Genetics QOD
You are called to examine a newborn girl who has multiple
congenital anomalies. On physical examination, you
notice several "punched-out" scalp ulcers,bilateral cleft
lip and palate, postaxial polydactyly (extra digit on the
ring finger side) of the hands, and a small omphalocele.
Of the following, this infant's karyotype
MOST likely is
1.
2.
3.
4.
5.
45,X
45,X/47,XXX
47,XX+13
47,XX+18
47,XX+21
Question 1 Answer C
•
The newborn described in the vignette has a 47,XX+13 karyotype consistent with trisomy 13. Her
unusual features of "punched-out" scalp lesions (also known as "aplasia cutis"), bilateral cleft lip
and palate, and polydactyly are present in at least 50% of newborns who have this diagnosis.
Other common anomalies in affected individuals include holoprosencephaly (incomplete septation
of the frontal lobes), microcephaly, and cardiac defects (80%). Trisomy 13 has a poor prognosis,
with approximately 50% of affected individuals dying by 2 weeks of age and 90% dying by 1 year.
Approximately 50% of individuals who have Turner syndrome have a 45,X karyotype; the
remainder have a mosaic karyotype that includes a cell line consistent with Turner syndrome,
such as 45,X/47,XXX, or a karyotype with 46 chromosomes wherein one of the X chromosomes is
aberrant (eg, ring X, isochromosome Xq). Affected newborns may exhibit dysmorphisms or may
appear completely normal. Unusual features include webbed neck with low posterior hairline,
broad chest with widely spaced nipples, narrow and hyperconvex nails, and cardiac defects, most
commonly bicuspid aortic valve.
Individuals who have trisomy 18 usually have a 47,XX(or XY)+18 chromosome complement.
Characteristic features include intrauterine growth restriction, prominent occiput, small facial
features, clenched hands with overlapping of the second finger over the third and the fifth finger
over the fourth, and hypertonia. Trisomy 18 has a poor prognosis; approximately 50% of affected
individuals die by 2 weeks of age and 90% die by 1 year.
47,XX(or XY)+21 is the most common karyotype seen in individuals who have Down syndrome.
Affected newborns typically exhibit midface hypoplasia with epicanthal folds, upslanting palpebral
fissures, small ears with overfolded pinnae, redundant nuchal skin, and hypotonia. Many affected
individuals have fifth finger clinodactyly (in-curving) (Item C39), and almost 50% have a single
transverse palmar crease. Approximately 45% of affected individuals have congenital heart
defects.
American Board of Pediatrics Content Specification:
•
Recognize the prominent features of trisomy 13 in a newborn infant
You care for a 5-year-old girl who recently
received a diagnosis of neurofibromatosis
type 1 (NF1). Her parents tell you that they
have read that NF1 is associated with an
increased risk for cancers, and they ask
you for more information.
Of the following, the MOST accurate statement
regarding cancers associated with NF1 is that
1.
2.
3.
4.
5.
leukemia is an unlikely cancer type
Lisch nodules predispose to tumors of the eye
optic glioma most commonly presents at the onset of
puberty
pheochromocytoma is common in early childhood
plexiform neurofibromas may show malignant
transformation
Question 2 Answer E
•
Neurofibromatosis type 1 (NF1) is among the most common genetic conditions affecting humans, occurring in 1 in 3,000
births worldwide, regardless of ethnicity or geographic location. NF1 is caused by mutations in the NF1 gene on
chromosome 17; this gene encodes the protein neurofibromin, which acts as a tumor suppressor by downregulating the ras
signal transduction pathway. NF1 is an autosomal dominant condition, and 50% of cases are due to spontaneous gene
mutations. Mutations in NF1 result in the production of cells that have only half the normal amount of intracellular
neurofibromin. The subsequent somatic mutation of the normal NF1 gene leads to tumor formation in affected tissues.
NF1 is a highly variable condition, even within families. Diagnosis is based on the finding of at least two features from the list
of National Institutes of Health diagnostic criteria for NF1 (Item C87A). Using these criteria, approximately 95% of affected
individuals can be diagnosed by age 11 years.
Although most of the tumors associated with NF1 are benign (eg, cutaneous and subcutaneous neurofibromas), affected
individuals are at increased risk for malignancy (approximately 35% to 37% lifetime risk versus approximately 30% risk in the
general population). Plexiform neurofibromas, which occur in about 25% of individuals who have NF1, are a special type of
neurofibroma that may exist largely beneath the skin's surface (Item C87B) or entirely internally. Plexiform neurofibromas
undergo malignant transformation to neurofibrosarcomas in 10% to 15% of patients who have them. Signs of malignant
transformation include the sudden onset of rapid tumor growth and pain at the site. Expeditious medical evaluation is
warranted in such circumstances.
Lisch nodules are hamartomas that resemble freckles and are located in the iris stroma (Item C87C). They can be
appreciated in light-colored eyes with the use of a direct ophthalmoscope; a slitlamp is helpful for detecting them in darkly
pigmented irises. Although not pathognomonic for NF1, the presence of two or more is a diagnostic criterion for the
condition. They are benign and have no impact on vision.
Optic glioma occurs in approximately 15% of individuals who have NF1 and typically develops before 6 years of age. Of
note, optic glioma may be discovered at an older age upon head imaging performed for any purpose, but if it is not present
by age 6 years, it typically does not occur. These benign tumors may cause problems due to their location along the optic
nerves (Item C87D).
Myeloproliferative and myelodysplastic leukemias are among the malignancies associated with NF1. Individuals who have
NF1 have an increased incidence of pheochromocytoma, which typically occurs in adulthood. Individuals who have NF1 do
not appear to be at increased risk for developing the common cancers affecting the breast, colon, and prostate.
American Board of Pediatrics Content Specifications:
•
•
Know that neurofibromatosis is an autosomal dominant disease with extremely variable expression that produces tumors
Recognize that neurofibromatosis is inherited as an autosomal-dominant trait with a high spontaneous mutation rate
You are seeing a 4-year-old boy who is new
to your practice for a health supervision
visit. While reviewing the family history,
you learn that his father has
neurofibromatosis type 1 (NF1). Careful
examination of the boy's skin using a
Woods lamp reveals six café au lait
macules measuring at least 5 mm, but no
other lesions.
Of the following, the MOST likely feature(s)
of NF-1 to develop next in this boy is (are)
1.
2.
3.
4.
5.
cutaneous neurofibromas
Lisch nodules
plexiform neurofibroma
pseudarthrosis of the tibia
skinfold freckling
Question 3 Answer E
•
Neurofibromatosis type 1 (NF1) is among the most common genetic disorders in humans, occurring in
approximately 1 in 3,000 individuals worldwide. The diagnosis is based on clinical criteria established by the
National Institutes of Health Consensus Development Conference in 1987 (Item C215A). To meet the diagnostic
criteria for NF1, a person must have at least two of the criteria listed.
Typically, the first feature to appear is café au lait macules (Item C215B), as described for the boy in the vignette.
The diagnosis should be considered in any prepubertal child who has six or more café au lait macules measuring
at least 5 mm at their greatest dimension. The macules may be present at birth or appear in infancy.
Approximately 80% of individuals who have NF1 have at least 6 café au lait macules by age 5 years. These may
be difficult to see initially, and a Woods lamp may be helpful. Sun exposure causes them to darken.
It is important to recognize that the appearance of the diagnostic features of NF1 is largely age-dependent. This
fact, together with the extreme variability of the condition at any age, can make the diagnosis challenging. Most
commonly, the second feature to appear is skinfold freckling (Item C215C), usually in the axillae and groin; this
commonly occurs between ages 3 and 5 years. Cutaneous or subcutaneous neurofibromas are often the third
feature to appear, and they typically herald the onset of puberty. Lisch nodules, frecklelike hamartomas (Item
C215D) in the iris stroma, may not be evident until early adulthood.
Plexiform neurofibromas occur in approximately 25% of individuals who have NF1 and are often congenital (Item
C215E). They can remain quiescent for indefinite periods of time, grow steadily, or grow intermittently. These
lesions can be disfiguring.
Tibial pseudarthrosis is either congenital or occurs following fracture due to congenital tibial bowing (Item C215F).
Children who have tibial dysplasia should be referred promptly for orthopedic care.
Although genetic testing is available for NF1, implementation is not often necessary. By the age of 11 years, 95%
of affected individuals meet clinical diagnostic criteria.
American Board of Pediatrics Content Specifications:
•
•
•
Know the clinical features of neurofibromatosis
Know that six or more café au lait spots >.5 cm in diameter suggest the diagnosis of neurofibromatosis.
Be aware that neurofibromas usually do not appear until after puberty
• You are asked to consult on a baby in the neonatal
intensive care unit who has severe respiratory distress
and unusual physical features. The baby is receiving
maximum ventilatory support, but his oxygen saturation
is in the 80s. His nose is deviated to one side, his ears
are overfolded, and his hands and feet are unusually
positioned. You review his chest radiographs and note
bilateral pulmonary hypoplasia.
Of the following, the test that is likely to be MOST
helpful in determining the cause of this infant's
abnormalities is
1.
2.
3.
4.
5.
chromosome analysis
Echocardiography
head magnetic resonance imaging
renal ultrasonography
toxicology screen
Question 4 Answer D
•
In 1946, Potter described the clinical features associated with bilateral renal agenesis. Subsequently,
fetuses and infants that had similar findings were referred to as having "Potter syndrome." More recently,
however, it has been recognized that the constellation of features associated with Potter syndrome
actually are caused by a cascade of effects due primarily to oligohydramnios, and the term
"oligohydramnios sequence" has come into favor.
The term "oligohydramnios tetrad" sometimes is used to refer to the four primary clinical features
associated with a prolonged reduction in amniotic fluid: abnormal, "pugilistic" facies; lung hypoplasia;
limb deformation; and renal agenesis or, variably, fetal growth deficiency. In fact, renal agenesis is not
necessary for oligohydramnios sequence to occur; any circumstance that leads to significant,
longstanding oligohydramnios, such as renal dysplasia with reduced urinary output, posterior urethral
valve, and chronic leakage of amniotic fluid, can be causative. Reduction in amniotic fluid volume before,
or beginning at the middle, of the second trimester interferes with normal fetal "breathing," resulting in
lung hypoplasia. Affected newborns cannot be ventilated adequately, and pulmonary insufficiency usually
is the cause of death. Reduced amniotic fluid also leads to fetal constraint that, in turn, causes facial
deformities (compression of the nose, overfolding of the ears) and unusual positioning (deformation) of
the limbs.
The physical findings described for the infant in the vignette are consistent with oligohydramnios
sequence, and the most appropriate next step in management is evaluation of the urinary tract by renal
ultrasonography. If the imaging indicates renal agenesis, supportive care can be offered. If a urinary tract
outflow obstruction is present, the clinician must determine whether surgical correction would offer
benefit.
It is important to consider that this infant could have a chromosome abnormality underlying his anomalies
and might have other birth defects affecting the heart or brain. However, absent or dysplastic kidneys or
other genitourinary tract anomaly is likely to be the direct cause of his presentation. In addition, he may
have been exposed to substances prenatally that have affected his genitourinary system, such as
cocaine or angiotensin-converting enzyme inhibitors, but such knowledge has no impact on immediate
medical management.
American Board of Pediatrics Content Specification:
•
Know that any infant with features of the oligohydramnios tetrad (Potter facies) warrants a detailed
evaluation of the genitourinary system
A couple comes to you for counseling following the delivery
of a stillborn fetus that had multiple anomalies 1 year
ago. They would like to have another baby, but they are
concerned about the possibility of recurrence. The
couple declined autopsy after the fetus was delivered,
but they bring you photos for review. You note a cleft
extending diagonally across the face, a constriction ring
around one arm, and multiple digital amputations on the
ipsilateral hand with attached strands of tissue.
Of the following, the MOST accurate statement
regarding this condition is that it stems from an
abnormality that usually occurs
1. at conception
2. in association with amniocentesis
3. in association with chorionic villus sampling
4. in the first trimester
5. in the second or third trimester
Question 5 Answer D
•
The infant described in the vignette has amniotic band sequence (also known as amniotic rupture
sequence and amniotic band disruption sequence); the strands of tissue attached to the hand with
digital amputations are important clues to the diagnosis. Amniotic band sequence refers to the
fetal anomalies that can occur as a result of early amnion rupture. Once this diagnosis is
established, it is appropriate to tell the parents that this is a sporadic occurrence, and recurrence
risk for future pregnancies is negligible.
Although multiple theories have been proposed about the cause of this phenomenon, one of the
most widely held is that it is due to early, primary rupture of the amnion before 12 weeks'
gestation. Prior to 12 weeks' gestation, the amnion and chorion are separate membranes, making
the amnion more susceptible to rupture. Fetal entrapment can occur any time throughout the
remainder of the pregnancy. Following rupture, strands of amnion can wrap around developing
fetal structures, leading to constriction and reduced distal blood flow that results in hypoplasia,
syndactyly, or amputation. The tissue strands also can transect the body and head, resulting in
abdominal wall defects and facial clefts, respectively. Furthermore, amniotic bands may cause
changes, such as limitation of movement, that lead to unusual fetal position and result in fetal
deformation. It is important to look for evidence of amniotic bands in the newborn who has limb
deficiencies; they often are washed away with the first bath. Examination of the placenta also may
allow for confirmation of amniotic rupture.
There are rare reports of amniotic bands occurring in association with maternal trauma such as a
bad fall within the first 12 weeks of pregnancy, resulting in amniotic rupture. Amniotic bands are
not associated with procedures such as chorionic villus sampling or amniocentesis.
American Board of Pediatrics Content Specification:
•
Know that amniotic bands can become adherent to any part of the fetal body, thereby causing a
variety of disruptions (eg, ring-like constrictions of limbs, amputation of digits, disruptive cleft of
the face)
• The parents of one of your patients, who
has spina bifida, would like to have a
second child. They want to do everything
possible to reduce the risk of having
another baby affected by a neural tube
defect. You discuss the benefits of
maternal folic acid supplementation, citing
the recommendations from the Centers for
Disease Control and Prevention.
Of the following, the percent reduction in neural tube
defects that has occurred since implementation of these
recommendations is CLOSEST to
1.
2.
3.
4.
5.
5% to 15%
15% to 25%
25% to 50%
50% to 70%
70% to 90%
Answer C
•
Neural tube defects (NTDs) are among the most common of the birth defects, with a
worldwide incidence of 1 per 1,000 births. They are caused by both environmental
and genetic factors. Of the environmental factors that play a role in neural tube
closure, folic acid has proven to be the most significant thus far.
Folic acid is a water-soluble B vitamin (vitamin B9) that is essential to humans and is
abundant in leafy, green vegetables; legumes (such as peas and beans); and some
seeds (such as sunflower). Folate, the naturally occurring form of folic acid, plays an
important role in conditions involving rapid cell division, such as pregnancy. Folate
also is important in purine production, which is required for DNA and RNA synthesis
and repair, as well as other biochemical pathways.
Numerous well-designed studies have shown that oral supplementation with 0.4
mg/day of folic acid from 1 month prior to conception through the first trimester in
women who have not had a previous child affected by an NTD reduces the current
fetus' NTD risk by up to 75%. For women who have had a previously affected child, a
dose of 4.0 mg/day is recommended for the same time period and reduces the
recurrence risk by up to 75%.
•
Despite the previously cited recommendations for supplementation, the expected
decline in NTD rate did not occur, and in 1998, mandatory fortification of cereal grain
products with folic acid went into effect in the United States. Unfortunately, the
hoped-for reduction in NTD rate has not occurred since that time. Instead, the
reduction in rate of NTDs has been approximately 25% to 50%. Factors contributing
to this lower reduction rate include lack of patient education, reduced patient
compliance, and barriers to prenatal care.
NTD research continues, with a focus on genes and epigenetic (factors that influence
gene expression) variables that play a role in NTDs. The role(s) of folic acid in these
processes largely remain(s) a mystery.
American Board of Pediatrics Content Specification(s): Understand the role of
folic acid in the prevention of neural tube defects
• A 4-year-old girl presents to your clinic for evaluation of
developmental delays and dysmorphic features. On
physical examination, you document unusual facial
features and multiple major anomalies. Review of a
recent developmental evaluation reveals significant
global delays. Family history is negative for any
individuals who have birth defects or intellectual deficits.
You consult a medical geneticist, who does not
recognize a pattern to this child's features and
recommends genetic testing. The high-resolution
chromosome analysis yields normal results.
Of the following, the testing strategy that is MOST likely to
be helpful in determining the cause of this child's anomalies
is
1.
2.
3.
4.
5.
comparative genomic hybridization
DNA testing for fragile X syndrome
fluorescence in situ hybridization
urine organic acid analysis
X-inactivation studies
Answer A
•
Genetic testing for individuals who have intellectual disabilities, multiple anomalies,
and dysmorphic features is evolving rapidly. High-resolution chromosome analysis,
which requires dividing cells, has a resolution of 5 to 19 megabases (Mb), making it
impossible to detect deletions, duplications, or rearrangements that could contain
hundreds of genes. Therefore, additional testing is required for the girl described in
the vignette.
Fluorescence in situ hybridization (FISH), which uses fluorescently labeled DNA
probes that hybridize to dividing or resting cells, has a higher resolution than
chromosome analysis and is excellent in detecting missing, extra, or relocated
chromosomal regions. However, it does not detect single-gene mutations, and it
requires that the physician request testing for a specific region, or regions, of interest.
Without a recognized pattern to the features for the child in the vignette, a specific
request is not possible. FISH is useful for identifying contiguous gene deletions, as
can be seen in Prader-Willi, Angelman, Williams, Smith-Magenis, and Miller-Dieker
syndromes. The combined diagnostic yield of chromosome analysis and targeted
FISH testing approaches 10% in children who have intellectual disabilities and
dysmorphisms.
•
Microarray-based comparative genomic hybridization (CGH) is a revolutionary testing
strategy for the detection of DNA copy number variations throughout the human
genome that may be associated with disease. Depending on the platforms used,
which vary largely according to the size of the probes used (the smaller the probe,
the greater the resolution) and the amount of the genome covered, microarray CGH
can detect clinically significant abnormalities in up to 20% of individuals who have
unexplained intellectual disability. Therefore, it is the most helpful choice for
determining the cause of this child's anomalies. It is important to note, however, that
this modality also detects variations of unclear clinical significance as well as
variations of no clinical significance.
The array CGH procedure employs thousands to millions of probes (synthetic DNA
sequences that hybridize with genomic DNA) that are affixed to glass or silicon
wafers (chips) or beads. Added to this matrix are a sample of the patient's DNA
labeled with a green dye, for example, and a sample of reference DNA labeled with a
red dye, for example. Following hybridization of the samples to the chip, sophisticated
equipment is used to interpret the results. Simply speaking, wherever there are equal
amounts of patient DNA and reference DNA on the chip, a yellow color is present. If
there is excess patient DNA on a probe, the region appears green, and if there is
excess reference sample on a probe, the region appears red.
•
Microarray CGH does NOT replace high-resolution chromosome analysis for
identifying all genetic abnormalities of clinical significance. Abnormalities that can be
detected on chromosome analysis but not on microarray CGH at the time of this
writing include balanced chromosomal rearrangements (that theoretically can transect
a gene and may have reproductive significance for parents of the proband who are
potential carriers of the rearrangement), free-standing trisomy versus translocationrelated trisomy, and low-level chromosomal mosaicism.
Fragile X syndrome typically is not associated with multiple major anomalies and is
seen most commonly in boys. Organic acid analysis is most helpful in the evaluation
of children who have metabolic derangements, which are not part of this child's
presentation. Finally, X-inactivation studies generally are used if a girl is believed to
have a presentation typically only seen in a boy who has an X-linked disorder, in
which case she may have preferential inactivation of the X chromosomes containing
the normal copy of the gene in question.
•
American Board of Pediatrics Content Specification(s): Understand that
comparative genomic hybridization has replaced high-resolution chromosome
analysis to screen patients suspected of having a chromosome abnormality
Know the common gene defects that can be diagnosed with fluorescence in situ
hybridization
• A couple comes to you with questions following
the diagnosis of trisomy 21 in their now 18-week
fetus. They ask what medical problems may be
anticipated for a child who has Down syndrome.
Of the following, the medical problem that is
encountered MOST frequently in infants who have
trisomy 21 is
1.
2.
3.
4.
5.
a cardiac defect
duodenal atresia
hypotonia
polycythemia
strabismus
Answer C
•
A syndrome is a recognizable pattern of features owing to a specific cause. Down
syndrome (DS) is caused by trisomy for all, or a critical portion of, chromosome 21.
Almost 99% of affected individuals have extra chromosome 21 material in every cell
in their bodies; approximately 1% have a mosaic chromosome complement
(46,XX/47,XX+21 or 46,XY/47,XY+21). Chromosome 21 is composed of about 400
genes. An extra copy of some or all of these genes causes a variety of potential
medical problems, which should be discussed with the parents who are expecting an
affected baby. It is important to note that each child who has DS is unique, and there
is a spectrum of potential outcomes. Of note, individuals who have mosaic DS are
anticipated to have similar features/cognitive ability to those who have full trisomy 21
because it is not possible to know which tissues contain the abnormal chromosome
complement. If these individuals are affected more mildly than the typical person who
has DS, this fact becomes evident over time.
Hypotonia is one of the most common abnormalities in babies who have DS,
occurring in up to 90%. The degree of hypotonia varies from child to child, but usually
it is not so severe as to interfere with feeding in the newborn period, and most babies
who have DS are able to breastfeed effectively (assuming there is not a cardiac
abnormality that precludes this). Early intervention programs should address
hypotonia by offering appropriate therapies. The natural history of low muscle tone in
DS is that it improves over time.
•
•
Approximately 12% of children who have DS are born with anomalies of the
gastrointestinal tract, including Hirschsprung disease, esophageal atresia,
tracheoesophageal fistula, and pyloric stenosis. Duodenal atresia occurs in
approximately 4%.
Cardiac abnormalities are present in approximately 45% of newborns who have DS.
Most are atrioventricular canal defects (almost 50%), followed by ventricular septal
defects (~33%), but a variety of anomalies can occur. All newborns who have DS
should undergo echocardiography, regardless of their physical examination findings.
Polycythemia is a complication during the newborn period in approximately 18% of
individuals who have DS. Polycythemia can interfere with oxygenation, and
sometimes partial exchange transfusion is recommended for treatment. Otherwise,
this problem typically is self-limiting.
Problems affecting the eye occur in approximately 60% of children who have DS and
include cataracts, lacrimal duct stenosis, nystagmus, and refractive errors.
Strabismus occurs in up to 50%. Direct ophthalmoscopic examination should be
performed regularly during pediatric visits, with referral to a pediatric ophthalmologist
for baseline evaluation between 6 and 12 months of age. Ophthalmology follow-up is
tailored to the child's needs but should take place at least every 2 years.
American Board of Pediatrics Content Specification(s): Know the associated
medical problems in children with Down syndrome
• You have sent one of your patients, who has
achondroplasia, for follow-up evaluation in the genetics
clinic. When discussing achondroplasia with the medical
student after the evaluation, the medical geneticist points
out that approximately 80% of individuals who have this
diagnosis have spontaneous mutations in the fibroblast
growth factor receptor 3 (FGFR3) gene.
Of the following, the mutation that causes
achondroplasia MOST commonly is a(n)
1.
2.
3.
4.
5.
autosomal recessive trait
contiguous gene deletion
deletion of FGFR3 only
duplication of FGFR3
single base-pair substitution
Answer E
Achondroplasia, the most common form of dwarfism, is an autosomal dominant
condition. In 99% of affected individuals, it is caused by a single base-pair change
(guanine-to-adenine or guanine-to-cytosine) at nucleotide 1138 in the fibroblast
growth factor receptor 3 gene (FGFR3). Both of these changes result in the
substitution of an arginine for a glycine in the encoded protein, leading to increased
activation of the growth factor receptor. Because the normal action of the receptor is
to reduce bone growth, its increased activity leads to shorter bones and smaller
stature.
It is important to note that DNA point mutations (substitutions, deletions, or
insertions of a single base-pair) can cause a wide range of outcomes, some of which
are dramatic. Point mutations can result in the production of nonfunctional proteins
(nonsense mutations), different amino acids than expected (missense mutations),
and alterations in the amino acid or protein that have no functional significance (silent
mutations).
One of the best known examples of a point mutation causing severe disease is
that seen in sickle cell disease (SCD). SCD is caused by a single base-pair
substitution in the beta-globin gene, resulting in the production of a valine instead of a
glutamic acid in the protein. The resultant hemoglobin molecule is malformed, such
that it cannot carry oxygen effectively.
Although contiguous gene deletions, as well as gene deletions and duplications, are
associated with numerous genetic disorders, they do not play a significant role in
causing achondroplasia.
American Board of Pediatrics Content Specification(s): Understand that a single
base pair substitution or deletion can lead to a gene defect with major consequences
• The attending neonatologist notifies you that she is caring for a
newborn boy in your practice who has multiple congenital
anomalies. The baby was transferred from the newborn nursery to
the intensive care unit due to cyanosis. Echocardiography reveals
findings consistent with tetralogy of Fallot. The infant has a cleft
palate. Chest radiographs show multiple thoracic hemivertebrae.
Renal ultrasonography documents unilateral renal agenesis. On
physical examination, the infant has hypoplastic thumbs. The baby
is normally grown and vigorous.
Of the following, the MOST likely diagnosis for this
infant is
1.
2.
3.
4.
5.
CHARGE syndrome
Fanconi anemia
trisomy 18
22q11 deletion syndrome
VACTERL association
Answer D
•
The combination of tetralogy of Fallot, hypoplastic thumbs, cleft palate, and a renal
abnormality described for the infant in the vignette is highly suspicious for 22q11
deletion syndrome. This syndrome can be diagnosed by fluorescence in situ
hybridization or comparative genomic hybridization microarray. The incidence of
22q11 deletion syndrome is believed to be approximately 1 in 4,000, making it one of
the most common multiple congenital anomaly syndromes. Fanconi anemia is an
autosomal recessive condition that is extremely rare (1 in 100,000 to 1 in 350,000)
and is associated with physical abnormalities (thumb hypoplasia, heart defect, renal
anomalies, and more) in 60% of affected individuals as well as bone marrow failure
and significant cancer risk. It is more common among persons of Ashkenazi Jewish
heritage.
Trisomy 18 occurs in approximately 1 in 3,000 births. Affected infants may share a
number of the features with the infant in the vignette, but they typically are small for
gestational age and usually are feeble. In medical genetics, the term "association" is
used to describe abnormalities that occur together more than would be expected by
chance but that do not have a common cause. Probably the most well known of these
is the VATER association, where V=vertebral anomalies, A=anal atresia,
TE=tracheoesophageal fistula, and R=renal anomalies (Item C183). The VATER
association has been expanded since its original description to "VACTERL"
association, wherein C=cardiac defects, and L=(radial)limb anomalies. To consider
VACTERL association as a possibility, at least one anomaly in each of three
geographic regions of involvement (pelvis/lower abdomen, limb, and thorax) is
deemed necessary, but no official minimum criteria are established.
•
It is important to recognize that associations are better classified as descriptions than
as diagnoses. For an infant to receive the label of VACTERL association, all other
reasonable possibilities should be ruled out, including chromosomal and microarray
abnormalities, teratogenic exposures, and syndromic diagnoses.
CHARGE (C=coloboma, H=heart, A=atresia choanae, R=retardation of growth and/or
development, G=genital anomalies, E=ear anomalies) was considered an association
until it was described in more detail and ultimately discovered to be caused by
alterations in the CHD7 gene in 2006. It is now appropriately called "CHARGE
syndrome," and the features that are most consistent with this diagnosis have been
delineated even further. For example, cranial nerve dysfunction and internal ear
anomalies are more prevalent than once thought, and intelligence often is normal.
•
American Board of Pediatrics Content Specification(s): Recognize multiple
congenital anomaly associations such as VATER, CHARGE
Recognize the clinical manifestations of genetic associations (eg, CHARGE,
VACTERL, VATER)
• You are called to the newborn nursery to evaluate a term
female infant who has dysmorphic facial features. She
was born to a woman who received no prenatal care.
Labor and delivery were uncomplicated. The infant has
normal weight, length, and head circumference. On
physical examination, you document notched lower
eyelids, hypoplastic zygomatic arches, malar hypoplasia,
a hypoplastic ear on one side with two preauricular tags
on the same side, and retrognathia. The remainder of
the findings are normal.
Of the following, the condition with which this
infant's features are MOST consistent is
1.
2.
3.
4.
5.
diabetic embryopathy
Pierre Robin sequence
Stickler syndrome
Treacher Collins syndrome
22q11 deletion syndrome
Answer D
•
The infant described in the vignette has features of mandibulofacial dysostosis, a
description that applies to a group of disorders in which there is underdevelopment of
the mandible and variable facial and ear anomalies. The best characterized of the
mandibulofacial dysostoses is the Treacher Collins syndrome (TCS).
TCS is an autosomal dominant condition that is highly variable and is caused by
spontaneous gene mutations in 60% of affected individuals. Unusual features
associated with TCS include downslanting eyes with lower lid coloboma (notching)
and absent eyelashes medial to the notch, malar hypoplasia, hypoplastic/malformed
external ears with conductive and/or sensorineural hearing loss, and
microretrognathia that has the potential to compromise the airway. Features may be
highly variable, even within the same family.
TCS is known to be associated with only one gene, TCOF1, and most individuals who
meet clinical diagnostic criteria for TCS have detectable mutations in this gene.
Clinical molecular testing is available and may serve to establish recurrence risk for
very mildly affected or apparently unaffected individuals.
•
The management of TCS is supportive. Special attention should be given to the
airway because of the potential for choanal stenosis/atresia or glossoptosis (posterior
displacement of the tongue). The newborn should be examined carefully for cleft
palate and swallowing difficulties. Formal audiologic evaluation is important to
establish a baseline and to detect possible hearing loss. Ophthalmology referral is
indicated in early infancy due to increased risk for corneal damage, strabismus, and
refractive errors. Craniofacial computed tomography scan with three-dimensional
reconstruction may be indicated in the first 6 months to define anatomy better in
anticipation of future treatments such as plastic surgery.
Diabetic embryopathy can include malformation/hypoplasia of the ears. However,
affected individuals do not have notched lower eyelids or malar hypoplasia, as seen
in TCS, and they frequently have heart defects and other anomalies.
Pierre Robin sequence (retrognathia, retroglossia, and cleft palate) may be isolated
or may be part of a bigger picture, such as Stickler (Item C199) and 22q11 deletion
syndromes. In each case, there is marked retrusion of the mandible, but the eye
findings associated with TCS are not present, and although the ears may be unusual
in 22q11 deletion, typically they are not severely malformed.
•
American Board of Pediatrics Content Specification(s):
Know the clinical features of Treacher Collins syndrome and that it is due to a single
gene defect
• You are called to the newborn nursery to
evaluate an infant who has had two dusky
episodes unrelated to feedings. Serum glucose
values are normal. Oxygen saturation on pulse
oximetry is 98% with the infant sleeping
comfortably on her side. Cardiac examination
yields normal results. You notice features
consistent with Pierre Robin sequence (PRS)
Of the following, the series of events that MOST
commonly causes PRS is
1.
2.
3.
4.
5.
cleft palate → glossoptosis → airway obstruction
depressed midface → choanal stenosis → airway
obstruction
glossoptosis → cleft palate → cleft larynx → airway
obstruction
macroglossia → cleft palate → airway obstruction
retrognathia → glossoptosis → cleft palate → airway
obstruction
Answer E
•
A sequence is a cascade of events that occurs subsequent to a primary abnormality
in the developing embryo/fetus. One of the best known of these is the Pierre Robin
sequence (PRS), also called "Robin sequence". It is named after the French
physician who, in 1933, described the pattern of micrognathia, glossoptosis (posterior
displacement of the tongue), and cleft palate.
The primary cause of PRS is believed to be hypoplasia of the mandible before 9
weeks' gestation. At 9 weeks, the palatal shelves, which "hang down" on either side
of the tongue, normally swing up and close, anteriorly to posteriorly. If the mandible is
small (micrognathia) or posteriorly placed (retrognathia), the tongue is pushed back
and mounded up, making it impossible for the palatal shelves to "clear" the tongue as
they try to close over it.
There are myriad causes of PRS, including uterine constraint, single gene disorders,
chromosome abnormalities, teratogenic exposures, disruptions, and unknown
reasons. It is incumbent upon the physician caring for the child who has PRS to
investigate underlying causes because a unifying diagnosis is important in defining a
management strategy, the natural history of the disorder, and recurrence risk.
•
The clinical presentation of PRS varies. Some affected individuals have relatively mild
micrognathia, a small and soft palatal cleft, and minimal-to-no difficulties with feeding
and breathing. Some have oxygen desaturations that can be treated effectively with
side or prone positioning. Others are severely affected and have marked
micrognathia, large palatal clefts, and severe glossoptosis, leading to airway
compromise and frequent cyanotic spells. Furthermore, there may be swallowing
difficulties. Medical intervention is required in these cases and includes feeding tubes
(usually nasogastric) and various methods of maintaining airway integrity, including
tongue-lip adhesion, intubation, tracheostomy, and mandibular traction.
Of note, some studies have shown that infants and children who have PRS may have
oxygen saturations less than 90% for prolonged periods without evidence for airway
obstruction. They are at increased risk for pulmonary hypertension that ultimately can
cause cor pulmonale and failure to thrive. Although no formal recommendations exist
for surveillance in PRS, it may be prudent to monitor oxygen saturations and refer for
echocardiography at regular intervals.
•
American Board of Pediatrics Content Specification(s): Know that upper airway
obstruction caused by glossoptosis may cause cor pulmonale in infants with PierreRobin sequence
Know that the features of Pierre-Robin sequence are secondary to micrognathia
• The parents of a 12-year-old boy bring him to the clinic
because they are concerned about his lack of interest in
socializing and physical activity. He was held back in
school this year due to learning problems, primarily in
reading and writing. He has no close friends, and his
favorite activity is watching television. On physical
examination, the pleasant and attractive youngster
converses with you easily. His weight is at the 50th
percentile and his height at the 95th percentile. He wears
thick glasses due to high myopia. He has mild scoliosis
in the thoracic spine. He shows no signs of puberty.
Using a Woods lamp, you identify five café au lait
macules on his trunk and extremities.
Of the following, the MOST likely diagnosis for this
boy is
1.
2.
3.
4.
5.
Asperger syndrome
Klinefelter syndrome
Marfan syndrome
neurofibromatosis
Stickler syndrome
Answer B
•
The combination of poor social interaction with same-age peers, a tendency to be a
loner, difficulties with reading and writing, and tall stature described for the boy in the
vignette should raise suspicion for the diagnosis of Klinefelter syndrome (KS). KS
typically is associated with a 47,XXY karyotype, although the term applies to boys
who have at least one extra X chromosome or a mosaic chromosome complement
with at least one cell line having more than one X.
KS is relatively common, with a birth incidence of 1.2 per 1,000 males. There are
three times in the lifespan when KS is likely to be diagnosed: 1) prenatally, on
amniocentesis performed due to advanced maternal age; 2) in adolescence, due
primarily to gynecomastia (present in one third of affected boys); and 3) in adulthood,
due to infertility.
Boys who have KS typically do not have dysmorphisms. They are tall compared with
their chromosomally normal siblings, and they often have mild skeletal differences,
such as an increased carrying angle or gynecoid pelvis. Scoliosis is common in boys
who have KS. Puberty usually is delayed, and after puberty, affected boys may have
reduced facial or body hair, gynecomastia, and small testes. Obesity and poor
muscular development may be evident. Elevations in luteinizing hormone and folliclestimulating hormone are associated with reduced testicular function and lack of
feedback inhibition by testosterone. In adulthood, individuals who have KS are at
increased risk for Leydig cell neoplasia, and a history of gynecomastia is associated
with a 20- to 50-fold increased risk for breast cancer compared with the general male
population.
•
From developmental and behavioral standpoints, there is wide variation among boys
who have KS, but common problems include delays in motor skills, speech and
language, and reading. A commonly described feature is the "the tip of the tongue"
phenomenon, wherein the boys are unable to retrieve the correct phrase or response
to a question. The boys tend to be immature, to adapt poorly to unfamiliar situations,
and possibly to be inappropriately aggressive. Inattentiveness may be a problem, and
social skills are often lacking, although the boys may relate better to adults than to
their peers. Intelligence quotient (IQ) is usually within the normal range, although the
average IQ is typically 10 to 20 points less than in otherwise healthy siblings.
Asperger syndrome (AS) is a multifactorial autism spectrum disorder associated with
deficits in social interaction that involves relative preservation of language and
cognitive function. AS has an estimated incidence of 1 in 5,000. Affected individuals
are not typically tall, and they have an unusual conversational style, sometimes
speaking in a monotone, showing few facial movements, or displaying restricted body
movements.
Marfan syndrome is an autosomal dominant connective tissue disorder associated
with tall stature and skeletal abnormalities, including arachnodactyly, pectus
deformity, and scoliosis as well as dilation of the aortic root and subluxed lenses of
the eye. Thus far, an association with learning problems is not documented.
Socialization is average for age.
•
Stickler syndrome is an autosomal dominant connective tissue disorder that may
have skeletal features overlapping with Marfan syndrome in childhood. Cardinal
features are prominent eyes and malar hypoplasia as well as rapidly progressive high
myopia. Scoliosis is a complication of the disorder. Learning problems are not part of
the picture, and socialization is normal.
Neurofibromatosis (NF) type 1 is an autosomal dominant neurocutaneous syndrome
that has an incidence of 1 in 3,500. Café au lait macules (CALMs) typically are the
first sign to appear, and six or more CALMs measuring at least 5 mm in diameter in a
prepubertal child should raise suspicion for this diagnosis. Individuals who have NF1
are at increased risk for intellectual and learning disabilities. NF1 is not associated
with tall stature, and socialization typically is normal.
American Board of Pediatrics Content Specification(s): Know the major clinical
manifestations of Klinefelter syndrome
• 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. 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
1.
2.
3.
4.
5.
bone marrow transplant is curative
enzyme replacement therapy is now available
gene therapy trials soon will be under way
megavitamin therapy is beneficial
supportive care is all that can be offered
Answer E
•
The infant described in the vignette has early signs and symptoms of Tay-Sachs
disease (TSD), an autosomal recessive, neurodegenerative disorder due to nearabsent-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.
American Board of Pediatrics Content Specification(s): Be familiar with the longterm prognosis and chronic management of Tay-Sachs disease
• 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
1.
2.
3.
4.
5.
fatty acid oxidation defect
glycogen storage disease
lipid storage disease
lysosomal storage disease
urea cycle defect
Answer E
•
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.
American Board of Pediatrics Content Specification:
Recognize urea cycle defects
• 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, oliveskinned 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
1.
2.
3.
4.
5.
alkaptonuria
homocystinuria
nonketotic hyperglycinemia
oculocutaneous tyrosinemia
phenylketonuria
Answer B
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 lighthaired 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.
American Board of Pediatrics Content Specification:
Recognize the clinical findings of a disorder of amino acid metabolism
A 16-year-old boy complains of pain in his feet after running long
distances as well as intermittent numbness and tingling in his fingers
and toes for the past 4 months. On physical examination, the only
finding of note is somewhat high arches (pes cavus). Consultation
with an orthopedist results in referral for electromyography and
nerve conduction studies, and the finding of low-normal nerve
conduction velocities is suggestive of Charcot-Marie-Tooth Disease
type 2 (CMT2). Review of the family history reveals that neither of
the boy’s parents nor his younger sister have any signs or
symptoms of hereditary motor and sensory neuropathy. His
maternal grandfather “may have had” had high foot arches and later
in life had an awkward gait believed to be a result of poor balance.
This grandfather also had a brother who had foot drop, and their
mother had to retire from working on an assembly line in a factory in
her forties due to hand weakness, but she never had any
recognizable problems with her feet.
Of the following, the MOST likely cause for CMT2
in this patient is
1.
2.
3.
4.
5.
a new (de novo) autosomal dominant mutation in
one of the CMT2 genes
an unbalanced chromosomal translocation that
disrupts one of this boy’s CMT2 genes
incomplete penetrance of this autosomal dominant
gene passed down through his mother
preferential gender expression of this autosomal
dominant gene, with males more likely to be
symptomatic
variable expression of a mitochondrial gene passed
to him from his mother and to his other affected
relatives from their mother
Answer C
•
•
The teenage boy described in the vignette has symptoms of a peripheral sensory and
motor neuropathy that is confirmed on electrophysiologic testing and believed to be
Charcot-Marie-Tooth Disease type 2 (CMT2). As with many autosomal dominant
conditions, there is great variability in the expression of this condition among family
members, and this boy is exhibiting more clinical symptoms at a younger age than
other possibly affected maternal family members. The complete lack of symptoms in
the boy’s mother (which occurs in up to 25% of CMT2 carriers) could be attributed to
incomplete penetrance, which is the complete absence of symptoms despite carrying
an autosomal dominant condition or trait. However, there is still some potential for her
to develop symptoms later in life like her father, uncle, and paternal grandmother. If
she ultimately develops symptoms, the CMT2 would be considered variable
expression rather than incomplete penetrance.
Although de novo mutations occur in a number of patients who have CMT, the
presence of symptoms such as pes cavus and gait difficulties in the boy’s maternal
grandfather, foot drop in his maternal great-uncle, and peripheral neuropathy in his
maternal great-grandmother are much more suggestive of autosomal dominant
transmission. An unbalanced translocation disrupting a CMT gene in this young man
would be expected to cause additional problems such as intellectual disabilities or
congenital anomalies; even a balanced translocation would be a rare cause of CMT
and might be suspected if there was a history of recurrent pregnancy losses.
Although preferential sex expression or increased severity of expression in one sex
over another is described in a few autosomal dominant conditions (such as Alport
syndrome), there does not appear to be any such bias in expression of symptoms in
CMT.
•
•
The variability in clinical features described in this scenario is probably simply chance
and not sex-specific. Mitochondrial transmission has not been described in CMT and
could not explain this family history because the boy’s maternal grandfather could not
pass a mitochondrial trait to any of his children; the mitochondrial genome is
transmitted exclusively from mothers to their offspring in the cytoplasm of oocytes at
conception.
CMT is a group of hereditary sensory and motor neuropathies associated with
variable symptoms such as pes cavus, distal hand or foot muscle weakness and
atrophy, mild-to-moderate sensory loss, and sometimes depressed deep-tendon
reflexes. Diagnosis may be made using electromyelography and nerve conduction
velocity testing, with molecular studies sometimes helpful in confirming a suspected
diagnosis or used in family planning. Although autosomal recessive and X-linked
CMT exist, they represent the minority of cases. Patients who have CMT1 typically
develop symptoms between the ages of 5 and 25 years, whereas those who have
CMT2 may have a slightly less severe course and less significant changes in their
nerve conduction velocities. There are 15 molecular subtypes of CMT2, making
molecular diagnostic testing very expensive and difficult to obtain. Although few
patients who have CMT1 or CMT2 become wheelchair-bound, they do experience
significant disability and pain. Care requires a multidisciplinary team of specialists that
may include neurologists, physiatrists, orthopedists, orthotists, and occupational and
physical therapists. Both nonsteroidal anti-inflammatory agents and tricyclic
antidepressants or GABA analogs such as gabapentin may be used to treat pain.
• A couple who is planning to bring their child to you for
care, present for a prenatal consultation at 28 weeks’
gestation. After reviewing basic information about your
practice, the wife explains that she is one of six children,
four of whom are currently alive. She had a sister and a
brother who both died between the ages of 3 and 4
years. Although normal at birth, both children had
progressive loss of milestones beginning at about 1 year
of age, with hypotonia and later severe muscle
weakness, difficult-to-control seizures, visual loss, and
eventual death. No other individuals in the extended
family had such problems. The woman is concerned
about this family history and wishes to know possible
risks for her children as well as advice about testing for
her newborn.
Of the following, you are MOST likely to tell her
that her affected siblings probably had
1.
2.
3.
4.
5.
an autosomal dominant condition with incomplete
penetrance, and the risk to her unborn child may be
as high as 50%
an autosomal recessive condition, and the risk to her
unborn child is probably low
a mitochondrial condition, and the risk to her unborn
child may be as high as 100%
an X-linked dominant condition, and the risk to her
unborn child may be as high as 50%
an X-linked recessive condition, and the risk to her
unborn child may be as high as 50% if she gives birth
to a son
Answer B
•
•
The family history described in the vignette is most suggestive of a progressive,
neurologically devastating autosomal recessive condition, such as Tay Sachs disease
or metachromatic leukodystrophy, which can occur in both male and female
siblings. No other family members are affected in other generations, and it is not
known if the parents of the affected children are blood relatives (consanguineous). In
the absence of consanguinity in this pregnancy, risks for the woman described in the
vignette to have an affected child likely are small, based on this rare autosomal
recessive condition in her siblings. There would be more of a concern for this
pregnancy if her siblings had a relatively common recessive condition such as cystic
fibrosis (CF) or sickle cell anemia because the general population carrier frequency
for these conditions is relatively high. Her own risks of being a carrier of this
autosomal recessive condition is 2 in 3, so risks to her pregnancy would rely on the
estimated risks that her partner is also a carrier. If this patient is from an ethnic group
that has a higher risk for autosomal recessive disorders such as Tay-Sachs disease
in individuals of Ashkenazi Jewish descent (and her siblings had a disorder
associated with this particular ethnic group), then the risks to her child may be greater
because of the carrier frequency for this condition in this particular population.
•
•
An affected male and female in a single sibship is not suggestive of an autosomal
dominant, X-linked dominant, or X-linked recessive condition because if the condition
was autosomal or X-linked dominant, one of the parents should be affected and if the
condition was X-linked recessive only boys should be affected. With mitochondrial
inheritance, all children born to a mother who harbors the mitochondrial mutations in
a certain proportion of her mitochondrial genomes would be expected to be affected
as well as potentially the mother herself. Although the onset of symptoms and
severity of disease can vary and may be modified by the relative percentages of
normal and abnormal mitochondrial genes within a given individual, the history
provided by the expectant mother is far more suggestive of a life-limiting
neurodegenerative autosomal recessive condition.
For some of the more common autosomal recessive conditions, carrier screening
may be available. Such screening should be considered before conception to allow
couples to have the opportunity for preconception counseling.