Genetic Diagnosis and Counseling

In document Board Review From Medscape (Page 129-139)

12. A 37-year-old man presents to the local emergency department with a swollen and tender right calf. The patient has had these symptoms for 4 days. He denies having undergone any trauma. He has no histo-ry of cancer, and he has had no similar episodes in the past. He denies having a family histohisto-ry of venous thrombosis. Ultrasound confirms deep vein thrombosis, and the patient is provided with appropriate anticoagulation. Several days later, the patient sees you for a follow-up visit. The laboratory studies made in the emergency department included a factor V Leiden mutation analysis.

Which of the following statements is true regarding this patient's test for factor V Leiden mutation?

❑ A. The clinical setting and the patient's risk factors for deep vein throm-bosis have no bearing on the decision to conduct factor V Leiden mutation testing

❑ B. It is estimated that 25% of whites and 50% of those with venous thromboembolism are heterozygous for factor V Leiden mutation

❑ C. Factor V Leiden mutation analysis is a DNA test with low sensitivity, low specificity, and high positive predictive value for this mutation

❑ D. Factor V Leiden mutation analysis is a DNA test with high sensitivity, low specificity, and low positive predictive value for this mutation

Key Concept/Objective: To understand the limitations and characteristics of DNA-based testing

The clinical setting and risk factors given for a particular patient have great implications on the use of genetic testing. Although factor V Leiden is the most common known throm-bophilic risk factor, only a small proportion of patients with this genetic disorder ever experience an episode of thrombosis (the risk of thrombosis is 2.4-fold greater in those

with the mutation than in those without the mutation). It is estimated that 5% of whites are heterozygous for factor V Leiden and that approximately 20% of all persons with venous thromboembolism are heterozygous for factor V Leiden. Factor V Leiden mutation analysis, the most commonly ordered genetic test, is an example of a direct DNA-based test with 100% sensitivity but low specificity and low positive predictive value. (Answer: D—

Factor V Leiden mutation analysis is a DNA test with high sensitivity, low specificity, and low positive predictive value for this mutation)

13. A 21-year-old man comes to your office to establish primary care. He states that he has been generally healthy but that he has multiple colon polyps. He states that he tested positive for familial adenomatous polyposis (FAP). He says that his former physician told him that this illness can run in families, and he asks your opinion on whether or not his family needs further testing.

Which of the following statements regarding FAP and the APC gene mutation is true?

❑ A. Persons with the APC gene mutation develop colorectal adenomas starting at around age 30

❑ B. FAP is an autosomal dominant disorder with 50% to 70% penetrance of the disease-causing gene mutation

❑ C. Presymptomatic testing has never been shown to reduce morbidity or increase life expectancy

❑ D. Testing of the APC gene has been shown to be cost-effective when used to identify carriers of the APC gene mutation among at-risk relatives of individuals with FAP

Key Concept/Objective: To understand the value and utility of presymptomatic genetic testing

FAP is a devastating, life-shortening condition when it is not recognized. FAP is an auto-somal dominant disorder with 100% penetrance of the disease-causing gene. Persons with an APC gene mutation develop adenomas in the colorectum starting at around 16 years of age; in these individuals, the number of adenomas increases to hundreds or thousands, and colorectal cancer develops at a mean age of 39 years. The mean age at death is 42 years in those who go untreated. Testing of the APC gene has been shown to be cost-effective when used to identify carriers of the disease-causing APC gene mutation among at-risk rel-atives of individuals with FAP. Early diagnosis via presymptomatic testing reduces mor-bidity and increases life expectancy through improved surveillance and timely prophy-lactic colectomy. FAP is an example of a condition in which presymptomatic testing may be lifesaving. (Answer: D—Testing of the APC gene has been shown to be cost-effective when used to identify carriers of the APC gene mutation among at-risk relatives of individuals with FAP)

14. A 23-year-old female patient presents to your office for a routine annual visit. She mentions that her mother tested positive for the "breast cancer genes." She asks you for general information regarding these tests and about the need for her and her family to be tested for these mutations.

Which of the following statements is correct regarding BRCA1 and BRCA2 testing?

❑ A. It is clear that all women should have genetic testing for the BRCA1 and BRCA2 mutations, because the efficacy of measures to reduce can-cer risk for individuals with these mutations is well described

❑ B. In general, breast cancer is a simple disorder caused by heritable gene mutations only

❑ C. Only 5% to 10% of cases of breast cancer are attributed to mutations in single genes, including BRCA1 and BRCA2

❑ D. If this patient tests negative for the BRCA1 and BRCA2 mutations, she will have no future need for routine breast cancer screening

Key Concept/Objective: To understand the importance and limitations of testing for BRCA mutations

The efficacy of measures to reduce cancer risk for individuals with BRCA1 and BRCA2 can-cer-predisposing mutations is unknown. Breast cancer, like such other common disorders as coronary artery disease, diabetes mellitus, and Alzheimer disease, is regarded as a com-plex disorder. Comcom-plex disorders have multiple etiologies, including heritable single genes, multiple genes with an additive effect that interact with often undefined environ-mental influences, and acquired environenviron-mental or genetic changes. Single heritable genes may represent a relatively small contribution to the overall incidence and morbidity from common diseases, including breast cancer, which affects one in nine women. Only 5% to 10% of cases of breast cancer are attributed to mutations in single genes, including BRCA1 and BRCA2. For a woman whose relatives have a known BRCA1 mutation but who has tested negative for the mutation known to be in the family, the chance of the development of breast cancer is still one in nine. This patient therefore has the same need for close sur-veillance as women in the general population. (Answer: C—Only 5% to 10% of cases of breast cancer are attributed to mutations in single genes, including BRCA1 and BRCA2)

15. A 24-year-old man with a history of increasing muscle cramps, myalgias, and calf muscle hypertrophy was recently diagnosed with Becker muscular dystrophy (BMD) through muscle biopsy. The lab report of the patient's leukocyte DNA analysis, however, states, "no mutation known to be associated with BMD found." On further questioning, you discover that the patient has a reportedly healthy 2-year-old daugh-ter; a 16-year-old maternal cousin who recently began suffering from muscle cramps similar to those of the patient; a sister in her teens who is reportedly healthy; a mother with a "big heart"; and a maternal grandfather who died of an unspecified heart problem 20 years ago. You suggest further genetic linkage analysis and counseling for this patient and his extended family.

Which of the following facts would serve as the basis of your recommendation?

❑ A. Even though the patient cannot pass on the gene for BMD, his appar-ently healthy sister might be a carrier

❑ B. This patient's offspring and other relatives are at risk for BMD, and a genetic linkage analysis would help define their genotypic risk status

❑ C. Analysis of family members might help define the mutation in this patient and therefore help guide his therapies

❑ D. You should not suggest further counseling or testing because the lack of a specific gene mutation in the proband means you will not be able to determine the degree to which the patient's asymptomatic relatives are at risk

❑ E. The mother's mutation probably represents germline mosaicism; link-age analysis would help determine both her risk and her other chil-dren's risk

Key Concept/Objective: To understand the pattern of inheritance of X-linked diseases and to know their implications

Because dystrophinopathes are inherited in an X-linked recessive manner, the risk to the siblings of a proband depends upon the carrier status of the mother. In this case, the moth-er is an obligate hetmoth-erozygote (because both hmoth-er son and nephew have a disease-causing gene). As such, she is a carrier with a 50% chance of transmitting the BMD mutation to each of her children. Her sons who inherit the mutation will develop clinical symptoms of BMD; her daughters who inherit the mutation will be carriers. Were men with BMD to have daughters, those daughters would be carriers; were men with BMD to have sons, those sons would inherit their father's BMD mutation. When it is likely that a family mem-ber of a pregnant woman has the BMD gene, prenatal testing of the fetus for the presence of the gene is possible; such testing involves a search for linked markers. It is important that all female carriers be identified so that they can be advised of their risk for dilated car-diomyopathy and that the appropriate surveillance can be provided. Unfortunately, there is no therapy for BMD. (Answer: B—This patient's offspring and other relatives are at risk for BMD, and a genetic linkage analysis would help define their genotypic risk status)

16. A 34-year-old banker has just finished 6 months of warfarin therapy after a pulmonary embolus result-ing from deep vein thrombosis. Durresult-ing her hospital stay, she was told she has a factor V Leiden muta-tion, which makes her prone to clotting. Her husband and two children have now all been tested as well;

those test results are as follows:

Patient: Arg 506 Gln; increased activated protein C (APC) resistance Husband: Normal

Daughter 1: Arg 506 Gln; increased APC resistance Son 1: Normal

On the basis of these test results, what steps should be taken now?

❑ A. The proband and the daughter carrying her mutant allele will require anticoagulation for a minimum of 6 months to 2 years

❑ B. The patient and her family should be advised that heterozygosity for factor V Leiden is associated with neither an increase in mortality nor a reduction in normal life expectancy

❑ C. The daughter with a factor V Leiden mutation should be counseled not to take oral contraceptives

❑ D. The family should be tested for other thrombophilic disorders as well, such as lupus anticoagulant

❑ E. The proband should be counseled about her need for anticoagulant therapy if she should choose to become pregnant again

Key Concept/Objective: To understand that in cases involving factor V Leiden mutation, treat-ment decisions should be guided by the clinical situation of each patient and family member, not the presence or absence of a mutation

Heterozygosity for the factor V Leiden allele confers only a mildly increased risk of throm-bosis. Routine testing of family members at risk is not recommended. In the absence of evi-dence that early diagnosis of the heterozygous state reduces morbidity or mortality, the decision to test family members who are at risk should be made on a case-by-case basis.

Individuals requesting screening for factor V Leiden should be counseled regarding the implications of the diagnosis. Specifically, they should be informed that although the fac-tor V Leiden mutation is an established risk facfac-tor, it does not predict the occurrence of pathologic thrombosis with certainty, even among heterozygotes of the same family. With this in mind, symptomatic individuals with a known factor V Leiden mutation should be screened for other potentially comorbid thrombophilias. Finally, the minimum period that symptomatic patients with factor V Leiden mutations should remain on anticoagu-lant therapy is unclear; current recommendations are that they receive therapy for a min-imum of 6 months. (Answer: B—The patient and her family should be advised that heterozygosity for factor V Leiden is associated with neither an increase in mortality nor a reduction in normal life expectancy)

17. A 12-month-old baby is brought in for a well-baby visit, during which the baby is noted to have leukoko-ria (a white pupillary reflex). On further evaluation, it is determined that the child has an ablatable, uni-focal retinoblastoma, with an RB1 cancer-predisposing mutation in a tumor and no evidence of a germline RB1 in white cell DNA. The parents are concerned about the risk of retinoblastoma if they have other children.

Regarding these parents’ concern, which of the following statements is true?

❑ A. Absence of a germline RB1 mutation on the patient's DNA screening reduces the risk in the rest of the family to chance; there is no need for further family testing

❑ B. Both parents should be screened; if a germline mutation is not identi-fied, the risk to future siblings is not increased

❑ C. The patient's future siblings may be at increased risk and should have aggressive surveillance and genetic screening

❑ D. The patient's future siblings would not be at increased risk, but the patient's offspring would be and should be screened for RB1 mutations prenatally

❑ E. Testing for RB1 is presymptomatic, and the patient—but not future sib-lings—will need continued aggressive surveillance to ensure that another retinoblastoma does not arise de novo

Key Concept/Objective: To understand genetic mosaicism

The gold standard for detecting RB1 gene defects is gene sequencing, which detects muta-tions in 80% of patients. Because the proband does not have a germline mutation for RB1, there is most likely a genetic mosaicism for the mutation, which must have arisen as a postzygotic event. This means that the parents and future siblings are not at increased risk for retinoblastoma, but the patient's children would be (they would have a 3% to 5% risk).

DNA-based testing of the proband's children, however, could reduce the need for screen-ing for retinoblastoma. Without DNA screenscreen-ing, offsprscreen-ing would need to be reevaluated regularly by an ophthalmologist. Children who test negative for an RB1 mutation could be spared unnecessary screening protocols. It is important to note that DNA screening for RB1 is predispositional, and even patients who have unilateral retinoblastoma with RB1 cancer-predisposing mutations in a tumor and no evidence of a germline RB1 cancer-pre-disposing mutation are at increased risk for developing additional tumors. (Answer: D—The patient's future siblings would not be at increased risk, but the patient's offspring would be and should be screened for RB1 mutations prenatally)

18. A 25-year-old Ashkenazi Jewish woman is concerned about her risk of breast cancer. Her 60-year-old mother was recently diagnosed with stage II breast cancer and underwent bilateral mastectomy. Her grandmother was killed in World War II, so she does not know whether her grandmother had breast can-cer. She read in a newspaper article that the prevalence of BRCA1 and BRCA2 genes is increased in Ashkenazi Jewish women and that, as a result, this population is at increased risk for breast cancer. Now she would like to be tested for these genes because she is concerned about her risk status and wonders whether she needs a prophylactic mastectomy.

Of the following statements, which would be appropriate to tell this patient?

❑ A. Testing for the BRCA1 and BRCA2 genes is not indicated, because the efficacy of measures to reduce risk in asymptomatic patients, even those with a mutation, is not known

❑ B. You would be happy to arrange for BRCA mutation screening, but she should undergo testing in conjunction with appropriate genetic coun-seling

❑ C. It would be more appropriate for the patient's mother to be tested first;

if a cancer-predisposing mutation were found, then—and only then—

would genetic testing for the patient be appropriate

❑ D. Testing in this patient is not indicated; even if she tests negative for an inherited cancer-predisposing mutation in the BRCA1 or BRCA2 gene, she may still have a mutation in another gene that predisposes to breast cancer

❑ E. It is very important that the patient and her family undergo genetic analysis of both the BRCA loci and other cancer-predisposing loci as soon as possible, because her mother's breast cancer demonstrates that her family is at increased risk

Key Concept/Objective: To understand the role of testing in determining whether a disease-modi-fying gene is contributing to a complex disorder

BRCA1 or BRCA2 mutations are more likely to be found in families of Ashkenazi Jewish ancestry; in families in which a family member was diagnosed with breast cancer before 50 years of age; and in families in which a family member was diagnosed with bilateral breast cancer, ovarian cancer, or both breast cancer and ovarian cancer. It is important to

note, however, that BRCA1 and BRCA2 mutations cause only a small increase in the over-all incidence of breast cancer. In patients undergoing genetic testing because of a sugges-tive family history, it is highly recommended that there be pretest and posttest counseling.

If a cancer-predisposing mutation is identified, BRCA1 or BRCA2 mutation analysis is more informative for unaffected relatives. However, depending on the type of analysis done, mutations of uncertain clinical significance may be identified; such findings are dif-ficult (at best) to interpret. If a cancer-predisposing mutation is found in the mother, the patient should be counseled not to desist from rigorous screening for breast cancer.

Given the high prevalence of breast cancer in the general population and in the Ashkenazi Jewish population in particular, regardless of this patient's BRCA status, a neg-ative result would not indicate that she is at reduced risk relneg-ative to that of the general pop-ulation. Furthermore, in individuals from high-risk ethnic groups, such as Ashkenazi Jews, it might be reasonable to test for all the cancer-predisposing mutations known to be com-mon in that population, even if a single cancer-predisposing mutation had already been identified in an affected family member. Unfortunately, there are no unique interventions of proven benefit for those individuals in whom a genetic susceptibility to breast cancer is found, beyond the routine mammography screening recommended for women of average risk beginning at 40 or 50 years of age. Additional recommendations for women in high-er risk categories are made on the basis of presumptive benefit and have not yet been sup-ported in clinical studies. (Answer: C—It would be more appropriate for the patient's mother to be tested first; if a cancer-predisposing mutation were found, then—and only then—would genetic testing for the patient be appropriate)

For more information, see Pagon RA: 3 Endocrinology: VIII Genetic Diagnosis and Counseling. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds.

WebMD Inc., New York, May 2002

Hypoglycemia

19. A 32-year-old man presents to your clinic for a routine follow-up visit. He complains of intermittent episodes of shaking, palpitations, sweating, and anxiety. The episodes generally occur between meals. He has a friend who is a hypoglycemic and is on a special diet, and he wonders if he too may have low blood sugar. While in the waiting room, he develops symptoms, and your nurse obtains a blood glucose level.

19. A 32-year-old man presents to your clinic for a routine follow-up visit. He complains of intermittent episodes of shaking, palpitations, sweating, and anxiety. The episodes generally occur between meals. He has a friend who is a hypoglycemic and is on a special diet, and he wonders if he too may have low blood sugar. While in the waiting room, he develops symptoms, and your nurse obtains a blood glucose level.

In document Board Review From Medscape (Page 129-139)