Download GeneticsforNursesinAdultDisciplines

Genetics for Nurses in Adult
A guide to recognitionDisciplines
and referral of congenital and genetic disorders
AUTHORS:
Golder N. Wilson MD PhD,1 Vijay Tonk PhD,2
REVIEWERS:
Shirley Karr BSN RN,3 Joanna K. Spahis BSN CNS,4 Shirley Myers,5 RNC, MSN,
FNP, and Sherry Letalian RN6
1Clinical Professor of Pediatrics, Texas Tech University Health Science Center at Lubbock and Private Practitioner,
KinderGenome Genetics, Dallas Texas; 2Professor of Pediatrics and Obstetrics-Gynecology; Director, Cytogenetics
Laboratory, Texas Tech University Health Science Center at Lubbock; 3Genetics Coordinator, Maternal-Fetal Medicine and
Genetics, Texas Tech University Health Sciences Center at Amarillo;4Pediatric Clinical Nurse Specialist in Genetics and
Coordinator of the Down Syndrome Clinic, Department of Genetics, Children’s Medical Center of Dallas5Women’s Health
Nurse Practitioner, Maternal-Fetal Medicine and Genetics, Texas Tech University Health Sciences Center at
Amarillo;6Pediatric Clinic Coordinator, Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock
Acknowledgement:
This presentation was designed as part of the GEN-ARM (Genetics Education
Network for Nursing Assessment, Recognition, and Management) for the Mountain
States Region Genetics Collaborative (MSRGCC); contact www.mostgene.org or
Ms. Joyce Hooker at [email protected]
Genetic Disorders are Common
Genetic diseases affect 5-10% of children
Nurses can recognize and refer genetic disorders without
need for esoteric genetic knowledge
We will now present cases where your nursing skills and
alertness (REYDAR=Recognize, EYDentify, Assess,
Refer) can greatly benefit children with genetic diseases.
These cases will introduce you to simple principles of
genetics that will give you confidence in recognizing
these patients and foster a medical home
These cases and principles are geared to the nursing
genetics primer and resources on the GENARM CD
Think genetics when something is
unusual or extreme
• Case A: A term AGA newborn product of a pregnancy
with little prenatal care has an enlarged and distorted
head, blue-gray sclerae (whites of the eyes), and
deformed limbs. X-rays show multiple fractures, and
the mother blames this on an auto accident at 7
months gestation. Do you agree?
Newborn with large head and deformed bones with fractures by x-ray
This unusual presentation should prompt
REYDAR for a genetic disease
•
More detailed family history would be useful, although many genetic
disorders occur as new changes (new mutations)
•
The symptoms of blue sclerae and multiple fractures could be searched on
the website Online Mendelian Inheritance in Man (go to
http://www.ncbi.nlm.nih.gov/entrez/ or enter OMIM in search engine). They
point to a disorder called osteogenesis imperfecta (166210
•
OMIM contains >6000 diseases that can be searched by symptom, name,
or number; associated databases contain genetic education, medical
literature (PubMed), and even the complete human genome sequence/gene
map.
•
Also useful is the companion database www.genetests.org that lists testing
(when available) for the particular genetic disease (go to the clinical
laboratory section and search by disease name
The family history indicated that the mother and other
relatives had mild features of osteogenesis imperfecta or
brittle bone disease (see Chapter 2)
Family history
Pedigree
Suspicion of genetic disease underlying this unusual infant led to
referral and genetic counseling for this autosomal dominant disease—
mother’s guilt about her accident was assuaged and she learned she
had a 50% chance each of her future children would have OI
• Case example 1: Nurses in adult
disciplines might have identified the
mother or maternal relatives with OI,
giving them the advantages of genetic
counseling for a 50% recurrence risk and
potential therapy with pamidronate that
can decrease the risk for fractures
Think genetics when something is unusual
or extreme
• Case example 2: A school physical
• A 14-year-old male is seen for a routine school physical and asks
clearance to participate in sports. His mother mentions he has had
surgery for fused sutures (craniosynostosis) including reconstruction
of his nasal bridge. He has also had a history of mild mental
disability, and the school nurse notices long fingers and a concave
chest, prompting recall about Marfan syndrome and heart disease.
The nurse decides to postpone approval for sports participation and
refers the young man for genetic evaluation. Do you agree?
• In case example 2, the recollection of Marfan syndrome
(154700) was appropriate because of the boy’s long
“spider” fingers (arachnodactyly). Echocardiographic
studies would show a dilated aorta and he should
certainly not participate in collision or high-intensity
sports. Genetics referral would establish that this child
had a disorder called Shprintzen-Goldberg syndrome
(118212) that was similar to Marfan but different in
having craniosynostosis and mental disability.
Shprintzen-Goldberg syndrome is also autosomal
dominant, meaning that the boy’s normal parents would
have a minimal recurrence risk for future affected
children and the boy himself would have a 50% chance
to transmit the condition with each future pregnancy.
Preventive management in his case allowed protection
from harmful activities and access to medications such
as propranolal or Losartan that may be helpful in treating
aortic aneurysms.
• Case example 2: Recognition of a genetic
condition and preventive management for this
teenager allowed protection from harmful
activities and access to medications such as
propranolal or Losartan that may be helpful in
treating aortic aneurysms. A family with Marfan
syndrome is discussed in chapter 2, showing the
advantages of recognizing this disease with its
risks for heart and eye complications.
• Note that simple recognition and assessment of
possible genetic disease, not sophisticated
knowledge, optimized nursing care of for the
example families.
• Nurses with additional interest in genetics can
learn to construct pedigrees, interpret
inheritance mechanisms, and provide
recurrence risks for the parents (genetic
counseling)
• Nurses are ideally positioned to be genetic
counselors with their hands-on contact,
emphasis on education, and focus on prevention
• Read chapters 2-4 in the primer to acquire the
skills for genetic counseling
Categories of genetic disease relate to the steps
from gene to family (genetic hierarchy)
• A family has people with unusual symptoms
• A person has abnormal form or function (disease)
• A tissue (cell to organ) has abnormal structure
(metabolic disorders)
• A chromosome is extra or missing (chromosome
disorders)
• Several genes (plus environment) are abnormal
(multifactorial disorders or susceptibilities)
• A gene (DNA to RNA to protein) is abnormal (Mendelian
disorders
Genetic disease can be defined by abnormal
genes, tissues, or chromosomes (genetic testing)
Categories of genetic or congenital disease
Disease category1
Number of
diseases
Aggregate
frequency2
Shortened
lifespan
Major
handicap
(%)
Mendelian
> 4500
1
++3
+++
Chromosomal
> 100
0.5
++++
++++
Multifactorial
> 100
5-10
++
+++
Metabolic errors
> 500
0.3
+++
++++
Syndromes
> 1000
0.7
+++
++++
Isolated anomalies
> 200
2-3
+
++
Total
> 5000
10-12
++
+++
• Mendelian diseases like osteogenesis
imperfecta have distinctive family patterns
• The pattern of affected relatives is caused by
transmission of single genes, each with a unique
position (locus) on the chromosome.
• The paired chromosomes 1-22 and XX in
females imply paired genes except for X and Y
genes in the male
• Dominant or recessive diseases result when one
or both gene partners (alleles) are abnormal.
• Abnormal alleles can be predicted (genetic risks)
and sometimes diagnosed through their
abnormal DNA sequence or RNA/protein
expression.
Sickle cell anemia is
recessive, requiring
both β-globin alleles to
be abnormal (SS versus
AS trait or AA normal).
Sickle cell anemia can be
predicted (25% risk for
next child) and tested
(abnormal S protein or gene)
Other inherited anemias
can be related to
different abnormal
globin alleles (C, D, E,
thassemias).
A
or
S
• OI is caused by one abnormal
allele at a collagen gene
(genotype Oo)
• Different phenotypes of OI
relate to different collagen
alleles
• The >6000 Mendelian
diseases thus relate to a
similar number of different
genes and abnormal alleles.
• Characterization of abnormal
alleles provides DNA testing—
few of the >1600 characterized
disease genes are available to
the clinic.
• Simultaneous analysis of
multiple genes (DNA chips,
arrays) is not yet practical in
the way that karyotypes define
any abnormal chromosomes
Know categories, not rare diseases
Mendelian diseases reflect transmission of single
genes (abnormal alleles) = DNA diagnosis
• Single genes altering development cause birth defects and syndromes
• Single genes altering enzyme pathways cause inborn errors of metabolism
•Single genes altering organ function(s) produce extreme or early–onset
examples of common disease (e.g., neonatal diabetes)
Multifactorial diseases reflect multiple abnormal
genes plus environment = DNA/HLA markers
Many genes altering development cause isolated birth defects like cleft palate
Many genes altering enzyme pathways cause common metabolic diseases
(e.g., adult-onset diabetes, hyperlipidemia)
Many genes altering organ function(s) produce adult diseases (e.g., schizophrenia)
Chromosomal diseases imbalance multiple genes
and cause multiple birth defects = Karyotype
REYDAR of common adult presentations
Recognition → Category → Referral ↔ Medical home
• Case 10P—Diabetic woman who becomes
pregnant
• Case 11P—A pregnant couple and cystic
fibrosis screening
• Case 12P—A pregnant couple with
infertility and two miscarriages
• Case 13P—Couple with maternal history
of mental retardation
(see Chapter 1)
Case 10P. Diabetic woman who
is 10 weeks pregnant
• A 25-year-old woman with juvenile diabetes has been
managed by her family practitioner for several years.
She calls and asks for referral to obstetrics because
she is approximately 6 weeks pregnant. She has had
several hospitalizations for diabetic control and states
that her blood sugars have been high for the past few
weeks. The obstetric nurse discusses the risks of
hypoglycemia, respiratory distress, and polycythemia
for infants of poorly controlled diabetic mothers, but
does not mention another risk for the fetus, which is?
Women with poorly controlled diabetes
have a 3-5 fold increased risk for
congenital anomalies in their fetus
that can be remembered by 3Cs—
cranial, cardiac, and caudal
anomalies. Cranial defects can
include anencephaly as in case 9P
or holoprosencephaly (photo at
right); caudal defects
underdevelopment of the
sacrum/lower limbs (caudal
regression) or spina bifida. Anomaly
patterns like the VATER association
(192350) or Goldenhar syndrome
(164210) also occur at higher
frequency in infants of diabetic
mothers.
Preconception counsel
• Stringent diabetic control in later pregnancy can
eliminate neonatal physiologic changes like
hypoglycemia, hypocalcemia, polycythemia, and
respiratory problems. Lowering the risks of
diabetic pregnancy illustrates the potential
collaboration of pediatric or adult and obstetric
nurses in preconception counsel. Nurses in adult
disciplines can recognize women or couples with
increased pregnancy risks and refer them for
pregnancy planning.
Case 14P: Man whose father had heart attack at age 41
(hypercholesterolemia)
A nurse practitioner in a family practice clinic performs a routine physical on a
man of 35 for insurance purposes. He notes on his preassessment form
mention of the man’s father who died of a heart attack at age 41. He
completes a more detailed family history indicating that the man has two older
brothers and two younger sisters, and that one of the older brothers has had
two heart attacks and bypass surgery at age 45. The man’s father was
adopted, and his mother is in good health with no heart disease in her family.
What concerns should be raised?
• Case 14P: Discussion
• Besides revealing patterns of disease suggestive of
Mendelian inheritance, a family history can reveal
susceptibilities or risk factors that lead to screening
preventive strategies. Common disorders like isolated
birth defects, coronary artery disease, diabetes mellitus,
or hypertension follow a model of multifactorial
determination. This model implies the interaction of
multiple genes with the environment and a threshold
above which susceptibility becomes disease. A growing
number of laboratory tests are being devised to measure
individual gene effects that combine with other genetic
and environmental factors to produce disease. Coronary
artery disease follows the multifactorial model and is
associated with several genetic and environmental risk
factors—blood lipid or homocystine levels, obesity,
hypertension, diabetes, and certain clotting factors.
• Case 14P: Discussion
• A family member with extreme or unusual
presentation of a common disease (e.g., young
age or multivessel obstruction in coronary artery
disease) indicates increased susceptibility to that
disease (lower threshold) that may be
transmitted to offspring. The man’s father with an
early onset coronary gives him a higher risk (35%) to develop coronary artery disease and
justifies laboratory testing for the disease (e.g.
stress test for early coronary occlusion) or
factors (e.g., blood pressure, blood sugarcholesterol-lipoprotein-homocysteine-clotting
factor abnormalities) that predispose to disease.
• Case 14P: Discussion
• Abnormal laboratory findings can lead to medical
(statins, heparin) or dietary (low cholesterol, folic acid)
therapies and improved outcome when the hereditary
risks are recognized. Among the several genes
interacting to cause multifactorial diseases may be
occasional ones of major effect—such was the case for
the low-density lipoprotein receptor where mutations
caused very high cholesterol in the dominant condition
familial hypercholesterolemia ( 144010). Extreme or
unusual presentations of common diseases may also
point to Mendelian disorders as well as to predisposing
risk factors. The Surgeon General has recommended
that all individuals know their family histories, an
obligation that nurses of all disciplines can greatly assist.
Review of genetic testing
• Mendelian disorders—DNA tests for specific
mutant alleles. LIMITATION: Only a few
diseases are sufficiently common that DNA
testing is commercially feasible
• Chromosome disorders—routine karyotypes on
blood, amniocytes, bone marrow or solid tumors;
FISH testing for subtle changes. LIMITATION:
Chromosome testing cannot analyze component
genes
• Multifactorial disorders—DNA tests for
associated DNA variants (DNA markers) that
indicate susceptibility to disease. LIMITATION:
DNA marker testing is still in the research stage
• Single gene (Mendelian disorders) that are
sufficiently common can be diagnosed by DNA
testing for changes in gene sequence or structure;
the man with family history of heart attacks (case 14)
could have blood cholesterol studies and DNA
testing for mutations in the LDL receptor
Diagram of gene and its encoded LDL receptor protein that imports
cholesterol into cells—the position of mutation (shown below gene) determine the
severity of hypercholesterolemia
Chromosome disorders can be diagnosed by a routine karyotype, performed on
cells from individuals (blood) or fetuses (blood by fetoscopy, dividing villus cells
from chorionic villus sampling, amniotic fibroblasts from amniotic fluid). This
testing requires at least 5-7 days for results.
Now a rapid FISH test is available that does not require stimulation of cell division and gives results
within 2-4 hours. Rapid FISH highlights chromosomes commonly involved in disorders—e.g., 13
(Patau syndrome), 18 (Edwards syndrome), or 21 (Down syndrome), showing three versus the
normal two FISH signals in each cell nucleus (X and Y probes also show Turner syndrome or
document sex in cases of ambiguous genitalia)
Cloned DNA segment
from target chromosome
13
18
21
X
Y
FISH probes
Fluorescent label
13, X, Y
No culture or need for
metaphase spreads
18
21
Male with
trisomy 13
Chromosome disorders
•
•
•
•
•
•
Miscarriages (50-60%), liveborn children (0.5%), cancer tissue (many have
diagnostic changes)--over 200 chromosomal diseases due to extra or missing
chromosome or parts of chromosomes (p small or q long arms)
Hallmarks are multiple major or minor anomalies (unusual appearance) with
mental disability
Most recognized by a routine karyotype, but FISH is required to detect
submicroscopic deletions (e.g., DiGeorge) or the 3% of suspect children who
have changes on subtelomere FISH after normal karyotypes
Individual submicroscopic deletions are found in Williams (7q), hereditary
retinoblastoma (13q), Prader-Willi (15q), Shprintzen-DiGeorge spectrum (22q),
and ~15 others.
Consider chromosomes in any child with unexplained mental disability and/or
multiple birth defects, couples with >2 miscarriages, prenatal diagnosis for
women over age 35
Prenatal diagnosis of chromosome disorders can be performed by
preimplantation diagnosis (first week), chorionic villus sampling (10-12 weeks),
or amniocentesis (15-18 weeks).
See Chapter 7 for more information
Multifactorial Disorders
Table 4.1. Multifactorial Disorders in the United States
Disorder or
category
Cause of
death
Prevalence
Numbers
affected
(rank)
(%
population)
(millions)
Hereditability
[Genetic risk factors]
(high ++++ to low +)
Heart disease
1
3
7
++ [Cholesterol uptake]
Cancer
2
5
6
++ [Oncogenes]
Stroke
3
<1
0.6
+ [Cholesterol, blood
clotting]
Accidents
4
<1
3
+
Diabetes
mellitus
7-8
4
11
++ [Insulin secretion,
action]
Suicide
8-9
<1
0.1
++ [Schizophrenia,
alcoholism]
Congenital
anomalies*
9-10
5
3
++ [Developmental genes]
[Alcohol and drug use]
*Ranks first for neonatal causes of death; approximate scale: ++++ (100% of predisposition due
to genetic factors as for Mendelian disorders) to + (20% of predisposition due to genetic factors)
Multifactorial Disorders
• Most isolated birth defects like cleft palate,
hypospadias, heart defects, spina bifida
• Many common diseases like diabetes mellitus,
hypertension, mental illness, mild
mental/learning disabilities
• Multiple genes involved, giving lower
transmission risks (about 3% for offspring of
affected parent, sibling to affected child)
• Therapeutic goals are to manipulate
environment (e.g., folic acid) either generally or
for specific high-risk individuals identified by
associated DNA markers (more diverse and
sensitive than HLA haplotypes
Multifactorial disorders: For some (e.g., coronary artery
disease), single genes of major effect (e.g., those
regulating cholesterol) are good risk markers)
Recognizing at-risk children or adolescent females
provides important opportunities for nursing education and
prevention (see chapter 4)
• Case 14P: Discussion
• A major initiative of modern genetics is to expand
recognition of disease susceptibilities by examining
variable regions of DNA. The human genome project
revealed a difference in DNA sequence for unrelated
individuals every 1 in 200 to 500 nucleotides, implying at
least a million DNA differences per person. Most of
these are single base pair differences that do not lead to
clinical differences—single nucleotide polymorphisms
(SNPs). DNA markers that travel with disorders like
schizophrenia (OMIM #181500) or Alzheimer disease
(OMIM #104300, others) potentially allow measurement
of individual susceptibility in the way that cholesterol
conveys risk for coronary artery disease. With further
study, DNA markers may provide tests for susceptibility
and even prevention through modified expression of their
associated genes.
• Case 15P: Woman whose mother and
grandmother had breast cancer at young ages.
• An obstetric nurse assesses a woman aged 37 who is
about 6 weeks along in her current pregnancy. The
woman has two prior children and has no chronic
illnesses; her husband is age 40 with a benign family
history. The nurse ascertains that the woman has two
sisters, aged 35 and 32, each with two children and no
health problems. The woman’s mother is a breast cancer
survivor, having her first cancer at age 31. Her mother’s
mother also had early breast cancer at age 36, dying by
age 45. Her mother has two sisters, one of whom died
from ovarian cancer at age 47 and another who has had
cautery for cancer in situ of the cervix. What information
should the nurse provide to this couple?
Case 15P: Discussion
Besides recognition of “advanced” maternal age with
discussion of increased risks for chromosome
abnormalities, the nurse should address increased
susceptibility to breast and ovarian cancer. Although not
necessarily pertinent to the current pregnancy, the
woman has increased risks for breast cancer and should
know about options for breast cancer gene testing.
Mutations in the breast cancer genes BRCA1 (OMIM
#113705) and BRCA2 (OMIM #600185) account for
about 10% of breast cancer, characterized by its early
onset and association with ovarian cancer. Testing would
ideally be performed on one of the woman’s affected
relatives, ascertaining the presence of BRCA mutations
versus usually multifactorial breast cancer. If positive, the
woman should be informed about her 50% risk to
transmit the mutation to each child.
• Case 15P: Discussion
• Cancers are additional examples of multifactorial
disorders like coronary artery disease that were
discussed in the previous section. Most will confer low
risks for family members unless the same cancer is
present in multiple relatives or a given cancer has an
unusual or extreme presentation (e.g., early onset,
associated features). Single gene diseases can also be
concealed amidst multifactorial cancers, exemplified by
the BRCA genes or cancer syndromes like Li-Fraumeni
(bone, breast, brain cancers—OMIM #151623) or
Gardner disease (colon cancer-- OMIM #175100) that
are due to single gene mutations. Alertness for early
onset or recurrent types of cancers in families allows
evaluation for a growing number of cancer genes or
susceptibility markers.
Rules from Chapter 1
• RULE : Recognition of family histories with
multiple affected individuals or those with
unusual/extreme presentations of common
diseases (e.g., heart attacks) allows
definition of risk factors (e.g., cholesterol)
and preventive management.
.
Case 13P: Couple with maternal history of mental
retardation
Bob and June present to a nurse practitioner for prenatal care at an
estimated 6 weeks of pregnancy. Bob is 26, June 24, and they had a normal
daughter Karen two years ago with no pregnancy or delivery problems. Both
are healthy and of Caucasian ancestry, and Bob’s family history is normal
The nurse finds that June is an only child, but that her mother Gail has two
brothers who have mental retardation. In addition, Gail has a sister Joan
with with two boys and a girl, and one boy Eric has mental retardation
thought due to birth injury. Gail’s other sister Jill has three boys and two
girls, and her eldest son Jim has mental retardation of unknown cause. One
of Jill’s daughters has also had learning problems that caused her to drop
out of high school, and she has a preschool son Bert with speech delay.
What concerns should the nurse address?
Case 13P: Discussion
Besides the usual options for genetic and fetal screening
(ultrasound, quad screen, cystic fibrosis screening), the
nurse should recognize the positive family history and
recommend genetic evaluation. The presence of several
relatives with the same condition (mental disability)
brings up the possibility of Mendelian disease, and
sketching of the family pedigree (below) would suggest
an X-linked disorder associated with mental retardation.
Genetic evaluation would inform June that her mother
Gail has a 50% chance and she a 25% chance to be a
carrier for the X-linked disease.
Gail
Joan
Jill
June
Case 13P: Discussion
The X-linked fragile X syndrome (OMIM #300624)
is the most common genetic cause of mental
disability with an estimated incidence of 1 in
2000 males. Since June is early in her
pregnancy, a fragile X DNA test could be
performed on one of her male relatives to
confirm or exclude this diagnosis. It would be
ideal if one of her affected male relatives could
be evaluated by a clinical geneticist so that the
diagnosis of fragile X syndrome or another of the
>20 syndromes associated with X-linked mental
disability could be suspected.
• If the diagnosis of fragile X were confirmed in a male
relative, June could have fragile X DNA testing to
determine if she was a carrier. If her relatives were not
available, or if their evaluation could not be
accomplished in a time frame to accomplish June’s
testing and options for prenatal diagnosis, then June
could have the fragile X DNA test but realize that a
negative result would not exclude other X-linked mental
retardation syndromes. Preconception knowledge of
fragile X syndrome in her family with recognition of her
carrier status would have allowed Jill and Bob to
consider other options such as surrogate egg donor or in
vitro fertilization with preimplantation genetic diagnosis
(PGD) and implantation of an unaffected embryo. Their
case emphasizes the value of recognizing suspect family
histories as early as possible in order to provide genetic
counseling and reproductive options.
Common disorders (like mild mental or learning disabilities
often exhibit multifactorial determination
• Case 13P: Discussion
• If Jill or Bob had only one relative with mental
disability with no obvious pedigree pattern, then
multifactorial determination of the mental
disability would be most likely. The odds of
multifactorial disability would be increased if the
affected person was mild and did not have an
unusual appearance or biochemical
abnormalities. Multifactorial disorders confer a 23% risk for primary relatives—i.e.,
siblings/parents/children. Since Jill and Bob had
normal intellect, their risks from one relative with
mental disability would be less than 2-3%.
Review Questions
11. A woman is diagnosed with Crohn’s disease,
and wishes to know the risk that her daughter
will develop the disease. She is otherwise
normal with an unremarkable family history.
The likely inheritance mechanism and her
daughter’s risk would be:
A. Autosomal dominant with a 50% risk
B. Autosomal recessive with a 25% risk
C. X-linked recessive with a 25% risk
D. Chromosomal with a 10-15% risk
E. Multifactorial determination with a 5-7% risk
•
A.
B.
C.
D.
E.
12. A 24-year-old Ashkenazi Jewish woman
develops bilateral breast cancer. Her mother
and grandmother died of ovarian cancer, and a
maternal aunt also had early onset breast
cancer. She has two daughters aged 12 and
16. The most probable mechanism and risk to
her daughters would be:
Multifactorial determination with a 1-2% risk
Autosomal dominant with a 50% risk
Autosomal dominant with a 25% risk
X-linked dominant with a 50% risk
X-linked dominant with a 25% risk
•
A.
B.
C.
D.
E.
13. A male teenager presents for a school
physical with tall stature, thin body build,
concave chest (pectus), long fingers, flat feet,
and increased joint laxity. His father died at
age 35 with a heart attack. He wants approval
to play basketball. An important disease
category and disorder to consider would be:
Coronary artery disease and myocardial
infarction
Coronary artery disease and congestive
heart failure
Connective tissue disease and aortic
dilatation
Connective tissue disease and myocardial
infarction
Connective tissue disease and aortic
coarctation
•
A.
B.
C.
D.
E.
14. A 30-year-old man has hypertension
controlled by diet and medication, and one of
his three siblings is affected. His father died of
kidney failure, and one of the man’s three sons
had urinary tract infections with cystic kidneys
on ultrasound. The most likely diagnosis is:
Multifactorial predisposition to renal failure
Isolated congenital anomaly of the urinary
tract
Autosomal dominant polycystic kidney
disease
Autosomal recessive polycystic kidney
disease
X-linked recessive polycystic kidney
disease
Answer 1E
• 1. Crohn’s disease is a multifactorial
disorder with a 7.5% risk for siblings of
affected individuals to develop the
disease (see Chapters 4 and 12).
Approximately the same risk would
apply to other primary relatives such as
the woman’s daughter.
Answer 12B
• 12. The early onset and family history of cancer is
suggestive of Mendelian disease (e.g., BRCA—
113705--or Li-Fraumeni syndrome—112480--gene
mutations, see chapter 12). The daughters would be
at 50% risk for breast cancer, and DNA testing on the
mother could determine if a particular BRCA1,
BRCA2, or p53 (Li-Fraumeni) tumor suppressor gene
were present. BRCA mutations are more common in
Ashkenazi Jews. The BRCA genes account for about
10% of breast cancer, the rest being multifactorial.
Thus, negative DNA tests do not eliminate the need
for annual screening. Testing of the minor daughters
would raise the ethical issues of informed consent
and autonomy (parent versus child), but would
probably be pursued because of the advantages of
early screening or prophylactic mastectomy.
Answer 13C
• 13. The physical findings are characteristic
of diseases with loose connective tissue, and
the father-son affliction most suggestive of
autosomal dominant diseases like Marfan
syndrome (154700). These individuals are at
risk for aortic dissection and sudden death
and should not participate in collision or
high intensity sports. Note that the history of
“heart attack” in the father was probably an
aortic dissection, stressing the need for
medical and autopsy information to
discriminate among cardiac causes of
sudden death (see Chapter 12).
Answer 14C
• 14. The family history and presence of
hypertension is suggestive of an autosomal
dominant renal disorder, and the dominant form
of polycystic kidney disease (173900) could be
found in OMIM. This disease may be silent,
causing severe hypertension and presenting
with strokes at an early age. Early diagnosis in
at-risk individuals (this man was at 50% risk) is
important for treatment of hypertension. The 30year-old man should have imaging studies to
confirm the diagnosis followed by imaging
studies of his two apparently normal sons and
siblings.