of inborn errors of metabolism, but these conditions would not present with coarse facies,
finger contractures, or an umbilical hernia.
SUGGESTED READING:
Muenzer J, Wraith JE, Clarke LA; and the International Consensus Panel on the Management and
Treatment of Mucopolysaccharidosis. Mucopolysaccharidosis I: management and treatment guidelines.
Pediatrics. 2009;123(1):19 -29. doi:10.1542/peds.2008-0416
Wraith JE, Beck M, Lane R, et al. Enzyme replacement therapy in patients who have
mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant
human α-L-iduronidase (laronidase). Pediatrics. 2007;120(1):e37-e46. doi:10.1542/peds.2006-2156

Question: 79
A 3-year-old girl in your practice was diagnosed with glycogen storage disease type 1 (GDSD1) at birth
after an episode of hypoglycemia. Initial management included continuous nasogastric (CNG) feedings
during the first 6 months after birth, followed by overnight CNG feedings with formula and subsequent
milk-based liquid protein supplements. Because her glucose levels have been relatively stable over the
past few months, her parents are asking about future management strategies when their daughter is
ready to discontinue overnight feedings.
Of the following, the strategy for maintaining blood glucose levels in older children that you are MOST
likely to recommend is
A. CNG feeds only for bedtime glucose levels <80 mg/dL
B. daily and nightly oral raw cornstarch feedings
C. midnight and 4 am concentrated glucose feedings
D. nightly intramuscular glucagon administration
E. no supplements once bedtime glucose levels are >70 mg/dL

Critique: 79 Preferred Response: B
The young girl described in this vignette has a typical presentation of glycogen storage disease type
1 (GSD1) with neonatal hypoglycemia. In this condition, the hypoglycemia results from deficiency of
hepatic glucose-6-phosphatase, leading to an inability of the liver to release free glucose. Untreated, this
condition leads to massive hepatomegaly and life-threatening hypoglycemia; repeated episodes of
hypoglycemia often result in brain damage.
The foremost goal of treatment is to maintain normal glucose levels and prevent episodes of
hypoglycemia while providing adequate nutrition to sustain normal growth and development. From the
time of diagnosis, frequent small meals and snacks containing complex carbohydrates are
recommended during the day and before bedtime with continuous nasogastric or gastrostomy tube
glucose infusions overnight. Oral cornstarch feedings are especially helpful between meals and before
bedtime and can be given throughout childhood and into adulthood. In older children and adults with
more stable glucose measurements, continuous nighttime feeds may be replaced with raw cornstarch
feeds at bedtime and in the early morning hours. This transition often occurs at 2 to 3 years of age when
pancreatic amylase activity is sufficient to maintain normal glucose levels overnight. Because of the
dangers of prolonged fasting, a single measurement of serum glucose at bedtime is insufficient to
predict how the child will do without continuous feeds overnight. Bolus feeds of glucose at midnight and
4 am are also not recommended because it is more disruptive than continuous feeds and would not be
needed if the child has reached a point where cornstarch feeds at bedtime are sufficient. Glucagon is
not a treatment for hypoglycemia in GSD1 because children who have GSD1 cannot breakdown
glycogen to glucose because of their enzyme deficiency, and glucagon administration can result in a
significant increase in plasma lactate in these patients.
The hepatomegaly and renomegaly in GSD1 result from accumulation of glycogen and fat in these
organs and respond well to dietary treatment. Children and adults with GSD1 often experience
hyperuricemia and hyperlipidemia that may require medical treatment even with optimal metabolic
control. Patients may benefit from expert management by metabolic specialists who can make
recommendations regarding dietary therapy, glucose monitoring, and surveillance for long-term
complications. Impaired platelet function is a well-recognized complication of GSD1 and can lead to
frequent episodes of epistaxis. Patients with GSD type 1b are also at risk for impaired neutrophil and
monocyte function and may have chronic neutropenia early in life. This can lead to oral and intestinal
ulcers and recurrent bacterial infections.
Long-term consequences of GSD1 include growth failure, delayed puberty, polycystic ovaries,
hepatic adenomas, renal disease, and osteoporosis. Citrate supplementation has been shown to
decrease risks for renal stones in patients with GSD1, but proteinuria, hypertension, and
nephrocalcinosis may still progress to end-stage renal disease, which is associated with interstitial
fibrosis. After the age of 10 years, most patients with GSD1 have evidence of hepatic adenomas, which
need to be monitored for intrahepatic hemorrhage and development of hepatocellular carcinoma. Annual
liver sonography after age 10 years and then every 3 to 6 months once an adenoma is identified is
recommended for individuals with GSD1.

SUGGESTED READING:
Bali DS, Chen YT, Goldstein JL. Gene Reviews: Glycogen Disease Type I. Seattle, WA: University of
Washington; 2011. http://www.ncbi.nlm.nih.gov/books/NBK1312/?report=printable
Kahler SG. Metabolic disorders associated with neonatal hypoglycemia. NeoReviews.

2004;5(9):e377-e381. doi:10.1542/neo.5-9-e377
Safouh H, Elsayyed R, Mansour S, Taha G, Elshabrawy M, Elkaraksy H. Renal involvement in

children with glycogen-storage disease. Pediatrics. 2008;121(supp 2):s143-s144.
doi:10.1542/peds.2007-2022TTTTT

Question: 113
You order a fasting lipid profile for an 11-year-old boy in your practice because of a history of
dyslipidemia in his mother and cardiovascular disease and myocardial infarction at 48 years of age in his
father. This child has no other risk factors, such as obesity, hypertension, or diabetes mellitus. He is
physically active and has a fairly balanced dietary intake according to his parents. His low-density
lipoprotein concentration is high at 175 mg/dL, his total cholesterol is slightly high at 215 mg/dL, and his
high-density lipoprotein level is at the 10th percentile for his age at 40 mg/dL.
Of the following, the recommendation you are MOST likely to make to improve his lipid profile is
A. increase his intake of soluble fiber
B. increase his physical activity
C. initiate treatment with a statin
D. restrict dietary cholesterol
E. restrict dietary saturated fats

Critique: 113 Preferred Response: C
The young man in this vignette falls into a high-risk category because of his fathers' history of
cardiovascular disease (CVD), his mothers' history of dyslipidemia, and his own mildly elevated total
cholesterol and low high-density lipoprotein (HDL) level. Current recommendations from the American
Academy of Pediatrics Committee on Nutrition for pharmacologic intervention include any child over the
age of 8 years with one of the following:
(a) a low-density lipoprotein (LDL) concentration greater than or equal to 190 mg/dL
(b) an LDL concentration greater than or equal to 160 mg/dL with a family history of early heart
disease or 2 or more additional risk factors (eg, family history of premature CVD or dyslipidemia)
(c) an LDL concentration greater than or equal to 130 mg/dL plus diabetes mellitus
Therefore, consideration for pharmacologic treatment in this boy is warranted. While some studies
have shown that fiber may reduce plasma LDL concentrations by up to 7%, other studies have not
demonstrated benefit. While increasing physical activity may increase his HDL level, it is unlikely to
correct his dyslipidemia. Restriction of dietary cholesterol may provide some benefit and should be
initiated if the family is not already limiting cholesterol intake, but restriction alone may not be sufficient
to reduce his total cholesterol and LDL concentrations. Similarly, reduction of dietary saturated fats is
recommended but alone may be insufficient to correct the lipid profile.
Lipid goals for this young man would be to lower LDL to less than 160 mg/dL and possibly even as
low as 130 mg/dL in light of his family history of premature CVD. Dietary counseling and initiation of a
low-cholesterol diet with limited saturated fats may augment therapy and permit use of a lower dose of a
pharmacologic agent.
SUGGESTED READING:
Daniels SR, Greer FR; and American Academy of Pediatrics Committee on Nutrition. Lipid screening
and cardiovascular health in childhood. Pediatrics. 2008;122(1):198-208. doi:10.1542/peds.2008-1349
Ritchie SK, Murphy ECS, Ice C, et al. Universal versus targeted blood cholesterol screening among
youth: the CARDIAC Project. Pediatrics. 2010;126(20):260-265. doi:10.1542/peds.2009-2546

Question: 177
You are following a 7-week-old, 6.5-kg infant who has congenital hyperinsulinism. He has had
persistent hypoglycemia with any period of fasting despite maximal doses of diazoxide and octreotide. A
fluorine-18 dihydroxyphenylalanine positron emission tomographic scan demonstrates diffuse uptake of
the tracer throughout the pancreas. You decide to refer this infant to a specialized center for further
treatment.
Of the following, the specialized center is MOST likely to

A. initiate a trial of glucocorticoids
B. initiate a trial of growth hormone
C. initiate a trial of oral corn starch
D. perform a 50% pancreatectomy
E. perform a 95% pancreatectomy

Critique: 177 Preferred Response: E
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants
and children. CHI is a group of disorders characterized by the inappropriate secretion of insulin in the
presence of severe hypoglycemia. The hypoglycemia associated with hyperinsulinism is particularly
dangerous to the developing brain because it is associated with an inability to produce alternative brain
fuels, such as ketone bodies. There are both transient and permanent forms of CHI. The transient forms
are not associated with any known gene defects and typically resolve by 1 month of age. Permanent CHI
is most often associated with recessive mutations of the β-cell adenosine triphosphate-sensitive
potassium (KATP) channel and comes in 2 distinct histologic forms: (1) diffuse congential
hyperinsulinism and (2) focal CHI. KATP channel defects explain more than 90% of permanent CHI
cases.
When medical therapy fails, infants who have CHI should be referred to a center that specializes in
the evaluation of CHI for surgical intervention because prolonged hypoglycemia can result in significant
intellectual disability. The infant described in the vignette has diffuse disease, as evidenced by the
uptake throughout the pancreas on the fluorine-18 dihydroxyphenylalanine positron emission
tomographic scan. Children with diffuse CHI in whom medical therapy fails require a 95% to 99%
pancreatectomy to potentially achieve a cure. If this infant had focal disease, a 50% partial
pancreatectomy is sometimes effective.
The biochemical diagnosis of CHI requires concurrent measurement of hypoglycemia (blood glucose
<50 mg/dL [2.8 mmol/L]), detectable insulin levels (>2 µIU/mL [13.9 pmol/L]), low levels of free fatty
acids (<42 mg/dL [1.5 mmol/L]), and low levels of serum ketones (<2 mmol/mL). In addition, the
increase in blood glucose concentration by more than 30 mg/dL (1.7 mmol/L) after 1 mg of glucagon
given at the time of hypoglycemia indicates hyperinsulinism. Once the biochemical diagnosis is made,
treatment should be initiated to maintain normal blood glucose levels. The first-line therapy for CHI is
oral diazoxide. It is a potassium channel activator and therefore acts to reduce inappropriate insulin
secretion. When diazoxide therapy fails, the second agent used is octreotide, a somatostatin analog that
inhibits insulin secretion by reducing the calcium influx and insulin secretion that typically follow.
However, octreotide has limited long-term use because therapy requires multiple daily injections or
subcutaneous infusion and is associated with tachyphylaxis. Some patients who have mild forms of CHI
can be managed successfully with either diazoxide or octreotide.
The combination of glucocorticoid and growth hormone replacement is an effective strategy for
hypoglycemia secondary to panhypopituitarism but is not an effective therapy for severe CHI. Similarly,
oral corn starch is an excellent therapy for glycogen storage diseases but is not well tolerated in infancy
and is not the therapy of choice for CHI.
SUGGESTED READING:
Arnoux JB, de Lonlay P, Ribeiro MJ, et al. Congenital hyperinsulism. Early Hum Dev. 2010;86(5):287-
294.

Hardy OT, Hernandez-Pampaloni M, Saffer JR, et al. Diagnosis and localization of focal congenital
hyperinsulinism by 18F-fluorodopa PET scan. J Pediatr. 2007;150(2):140-145.
doi:10.1016/j.jpeds.2006.08.028
Langdon DR, Stanley CA, Sperling MA. Hypoglycemia in the infant and child. In: Sperling MA, ed.
Pediatric Endocrinology. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2008:422-433
Macmullen CM, Zhou Q, Snider KE, et al. Diazoxide-unresponsive congenital hyperinsulinism in

children with dominant mutations of the β-cell sulfonylurea receptor SUR1. Diabetes. 2011;60(6):1797-
1804. doi:10.2337/db10-1631

Question: 232
You receive a call from your state newborn screening laboratory on Friday at 6pm regarding a one-
week-old newborn who will soon be coming to your practice. You are told that there is an elevation in the
C5-OH acylcarnitine on the newborn screening assay that could be associated with an organic acidemia.
You know this family quite well because you already care for their other three children (ages 7 years, 5
years, and 2 years) and know them to be very reliable and experienced parents. You call the parents at
home and are told that their newborn daughter is breastfeeding well and in no apparent distress.
Of the following, you are MOST likely to recommend that they should bring their infant daughter
A. to a blood drawing center tomorrow with your prescription for baseline blood work
B. to the emergency department immediately for blood work and a clinical evaluation
C. to the regional metabolic center with a call for an appointment first thing Monday morning
D. to your office Monday morning for baseline blood work and a clinical evaluation
E. to your office tomorrow morning during walk-in hours for a clinical evaluation

The newborn depicted in this scenario has screened positive for C5-OH acylcarnitine, which could be
indicative of an organic acidemia. Despite the trust you have in this familys experience and the
reassurance that the newborn is breastfeeding well, the positive screening constitutes a medical
emergency and needs to be addressed immediately. Because the goals of newborn screening are to
identify newborns with treatable and potentially life-threatening metabolic disorders before they cause
problems, it is not unusual to identify a neonate in this way prior to metabolic decompensation. While it is
often helpful to reach out to a metabolic specialist, you are in a position to begin the evaluation by
having the baby brought to an emergency department immediately for blood work to determine if there
are signs of a metabolic problem, such as hypoglycemia, ketonuria, or metabolic acidosis. If any of
these are found on the initial screening blood tests, then the newborn should be transferred to a tertiary
care center where a metabolic specialist can initiate specific diagnostic testing and treatment.
Confirmatory tests may include urine organic acids (may require both newborn and maternal urine
samples), plasma acylcarnitines, and a biotinidase assay.
It would be unwise to send the child to a blood drawing center in the morning because of the potential
for a serious problem arising overnight. These tests need to be done as quickly as possible. Setting up
an appointment for Monday morning with you or a metabolic specialist is also risky, as is waiting for a
clinical evaluation in your office in the morning. While the screening test may turn out to be a false-
positive result, the onus is on the physician to act immediately to determine with certainty that this
newborn is not on the verge of metabolic decompensation. The high morbidity and mortality associated
with delayed diagnosis and treatment is the driving force behind such rapid response to a positive
screening test for metabolic conditions. By having the newborn immediately evaluated in the emergency
department and doing screening blood work, you may avert serious complications; if evaluations show
the newborn to be well, you have caused the family some temporary distress but have acted responsibly
and in the best interest of the newborn and parents.
SUGGESTED READING:
Kaye CI; and American Academy of Pediatrics Committee on Genetics. Newborn screening fact
sheets. Pediatrics. 2006;118(3):e934-e963. doi:10.1542/peds.2006-1783
Newborn screening overview. National Center for Medical Home Implementation Web site.
http://www.medicalhomeinfo.org/how/clinical_care/newborn_screening.aspx
Newborn screening. American Academy of Pediatrics Web site.

http://www.aap.org/healthtopics/newbornscreening.cfm
Newborn screening ACT sheets and confirmatory algorithms. ACMG ACT Sheets and Confirmatory
Algorithms. Bethesda, MD: American College of Medical Genetics; 2001. NIH publication NBK55827.

http://www.ncbi.nlm.nih.gov/books/NBK55827/

Question: 249
A 14-year-old girl in your practice has been noted to have progressive fatigue and complains of pain in
her thighs for the past 2 months. On examination, you note that she is pale and has a palpable spleen 3
cm below the left costal margin. Laboratory studies reveal that she has mild normocytic anemia and
radiographs of her lower extremities reveal Erlenmeyer flask deformities of the distal femurs (Item
Q249). Because of these findings and because you know that she is of Ashkenazi Jewish ancestry, you
perform testing for Gaucher disease and determine that she has 2 mutations known to be associated
with this condition. Her parents wish to know more about Gaucher disease and what this means for her
future.
Based upon this diagnosis, you are MOST likely to tell them that their daughter
A. is at increased risk for developing acroparesthesias
B. is likely to have cherry-red spots noted on ophthalmoscopy
C. may benefit from intravenous enzyme replacement therapy
D. may respond to dietary restriction of certain fatty acids

The girl in this vignette has typical features of the nonneuronopathic form of Gaucher disease that is
quite common in the Ashkenazi Jewish population. While some forms of Gaucher disease and other lipid
storage disorders are panethnic and can cause multiorgan dysfunction and progressive neurologic
deterioration, this form does not cause central nervous system dysfunction and is amenable to
intravenous (IV) enzyme replacement therapy. Type 1 Gaucher disease occurs in about 1 in 1,000
individuals of Ashkenazi Jewish (AJ) descent, and about 1 in 18 AJ individuals is a gene carrier of an
autosomal recessive gene mutation. Gaucher disease results from a deficiency of acid β-glucosidase,
which is a lysosomal hydrolase responsible for glycolipid degradation. Affected patients experience
accumulation of glucosylceramide in cells of the mononuclear phagocyte system (previously known as
the reticuloendothelial system), which results in progressive hepatosplenomegaly and painful bony
deformities.
Acroparesthesias are not typically seen with Gaucher disease but can be seen with the X-linked lipid
storage condition Fabry disease. Cherry-red spots are noted in patients with GM1 gangliosidosis, Tay-
Sachs disease, Sandhoff disease, Farber disease and 2 types of Niemann-Pick disease, but not
Gaucher disease. Dietary restriction has no impact on any of the lipid storage disorders because the
accumulating by-products arise from normal intracellular metabolic processes. Splenectomy has been a
therapeutic option in the past for patients with Gaucher disease and for patients who have significant
hypersplenism, but since the advent of IV enzyme replacement therapy, which results in dramatic
shrinkage of the liver and spleen, splenectomy rarely needs to be considered.
SUGGESTED READING:
Andersson H, Kaplan P, Kacena K, Yee J. Eight-year clinical outcomes of long-term enzyme

replacement therapy for 884 children with Gaucher disease type 1. Pediatrics. 2008;122(6):1182-1190.
doi:10.1542/peds.2007-2144
McGovern MM, Wasserstein MP, Giugliani R, et al. A prospective, cross-sectional survey of the
natural history of Niemann-Pick disease type B. Pediatrics. 2008;122(2):e341-e349.
doi:10.1542/peds.2007-3016
Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E. Lysosomal storage

disorders in the newborn. Pediatrics. 2009;123(4):1191-1207. doi:10.1542/peds.2008-0635

Question: 147
A 10-year-old girl and her 14-year-old brother in your practice both had phenylketonuria (PKU)
diagnosed at birth. With early identification and initiation of dietary restriction, both children have done
well academically and socially. Their mother is looking ahead to their college years and asks about
recommendations regarding ongoing dietary management.
Of the following, you are MOST likely to tell her that dietary restriction can be lifted after age 15
years
A. for both children
B. but must be reinstituted for the girl before she becomes pregnant
C. but must be reinstituted for the girl during pregnancy
D. for the boy only

In the past, children who had PKU were advised that they could relax dietary restrictions beyond
childhood, but most metabolic centers in the United States today recommend lifelong dietary treatment
for all patients. This is especially critical for affected girls because fetal exposure to high concentrations
of phenylalanine circulating in the maternal bloodstream pose high risks for teratogenic effects and may
result in congenital anomalies, microcephaly, and intellectual disabilities through in utero exposure.
Accordingly, neither child in the vignette should alter his or her dietary protocols. Past studies have
demonstrated altered concentration abilities and reaction times for individuals who have PKU when they
are off dietary restriction and have elevated circulating phenylalanine concentrations. If a female has
PKU and is not compliant with her phenylalanine-restricted diet, it is essential for her to reinstitute dietary
therapy before conception, with the goal of achieving phenylalanine concentrations of less than 6 mg/dL
(363.3 mcmol/L) at least 3 months before conception. Phenylalanine concentrations should be
maintained between 2 and 6 mg/dL (121.1 and 363.3 mcmol/L) throughout the pregnancy to minimize
potential adverse fetal effects.
Although screening for PKU has been performed in the United States for more than 40 years,
children born outside of the United States may not be screened and rarely are diagnosed before 6
months of age. Rapid evaluation of a positive screening test and prompt institution of dietary protocols
once the diagnosis is confirmed results in normal physical and intellectual development. Dietary
treatment includes the use of foods and medical protein sources (such as special formulas) that are low
in phenylalanine, with the judicious addition of natural proteins to the diet to provide the necessary
amount of phenylalanine for optimal growth and development. Untreated PKU may lead to acquired
microcephaly, delayed speech acquisition, seizures, eczema, permanent intellectual disabilities, and
behavioral abnormalities. More recently, individuals who have hyperphenylalanemia and even classic
PKU have attained some biochemical benefit from the addition of oral tetrahydrobiopterin (a cofactor for
the enzyme phenylalanine hydroxylase) to standard dietary management.
SUGGESTED READING:
Committee on Genetics. Maternal phenylketonuria. Pediatrics. 2008;122:445-449. DOI:

10.1542/peds.2008-1485. Accessed December 2010 at:
http://pediatrics.aappublications.org/cgi/content/full/122/2/445
Kaye CI and the Committee on Genetics. Newborn screening fact sheets. Pediatrics. 2006;118:e934-
e963. DOI: 10.1542/peds.2006-1783. Accessed December 2010 at:
http://pediatrics.aappublications.org/cgi/content/full/118/3/e934
Mitchell JJ, Scriver CR. Phenylalanine hydroxylase deficiency. GeneReviews. 2010. Accessed
December 2010 at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pku

Question: 165
A 2-year-old boy in your practice is doing well because of immediate institution of dietary galactose
restriction following the diagnosis of classic galactosemia at 14 days of age. Although he initially had
mild jaundice, his liver function is normal, and the mild cataracts noted in infancy seem to have resolved.
His parents ask about long-term developmental and medical consequences of galactosemia.
Of the following, you are MOST likely to tell them that
A. affected individuals are at high risk for the development of cataracts in early adulthood
B. affected men have significant risks for infertility
C. affected school-age children are at risk for learning disabilities
D. dietary nonadherence is associated with long-term neurologic deficits
E. preschool children on dietary restriction rarely have any speech delays

Although dietary control can eliminate some of the more severe or life-threatening consequences of
high concentrations of galactose in galactosemia, potential sequelae still can occur. Developmental
delays and speech delays are seen with high frequency even in children who maintain good dietary
control. Developmental challenges include attentional difficulties, visuospatial problems, and difficulties
with mathematics. In prospective studies, more than 50% of children being treated for galactosemia had
speech defects, including decreased vocabulary acquisition, articulation problems, or verbal apraxia.
Almost 50% of these children also exhibited developmental delays when followed to 6 years of age, with
formal testing showing mildly depressed developmental or intelligence quotients.
Although cataracts are identified in about 30% of affected infants, 50% of these are mild, transient,
and primarily evident in the neonatal period. The risk for premature ovarian failure in girls who have
galactosemia is high (>80%), but affected boys have normal fertility. As noted previously, good dietary
therapy does not completely prevent developmental consequences, but such delays are more significant
in infants initially treated after 2 months of age. Specific neurologic deficits, including tremors and
extrapyramidal signs, may be identified in about 18% of affected individuals older than 5 years of age,
and they are not reduced by good dietary control. Substantial growth restriction also may be seen in
affected children through adolescence, but many of these individuals eventually achieve normal adult
heights.
SUGGESTED READING:
Elsas LJ II. Galactosemia. GeneReviews. 2010. Accessed December 2010

at:http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=galactosemia
Kaye CI and the Committee on Genetics. Newborn screening fact sheets. Pediatrics. 2006;118:e934-
e963. DOI: 10.1542/peds.2006-1783. Accessed December 2010 at:
http://pediatrics.aappublications.org/cgi/content/full/118/3/e934

Question: 182
You are treating an 18-month-old child in whom glycogen storage disease type 1 (GSD1 or von
Gierke disease) was diagnosed at 2 months of age when she presented to the emergency department
with a hypoglycemic seizure and hepatomegaly. With prompt diagnosis and intervention, her condition
improved significantly, and she is doing well on overnight nasogastric cornstarch supplements, with
decreased hepatomegaly and rare episodes of symptomatic hypoglycemia. Her parents have questions
about future medical complications of GSD1 in addition to hypoglycemia and hepatomegaly.
Of the following, the MOST common long term medical problem found in children with GSD1 despite
optimal treatment is
A. chronic constipation
B. decreased growth rate
C. precocious puberty
D. splenomegaly
E. thrombophlebitis

The most likely long-term issue for the girl described in the vignette is decreased growth rate; most
children who have GSD1 experience failure to thrive, followed by suboptimal growth velocity and short
stature in adulthood. Strict dietary management and better metabolic control has resulted in improved
final adult height in recent decades, but growth issues continue to be a concern. Constipation is not a
specific problem in children who have GSD1, and delayed rather than precocious puberty is seen in
poorly controlled or untreated patients. Hepatomegaly and even renomegaly are seen in those who have
GSD1 due to accumulation of glycogen, but splenomegaly does not occur. The glycogen accumulation
is responsive to medical nutrition therapies aimed at maintaining a normal serum glucose concentration.
Thrombophilia or thrombosis is not more common in children or adults who have GSD1, although
impaired platelet function associated with GSD1 can result in bleeding tendencies and recurrent
epistaxis.
Newborns who have GSD1 may present with hypoglycemic seizures, but more often they are
diagnosed between 3 and 4 months of age with evidence of hepatomegaly, lactic acidosis, elevated lipid
and uric acid values, and symptomatic hypoglycemia. Other features may include full cheeks with thin
limbs, diarrhea, and cutaneous xanthomas. Metabolically, affected infants and children can develop
lactic acidosis and hypoglycemia after even very short periods of fasting. Therefore, treatment is
targeted at preventing hypoglycemia and providing sufficient nutrients to support normal somatic growth
and development. Affected infants receive frequent smaller feedings and often require overnight
continuous nasogastric (NG) feedings. Older children (>2 years) may be managed with oral cornstarch
feedings twice a day, but occasionally they also need NG feedings during the night. Allopurinol
sometimes is administered to prevent gout if uric acid concentrations do not decrease sufficiently with
dietary management. Renal stones and nephrocalcinosis are common and serious sequelae of GSD1
that can lead to progressive kidney dysfunction. Supplemental citrate may help to delay or prevent some
of the renal complications, and patients may benefit from ongoing surveillance by a pediatric
nephrologist. Lipid-lowering agents may be necessary to treat hyperlipidemia if this remains a concern
after achieving excellent metabolic control.
Hepatic adenomas are eventually seen in most patients who have GSD1 (usually appearing after 10
years of age) and pose a risk for intrahepatic hemorrhage and even a small risk for malignant
transformation. Osteoporosis is also a common complication, with significantly reduced bone mineral
density observed in children, even before adolescence. In middle childhood, rickets and anemia may
become clinically evident. Polycystic ovarian syndrome is seen in most girls who have GSD1, but it is
unclear whether this affects long-term fertility. Less common complications include pulmonary
hypertension and occasionally pancreatitis due to elevated triglyceride concentrations.
Genetically there are two major GSD1 subtypes: type 1a due to glucose-6-phosphatase deficiency
and type 1b due to glucose-6-phosphate translocase deficiency. Although clinically similar, type 1a is
associated with the platelet dysfunction and bleeding tendency noted previously, and type 1b is
associated with impaired neutrophil and monocyte function with a poor respiratory-burst response to
stimuli that leads to secondary neutropenia and increased susceptibility to gram-positive infections as
well as oral and gastrointestinal ulcers.

SUGGESTED READING:
Bali DS, Chen Y-T, Goldstein JL. Glycogen storage disease type 1. GeneReviews. 2010. Accessed
December 2010 at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gsd1
Dagli AI, Zori RT, Heese BA. Testing strategies for inborn errors of metabolism in the neonate.
NeoReviews. 2008;9:291-298. DOI: 10.1542/neo.9-7-e291. Accessed December 2010 at:
http://neoreviews.aappublications.org/cgi/content/full/9/7/e291
Levy PA. Inborn errors of metabolism. Part 1: Overview. Pediatr Rev. 2009;30:130-138. DOI:
10.1542/pir.30-4-131. Accessed December 2010 at:
http://pedsinreview.aappublications.org/cgi/content/full/30/4/131
Safouh H, Elsayyed R, Mansour S, Taha G, Elshabrawy M, Elkaraksy H. Renal involvement in

children with glycogen-storage disease [abstract]. Pediatrics. 2008;121:S143-S144. DOI:
10.1542/peds.2007-2022TTTTT. Accessed December 2010 at:
http://pediatrics.aappublications.org/cgi/content/abstract/121/Supplement_2/S143-b

2011 PREP SA on CD-ROM
Question: 231
The parents of a 6-month-old boy in your care are concerned because his development seems to
be slowing. They also say that he has begun to startle easily to loud noises, and he is less
attentive than he once was. On physical examination, he appears normally grown and has no
dysmorphisms. He displays some roving eye movements and has reduced tone compared with
his previous examination at 4 months of age. You refer the infant for an ophthalmology evaluation,
which reveals cherry-red spots of the maculae (Item Q231). Blood analysis of hexosaminidase A
activity reveals that it is undetectable.
Of the following, the MOST accurate statement regarding care/treatment for this child is that
A. bone marrow transplant is curative
B. enzyme replacement therapy is now available
C. gene therapy trials soon will be under way
D. megavitamin therapy is beneficial
E. supportive care is all that can be offered
Copyright © 2010 by the American Academy of Pediatrics page 1

Question: 231
(Courtesy of RG Weaver, Jr)

Macular spot, as described for the infant in the vignette.

The infant described in the vignette has early signs and symptoms of Tay-Sachs disease
(TSD), an autosomal recessive, neurodegenerative disorder due to near-absent-to-absent
hexosaminidase A activity. Hexosaminidase A serves to break down a specific glycolipid, GM2
ganglioside, in the lysosomes of cells in the central nervous system. When this enzyme is
markedly reduced or absent, GM2 ganglioside builds up in the cells, ultimately rendering them
nonfunctional. Historically, 90% of children who have TSD have been of Ashkenazi Jewish
descent due to a carrier frequency of 1 in 30 in this population. However, since the advent of
carrier screening programs and education pertaining to TSD in the Jewish population, a higher
percentage of affected individuals belong to other ethnic groups at this time.
Individuals who have TSD typically appear normal at birth. Beginning between 3 and 6
months of age, they may develop mild motor weakness and myoclonic jerks as well as an
exaggerated startle to loud noise. Between 8 and 10 months of age, they fail to attain new motor
milestones, and they have reduced visual attentiveness, with abnormal eye movements.
Ophthalmologic examination performed at this time reveals a "cherry red spot" caused by
prominence of the fovea centralis due to deposition of GM2 ganglioside in the surrounding
macula. By 12 months of age, there is rapid neurologic deterioration, with loss of voluntary
movements and reduced responsiveness. Seizures commonly appear at this time and are
progressively more severe. By 18 months, the head begins to enlarge due to progressive,
reactive cerebral gliosis. Between 2 and 4 years of age, affected children have swallowing
difficulties, worsening seizures, unresponsiveness, and decerebrate posturing. Death most
commonly occurs due to complications of bronchopneumonia.
The management of TSD is purely supportive and is aimed at providing adequate nutrition,
protecting the airway, and controlling seizures. Bone marrow transplant, enzyme replacement
therapy, and gene therapy are not used to treat TSD, and megavitamin therapy is not known to
be helpful.
Suggested reading:
Kaback MM. Hexosaminidase A deficiency. GeneReviews. 2006. Available at:

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=tay-sachs
Nyhan WL, Barshop BA, Ozand PT. Tay-Sachs disease/hexosaminidase A deficiency. In: Atlas of
Metabolic Diseases. 2nd ed. London, United Kingdom: Hodder Arnold; 2005:609-615

Question: 167
You are called urgently to the nursery to evaluate a newborn who exhibits possible seizures.
The baby is a 2-day-old boy who has been healthy and breastfeeding well. Over the past 12
hours, he has become increasingly difficult to arouse and now is refusing to feed. Physical
examination reveals a normally formed baby who has hypertonia and obtundation and responds
weakly to painful stimuli. A bedside glucose determination is 60 mg/dL (3.3 mmol/L), and vital
signs are stable. While arranging for further laboratory testing and transfer to the neonatal
intensive care unit, you observe a generalized seizure.
Of the following, this presentation is MOST suggestive of a
A. fatty acid oxidation defect
B. glycogen storage disease
C. lipid storage disease
D. lysosomal storage disease
E. urea cycle defect

The signs of a progressive encephalopathy within days after birth described for the term
newborn in the vignette could indicate the presence of a urea cycle defect (ornithine
transcarbamylase deficiency, citrullinemia, carbamyl phosphate synthetase deficiency,
argininosuccinic aciduria, or argininemia). The urea cycle, which is the primary pathway for the
excretion of nitrogenous waste, contains five enzymes, any of which may be deficient. The first
symptoms of this group of inborn errors of metabolism include poor feeding and lethargy that, if
untreated, progress to coma. At the first signs of obtundation, it is important to measure plasma
ammonia concentrations as part of a metabolic evaluation. If the infant does not display acidosis
but does exhibit hyperammonemia, a urea cycle defect is likely. Amino acids should be measured
for infants who have plasma ammonia concentrations greater than 210 mcg/dL (150 mcmol/L) to
aid in diagnosis. Strong evidence suggests that the extent of neurologic damage in survivors is
related directly to the duration of hyperammonemic coma, so treatment should be initiated
promptly. Treatment is aimed at removing ammonia from the blood and may include hemodialysis
and arginine infusion. Initially, protein is removed from the diet, but it must be replaced slowly and
limited thereafter.
Fatty acid oxidation defects typically present with hypoglycemia and metabolic acidosis with
increased anion gap. If left untreated, hyperammonemia can occur. The normal bedside glucose
determination reported for the infant in the vignette makes this diagnosis unlikely, although serum
glucose also should be measured.
Glycogen storage diseases can present from days to years after birth. The major presenting
features include hypoglycemia and hepatomegaly in type I and hepatomegaly in type III. Type II
(Pompe disease) is a lysosomal storage disorder and may present with poor feeding and failure
to thrive followed by progressive cardiac failure.
The lipid and lysosomal storage diseases typically do not present with early-onset
obtundation. Clinical features include neurodegeneration and organomegaly. The findings of
coarsening of the facial features or cherry red macular spots (as seen in GM1 gangliosidosis
and Tay-Sachs disease, for example) may be helpful in diagnosing these conditions.
References:
Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics.

1998;102:e69. Available at: http://pediatrics.aappublications.org/cgi/content/full/102/6/e69
Burton BK. Urea cycle disorders. Clin Liver Dis. 2000;4:815-830. Abstract available at:
http://www.ncbi.nlm.nih.gov/pubmed/11232359
Nyhan WL, Barshop BA, Ozand PT. Glycogen storage disease: introduction. In: Atlas of
Metabolic Diseases. 2nd ed. London, England: Hodder Arnold; 2005:382-408
Nyhan WL, Barshop BA, Ozand PT. GM1 gangliosidosis/beta-galactosidase deficiency. In: Atlas
of Metabolic Diseases. 2nd ed. London, England: Hodder Arnold; 2005:599-615

Nyhan WL, Barshop BA, Ozand PT. Introduction to hyperammonemia and disorders of the urea
cycle. In: Atlas of Metabolic Diseases. 2nd ed. London, England: Hodder Arnold; 2005:193-227

Question: 199
A 7-year-old boy who is new to your practice comes in for evaluation of developmental delay
and poor school performance. He began speaking in sentences at age 4. He repeated
kindergarten and is struggling in first grade. On physical examination, you note that he has fair
hair and light skin compared with his brown-haired, olive-skinned younger brother and mother.
He is wearing thick glasses, and his mother says that he was diagnosed as being near-sighted
when he was 2 years old. He has a lanky build with long fingers, and on forward bending, there
is a curve in the thoracolumbar spine.
Of the following, the condition that is MOST consistent with this presentation is
A. alkaptonuria
B. homocystinuria
C. nonketotic hyperglycinemia
D. oculocutaneous tyrosinemia
E. phenylketonuria

Inborn errors of amino acid metabolism (aminoacidopathies) result from the abnormal
breakdown of amino acids in the cytosol. The symptoms associated with this group of disorders
are due to the accumulation of toxic intermediates, such as phenylalanine, that cause organ
damage. Disorders of amino acid metabolism are diagnosed with the aid of plasma and urine
amino acid quantitation; sometimes, measuring urine organic acids also is helpful. The treatment
of aminoacidopathies involves generally limiting protein intake, specifically limiting intake of the
offending protein, and avoiding catabolic states. These conditions are typically autosomal
recessive.
Individuals who have homocystinuria are deficient in the enzyme cystathionine synthase,
which leads to increased methionine in the blood. There are two subtypes of homocystinuria: B6-
responsive and B6-nonresponsive. Excess methionine may be associated with a noticeable,
unpleasant odor. Affected individuals often have more lightly pigmented eyes, skin, and hair than
their unaffected family members, as described for the boy in the vignette. Dislocation of the
lens(es) of the eye(s) is usually apparent by 10 years of age, and the lenses typically sublux
downward. Other eye anomalies include myopia, optic atrophy, cataracts, and retinal
detachment. Skeletal abnormalities are a prominent feature of homocystinuria and overlap with
those seen in Marfan syndrome; they include tall stature with thin body habitus, pectus
excavatum or carinatum, narrow palatal contour, and scoliosis. Some individuals have
arachnodactyly (long fingers), such as the boy in the vignette. Thromboembolism is the most
common cause of morbidity and premature death. The average intelligence quotient (IQ) for
individuals who have the B6-responsive form of the disease is 79, whereas the average IQ for
those who have the B6-nonresponsive form is 57. It is important to identify those individuals
who are B6-responsive to mitigate poor intellectual outcome. Newborn screening for
homocystinuria is required by law in most states in the United States.
Individuals who have alkaptonuria are deficient in the enzyme homogentisate 1,2-
dioxygenase, which is involved in the tyrosine degradation pathway. Affected persons are
typically asymptomatic in childhood. With age, they develop dark gray or black pigmentation of
the sclerae or ear cartilage. Sweat may be dark, and cerumen may be almost black. At all ages,
the urine of an affected individual, when left to stand, turns dark. Arthritis starts to develop in
early adult life and progresses to marked limitation of movement and ankylosis of the spine.
Individuals who have alkaptonuria have a high incidence of heart disease, and myocardial
infarction is a common cause of death. Intelligence is typically normal.
Nonketotic hyperglycinemia results from deficient activity of proteins in the glycine cleavage
system. The classic form of the disease presents in the first few days after birth, coinciding
with intake of protein-containing feedings. Affected children develop anorexia and lethargy,
which progresses to coma. Most affected individuals die at this time. Those who survive the
acute neonatal crisis subsequently develop spastic cerebral palsy, with no evidence of
psychomotor development.
Oculocutaneous tyrosinemia (tyrosinemia type II) is caused by hepatic deficiency of the
enzyme tyrosine aminotransferase in the cytosol. The most important clinical manifestations of
this disorder involve the eye due to the accumulation of tyrosine. Corneal erosions, ulcers, and
plaques can occur and ultimately lead to corneal clouding and visual impairment. Affected

children may present with tearing, photophobia, and eye redness and pain. Cutaneous
manifestations include painful keratoses occurring most often on pressure-bearing regions,
such as the palms and the soles. Treatment of oculocutaneous tyrosinemia includes the
institution of a diet low in tyrosine and phenylalanine. It is not entirely clear whether
oculocutaneous tyrosinemia is associated with an increased incidence of intellectual disability; a
previously described positive association may be due to ascertainment bias.
Phenylketonuria (PKU) is caused by complete or near-complete deficiency of the enzyme
phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Sometimes, the only
manifestation of untreated PKU is intellectual disability. However, vomiting can be an early
symptom, and irritability, an eczematous rash, and an unusual odor (described as mousy, barny,
wolflike, or musty) also may be present. More than 90% of affected individuals are light-eyed,
fair-skinned, and light-haired compared with their unaffected family members. Developmental
delays usually are apparent in untreated individuals within the first 6 postnatal months; if left
untreated, affected individuals suffer severe-to-profound intellectual disability. Spasticity and
seizures also may occur. PKU is treated with a diet that is low in phenylalanine in conjunction
with tyrosine supplementation. Early treatment can prevent the symptoms and signs of disease.
Every state in the United States has required neonatal screening for PKU.
References:
Introne WJ, Kayser MA, Gahl WA. Alkaptonuria. GeneReviews. 2007. Available at:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alkap
Kaye CI and Committee on Genetics. Technical report: introduction to the newborn screening
fact sheets. Pediatrics. 2006;118:1304-1312. Available at:
http://pediatrics.aappublications.org/cgi/content/full/118/3/1304
Mitchell JJ, Scriver CR. Phenylalanine hydroxylase deficiency. GeneReviews. 2007. Available at:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pku
Nyhan WL, Barshop BA, Ozand PT. Alkaptonuria. In: Atlas of Metabolic Diseases. 2nd ed.
London, England: Hodder Arnold; 2005:121-135
Nyhan WL, Barshop BA, Ozand PT. Homocystinuria. In: Atlas of Metabolic Diseases. 2nd ed.
London, England: Hodder Arnold; 2005:146-152
Nyhan WL, Barshop BA, Ozand PT. Nonketotic hyperglycinemia. In: Atlas of Metabolic
Diseases. 2nd ed. London, England: Hodder Arnold; 2005:183-189
Nyhan WL, Barshop BA, Ozand PT. Oculocutaneous tyrosinemia/tyrosine aminotransferase

deficiency. In: Atlas of Metabolic Diseases. 2nd ed. London, England: Hodder Arnold; 2005:168-
174

Picker JD, Levy HL. Homocystinuria caused by cystathionine beta-synthase deficiency.

GeneReviews. 2006. Available at:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=homocystinuria

American Academy of Pediatrics Metabolic Disorders 2014 Practice Test

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

American Academy of Pediatrics Metabolic Disorders 2014 Practice Test

Uploaded by

Copyright:

Available Formats

American Academy of Pediatrics PREP 2014

A. normal bone mineral densities in adulthood if maintained on the PKU diet

American academy of pediatrics 1

Untreated PKU is associated with severe neurocognitive deficits; however, the

American academy of pediatrics 2

American Board of Pediatrics Content Specification(s):

American academy of pediatrics 3

American academy of pediatrics 4

American academy of pediatrics 5

American Board of Pediatrics Content Specification(s):

American academy of pediatrics 6

Of the following, the MOST likely diagnosis for this child is

A. infantile Gaucher disease

American academy of pediatrics 7

The diagnosis of TSD is made by hexosaminidase A assay. Molecular genetic testing

American academy of pediatrics 8

American Board of Pediatrics Content Specification(s):

American academy of pediatrics 9

B. plasma amino acids

E. urine organic acids

Copyright 2013 © American Academy of Pediatrics 1

Critique: 28 Preferred Response: D

Copyright 2013 © American Academy of Pediatrics 3

B. daily and nightly oral raw cornstarch feedings

C. midnight and 4 am concentrated glucose feedings

D. nightly intramuscular glucagon administration

E. no supplements once bedtime glucose levels are >70 mg/dL

Copyright 2013 © American Academy of Pediatrics 4

Critique: 79 Preferred Response: B

Copyright 2013 © American Academy of Pediatrics 5

Kahler SG. Metabolic disorders associated with neonatal hypoglycemia. NeoReviews.

Safouh H, Elsayyed R, Mansour S, Taha G, Elshabrawy M, Elkaraksy H. Renal involvement in

Copyright 2013 © American Academy of Pediatrics 6

B. increase his physical activity

C. initiate treatment with a statin

D. restrict dietary cholesterol

E. restrict dietary saturated fats

Copyright 2013 © American Academy of Pediatrics 7

Critique: 113 Preferred Response: C

Copyright 2013 © American Academy of Pediatrics 8

Of the following, the specialized center is MOST likely to

B. initiate a trial of growth hormone

C. initiate a trial of oral corn starch

D. perform a 50% pancreatectomy

E. perform a 95% pancreatectomy

Copyright 2013 © American Academy of Pediatrics 9

Critique: 177 Preferred Response: E

Copyright 2013 © American Academy of Pediatrics 10

Macmullen CM, Zhou Q, Snider KE, et al. Diazoxide-unresponsive congenital hyperinsulinism in

Copyright 2013 © American Academy of Pediatrics 11

Copyright 2013 © American Academy of Pediatrics 12

Critique: 232 Preferred Response: B

Newborn screening. American Academy of Pediatrics Web site.

Copyright 2013 © American Academy of Pediatrics 13

Copyright 2013 © American Academy of Pediatrics 14

B. is likely to have cherry-red spots noted on ophthalmoscopy

C. may benefit from intravenous enzyme replacement therapy

D. may respond to dietary restriction of certain fatty acids

Copyright 2013 © American Academy of Pediatrics 15

Critique: 249 Preferred Response: C

Andersson H, Kaplan P, Kacena K, Yee J. Eight-year clinical outcomes of long-term enzyme

Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E. Lysosomal storage

Copyright 2013 © American Academy of Pediatrics 17

A. for both children