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Genetics
Metro NY/NJ Pediatric Board
Review Course
Joy M. Samanich, M.D.
Robert W. Marion, M.D.
Albert Einstein Col of Med/
Children’s Hosp at Montefiore
Question 1:
In the NICU, you’ve just examined a newborn with hypotonia
and dysmorphic features that included epicanthal folds,
upward slanting of the palpebral fissures, flat nasal bridge
with anteverted nares and midface hypoplasia.
Among the following, the medical complication that is
MOST likely to present in the newborn period in this infant is:
1.
2.
3.
4.
5.
atlantoaxial instability
hypothyroidism
leukemia
obstructive bowel disease
seizures
10
0%
1
0%
0%
2
3
0%
0%
4
5
Question 1: Preferred Response: D

The baby has features of Down syndrome. He should be
observed for:
 Obstructive gi tract abnormalities (~10%) including
duodenal atresia, annular pancreas, anal atresia, and TEF.
 Cardiac anomalies (~40%) including ECCD. ALL
INFANTS WITH DS SHOULD HAVE ECHOCARDIOGRAM BEFORE DISCHARGE FROM THE
NURSERY!
 Polycythemia and leukemoid reaction (which can look
like leukemia but is self-limited); ALL INFANTS WITH DS
SHOULD HAVE A CBC!
 Congenital hypothyroidism (~1%)
Question 1: Preferred Response: D (GI obstruction)





Atlantoaxial instability, which can lead to compression
of the cord, occurs in ~10%, but is not a problem in
the newborn period. Neck films (lateral in neutral,
flexion and extension) should be performed after age 3.
Pts with DS have a higher incidence of leukemia, which
approaches 1% (but is also not a problem in the NB).
Seizures occur in a small number of patients with DS .
All patients with DS display cognitive impairment,
(most with IQs in the mod MR range). Early
intervention to maximize development in early
childhood is recommended.
HE SHOULD ALSO HAVE CHROMOSOME
TESTING:
Question 2:
You tell the infant’s parents of your concern that
their baby has Down syndrome. After the initial
shock, the mother asks about her risk of having
another child with a chromosomal abnormality.
The statement that you are MOST likely to include
in your discussion is that her risk:
A. can be estimated by determination of maternal
serum alpha-fetoprotein in all future pregnancies
B. cannot be estimated until her infant's
chromosome complement has been determined
C. is increased for Down syndrome, but not for any
other chromosomal abnormality
D. is no greater than that of other women her age
E. is not increased until she reaches the age of 35
Question 2: Preferred Response: B
Following the clinical diagnosis of Down syndrome, it’s
essential to obtain a karyotype, which will provide information
about parental risks in future pregnancies. In DS:
95% are due to trisomy 21 (46,XY,+21 or 46,XX+21)
 3% are due to unbalanced Robertsonian translocations
involving an acrocentric chromosome (13, 14,15, 21, or
22) ; ie: 46, XY, -14. t (14q21q)
 2% are due to mosaicism

If the condition is caused by trisomy, the recurrence risk
for any trisomy is 1%
Question 2:
Preferred Response: B
If the condition is due to an unbalanced translocation, it is
necessary to do a karyotype on the parents. In these cases:
 2/3 are de novo (both parents have normal karyotypes).
RR is ~1%
 1/3 result from unbalanced segregation of a balanced
Robertsonian translocation in one of the parents.
If mother is the translocation carrier (45,XX,-14,-21, t(14q21q),
RR=10-15%
 If father is the translocation carrier (45,XY,-1`4,-21,t(14q21q),
RR=2-5%.
 If the balanced translocation involves one chromosome 21
attached to the other (ie. 45,XY, -21,-21, t(21q21q), all progeny
will have Down syndrome!
 Once a balanced translocation is found, other family members
should be tested

Question 3:
As long as you’re already in the nursery, you’re asked
to see 3 infants born with cleft lip and/or palate. The
first has a left CL+P; exam is otherwise normal. You
tell his parents that this is apparently an isolated
birth defect.
During counseling about their risk for having another
similarly affected child, the statement that you are
MOST likely to include is that
A. because the defect is isolated, their risk is no
greater than that of any other couple
B. Isolated cleft lip and palate is a multifactorial trait
that has a 4% risk of recurrence
C. the recurrence risk can be estimated only after a
chromosome analysis has been obtained
D. the risk is increased for future females, but not
males
E. the risk would be increased only if one of the
parents had cleft lip and palate
Question 3: Preferred Response: B



Isolated CL+/-P is inherited as a multifactorial (MF) trait,
caused by the interplay of genetic and environmental factors.
Disorders showing MF inheritance occur more commonly in
individuals in a particular family than in the general
population, but at a lower rate than would be expected for
single gene traits. RR for MF traits have been derived by
analysis of many families that express the trait. For CL+/-P,
RR for a family in which neither parent is affected and
only one child is affected is 2-5%.
MF inheritance is seen in many common birth defects (CHD,
CDH, NTDs, pyloric stenosis, hypospadias, etc). In general,
the RR for all of these disorders is between 2 and 5%.
MF inheritance is also the cause of most disease of childhood
and adulthood, ie. asthma, DM, hypertension, cancer,
alcoholism, coronary artery disease, etc.
Question 3: Preferred Response: B



RR of MF traits is altered by a # of factors, including the
number of family members who are affected. The RR for
subsequent sib of a child who has clubfoot is 3%. However, if
one parent also had clubfoot, RR is 10-15%.
To provide accurate information about RR, a careful exam
should be done to identify additional anomalies. The
possibility that the most obvious defect is part of a genetic
syndrome, which may carry a higher risk, must be considered .
In general, chromosome analysis should be obtained in
pts with two or more major abnormalities (eg, clefting,
congenital heart disease) or one major anomaly and two or
three minor defects (eg, epicanthal folds, simian line).
Accordingly, chromosome analysis would not be indicated for
an infant with an isolated cleft lip and palate.
Question 4
The next baby you see in the
nursery, a boy, has bilateral CL+P.
Further exam reveals scalp defect
in the parietooccipital region,
microphthalmia, cryptorchidism, a
cardiac murmur and polydactyly.
Of the following, the MOST
likely underlying condition is:
A. holoprosencephaly sequence
B. retinoic acid embryopathy
C. trisomy 13
D. trisomy 18
E. valproate embryopathy
Question 4: Preferred Response: C
As noted in the last question, CL+/-P can occur in isolation
or as part of a multiple malformation syndrome. Syndromes
(groups of malformations caused by a single identifiable
etiology) can occur due to a chromosomal abnormality, a
single gene mutation, or as the result of exposure to a
teratogen. In the present patient, the pattern of findings is
most consistent with trisomy 13.
 Trisomy 13 (47,XX or Y,+13) occurs in 1 in 5-10,000
liveborns. Most affected infants die in the newborn period;
5% survive to 6 months.
 It is associated with advanced maternal age. Associated
features include holoprosencephaly, severe MR;
microcephaly; microphthalmia; coloboma; CL+/-P; ear
anomalies; distinctive scalp defects in the occipital area;
CHD; postaxial polydactyly and cryptorchidism in males.
Question 4: Preferred Response: C




Peripheral blood karyotype should be performed to
document dx and help provide genetic counseling about
future risks. In particular, it’s important to determine if the
child has a translocation inherited from one parent which
would increase the RR (see previous case).
Fetal valproate syndrome results in CHD, NTDs and
unusual facial features (narrow bifrontal diameter, high
forehead and epicanthi) as well as limb defects.
Retinoic acid embryopathy results in facial asymmetry,
microtia or anotia, & CHD.
Trisomy 18 is characterized by growth deficiency,
prominent occiput, low-set ears, micrognathia, clenched
hand, and structural defects of the heart and kidney.
Microphthalmia and clefting are not prominent features.
Question 5:
The next baby you visit in
the nursery has a CP and retrognathia, but no other anomalies.
Of the following, the MOST serious
complication that may occur in the
first 72 hours of this child's life is:
A. acute otitis media requiring
antibiotic treatment
B. congestive heart failure
C. difficulties with breastfeeding
D. upper airway obstruction with
oxygen desaturation
E. worsening airway obstruction when
placed in the prone position
Question 5: Preferred Response: D
The Pierre-Robin malformation sequence (PRMS) is
characterized by: (1) micrognathia, (2) glossoptosis; and
(3) a U-shaped cleft of the palate. The initial event in the
sequence is failure of mandibular growth in the 1st trimester. This results in displacement of the tongue & failure
of the palatal shelves to close, causing the U-shaped cleft.
 PRMS may occur in isolation or as part of a syndrome.
Associated ones include Stickler, 22q11 deletion and
CHARGE syndromes.
 In infants, the glossoptosis may occlude the airway,
especially when they are supine. Obstructive apnea with
desaturation is by far the most serious complication
that may develop within the first days of life. Such
obstruction may be severe enough to cause ischemic
encephalopathy.
Question 5: Preferred Response: D

Feeding difficulties are common in children with PRMS.
Posterior displacement of the tongue and the cleft may
contribute to a poor suck. In most cases, though, oral
feeding, including breastfeeding, is successful. Although
OM is quite common among children who have cleft palate,
it typically does not cause problems in early infancy.

PRMS is a medical emergency in the newborn!
The infant should be placed in the prone position, which
allows the tongue to fall forward, relieving the obstruction.
But this is only a temporary measure: definitive treatment
is essential to assure that the airway remains open.
Placement of a nasopharyngeal tube should occur, followed
by surgical management.
Question 6:
As long as you’re already in the nursery,
the resident asks you to see a newborn who
has some unusual features. Born by C/S
because of breech presentation, the baby
has a deformed cranium, torticollis, facial
asymmetry, a dislocated right hip, and
bilateral clubfeet. Findings on the remainder
of the physical examination are normal.
Of the following, the MOST likely cause
of this infant's abnormalities is
A.
a chromosomal abnormality
B.
a malformation syndrome
C.
an underlying CNS defect
D.
exposure to a teratogen in utero
E.
intrauterine compression
Question 6:


Preferred Response: E
Malformations are defined as abnormalities of form or
function that are caused by alterations in the tissue primordia
that forms a structure; as such, malformations occur in the
first trimester, can range from mild to severe, and usually
require surgical correction. They occur in ~3% of newborns.
Deformations result from abnormal external forces acting on
normally formed tissue. Unlike malformations, deformations
develop after the first trimester, are frequently mild, and
usually improve spontaneously once the external force has
been removed. One to 2% of neonates have one or more
deformations.
Question 6:


Preferred Response: E
The infant described has multiple features suggestive of a
deformation sequence due to intrauterine compression.
The most important factor contributing to deformation is
the restriction of fetal movement, which can be caused by
mechanical forces, malformations, or functional
abnormalities. However, mechanical causes are the most
common etiology. Frequently, more than one deformation is
present because the mechanical force exerts an adverse
effect on multiple body parts. 1/3 of all deformations occur
in infants who present in the breech position.
A chromosomal abnormality or teratogen exposure
associated with the multiple defects described for this infant
would be expected to cause malformations of internal organ
systems as well as external findings
Question 7:
You’re in Spina Bifida Clinic. Your first patient is an
infant recently D/C’d from the NICU after having her
myelomeningocele closed and a VP shunt placed.
She has typical problems of an infant with an L2
lesion: hydrocephalus, dislocated hips, club feet and
paraplegia. Her parents are concerned about
recurrence in future pregnancies.
Of the following, the statement you are MOST
likely to make is that their RR
1.
2.
3.
4.
5.
depends on the family's ethnic background
depends on the location of the defect along the
neural axis
is increased only if the defect is part of a
genetic syndrome
is the same as that for any other couple
will be reduced if the mother takes
periconceptional folate supplementation
0%
1
0%
0%
2
3
10
0%
0%
4
5
Question 7: Preferred Response: E


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
NTDs result from failure of the neural tube to close prior to the 27th
postconceptional day. Closure proceeds from mid-cervical area
caudally and rostrally. Anterior closure defects result in anencephaly;
posterior defects result in meningocele or myelomeningocele..
Before 1990, NTDs occurred in 1 in 1,000 births. Etiology is heterogeneous, including chromosome anomalies (trisomy 18), single gene
defects (Meckel-Gruber), and teratogenic exposures (Valproic acid).
Isolated NTDs exhibit MF inheritance. RR is 2-4%; such couples
should be offered prenatal monitoring in future pregnancies.
Isolated NTDs are more common in individuals from the British
Isles and less common in Asians; in NA, births of infants with NTDs
cluster in the late fall and early winter. This has led to the discovery
that periconceptual folic acid supplementation can decrease the
risk of having a child with NTD by 70%. This diminution in risk
exists for both women who have had a previous affected child as well
as those who have not had an affected child.
Question 7: Preferred Response:


It has been hypothesized that FA prevents NTDs by
stimulating certain enzymes (eg, methionine synthetase)
that otherwise are present in reduced levels in susceptible
women. It’s recommended that all women take folic acid:
women who have had a previously affected child are given
a dose of 4 mg/day; all others receive 0.4 mg/day.
RR in families in which there is a child who has an NTD
does not depend significantly upon the ethnic group. The
location of the defect along the neural axis also does not
influence RR. If the NTD is part of a syndrome, the
specific RR for the syndrome should be discussed.
Question 8:
While in Spina Bifida Clinic, you are
visited by a 42 y.o. primigravida who
is in her 16th week of pregnancy. She
is concerned about the possibility of
her child having myelomeningocele.
Of the following, the MOST useful
diagnostic evaluation is
A.
amniocentesis
B.
chorionic villus sampling
C.
cordocentesis
D.
fetal ultrasonography
E.
maternal alpha-fetoprotein
screening
Question 8: Preferred Response: D


Fetal sonography performed between 12 and 24 weeks of
pregnancy is most useful for detection of structural
anomalies such as NTDs. Its sensitivity and specificity can
be substantially improved if performed by an experienced
sonographer. It’s noninvasive, safe, & accurate in experienced
hands. Advantages of early fetal sonography include improved
dx of multiple gestation and accurate dating of the pregnancy.
Although levels of AFP in amniotic fluid are increased in the
fetus who has open NTDs, this test has limited sensitivity &
specificity for the dx of a myelomeningocele. Early amnio
(between 12 & 14 weeks) is most useful for detecting fetal
chromosomal abnormalities (ie trisomy 21) & genetic defects .
Question 8:



Preferred Response: D
CVS, which entails biopsy of the placenta between 8 and 11
weeks, is not useful for diagnosing NTDs. It’s most helpful
for detecting cytogenetic abnormalities, but it is an invasive
procedure and has risks.
Cordocentesis (aspiration of fetal blood by direct puncture of
the umbilical cord under sonographic guidance) is not useful
for the diagnosis of NTDs. It can aid in diagnosing conditions
such as coagulation disorders, blood cell abnormalities, and
congenital infections such as toxoplasmosis. This invasive
procedure has a great many risks.
We’ll discuss maternal serum AFP screening in the next
question:
Question 9:
At the end of Spina Bifida Clinic, you are talking to a group of
residents about NTDs. You explain that when the fetus has an
open NTD, elevated levels of maternal serum alphafetoprotein
(MSAFP) can be seen during the 16th-18th weeks of pregnancy.
Of the following, your discussion is MOST likely to include
the statement that:
A. chromosomal disorders can also cause high levels of MSAFP
B. further tests are required to confirm the diagnosis of an NTD
C. levels of AFP in maternal serum and amniotic fluid have
similar specificity
D. the majority of birth defects cause elevated levels of MSAFP
E. the presence of multiple fetuses will not affect the
interpretation of MSAFP levels
Question 9:




Preferred Response: B
AFP, the fetal equivalent of albumin, is produced only during fetal
life; thereafter, AFP is found only in the serum of pregnant women
and adults with liver disease (hepatoma).
Since the 1960s, an association between NTDs & elevated levels of
AF-AFP has been noted. The defect in the fetal skin causes AFP to
pass between the fetal circulation and the amniotic fluid. Elevated
AF-AFP levels also occur in fetuses with omphalocele, gastroschisis,
bladder exstrophy, cystic hygroma, as well as in multiple gestations,
impending fetal death, etc.
Since 1970s, the association between these defects and elevated
levels of MSAFP was also noted. Measuring MSAFP between the
16th and 22nd week of gestation has become a standard screening test
throughout the world.
As noted above, an elevated MSAFP level is not pathognomonic for
exposed neural tissue. It is not, however, elevated with most birth
defects. And trisomy 13, 18 and 21 are all associated with an
MSAFP level that is less than expected.
Question 9:



Preferred Response: B
A positive MSAFP requires confirmatory testing,
including sonogram (to verify dates and identify defects)
and amniocentesis (for chromosome analysis or
acetylcholinesterase activity).
The concentration of AFP in the maternal serum is an
order of magnitude lower than that in the amniotic
fluid; thus, it is more difficult to measure.
The development and refinement of obstetric sonography has led some authorities to question whether
this might be an adequate screening tool for NTDs.
However, ultrasonography will fail to detect some flat
or low myelomeningoceles.
Question 10:
In genetics clinic, you’re seeing a 5 y.o. girl who has
multiple café au lait spots and axillary freckling. Slitlamp
ophthalmic exam reveals the presence of Lisch nodules,
confirming the diagnosis of neurofibromatosis.
Of the following, the MOST appropriate statement
about the potential for the development of tumors in this
child is that:
1.
2.
3.
4.
5.
acoustic neuromas are common and annual screening
with MRI is indicated
all patients with neurofibromatosis eventually develop
plexiform neurofibromas
annual urinary catecholamine screening for the presence
of pheochromocytoma is indicated
cutaneous neurofibromas usually do not appear until
preadolescence
the overall lifetime risk for the development of a
malignancy is 50%
10
0%
0%
1
2
0%
0%
0%
0%
3
4
5
6
Question 10: Preferred Response: D

This child has features of NF-1. The diagnosis of NF-1 is
made on the basis of having two of the following 7
criteria:
 Café au lait spots: 6 or more of >0.5 cm in diameter
for prepubertal children or >1.5 cm post pubertally
 Axillary and/or inguinal freckles
 Neurofibromas: 2 or more, or 1 plexiform
 Optic glioma
 Lisch nodules
 Skeletal abnormalities, including scoliosis,
pseudarthrosis, sphenoid wing dysplasia
 Family history of a 1st degree relative with NF-1,
diagnosed using these criteria.
Question 10: Preferred Response: D

NF-1 is an autosomal dominant disorder and one of the
most common single-gene defects.
 The gene, NF-1, which is on chromosome 17, produces
neurofibronin, an inhibitor of nerve growth factor.
 The gene is huge, one of the largest in the human
genome; there are no “common mutations.” As such,
molecular diagnosis depends on sequencing the entire
gene, a strategy that is not practical.
 In about half of cases, the condition occurs as a
spontaneous mutation.
Question 10: (continued)



Other tumors that occur in pts with NF-1 include:
plexiform NFs (usually evident in the first 2 yrs of life).
These tumors, in ~5%, can undergo sarcomatous change
and frequently present a surgical challenge because of their
extensive vascular supply. CNS tumors, including optic
gliomas, occur in 2-3% of affected individuals. Overall, the
lifetime risk for the development of a malignancy in
patients who have NF-1 is ~5% (NOT 50%!).
Acoustic neuromas are a prominent feature of NF-2. They
are bilateral in ~ 85% of patients and unilateral in ~6%. In
NF-2, cutaneous findings are not as prominent.
Pheochromocytoma is a rare tumor in NF-1 (<1% of
patients), but it is common in patients who have von
Hippel-Lindau disease.
Question 11:
The next patient in clinic is the mother of a 13-mo-old boy
recently diagnosed with factor VIII deficiency hemophilia. The
woman is in the 1st trimester of her 2nd pregnancy, and is
interested in knowing if prenatal diagnosis is available.
Of the following, the statement about prenatal diagnosis
that you are MOST likely to include in your discussion is that:
A. factors VIII and IX deficiency hemophilia can be dx’d
prenatally in over 95% of families
B. factors VIII and IX deficiency hemophilia can be dx’d
prenatally only in 20% of families
C. neither type of hemophilia can be dx’d prenatally
D. only factor IX deficiency hemophilia can be dx’d prenatally
E. only factor VIII def. hemophilia can be dx’d prenatally
Question 11: Preferred Response: A


Molecular technology allows us to prenatally
diagnose mutations leading to Factor XIII and
Factor IX hemophilia in > 95% of families.
The genes for both diseases are located near the
terminus of Xq.
Hemophilia occurs in ~1 in 5,000 individuals in
the general population, with 80-85% of patients
having factor VIII deficiency hemophilia
(hemophilia A) and 10-15% having factor IX
deficiency (hemophilia B). Neither disorder has
apparent racial or ethnic predilection.
Question 11:


Preferred Response: A
The factor VIII gene is much larger, more complex, and has a strong
predisposition to spontaneous mutation:
 ~1/3 of affected individuals have no family history and appear to
represent new mutations.
 More than 200 different mutations have been identified, with the
most common being a gene inversion in the tip of Xq, which
accounts for ~45% of cases of severe hemophilia A and always is
associated with the severe form of the disease.
 Other mutations account for the remaining cases of severe
disease and most cases of moderate or mild disease.
The factor IX gene is considerably smaller and less complex. >400
mutations have been identified. Because the gene is smaller, DNA
sequencing can be employed to identify mutations and can be used
for carrier detection and prenatal dx. There is a very low rate of
spontaneous mutation, so the family history almost always is
positive.
It’s lunch time in Clinic. Time for some
quickies:
Of the following, the findings that are MOST
suggestive of the dx of Prader-Willi syndrome are:
1.
2.
3.
4.
5.
gigantism and visceromegaly
hyperactivity and ataxic
movements
hypocalcemia and a congenital
heart defect
MR and macroorchidism
obesity and small hands and
feet
0%
1
0%
0%
2
3
10
0%
0%
4
5
The answer is E

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


A describes Beckwith Wiedemann syndrome
B describes Angelman syndrome
C describes diGeorge (aka velocardiofacial,
Shprintzen, or 22q11.2 deletion syndrome)
D describes Fragile X syndrome
Children with PWS have a characteristic history:

Hypotonia in infancy, with poor sucking and FTT
Improvement in muscle tone by age 1 year
Development of a voracious, insatiable appetite

Development of obesity and related problems



PWS results from deficiency of the gene
product of the SNRPN gene. SNRPN
(15q11) is only expressed in the
chromosome 15 inherited from the
father. Thus, PWS results when a copy
of paternal chromosome 15 is missing.
This can be caused by:


Deletion of pat 15q11.2 (seen in 60-70%): Use
FISH to diagnose
Maternal uniparental disomy of chromosome
15 (yielding two copies of maternal
chromosome 15 and no copies of paternal
chromosome 15) (seen in 20%)
Another quickie:
All of the following are
associated with Williams
syndrome EXCEPT
A. “Cocktail party” personality
B. Hypercalcemia
C. Supravalvular aortic
stenosis
D. Short philtrum
E. Mental retardation
The answer is D




WS is a contiguous gene
syndrome caused by
deletion of 7q11.2 (use FISH
or array CGH to make
diagnosis)
Occurs in 1 in 5,000 births
Features include all those
listed in question except for
short philtrum (which is
seen in fetal alcohol
syndrome).
Heart disease occurs in 80%,
with SVAS in 67%
A third quickie:
Noonan syndrome is
characterized by each of
the following EXCEPT
A.
Autosomal recessive
inheritance
B.
Short stature
C.
Pulmonic stenosis
D.
Webbed neck
E.
Low set ears
The answer is A




Noonan syndrome is caused by a mutation in the
PTPN11 gene on chromosome 12.
Occurs in 1 in 10,000 births
Features include all those listed in question
except for AR inheritance
50% also have Factor 11 deficiency causing
prolonged PTT.
Yet another:
A child is born with esophageal atresia. Other
associated abnormalities might include all of the
following EXCEPT
A.
B.
C.
D.
E.
Cardiac defect such as VSD
Absence of the left radius
Renal malformations
Hemivertebra
Cataracts
The answer is E



Esophageal atresia, occurring alone or as part of a TEF, can
be isolated or part of a syndrome or association. The most
common association is VACTERL.
Association: a group of malformations that occur more
commonly together than would be expected by chance, but for
which no etiology can be identified.
Features of VACTERL include:
 Vertebral anomalies
 Anal anomalies (imperforate, stenotic, etc)
 Cardiac anomalies (VSD, ASD most common)
 Tracheo-Esophageal Fistula
 Renal anomalies
 Limb anomalies (specifically radial ray defects)
Last one:
Which of the following is typical of Ehlers Danlos
syndrome?





A. Osteoporosis
B. Hypotrichosis
C. Large head and short extremities
D. Joint laxity
E. Progressive neurologic and ophthalmologic
problems
The answer is D




Osteoporosis is seen in osteogenesis imperfecta.
Hypotrichosis occurs in anhidrotic ectodermal dysplasia.
Large head and short extremities describes
achondroplasia.
Ehlers Danlos is a disorder of collagen that leads to:
 Joint laxity
 Spontaneous joint dislocation
 Hyperelastic skin
 Poor scar formation (“cigarette paper” scars)
 Easy bruisability
Okay, really last one:
For which of the following disorders would you use PCR
testing for trinucleotide repeats to make the diagnosis?
A.
B.
C.
D.
E.
Crouzon syndrome
Fragile X syndrome
Cri-du-chat syndrome
MELAS syndrome
Down syndrome
Preferred Response: B
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Crouzon syndrome is a craniosynostosis syndrome, usually
diagnosed clinically. This is a single gene disorder, with
autosomal dominant inheritance, and DNA testing is available
for mutations in FGFR-2.
Fragile X syndrome is a trinucleotide repeat disorder, with an
excess number of CGG repeats leading to symptoms including
intellectual disability and characteristic facial features.
Cri-du-chat syndrome is a continuous gene disorder, diagnosed
by FISH or array comparative genomic hybridization (CGH).
MELAS syndrome is a mitochondrial disorder, diagnosed by
testing of specific mitochondrial DNA genes.
Down syndrome is an aneuploidy syndrome diagnosed by
karyotype or FISH, also detectable by array CGH.
OKAY, LUNCH IS OVER
TIME TO GO TO
METABOLIC CLINIC:
1st Patient in Metabolic Clinic:
The parents of a 2 y.o. boy with Tay-Sachs disease (TSD)
(hexosaminidase A deficiency) ask you about the availability of
prenatal testing during their next pregnancy.
Of the following, the MOST appropriate statement to include
in your counseling is that:
A. prenatal dx should be considered only after testing each
parent to determine carrier status
B. testing can be performed on chorionic villus cells obtained as
early as 10 weeks of pregnancy
C. testing is possible only if the parents' mutations in the
hexosaminidase gene are known
D. the results of prenatal diagnostic testing for TSD are
considered investigational
E. their risk of having another similarly affected child is no
greater than that of any other couple
Preferred Response: B
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TSD, an AR inherited inborn error of metabolism, results from absence
of HexA, a lysosomal enzyme. Parents of an affected child are obligate
carriers and together, have a RR of 25% for subsequent pregnancies.
HexA activity can be measured in fetal cells obtained by CVS, performed
as early as 10 weeks gestation, or via amnio (14-16 weeks).
Carrier frequency for TSD is highest in Ashkenazi Jews and French
Canadians, although the mutation can occur in any ethnic group. Among
Ashkenazim, the carrier frequency is ~1 in 25.
Screening programs to identify carriers have been conducted since the
1970s. These programs, relying on the measurement of hex activity in
serum or isolated leukocytes, have virtually eradicated the disease among
this population. In the past 10 years most infants dx’d with TSD have
been non-Jewish or have had one Jewish and one non-Jewish parent.
Thus, screening of couples in whom one member is Ashkenazi Jewish is
recommended.
Preferred Response: B
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The deficiency of HexA activity results in accumulation of
GM2 gangliosides in the CNS, liver, and spleen. Following
a 6 to 9 month period of normal development, affected
infants present with hypotonia, apathy, developmental
delay, and an exaggerated startle response. Exam reveals a
cherry red spot in the maculae, which represents lipid
accumulation in the ganglion cells (cherry red spots are
also seen in Type I GM1 gangliosidosis and Niemann-Pick
disease). Macrocephaly is common after age 1. The disease
progresses rapidly, with death occurring by 5 years.
The genes encoding HexA has been mapped, and specific
mutations have been identified, including several that are
common among Ashkenazim.
Next Pt. in Metab Clinic:
You’re seeing a 3 y.o. with Hunter syndrome (MPS2) for F/U. His parents tell you the boy’s newborn
brother has just been dx’d with this same disorder,
and they’ve heard that bone marrow transplantation can “cure” the baby of his condition.
Of the following, the statement you are MOST
likely to include in a discussion of transplantation
for Hunter syndrome and other inborn errors of
metabolism is that
A. family members who are carriers of the disorder
cannot be donors
B. infections are less common than in patients who
have a hematologic disorder
C. it is contraindicated in disorders that include
adverse neurologic symptoms
D. it never has been successful in the treatment of
enzyme deficiency disorders
E. successful transplantation may halt disease
progression for some disorders
Preferred Response: E
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Organ & bone marrow transplantation (BMT) may halt
progression of some metabolic disorders. Because more
effective immunosuppressants have been developed &
there are no other effective treatment strategies, BMT has
been used increasingly. Each case must be considered
individually and parents must be provided with detailed
info about associated morbidity and mortality to permit
them to make an informed decision.
Sometimes, BMT is undertaken to provide a source of
enzyme that’s not produced in sufficient quantities. For
example, it’s been used successfully in pts with ADA
deficiency. Sometimes, organ tx replaces an organ that’s
been damaged by the disease process (ie liver tx. in alpha1-antitrypsin deficiency, and renal tx in cystinosis).
Preferred Response: E
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BMT in pts with inherited metabolic disorders carries the same risks
as when performed for other indications. Risks include: infection;
graft-versus-host disease; and rejection. Identifying a histocompatible
donor frequently requires that a donor from within the family be
considered. Because most inherited metabolic disorders are
transmitted as AR traits, the parents of affected children are obligate
carriers, and unaffected siblings have 2/3 chance of being carriers.
Carriers are acceptable donors.
Because BMT is associated with high rates of morbidity and mortality,
selection of appropriate candidates is important. In particular, there
has been controversy over whether patients with metabolic disorders
that include neurologic symptoms should be candidates. Recent
studies with Hurler patients (MPS-IH) indicate that BMT can be
beneficial despite the presence of adverse neurologic symptoms.
Particularly when the diagnosis is made early and the transplantation is
carried out shortly thereafter, improved neurologic function and
increased survival have been reported.
Next Pt. in Metab Clinic:
You are called down to the ED to see a previously healthy 2 y.o. boy
who was brought to the ED by his mother, who reported that he has
had a cold and fever for the past 2 days. He has been taking only small
amounts of juice and no solid foods. When she tried to arouse him
after his nap today, he was lethargic and unresponsive. Results of
laboratory studies include a glucose concentration of 40 mg/dL, an
ammonia level of 200 mcg/dL, and an arterial blood pH of 7.4.
At this time, the MOST important study to obtain is
1.
2.
3.
4.
5.
plasma acylcarnitine profile
plasma insulin levels
serum acetylsalicylic acid concentration
urine and stool porphyrins
urine organic acids
0%
0%
0%
0%
10
0%
Preferred Response: A
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This clinical presentation is typical of one of the fatty acid oxidation
defects, AR traits that represent defects in mitochondrial beta-oxidation
of fatty acids (MBOFA) and include defects in plasma membrane
carnitine transport; carnitine palmityl transferase I and II
deficiency (CPTI, CPTII); and long-chain, medium-chain, and
short-chain acyl CoA dehydrogenase deficiencies.
Of these, MCAD (medium-chain acyl CoA dehydrogenase deficiency) is
most common. Pts usually presents by age 2 with lethargy after fasting,
typically associated with a URI or AGE. Lab findings during illness
include hypoketotic hypoglycemia and hyperammonemia. Definitive dx
requires that the plasma acylcarnitine profile be determined. Because dx
is complex, consultation with a biochemical geneticist is recommended.
MBOFA includes > 20 steps and requires metabolism of carnitine for
the transport of LCFA into mitochondria. Because MBOFA for the
production of energy is only required during periods of fasting, clinical
manifestations do not become apparent unless substantial fasting has
occurred. Thus, there can be great heterogeneity in clinical course.
Preferred Response: A
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Between episodes of illness, affected pts are normal. Unfortunately,
the 1st episode may result in death and is frequently mis-dx’d as
Reye syndrome or SIDS. Correct dx is essential for both proper Rx
and genetic counseling. Treatment includes avoidance of fasting,
carnitine supplementation, and dextrose during acute episodes.
Molecular diagnosis of MCAD is available; > 90% of mutant alleles
are accounted for by a single point mutation in the MCAD gene.
Wrong answers:
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An organic acidemia should be suspected in pts presenting with hypoglycemia
and hyperammonemia in the presence of metabolic acidosis.
Plasma insulin levels should be obtained in a child suspected of having
hyperinsulinemia, which may cause hypoglycemia but usually is not associated
with hyperammonemia.
Urine and stool porphyrin analysis is useful in the diagnosis of the porphyrias,
Acetylsalicylic acid poisoning usually presents with hyperventilation and
dehydration, but hyperammonemia is not typical.
GENETICS CLINIC IS OVER.
NOW COMES MILLER TIME!