Download Medical Genetics for the Practitioner

ARTICLE
Medical
Kathleen
Genetics
E.Toomey,
IMPORTANT
for the Practitioner
MD*
POINTS
1. Clinical genetic science has moved beyond classical
mendelian
principles
and classical
chromosomal
abnormalities
to discover and characterize
genetic processes
that begin to account for some of the unexpected
exceptions to general
principles.
2. These nontraditional
genetic processes
include germilne
mosaicism,
uniparental
disomy, mitochondrial
inheritance,
genomic imprinting,
and
anticipation.
3. These advances
in genetic science require that the clinician
not only be
familiar with classical principles,
but also be alert to details that may
reveal exceptions
or complications
of such principles,
then know what procedures
can be used to resolve questions
or clinical conundrums.
4. The clinician
must know how genetic counseling
may be affected
by these
advances,
both generally
and in detail, and when to consult with a genetic
specialist
or genetic counselor.
S. The clinician
should know when to recognize
or suspect that a developmental abnormality
is not primarily
genetic in origin, but due to environmental factors (eg, maternal
infection,
radiation,
maternal
smoking,
drugs,
diet).
Introduction
literature.
More than 3200 articles
per
year in the various
pediatric
journals
are concerned
with diseases
due totally or in part to a genetic
variation.
A
new vocabulary
has emerged.
Approximately
2500 to 3000 genetic
loci have been mapped.
The quintessential
catalogue
of genetic
disease
in
man (VA McKusick’s
Mendelian
inheritance
in Man,
Johns Hopkins
Press),
a catalogue
of single gene disorders,
now includes
more than 3300
disorders
definitively
categorized
as
autosomal
dominant,
autosomal
recessive,
or X-linked
and another
2400 believed
to have a single gene
mutation
etiology
but not yet definilively categorized.
These
numbers
do
not include
the infinite
possibilities
that exist for chromosomal
abnormalities or the major etiology
of disabling
conditions-multifactorial
inheritance-a
combination
of environmental
and genetic
factors.
The designation
of medical
genetics as a recognized
specialty
is a
landmark
in the evolution
of the practice of genetic
counseling
and clinical
genetics.
This designation,
in conjunction
with the ubiquity
of clinical
applications
for genetic
testing,
the
emergence
of commercially
available
molecular
testing,
and genetic
counseling services,
changes
the profile
of
the relationship
between
the genetic
specialist
and nonspecialist.
There
is
now a clear mandate
for the genetics
In the aggregate,
genetically
determined disease
is a major cause of
morbidity
and mortality.
Two studies
of the causes
of death of more than
1200 children
admitted
to hospitals
in
the United
Kingdom
identified
genetically determined
diseases
as causing
38% and 42% of total mortality.
Approximately
3% of all pregnancies
result in the birth of a child who has a
significant
genetic
disease
or birth
defect
that can cause crippling,
mental retardation,
or early death. A
recent
survey
of more than 1 million
consecutive
births in British
Columbia,
Canada,
indicated
that at
least 1 in 20 individuals
younger
than
25 years of age developed
a serious
disease
that had an important
genetic
component.
One third to one half of
pediatric
hospital
admissions
involve
a disease
that has a genetic
component. The chronic
nature
of many
genetic
diseases
imposes
a heavy
medical,
financial,
and emotional
burden
on affected
patients
and their
families
as well as on society
at large.
Patients
who have genetic
diseases
are hospitalized
more frequently
and
for longer
periods.
The impact
of progress
in medical
genetics
is reflected
in the pediatric
*Depament
Medical
of Pediatrics, Jersey Shore
Center,
Neptune,
Pediatrics in Review
NJ.
Vol. 17
No. 5
May
1996
community
to: I) define
its role in the
care of the patient
who has a known
or suspected
genetic
disorder,
2) establish
the standard
of care within the specialty,
and 3) provide
a solid
educational
framework
within
which
the pediatrician
can establish
his or
her own standard
of practice
and pattern of using the medical
geneticist.
The urgency
of this mandate
is
enhanced
by both the technological
and the managerial
changes
in the
American
health
care system.
The
managed
care movement
is effecting
a shift away from the reliance
on subspecialists
that characterized
much of
medical
practice
during
the past 30
years. Just as not every heart murmur
requires
the attention
of a cardiologist, not every genetic
question
requires
the attention
of a geneticist.
However,
this does not mean inattention. The general
pediatrician
should
develop
his or her own approach
to
the genetic
evaluation,
recognize
his
or her limitations,
and establish
criteria for referral
to a medical
geneticist
or genetic
counselor.
Genetic
Genetic
Evaluation
Counseling
GENETIC
EVALUATION
And
The process
of a genetic
evaluation
involves:
1 ) use of a complete
family
and medical
history,
physical
examination,
and appropriate
laboratory
and radiologic
testing
to arrive at a
diagnosis;
2) determination
of the
operative
genetic
mechanism;
and
3) development
and implementation
of a plan of management
(health
supervision)
for the patient
and family, based on the known
natural
history of the disorder,
which includes
genetic
counseling.
The importance
of a thorough
physical
examination
cannot
be overstated.
It often is the seemingly
insignificant
features
that make a
genetic
diagnosis-a
triphalangeal
thumb
(or other radial abnormality)
in the patient
who has complete
transposition
of the great vessels
(possible
Holt-Oram
syndrome);
syndactyly
of
the second
and third toes in the
female
patient who has microcephaly,
pyloric
stenosis,
and unusual
facies
163
GENETICS
Gefletlc Counseling
(possible
Smith-Lemli-Opitz
syndrome);
or polydactyly
in the
African-American
patient
who has
imperforate
anus (possible
PallisterHall syndrome).
The practitioner
should
be familiar
with the tables and
graphs
in Smith’s
Recognizable
Patterns
ofHuman
Malformation.
If
a feature
seems
to be unusual
and is
measurable,
measure
it. Not only will
this confirm
or refute the initial
impression,
but repetition
will help
commit
normal
ranges
to memory.
Try to identify
the “least nonspecific”
finding.
Congenital
heart disease,
failure
to thrive,
and mental
retardation are more nonspecific
than is
supravalvular
aortic stenosis
(Williams
syndrome).
Learning
disabilities
and mild short stature
are
more nonspecific
than coarctation
of
the aorta in a female
child (Turner
syndrome).
The findings
in an infant
parents.
of a structural
chromosomal
necessitates
chromosomal
The family
history
traditionally
is
recorded
in the diagrammatic
form of
the pedigree.
It is a visual
representation of the occurrence
of specific
traits, disorders,
or other reproductive
events
as well as the relationships
of
individuals
in the family.
In some
instances,
the pedigree
will provide
crucial
diagnostic
information.
This
is true especially
in autosomal
dominant disorders
that have variable
expressivity.
Extended
family
members taken as a group
may possess
enough
critical
features
to make possible a diagnosis,
whereas
any one
individual’s
findings
may not meet
the diagnostic
threshold.
The greatest
value of the pedigree
is to identify
additional
family
members
who could
be at risk for the disorder
in question,
who could be tested for carrier
status,
or whose
offspring
could be at risk.
The genetic
counseling
process
involves
decisions
about informing
extended
family
members
and appropriately
advising
them of the implications of the proband’s
diagnosis.
Radiographic
and laboratory
aids
to diagnosis
are limitless.
If a particular diagnosis
is suspected,
studies
should
be directed
at confirmation
as
164
well as management.
The most
notable
change
in laboratory
diagnosis is the availability
of molecular
testing
for single
gene disorders.
We
can only look forward
to the day of
the “DNA
laboratory
profile”
for various findings.
The costs of molecular
testing
are still quite high and may
not be covered
by insurance.
Specificity
is necessary
in most
instances,
although
some “panel”
testing
is emerging.
For example,
if a
patient
is suspected
of having
a collagen disorder
(one of the EhlersDanlos
syndromes
or osteogenesis
imperfecta),
laboratories
specializing
in collagen
testing
may offer a panel
that rules in or out a number
of these
disorders.
Using the same example,
if
a patient
presents
with signs of a collagen disorder
(loose jointedness
or
dislocations,
hyperelastic
skin), additional evaluation
might
include
an
abnormality
analysis
of both
echocardiogram,
bleeding
time, and
ophthalmologic
examination
whether
or not a specific
collagen
disorder
is
diagnosed.
The limits and capabilities
of chromosome
analysis
must be appreciated. FISH (fluorescent
in situ
hybridization)
analysis
is the cornbined application
of standard
cytogenetic technique
and molecular
technology.
Extremely
small chromosome
aberrations,
which possibly
may be
visible
on standard
high-resolution
chromosome
analysis,
may be found
by applying
specifically
labeled
probes
to the chromosome
preparation. The request
for such a test subrnitted
to the laboratory
must be specific because
most probes
are specific
for given disorders.
FISH analysis
would
not be ordered
for the clinical
suspicion
of Down
syndrome
unless
the clinical
features
were overwhelmingly in favor of that diagnosis
and
the standard
chromosome
analysis
was normal.
In such an instance,
FISH analysis
may find an extremely
small translocation
of a portion
of
chromosome
21 (virtually
at the molecular
level) within
the otherwise
normal-appearing
karyotype.
For sev-
eral other disorders,
FISH analysis
may be the most expedient
approach.
The syndromes
of Prader-Willi,
Angelman,
DiGeorge,
Miller-Dieker,
Wolf-Hirschorn,
and others
often
yield a normal
karyotype
yet may be
positive
on FISH analysis.
Communication
with the laboratory remains
critical
in the difficult
case. A clinical
description
of the
patient
should
accompany
the sample.
The medical
directors
of well-managed laboratories
should
offer assistance in determining
the most appropriate analyses
to perform.
Because
each test is expensive,
specific,
time-consuming,
and labor-intensive,
it is in everyone’s
(especially
the patient’s)
interest
to work
collaboratively.
GENETIC
COUNSELING
Genetic
counseling
is an attempt
by
one or more appropriately
trained
persons
to help the individual
or family to: 1) comprehend
the medical
facts, including
the diagnosis,
probable course
of the disorder,
and available management;
2) appreciate
the
way heredity
contributes
to the disorder and the risk of recurrence
in specific relatives;
3) understand
the
alternatives
for dealing
with the risk
of recurrence;
4) choose
the course
of
action
that seems
appropriate
in view
of their risk, their family
goals,
and
their ethical
and religious
standards
and to act in accordance
with that
decision;
and 5) make the best possible adjustment
to the disorder
in an
affected
family
member
and/or
to the
risk of recurrence
of that disorder.
The intensity
of the counseling
process
is dictated
by the needs of the
individuals
involved
as well as the
known
and expected
responses
to the
information
presented.
The most
common
resources
used in counseling
are the physician,
medical
geneticist,
genetic
counselor,
psychologist,
psychiatrist,
and members
of support
groups
or diagnosis-related
interest
groups.
It is important
to recognize
patients’
needs to receive
accurate
information,
a plan of management,
and direction
to resources
to aid in
the psychological
aspects
of dealing
with a difficult
or rare diagnosis.
The
National
Organization
for Rare
Disorders
(NORD)
is an invaluable
resource
for placing
the family
in
Pediatrics
in Review
Vol. 17
No.
5
May
1996
GENETICS
Genetic Counseling
communication
with interest
groups,
local support
groups,
specialists,
and
other affected
families.
The NORD
Literature
Order Form lists some 750
disorders
for which
information
is
available.
(See Suggested
Reading.)
Patterns
minor malformations,
4) ambiguous
genitalia,
and 5) a couple
who has
unexplained
infertility
or recurrent
pregnancy
loss.
Chromosomal
aberrations
may be
either numerical
or structural.
Numerical
abnormalities
include
aneuploidies
in which
there are either
one or three or more copies
of a single chromosome
instead
of the normal diploid
number
of two. These
include
trisomies
21 (Down
syndrome),
18 (Edward
syndrome),
and
13 (Patau
syndrome).
The most common aneuploidies
involving
the sex
chromosomes
are Turner
syndrome
(45,X)
and Klinefelter
syndrome
(47,XXY).
Other aneuploidies
have
been reported
but are quite rare, and
some have never been observed
in a
liveborn
child.
of Inheritance
Traditionally,
genetic
disorders
have
been divided
into three categories:
chromosomal
abnormalities,
mendelian
or single gene disorders,
and polygenic
or multifactorial
disorders. This review
includes
three additional
genetic
mechanisms
that Nora
has called
“nontraditional
inheritance” : germline
mosaicism,
uniparental
disomy,
and mitochondrial
inheritance.
Two newly
described
phenomena
that may modify
the traditional
notions
of inheritance
also
are included:
genomic
imprinting
and
anticipation
(Table
1). In some measure, these phenomena
explain
the
“exceptions
to the rules”
that have
been observed
in families
that have
what otherwise
appear
to be straightforward
genetic
disorders
with consistent
manifestations.
Teratogens
also are included
in this
review
because:
1) patients
who have
malformations
or retardation
attributable to prenatal
exposure
to teratogenic agents
often present
as phenocopies
of genetic
disorders;
2) a small
but growing
number
of disorders
in
infants
and children
are caused
by the
effects
of a maternal
genetic
disorder
such as phenylketonuria
or diabetes
mellitus;
and 3) the variability
of
response
of a fetus to a teratogen
is
influenced
by genetic
factors
as well
as by the traditional
factors
such
as dose, timing
of exposure,
and
placental
transfer
of the offending
substance.
TABLE!.
Traditional
Patterns
Structural
abnormalities
include
deletions
or duplications
of small
amounts
of chromosome
material,
inversions
of chromosome
material
within
the same chromosome,
and
translocations
of chromosome
material from one chromosome
to another.
Chromosome
translocations
may
be balanced
or unbalanced.
For
example,
1% to 2% of children
who
have Down
syndrome
are found to
have the extra number
21 chromosome attached
at the centromere
to
either another
number
21 chromosome or to one of the 13 to 15 group.
This is called
a Robertsonian
translocation.
Such a translocation
may
have arisen de novo or it may have
been inherited
from one of the parents who is a carrier
of a balanced
translocation.
When a parent
is a
of Inheritance
and
Modifiers
Inheritance
Chromosomal
Abnormalities
-Abnormalities
of chromosome
Trisomies
(13,
Monosomy
Other
number
18, 21, X, and Y)
X
polyploidies
-Abnormalities
of chromosomal
structure
Deletions
Duplications
Translocations
(balanced,
unbalanced)
Insertions
Inversions
Single
Gene
-Autosomal
Mutations
(gene
mutation
located
on chromosome
1 through
22)
Dominant
Recessive
-X-linked
(gene
mutation
located
on X chromosome)
Dominant
Recessive
TRADITIONAL
Chromosomal
#{149}
Multifactonal
INHERITANCE
Genetic
Abnormalities
Chromosomal
aberrations
occur in
approximately
1 in 150 live newborns. At least 60% of spontaneously
aborted
fetuses
have a chromosome
abnormality,
as do 5% to 10% of stillbirths.
The most common
reasons
for
ordering
cytogenetic
studies
are:
1) the presence
of multiple
malformations, 2) features
of Down syndrome
in the newborn
infant,
3) a child who
is mentally
retarded
and has several
Pediatrics in Review
Vol. 17
No. 5
May
Nontraditional
factors
(polygenic)
and environmental
factors
Inheritance
#{149}
Germline
mosaicism
#{149}
Uniparental
#{149}
Mitochondrial
Modifiers
Inheritance
disomy
DNA
of Inheritance
#{149}
Genomic
Patterns
imprinting
#{149}
Anticipation
1996
165
GENETICS
Genetic Counseling
translocation
carrier,
the likelihood
of
having
a liveborn
child who has the
unbalanced
chromosome
arrangement is increased.
It is not as high as
the theoretical
risk of conceiving
a
chromosomally
unbalanced
fetus,
however,
because
of fetal wastage
and perhaps
some inefficiency
of
the cytogenetically
aberrant
sperm
or egg.
Prenatal
anomalies
congenital
ultrasonography
can detect major fetal
(hydroor anencephalus,
myelomeningocele,
heart defects)
as early as 16 weeks gestation.
The number
of possible
chromosome rearrangements
is enormous.
Difficulty
arises when a child presents with a rare cytogenetic
abnormality
for which
little or no information can be found.
Even though
catalogues
of chromosome
abnormalities
exist, it is extremely
difficult
to compare cytogenetic
abnormalities
from
patient
to patient
accurately.
Apparently similar
aberrations
may have
slightly
different
breakpoints
involved
in the rearrangement.
Many
patients
will have to be dealt with as
“one of a kind” until the application
of molecular
cytogenetics
is refined
further.
The key to accurate
prognostication
is identifying
the molecular
effect of the structural
rearrangement
observed
at a very gross level of resolution through
the microscope.
Autosomal
Single
Gene
Disorders
The chromosome
pairs 1 to 22 are
referred
to as the autosomes
to distinguish them from the sex chromosomes
X and Y and the mitochondrial
chromosome.
Autosomal
single gene
disorders,
therefore,
are the result of
mutations
of genes
located
on these
22 pairs of chromosomes.
The site of
a gene is referred
to as the locus; the
individual
message
at that locus is
referred
to as the allele. All genetic
messages
on the autosomes
are present in pairs-a
maternal
and a paternal copy. (An exception
discussed
later is the case of uniparental
disomy.) If only one copy of an allele is
required
for expression
of the trait,
condition,
or disease,
the gene is
referred
to as being dominant.
Autosomal
dominant
genetic
traits
have the following
features:
1) verti166
cal transmission
in families;
2) males
and females
affected
equally;
3) male-to-male
transmission
(virtual
proof of autosomal
dominant
inheritance);
4) may occur as a new mutation and represent
the first instance
in
the family;
5) may exhibit
a wide
range of severity
or gamut of expression (variability
of expression);
and
6) one chance
in two with each preg-
nancy of passing
the gene to the offspring
of an affected
individual.
Variable
expressivity
and the possibility that a patient
represents
the
new mutation
in the family
presents
particularly
difficult
counseling
and
diagnostic
problems.
It may be necessary to test and examine
apparently
unaffected
parents
extensively
to be
assured
that they do not represent
extremely
mild expressions
of the
mutant
gene. For example,
to determine whether
one of the apparently
normal
parents
of a child who has
neurofibromatosis
(NF) actually
possesses
the gene for NF, it may be necessary
to take an extensive
family
history,
examine
the parents
thoroughly,
perform
a slit lamp examination for Lisch nodules,
and perform
computed
tomography
or magnetic
resonance
imaging
for evidence
of
hamartomas.
The caveat
presented
by
the possibility
of germline
mosaicism
also must be heeded
(see below).
If two matching
copies
of a gene
located
on an autosome
are required
for a trait to be manifested,
it is said
to be autosomal
recessive.
The parents of a child who has an autosomal
recessive
condition
are, by inference,
both heterozygous
carriers,
and the
affected
child is homozygous.
(Caveat:
uniparental
disomy).
Many
complex
malformation
syndromes
and the majority
of severe
metabolic
disorders
are autosomal
recessive.
Autosomal
recessive
conditions
are
characterized
by: 1) multiple
affected
siblings
whose
parents
are normal,
2) less variability
of expression
than
seen in dominant
conditions,
3) a 1 in
4 chance
of recurrence
for a sibling
of an affected
child and a 2 in 3
chance
of healthy
siblings
of an
affected
child being carriers
of the
gene, and 4) possibly
higher
carrier
rates in some ethnic
groups.
Cystic
fibrosis
is the paradigm
of autosomal
recessive
diseases.
X-Iinked
Single
Gene
Disorders
When a trait or condition
is X-linked,
the locus is located
on the X chromosome.
Because
males have only one
x chromosome,
the genetic
messages
on their X chromosome
are of maternal origin
and will represent
either
the maternal
grandmother’s
or maternal grandfather’s
X-linked
genes.
Males
are said to be hemizygous
for
the genes on the X chromosome.
In
terms of its ability
to express
its
effects,
a gene on a male’s
X chromosome will be expressed
whether
it
behaves
as a dominant
or recessive.
However,
in a female,
who has two X
chromosomes,
the genes will behave
with respect
to their dominance
or
recessivity,
similarly
to genes on the
autosomes.
Females
are mosaics
for the genes
on their X chromosomes
by virtue of
the process
known
as lyonization,
the
random
inactivation
of one X chromosome
per cell that occurs
early in
embryonic
life. On the average,
one
half of a female’s
cells express
the
genes located
on their paternally
derived
X chromosome
and one half
of the cells express
the genes on the
maternally
derived
X. This process
of
inactivation
of one of the X chromosomes
is random,
however,
and
females
may have other than a 50/50
distribution.
For example,
if a woman
has inherited
the X-linked
gene for
hemophilia
A (factor
VIII deficiency)
from her mother
and a normal
allele
from her unaffected
father,
she is a
carrier
of the X-linked
disease.
Whether
she is symptomatic
depends
on her degree
of lyonization.
If the
majority
of her cells, particularly
those involved
in factor VIII production, have her maternally
derived
X
active,
that is, the X bearing
the
mutant
gene, she may be symptomatic and demonstrate
very abnormal
levels of factor VIII. If the reverse
distribution
is true, this carrier
female
may have levels and clotting
features
well within
normal
ranges
even
though
she is a carrier
of the abnormal gene. The majority
of the women
who are carriers
will demonstrate
Pediatrics
in Review
Vol. 17
No.
5
May
1996
,
.
reduced
factor VIII levels and minor
aberrations
in clotting.
The following
are characteristics
of X-linked
recessive conditions:
1) the incidence
of
clinical
disease
is higher
in males
than females,
2) male-to-male
transmission
is not seen, 3) all daughters
of an affected
male are carriers,
4) the
risk of a male offspring
of a carrier
female
being affected
is I in 2, and
5) the pedigree
may show a number
of affected
males who are related
through
carrier
females.
(This is to be
distinguished
from mitochondrial
inheritance,
which
is matrilineal,
but
sons and daughters
are affected
equally-see
below).
X-linked
dominant
disorders
are
rare, and several
are lethal in males
but consistent
with survival
in
females.
An example
is incontinentia
pigmenti.
The following
are characteristics of X-linked
dominant
disorders:
1 ) all daughters
of affected
males are
affected,
2) there is no male-to-male
TABLE
2. Incidence
.
. ,
:
‘
,
transmission,
3) the likelihood
of
recurrence
to the offspring
of an
affected
female
is 1 in 2 regardless
of
the sex of the offspring,
although
males may be affected
more severely
than females,
and 4) affected
females
are more common
than affected
males.
X-linked
genetic
traits should
not
be confused
with sex-limited
or sexinfluenced
genetic
traits or disorders.
In the latter situations,
an autosomal
dominant
or recessive
condition
may
be manifested
only or predominantly
in males either
because
of other,
often hormonal,
differences
between
males and females
or because
the
predominant
feature
involves
an
aberration
of the genitalia
that is
expressed
more severely
in the male
than the female
.
.
.
.
Multifactorial
Disorders
The most common
and least understood of the categories
of genetic
dis-
and Recurrence
Risks
GENETICS
Genetic Counseling
.
.
for Common
ease are those that result from the
interaction
of a number
(usually
unknown)
of genes and environmental factors.
The majority
of common
disorders
such as diabetes
mellitus,
hypertension,
or mental
illness
as
well as common
birth defects
such as
cleft lip and palate,
congenital
heart
disease,
spina bifida/anencephaly,
pyloric
stenosis,
scoliosis,
dislocated
hip, and many isolated
malformations
such as intestinal
atresias
are the
result of this mechanism.
The following
are characteristics
of
multifactorial
inheritance:
I ) the
degree
of relatedness
of the at risk
individual
to the affected
individual
influences
the chance
of occurrence;
2) there may be a sex distribution
differential
for a disorder;
3) the risk of
recurrence
is greater
among
the relatives of more severely
compared
with
less severely
affected
infants;
4) the
chance
of recurrence
is higher
when
more relatives
are affected;
5) epi-
Multifactorial
Birth
RECURRENCE
WHEN AFFECTED
DEFECT
RATE
PER 1000
SEX RATIO
M/F
PARENT
Defects
RISK* (%)
RELATIVE
IS:
SIBLING
Cardiac
defects
Ventricular
septal defect
Tetralogy
ofFallot
Atrial septal defect
Pulmonic
stenosis
Aortic
stenosis
Coarctation
Atrioventricular
canal
2.5
1.1
1. 1
0.8
0.4
0.6
0.4
Anencephaly/Spina
3.0
0.8
Pyloric
stenosis:
Risk to:
Female
child of affected
father
Female
child of affected
mother
Male child of affected
father
Male child of affected
mother
Male child with affected
brother
Male child with affected
sister
Female
child with affected
brother
Female
child with affected
sister
3.0
5.0
Cleftlip/palate
1.0
1.6
4.0
2.9
Cleftpalate
0.45
0.7
5.8
4.3
Clubfoot
1.2
2.0
*Ranges
Pediatrics
represent
in Review
bifida
differences
Vol. 17
based
No.
5
3.0
2.4
2.0
2.0
2.0
3.0
3.0
3.4
2.5
2.4
7.0
5.5
18.9
3.8
9.2
2.7
3.8
on gender
May
2.0-6.0
6-10
1 .5-4.5
2.0-6.0
3.0-18
2.0-4.0
1-14
1996
2.9
of parent.
167
.
GENETICS
Genetic Counseling
genetic
counseling
may
discussion
of seemingly
sibilities
with uncertain
risks. This is an example
that there is an exception
demics
may be seen, and the epidemic may be an “epidemic
among
firstborns,”
“an epidemic
among
children
of smokers
or alcoholics,”
or other
similar
epidemics;
and 6) recurrence
Mutation
ofmitochondrial
is associated
with several
DNA
chronic
risks are based on empiric
data, and
although
they vary from defect
to
defect,
they generally
are in the range
of 1% to 3% after the birth of one
affected
individual
(Table 2).
The challenge
when dealing
with a
multifactorial
disorder
is to avoid the
pitfall of “placing”
a patient
into this
category
without
carefully
assessing
the patient
and family
history.
Failure
to note either a positive
family
history
or the presence
of subtle anomalies
in
the patient
other than the obvious
defect
may lead to erroneous
counseling and inappropriate
follow-up
and
management.
For example,
the presence of triphalangeal
thumbs
in conjunction
with an atrial septal defect
points to the possibility
of the autosomal dominant
condition
Holt-Oram
syndrome.
Careful
examination
of parents may reveal a subtle radial ray
defect as the only sign of the gene.
This observation
raises the likelihood
of recurrence
from the empiric
2% to
4% for isolated
congenital
heart
defects
to 50% for each subsequent
pregnancy.
Furthermore,
it indicates
that any individual
in the family
who
has a radial ray defect
should
have a
thorough
cardiac
evaluation.
NONTRADITIONAL
INHERITANCE
To those daily involved
in genetic
counseling,
it long has been obvious
that there are families
in which none
of the traditional
patterns
of inheritance provide
a suitable
explanation
for the pedigree.
The explanations
of
new mutation
or multifactorial
inheritance were invoked
in these instances,
or no explanation
was attempted
at all.
With advances
in molecular
genetics
and molecular
cytogenetics,
several
new explanations
have emerged
and
warrant
special
consideration;
their
existence
greatly
affects
genetic
counseling.
However,
documenting
any
one of these modes
of inheritance
is
difficult
in any given family,
and
168
contained
diseases.
Germline
consist
of a
abstract
posrecur-rence
of the rule
to every rule.
in 13 genes
Mosaicism
Mosaicism
is the presence
of two or
more cell lines with differing
genotypes or karyotypes.
It is due to a
mutation
that occurs
in a cell of the
developing
organism
some time after
fertilization.
Depending
on the timing
and developmental
destination
of the
cell in which the mutation
occurs,
the
adult organism
may bear only somatic
manifestations
of the mutation
or the
gonads
may be affected
as well. The
reproductive
adult, therefore,
may produce gametes
that have both the normal and abnormal
allele and yet not be
affected
clinically
with the disorder.
Germline
mosaicism
may be the
explanation
for a family
in which a
well-described,
easily diagnosed
autosomal
dominant
condition
without much variability
of presentation
has occurred
in two children
born to
unaffected
parents.
Such an example
would
be a family
consisting
of two
parents
of normal
stature
and two
children
who have achondroplastic
dwarfism.
In the past, the family
consisting
of normal
parents
and one
child having
an autosomal
dominant
disorder
would have been counseled
that the child was the result of a new
mutation
and that the likelihood
of
recurrence
was quite low, but not
zero. The “but not zero” caveat
may
be due partly to the phenomenon
of
germline
mosaicism
and warrants
some discussion
in the process
of
counseling
the family.
Uniparental
Disomy
Uniparental
disomy
refers
to the situation
in which
a child possesses
two copies
of one of one parent’s
chromosome
and no copies
of the
same chromosome
from the other
parent.
The result
is that the child is
homozygous
for all genes
located
on
that one chromosome.
If that chromosome
should
bear an allele that
causes
a recessive
condition
or dis-
ease, the child will be affected,
even
though
one parent
is not a carrier
of
the gene. This phenomenon
has been
described
several
times in patients
who have cystic
fibrosis,
an autosomal recessive
condition,
as well as
with the Prader-Willi
and Angelman
syndromes.
In the past, the occurrence of an autosomal
recessive
condition
in a family
where
only one
parent
could
be shown
to be a carrier
of the gene was considered
to be due
to nonpaternity
or remained
an enigma. It now is possible
to document
this phenomenon
through
analysis
of
DNA markers.
Similarly,
male-to-male
transmission of an X-linked
disease
raises
the possibility
that the son received
both sex chromosomes
from the
father’s
sperm
and no sex chromosome from his mother.
An alternative
explanation
is that the son was conceived
as an XXY zygote
with one X
from the mother
and an X and Y
from his father
and that a second
nondisjunction
event resulted
in the
early loss of the maternal
X, leaving
the son identical
to his father
with
respect
to the genes on his X and Y
chromosomes.
If both homologs
contributed
by
one parent
are identical,
the term
isodisomy
is used; if the parent
has
contributed
each of his or her
homologs
of the chromosome,
the
term is heteroisodisomy.
Mitochondrial
Inheritance
In addition
to the 22 pairs of autosomes
and the two sex chromosomes
contained
in each nucleated
cell, a
25th chromosome
is contained
in
each mitochondrion
within
the cytoplasm of the cell. During
the past
6 years,
mutations
of the mitochondrial DNA (mtDNA)
have been found
to be associated
with several
chronic
degenerative
diseases.
The mtDNA
contains
13 genes,
which,
together
with more than 50 nuclear
DNA-contamed
genes,
is responsible
for the
enzymes
involved
in the pathways
of
oxidative
phosphorylation,
the ATP
production
pathway.
Each cell contains many mitochondria
and, therefore, many copies
of the mtDNA.
However,
because
only the ovum
carries
a mitochondrion
into fertilization, mtDNA
is maternal
in origin.
Therefore,
a disease
that is caused
totally
or in part by a mutation
of the
Pediatrics
in Review
Vol. 17
No.
5
May
1996
GENETICS
Genetic Counseling
mitochondrial
genome
will be matrilineally
inherited.
The mutation
rate
of mtDNA
is many times greater
than
that of nuclear
DNA,
and because
each cell has a population
of
mtDNA,
each may contain
mutated
as well as normal
mtDNA.
This heterogeneity
is called
heteroplasmy
and is another
cause of extremely
variable
expressivity
within
the mitochondrial
diseases.
Organs
that are
highly
dependent
on energy
production will be the most severely
affected by mutations
of mtDNA.
The
organ
systems
affected
most commonly
are the central
nervous
system, muscle,
and heart. Table 3 lists
the five most common
diseases
due
to mutations
in the mtDNA.
Mitochondrial
DNA mutations
may be
missense
mutations,
single
base
mutations
and duplications,
and deletions.
Mutations
of mtDNA
also are
associated
intimately
with the
process
of aging and cell death at the
somatic
level.
Because
of the variable
expression
of mitochondrial
mutations
from
even within
different
tissues
of an
individual,
proper
evaluation
may
require
biopsies
of several
tissues
that then are subjected
to both enzymatic and DNA analysis.
Modifiers
Inheritance
Expression
GENOMIC
TABLE
#{149}
Leber
hereditary
ropathy
(loss
vision)
I
.
S
Myoclonic
epilepsy,
ragged
red fiber disease
(dementia,
seizures,
ataxia,
and
myopathy)
Mitochondrial
myopathy
episodes
encephaloand stroke-like
external
Kearns-Sayre
syndrome
(muscle
weakness,
cerebellar
damage,
and heart failure)
mendelian
inheritance
from generation
to generation.
The best human
example is the effect of imprinting
on a
small deletion
of the proximal
portion
of the long arm of chromosome
15.
When the deletion
is inherited
from
the father, the resulting
phenotype
is
that of Prader-Willi
syndrome;
when it
is inherited
from the mother,
the phenotype
is that ofAngelman
syndrome.
ANTICIPATION
Anticipation
refers
to progressively
earlier
manifestation
or more severe
expression
of a disease
with succeeding generations.
As the practice
of
clinical
genetics
has progressed,
we
tended
to explain
this observation
as
the result of greater
awareness
of
genetic
disease
and an increased
ability to diagnose
genetic
disease
earlier
through
better observation
and
advanced
testing
techniques.
However, it now is clear that several
genetic
disorders
increase
in severity
with successive
generations
and that
there is a biologic
basis for the phenomenon.
In at least two disorders,
fragile
X syndrome
and myotonic
dystrophy,
the gene mutation
is a
repeated
trinucleotide
sequence
that
lies in an untranslated
portion
of the
gene. This segment
is transcribed
into
mRNA,
but not translated
into protein. The number
of these repeated
sequences
(repeats)
correlates
directly with the severity
of the disorder
and may increase
with successive
IMPRINTING
Genomic
imprinting
has the effect of
converting
individuals
who should
be
clinically
affected
with a dominant
disorder
into nonexpressing
carriers
who still are capable
of transmitting
the gene to their offspring,
with the
phenotype
reappearing
after an apparent “skipped
generation.”
Geneticists
long rebelled
at the concept
of skipped
generations
and invoked
the explanations of incomplete
penetrance
or vanable expressivity
to explain
such pedigrees. Imprinting
is a process
that
results
in the differential
expression
of
genetic
material,
depending
on
whether
the material
has come from
the male or female
parent.
An allele is
imprintable
when it is capable
of
being suppressed
in its expression
by
either maternal
or paternal
factors,
possibly
another
gene or genes. Either
the normal
or abnormal
allele is
“imprinted”
but still follows
Vol. 17
optic neuof central
#{149}
Chronic
progressive
ophthalmoplegia
of Genetic
and Gene
Pediatrics in Review
3. Mitochondrial
Disorders
No. 5
May
1996
generations.
How these expansions
occur is not understood,
and many
questions
remain
unanswered.
Suffice
it to say that when molecular
testing
for such disorders
is reported,
reference is made to the number
of such
repeats
and is used in genetic
counseling to estimate
the risk of recurrence and to predict
severity.
Teratogenic
Disorders
Table 4 is a selected
list of known
or
suspected
human
teratogens.
The logical question
to ask is: Why isn’t
every pregnancy
that is exposed
to a
given agent affected
by the teratogen?
The answer
lies first in the obvious
difficulty
in determining
the timing
of exposure
during
gestation
and the
dosage
that is delivered
to the fetus.
Surely,
no two pregnancies
are identical in these parameters.
The answer
lies second
in the genetic
diversity
of
the mothers
and fetuses.
Even if
exposures
could be controlled
or
measured
accurately,
there probably
would
be differences
in response
based on polymorphic
differences
in
metabolism,
sensitivity
of target tissues, and the like. Yet, a few teratogens are capable
of producing
fairly
consistent
clinical
pictures
when they
do have an effect on the developing
fetus. If a teratogenic
agent can be
identified
as the causative
agent,
the
likelihood
of recurrence
is related
to
the likelihood
of subsequent
exposure. Additionally,
women
who have
a chronic
illness
such as Crohn
disease or sickle cell disease
and heavy
smokers
have an increased
incidence
of small-for-gestational-age
infants,
though
the risk of malformations
may
not be increased
in these infants.
Management
Disorders
Of Genetic
The management
aspects
of genetic
disorders
pervade
the life cycle from
preconceptual
planning
through
adulthood.
Through
meticulous
nosology
and long-term
follow-up
of
patients,
clinical
genetics
continues
to
contribute
to the bank of knowledge
of the natural
history
of genetic
disorders. This enables
the physician
to
develop
health
supervision
strategies
for patients
who have a given diagnosis, and in conjunction
with molecular genetics
research,
speeds
the iden169
GENETICS
Genetic Counseling
chorionic
villi.
For virtually
any disorder
External
Agents
that can be
Infections
diagnosed
postRubella
natally,
diagnoCytomegalovirus
sis is available
Toxoplasmosis
prenatally.
Sampling
of
Drugs,
Chemicals,
and Radiation
amniotic
fluid
Alcohol
(amniocentesis)
Amphetamines
somewhat
later
Antimetabolites
in
pregnancy
Anticoagulants
(warfarin)
(14 weeks
to
Anticonvulsants
term)
and
culHydantoin
turing of the
Tnimethadione
fetal cells conValproic
acid
tamed
therein
Cocaine
allow
similar
Lithium
analysis
as well
Mercury
as the perforRadiation
(high doses)
mance
of diagRetinoic
acid
nostic
tests,
Stilbestrol
which
may rely
Thalidomide
on enzymatic
reactions
or on
Maternal Conditions
the determinaLupus erythematosus
tion of a level
Diabetes
mellitus
of metabolite
in
Untreated
metabolic
disorders
(phenylketonuria
or
the tissue.
hyperphenylalaninemia
These
diagnosIn Utero Environmental
Conditions
tic studies
are
Amniotic
bands
limited
by
Oligohydramnios
whether
the
Uterine
fibroids
metabolic
Uterine
malformations
abnormality
is
Malpositioning
of the fetus (prolonged
face
demonstrable
in
presentation)
fetal fibroblasts. By the
14th to 16th
week of gestation,
a variety
of imagtification
of molecular
causes
of dising studies
may help determine
the
orders
and their variants.
presence
of structural
anomalies
such
as hydrocephalus,
anencephaly,
PRECONCEPTUAL
MANAGEMENT
myelomeningocele,
congenital
heart
defects,
renal anomalies,
gastroinWith the advent
of carrier
testing
testinal
abnormalities,
and limb
for autosomal
recessive
diseases,
defects.
For pregnancies
not othernotably
Tay-Sachs
disease,
sickle cell
wise “at risk,” screening
tests can be
disease,
and soon on a wide basis,
performed
to identify
pregnancies
at
cystic fibrosis,
individuals
planning
an increased
risk of abnormality,
to have children
are afforded
the
although
the screening
test is not
opportunity
to select in part the
diagnostic.
Maternal
serum alphagenetic
make-up
of the embryo
fetoprotein
testing
at 14 weeks’
gesta(fetus,
child)
at various
stages
in the
tion is used most commonly.
Both
process.
By virtue of in vitro fertilizaelevated
and decreased
levels have
tion, it is possible
to analyze
DNA
proven
of value in identifying
pregdirectly
on a sample
of the developing embryo
and to implant
selectively
nancies
in which
the fetus is at an
increased
risk of an open neural
tube
that which has a desired
genotype.
As early as the 8th to 11th week of
defect
(elevated)
or a chromosomal
abnormality
(decreased).
gestational
age, prenatal
diagnosis
Pregnancies
characterized
by evimay be performed
by sampling
the
TABLE
170
4. Recognized
Human
Teratogens
dence of intrauterine
growth
retardation, abnormalities
on ultrasonography, or poly- or oligohydramnios
should
be studied
cytogenetically,
even in the last trimest-er.
Management of the remainder
of the pregnancy may be influenced
by the knowledge of a serious
genetic
disorder
in
the fetus. A thorough
review
of prenatal testing
was presented
by
DiLiberti
in 1 992 (see Suggested
Reading).
MANAGEMENT
OF THE
NEWBORN
Newborn
screening
for certain
metabolic disorders
is performed
in all
states;
however,
beyond
testing
for
phenylketonuria
(PKU),
the library
of
disorders
varies from state to state.
The criteria
applied
in the decision
to
add a disease
to the newborn
screening panel include
incidence,
sensitivity and specificity
of the test, potential
for treatment,
invasiveness
of testing,
and cost. In addition
to PKU, newborn screening
is available
for
hypothyroidism,
maple
syrup urine
di sease, galactosemia,
biotinidase
deficiency,
and sickle cell disease.
The potential
for widespread
newborn screening
for cystic fibrosis
(CF) carries
tremendous
implications
for pediatricians
and geneticists.
CF
is the most common
genetic
disorder
in the Caucasian
population,
with a
live born incidence
of 1 in 2000 to 1
in 1600. The estimated
carrier
frequency
is I in 20 Caucasians.
Several
pilot programs
for newborn
screening
search
for the most common
mutation
found
in the CF population,
delta F
508. In addition
to the sheer numbers
of potential
positive
results,
the chief
difficulty
with newborn
screening
is
the genetic
heterogeneity
of CF.
There are 300 to 400 different
mutations that may cause a disease
state
that is characterized
clinically
by pulmonary
abnormalities
and pancreatic
insufficiency
with or without
an
abnormal
sweat chloride
value.
Delta
F 508 accounts
for 70% of the mutant
alleles;
another
25 to 30 mutations
account
for another
I 5% to 20% of
the mutant
alleles.
A normal
newborn
screening
result does not eliminate
the possibilities
that an individual
might be heterozygous
for a less
common
mutation
or either homozygous or doubly
heterozygous
for less
common
mutations.
Pediatrics
UJ
Review
Vol. 1 7
No.
5
May
1996
GENETICS
CounselIng
Genetic
Newborns
who have obvious
birth
defects
or dysmorphic
features
should
be evaluated
as soon as possible.
In
the immediate
newborn
period
the
objectives
of evaluation
are to determine the presence
of a recognized
syndrome,
establish
the etiology
of
the defects,
guide parents
and physician regarding
appropriate
management of each identifiable
problem,
and provide
an overall
picture.
When
a previously
described
syndrome
can be identified,
the physician may be alerted
to the possibility
of other defects
or metabolic
states
that, if treated,
will alter the outcome
for the infant.
For example,
an infant
born with imperforate
anus and polydactyly
is recognized
to have
Pallister-Hall
syndrome.
Although
only a few cases and even fewer survivors
of this rare syndrome
have
been reported,
recognition
of the syndrome
foretells
the possibility
of
hypothalamic
abnormalities
and
hamartomas.
Early investigation
allows
early treatment
of this aspect
of the syndrome
and an outcome
better than that experienced
by the
majority
of patients
reported
in the
literature.
Establishing
an accurate
diagnosis
often identifies
the etiology,
which
permits
accurate
counseling
about the
risk of recurrence
in future
pregnancies as well as the availability
of prenatal diagnostic
measures.
In the case
of stillbirth
or early neonatal
death,
it
is imperative
that the infant’s
features
be documented.
If the services
of a
clinical
geneticist
are not available,
all possible
data should
be gathered
either pre- or postmortem.
The ideal
data include:
photographs
and radiographs,
karyotype
on blood,
and the
establishment
of a fibroblast
culture
as either
a back-up
to failed peripheral blood karyotype
or to use for metabolic or molecular
studies.
Head and
renal ultrasonographic
examinations
should
be undertaken
if an autopsy
is
not performed.
An autopsy
performed
by a prosector
experienced
in malformations
is highly
desirable.
In many
instances,
a geneticist
will be called
on later to counsel
a family
in whom
there has been a stillbirth
or infant
death.
In the absence
of accurate
documentation,
counseling
only can be
very generalized.
For the otherwise
healthy
and stable infant who has one or more birth
Pediatrics
in Review
Vol. 17
No.
5
May
defects,
the pediatrician
in conjunction with a clinical
geneticist
should
outline
for the parents
an appropriate
plan of management.
This plan
includes
referral
to appropriate
specialists
promptly,
preferably
within
2 weeks
of birth, as well as the scheduling of any testing.
Most parents
are
not oblivious
to the possible
implications of even seemingly
minor abnormalities;
reassurance
should
not be
patronizing.
Mental
retardation
is a
cist. If the suspicion
of one of these
disorders
cannot
be confirmed
at the
hospital
of birth and transfer
is necessary for evaluation,
the referring
physician
should
accept
the infant
back once the diagnosis
has been
made at the second
hospital.
The
argument
that “our nursing
staff can’t
handle
this” is often unjustified.
Most
nursery
staffs respond
admirably
if
they are afforded
an explanation
of
the diagnosis,
reassured
as to the
In the case ofa stillbirth
or early neonatal
death, the
infant’sfeatures
must be indentified
(photographs,
radiographs,
karyotype
ofblood,
and establishment
of
afibroblast
culture)
plus an autopsy
and consultation
with a geneticist
obtained.
common
unexpressed
fear that should
be anticipated
and dealt with straightforwardly.
In the long run, parents
do
not appreciate
being misled,
even
though
the misleading
was done in
their best interest.
The most common
mistake
made by clinicians
is not failing to advise
of the possibility
of
retardation
when it exists,
but failing
to state that retardation
is not a
known
feature
of a given syndrome
or a common
accompanying
feature
of a particular
birth defect.
Common
examples
include
isolated
cleft
lip/palate,
achondroplasia,
isolated
limb defects,
isolated
intestinal
atresias, and sensorineural
deafness.
The following
are four key factors
in management
of the seriously
malformed
newborn:
1 ) expedient
diagnosis,
2) identification
of the infant,
3) recognition
of the sense of loss
of control
by the parents,
and 4) the
need for the parents
and physicians
to
be heard and understood.
The pediatrician
and neonatologists
should
be
able to diagnose
a small group of disorders
that are nearly
100% lethal or
have extremely
grave outcomes
for
the survivors
and for which
there is
no treatment
that improves
the quality of the infant’s
life. A short list
includes
trisomy
13 and trisomy
18,
thanatophoric
dwarfism,
and lethal
neonatal
osteogenesis
imperfecta.
Even for the small community
hospital, the use of telecommunication
devices
should
make it possible
to
diagnose
these entities
without
the
on-site
services
of a clinical
geneti1996
expected
outcome,
and guided
in the
management
of the dying infant and
his or her family.
Everything
possible
should
be
done to establish
an identity
for the
infant.
This includes
changing
paperwork associated
with the baby and
the plastic
card to include
the full
name. Many parents
have returned
for genetic
counseling
holding
on to
the only remnants
of this infant’s
existence
such as documents
with
“Smith BG,” even on a death certificate. We never have encountered
an
admissions
clerk, ward clerk, or nurse
who refused
to alter these once the
situation
was explained.
The issue of identification
is particularly
important
in cases of
ambiguous
genitalia,
whether
or not
the infant is transported
for evaluation. Forevermore,
a potential
source
of confusion
resides
in the medical
record
designation
Baby Girl or Baby
Boy. An example
of a valiant
attempt
gone awry is the case of an infant
who had multiple
malformations,
died shortly
after birth, and presented
with ambiguous
genitalia.
It was clear
that an accurate
medical
diagnosis
of
sex determination
would be forthcoming
upon completion
of appropriate studies
and an autopsy.
However,
the sex of rearing,
albeit for a few
minutes
or hours,
was clearly
male.
Somehow,
the ambiguity
of the situation reached
the admissions
office
where the plastic
card was drafted
for
“Jones,
Ambiguous.”
In some fortuitous instances,
the name of choice
171
GENETICS
Counseling
Genetic
prior to the birth of the child may be
suitable
for either a male or female.
Logan
was the chosen
name for a prenatally
cytogenetically
diagnosed
male born with a recessive
sex reversal syndrome
and raised female.
In
other instances,
a desired
name can
be made sex-indeterminate
temporarily and later formalized
to suit the sex
of rearing.
For example,
Chris can
become
Christine
or Christopher.
MANAGEMENT
OF THE PATIENT
WHO HAS A GENETIC
DISORDER
A body of literature
regarding
the
ongoing
management
of the patient
who has a genetic
disorder
is slowly
emerging.
Paradigms
for such a managed care approach
are neurofibromatosis
(NF), Marfan
syndrome,
Turner
syndrome,
Down syndrome,
and achondroplasia
(Table
5). The
Suggested
Reading
list includes
rec-
Parents
ofa chili! who has a gentic disorder
need to
believe
that they are capable
ofmaking
these decisions
based on accurate
and complete
information.
The birth of a child who has a serious malformation
or identified
syndrome
wrenches
from the parents
almost
any sense of control
they felt
they had over their future
as a family.
The diagnosis
is controlling
and the
physicians
are the operatives.
The
skillful
physician
will walk a tightrope gracefully,
balancing
medical
knowledge
and prevailing
medical
and ethical
opinion
on one hand and
the concerns
and uncertainties
of the
parents
on the other. When
faced
with difficult
decisions,
the most
common
question
parents
ask is,
“What
would
you do?” This question
is prompted
by a belief
that the
physician
knows
more than he or she
is revealing
and somehow
knows
the
“right”
thing to do. Parents
need to
believe
that they are capable
of making these decisions
and know that
they are basing
their decision
on
accurate
and complete
information.
Once this trust is established,
it is
rare for the same query
to be made a
second
time and for serious
ethical
conflicts
between
physician
and parents to arise. When
such conflicts
do
surface,
the availability
of another
sounding
board in the form of a
Hospital
Ethics
Committee
should
be
made known.
Such a committee
is
not an arbitration
or decision-making
body;
rather,
it is a forum
for hearing
the concerns
of both parents
and
physicians
and often only recommends
a course
of action
based on
the best interest
of all concerned,
most importantly,
the child. Again,
it
often is merely
the sense of having
been heard that is necessary
to help
both parties
agree.
172
ommendations
of the Section
on
Genetics
of the AAP for the health
supervision
of children
who have
Down
syndrome,
NF, and achondroplasia.
Patients
who have syndromes
characterized
by deviations
of
growth
also should
be followed
by
using an appropriate
growth
chart
when available.
(See Greenwood
Genetics
Center
in Suggested
Reading.)
Several
published
sources
iterate
the recommendations
for
assessing
patients
who have these disorders.
Not only are such recommendations
helpful
to the practitioner,
but
they justify
to insurers
that such testing, evaluations,
and procedures
are
in keeping
with the standard
of care
for a given disorder.
Such practice
is
the ultimate
in preventive
medicine
and in the long run will save the
insurer
large sums of money
by
avoiding
medical
catastrophes.
The
major debilitating
features
of a disorder require
attention
periodically.
Current
recommendations
should
be
available
from a clinical
genetics
center or may be published
in diseasespecific
newsletters.
Genetic
counseling
for patients
who need long-term
follow-up
is
ongoing,
with the questions
and concerns varying
from time to time.
Initially,
the diagnosis
should
be
described
as thoroughly
as possible.
The abstract
quality
of chromosomes
and genes may be rendered
more concrete by using pictures
and diagrams
during
the explanation
of etiology.
The counselor
should
be attuned
to
possible
misinterpretations
of terms
and concepts.
For example,
genetic
disorders
are not infectious.
The most
common
question
after the diagnosis
has been made is, “Where
do we go
from here?”
The plan of management
and follow-up
should
be described
as
specifically
as possible
and include
recommendations
for subspecialist
evaluation
and care of specific
problems.
As the child grows
and develops,
questions
may arise such as “What”
(do I have) (is wrong
with me)? and
“Why”
(do I have to keep going to
the doctors)
(did this happen
to me)?
These
questions
deserve
forthright
and truthful
answers
delivered
at a
level that can be understood
by the
child. Words
should
be chosen
carefully. “Differences”
is preferable
to
“normal”
and “abnormal.”
Acknowledge that this child is not the only
one known
who has this condition
by
referring
to “some
children
who are
born with more (less, different
amounts,
etc) of height
(vision;
hearing; length
of hands,
arms, legs, etc)
and by introducing
similarly
affected
individuals
to each other either in a
group or one on one. Diagnosis-specific support
groups
may be located
through
NORD,
newsletters,
national
organizations,
or local educational
agencies
or specialty
clinics.
If parents
are comfortable
answering their children’s
questions,
they
should
do so with support
from the
pediatrician
. Questions
never should
be dismissed.
Knowledge
and understanding
of self leads to self-esteem;
refusing
to answer
questions
is akin
to denying
the individual
as a unique
being.
We cannot
make limiting
or
handicapping
conditions
go away by
denying
their existence.
Acknowledging
the existence
of handicapping
conditions
leads to the development
of means
of coping
with them and
going on about the business
of living.
Advances
in Genetic
Testing
Keeping
up with the advances
in
genetic
testing
is difficult.
The
Human
Genome
Project
is a noble
attempt
to coordinate
the efforts
of
hundreds
of researchers
in both the
private
and public
sectors
to identify
gene mutations,
sequence
genes,
and
develop
diagnostic
tests. Tests
become
available
daily, and awareness of these developments
comes
from personal
discussions,
the media,
and finally,
the medical
literature.
Pediatrics
in Review
Vol. 1 7
No.
5
Ma
1996
GENCS
Genetic
TABLES.
Down
Evaluations
.
Counseling
for Management*
Syndrome:
#{149}
Cardiac
(echocardiography):
#{149}
Developmental:
#{149}
Hearing:
At 6 to 9 months
At 9 months
#{149}
Ophthalmologic:
(sooner
Newborn
#{149}
Cervical
spine
screen
and every
(sooner
and every
and spine
with
magnetic
and follow-up
if concerns)
and follow-up
based
with
program
as needed
At 3 years
assessments
resonance
in concert
to age 2 years;
instability:
follow-up
as needed
6 to 12 months
6 months
film for atlanto-axial
Neurofibromatosis:
(All initial evaluations,
and follow-up
if concerns)
At 9 months
#{149}
Thyroid:
#{149}
Head
At diagnosis
as needed
yearly
to age 5 years;
and yearly
to age
then,
10; then,
as indicated
as indicated
on individual)
imaging
#{149}
Developmental
#{149}
Ophthalmologic
#{149}
Hearing
#{149}
Blood
pressure
#{149}
Imaging
studies
of identified
affected
areas
as indicated
Thrner Syndrome:
(All
I
initial
evaluations,
with
follow-up
assessments
based
on individual)
Cardiac
#{149}
Renal
sonogram
#{149}
Ophthalmologic,
including
examination
for color-blindness
#{149}
Hearing
#{149}
Karyotype
#{149}
Developmental
#{149}
Pelvic
ultrasonography
#{149}
Possible
Marfan
assessment
referral
by age 3 years
at time
for growth
of referral
hormone
if not indicated
sooner
to endocrinology
therapy
for detection
of mild
learning
disabilities
prepubertally
in mid to late childhood
Syndrome:
#{149}
Cardiac
yearly
for mitral
#{149}
Ophthalmologic
#{149}
Counseling
valve
prolapse
and aortic
root
activities
as determined
size
yearly
regarding
physical
by joint
symptomatology
and cardiac
evaluation
Achondroplasia:
#{149}
Magnetic
resonance
thereafter;
imaging
if normal,
of foramen
repeat
*
therapy
focused
#{149}
Monitoring
of upper
#{149}
Orthopedic
evaluation
The recommendations
port and
Genetics
Reading.
Pediatrics
restriction,
if bowing
presuppose
educationaiprograms.
ofthe AAP have
in Review
on attainment
airway
Vol. 17
been
No.
5
at diagnosis;
if small,
repeat
at 3 to 6 months
and similarly
at 1 year
#{149}
Ultrasonography/computed
tomography
growth
exceeds
achondroplasia
growth
#{149}
Physical
magnum
or magnetic
resonance
curves or if symptoms
of gross
sleep
of the lower
a thorough
physical
These recommendations
formulatedfor
Down
May
1996
imaging
of brain at diagnosis;
repeat if head
of increased
intracranial
pressure
are present
and fine motor
apnea,
skills
and potential
extremities
examination,
for cor pulmonale
progresses
due to fibular
discussion
are those ofthe
author.
Syndrome,
neurofibromatosis,
ofetiology,
overgrowth
and
referral
to appropriate
Recommendations
ofthe
Committee
and achondroplasia.
See Suggested
supon
173
GENETICS
G enetic Counseling
The pediatrician
should
be aware
of one overriding
principle
in the
midst of the deluge
of news of breakthroughs
in genetics-genetic
heterogeneity.
The recent
news of the identification
of a gene (if not the gene)
for breast
cancer
is a good example.
The gene that was the subject
of the
media
releases
accounts
for about 5%
of all breast
cancers,
and although
this involves
a large absolute
number
of patients,
95% of cases of breast
cancer
have no available
genetic
screening
test or proven
etiology.
First and foremost,
be sure that the
discovered
gene is directly
applicable
to your patient.
Second,
determine
whether
the testing
is by direct
DNA
analysis
or by linkage
analysis.
If an
entity can be diagnosed
by direct
DNA analysis,
anyone
may be tested,
and such an analysis
may become
available
as a screening
test.
However,
if the testing
is performed
by linkage
analysis,
there are two
caveats
to applicability:
1) two or
more clinically
proven
cases in a
family
must exist, and 2) even if
these cases are present,
the testing
may be uninformative
if the marker
genes being analyzed
are not rare or
unique
enough
within
the family.
In
linkage
analysis,
genetic
polymorphisms
that are very close to the gene
in question
are analyzed
to try to
determine
which
members
of the
family
have inherited
either the
whole
chromosome
that carries
the
gene or at least that portion
of the
chromosome
that carries
the gene.
There
is no causal
relationship
between
the markers
being assessed
and the disease
gene, only a geographic
relationship.
Once it is established
that testing
is
appropriate
and applicable
to your
patient,
the process
is logistical.
Blood
samples
for DNA analysis
are
easy to handle
because
DNA is
extremely
stable.
The questions
remaining
include
cost, insurance
coverage
of the procedure,
where
the
specimen
is sent, whether
the test is
offered
as a service
or on an experimental
basis, and the nature
of the
report
generated,
if any. A further
consideration
is whether
the specimen is stored
and subjected
to further
analysis
as more is learned
about the
disease,
and if so, whether
this information
is transmitted
to the practitioner.
In some instances,
especially
174
if the research
is still experimental,
it
may be expeditious
for the patient
and family
to be in direct contact
with the laboratory
rather than giving
the pediatrician
the responsibility
for
following
developments
and transmitting results
as they become
available.
The pediatrician
should
make his or
her role very clear in this arrangement between
laboratory
and patient.
Concluding
Remarks
Hu,nan
Penn:
Saunders:
4th ed.
1988
Philadelphia,
Jorde
LB. Carey JC, White RL. Medical
Genetics.
St. Louis,
Mo: Mosby;
1995
NORD
Literature
Order Form: Rare Disease
Database
Articles:
NORD
Literature,
P0
Box 8923, New Fairfield.
CT 06812-1783
Rosenfeld
RG. Tesch LG, Rodriguez-Rigau
LI,
et al. Recommendations
for diagnosis,
treatment, and management
of individuals
with
Turner
syndrome.
The Endocrinologist.
I 994:4:351-358
Saul RA, Stevenson
RE, Rogers
RC, et al.
Growth
Referencesfroin
Conception
to
Adulthood.
Clinton.
SC: Jacobs
Press;
1988
The successful
diagnosis,
counseling,
and management
of children
and families who have genetic
disorders
is a
collaborative
effort of pediatrician,
clinical
geneticist,
genetic
counselor,
and other appropriate
specialists.
As
the first-line
manager
of most patients
who have genetic
disorders,
the pediatrician
must develop
skills and practice patterns
appropriate
for these disorders.
These skills include:
understanding
and being able to explain
causes
of genetic
disease,
performing
a careful
physical
examination
that
includes
assessment
of minor anomalies and their significance,
recording
the family
history,
and obtaining
appropriate
laboratory
and radiographic studies.
The pediatrician
should
be
knowledgeable
about genetic
screening, especially
its limitations.
He or
she should
be familiar
with advances
in genetic
testing
and how to order
such tests appropriately.
Finally,
the
pediatrician
should,
in consultation
with the clinical
geneticist,
be able to
outline
a plan of health care supervision that includes
genetic
counseling
and appropriate
referrals
for evaluation and care that exceed
his or her
capabilities.
SUGGESTED
Malformation.
WB
PIR QUIZ
6.
If it appears
to be clinically
certain
that a child has an autosomal
recessive disorder
such as cystic fibrosis
or Tay-Sachs
disease
but only the
father tests positive
as a carrier
(heterozygote):
A. Molecular
testing
for evidence
of uniparental
disomy
should be
ormed.
B. One may conclude
that the
patient
has a phenocopy
of the
disease.
C. The chance
of recurrence
is 1 in
4 (25%) for any subsequent
pregnancies.
D. This isacase
of pseudodominance.
7. If a man
to have
who has hemophilia
A were
a daughter
with the same
disorder,
the most likely genetic
process
among
the following
would
be:
A. A new mutation.
B. Maternal
heterodisomy.
C. Paternal
heterodisomy.
D. That the mother
is a carrier
of
hemophilia
A.
8.
Disorders
due to abnormalities
in
mitochondrial
DNA have which of
the following
patterns
of inheri-
tance?
A.
B.
C.
D.
READING
Committee
on Genetics
of the American
Academy
of Pediatrics.
Health
supervision
for children
with achondroplasia.
Pediatrics.
1995;95:443-45
I
Committee
on Genetics
of the American
Academy
of Pediatrics.
Health
supervision
for children
with Down Syndrome.
Pediatrics.
1995:93:855-859
Committee
on Genetics
of the American
Academy
of Pediatrics.
Health
supervision
for children
with Turner
syndrome.
Pediatrics.
1995;96:l
166-1173
DiLiberti
JH, Greenstein
MA, Rosengren
SS.
Prenatal
diagnosis.
Pediatrics
in Review.
1992; 13:334-342
Holmes
LB. Malformations
attributed
to multifactorial
inheritance.
Pediatrics
in Review.
I 985;6:269-273
Jones KL. Smith c Recognizable
Patterns
of
9.
Affect
only females.
Affect
only males.
Matrilineal
transmission.
Patrilineal
transmission.
A child who has typical
clinical
features of Down
syndrome
has a karyotype that appears
to be normal.
This finding
suggests
that:
A. Fluorescent
in situ hybridization
is indicated.
B. Germline
mosaicism
may be
present.
C. The condition is the result of
exposure
of the mother to a
teratogen.
D. The diagnosis
should
be regard-
ed as in error.
Pediatrics
in Review
Vol. 1 7
No.
5
May
1996