Highlights From the Annual Clinical Genetics Meeting

Siobhan Dolan, MD


April 07, 2003

In This Article

Adult Genetic Disease

Dr. Bruce Korf (University of Alabama at Birmingham) introduced a concurrent session on adult genetic disease. The session was aimed at broadening the horizons of adult genetic disease beyond some of the well-established applications such as cancer counseling or hemochromatosis. This information is relevant to obstetrician-gynecologists (ob/gyns) as they care for more women in their post-reproductive age years. It is also relevant to the counseling of pregnant patients as they consider their family history and its implications for their pregnancy.

The first talk was by Dr. Kate Nathanson, an internist and geneticist at the University of Pennsylvania in Philadelphia, who presented her perspective on the role of the geneticist in adult dysmorphology.[4] She began by presenting a case of a 30-year-old with mental retardation (MR) who was brought in for consultation for suspected Fragile X after the man's father saw a report on this disorder on the television program Nightline. She pointed out that, as in this case, referral patterns for adults with genetic disease can be rather unusual and do not always come through a doctor. She also pointed out that a challenge of seeing an adult for evaluation of genetic disease is that the early childhood developmental history and workup history are not always available, especially if some of the older family members are deceased. In the case of this patient, his mother had died and much of the pregnancy and early childhood history was unfortunately unavailable.

This is a scenario that ob/gyns may encounter. Often, the detailed family history that is taken at a preconception or new prenatal visit will elicit information about an adult relative with mental retardation or an unknown condition. Patients are anxious to know if that relative's condition imparts any specific risk to their pregnancy. As Dr. Nathanson pointed out, the patient who is pregnant or planning a pregnancy may be able to gather the most information by having her adult relative evaluated by an adult geneticist who may be able to offer additional information with implications for family members.

Dr. Nathanson reviewed the patients she has seen at the University of Pennsylvania and showed that the most frequent reasons for referral were to (1) rule out a syndrome, (2) rule out Prader-Willi, and (3) rule out Cowden syndrome.

After seeing the patients, the most common diagnoses made were:

  • Cowden syndrome/Bannayan-Riley-Ruvalcaba (BRR)

  • Chromosome anomaly, esp. 22q11

  • Developmental anomaly

  • Fragile X

  • X-linked MR

  • MR and obesity

Most relevant to the ob/gyn is the diagnosis of Fragile X. This disease follows an X-linked inheritance pattern, with males showing moderate MR and females demonstrating a milder phenotype. If Fragile X is suspected in a family due to the occurrence of males with moderate mental retardation or females with mild mental retardation, a woman contemplating pregnancy should be offered genetic counseling and testing to assess her risk. The counseling and testing can be quite complicated and often requires referral to a genetic counselor. This serious condition has obvious implications for pregnancy and warrants diagnosis before conception or during pregnancy, if at all possible. Further information about Fragile X is available from GeneReviews at: http://www.geneclinics.org/ servlet/access?db=geneclinics& site=gt&id=8888891&key= PKt0Z0s4nQCjv&gry=&fcn= y&fw=Scgd&filename= /profiles/fragilex/index.html

Information about testing for Fragile X is available from the following sources:

In evaluating MR, Dr. Nathanson also recommends considering psychiatric illness. Her evaluation includes MRI of the brain, ophthalmologic evaluation, karyotyping, telomere screening, Fragile X screening, and possibly metabolic testing.

There is little or no guidance in the literature as to management of adult genetic disease. Dr. Nathanson recommends that physicians who treat adults with genetic disease contribute to the literature for the future. She also reminds clinicians that adults with genetic disease face all of the regular risks of aging and need regular adult preventive care, such as mammogram and Pap smear for women, which is sometimes neglected. In addition, these adults may experience increased cancer risks (eg, Bloom syndrome).

Dr. Jerome Rotter (Cedars-Sinai Medical Center, Los Angeles, California) spoke about genetic risk assessment for diabetes and associated disorders. Dr. Rotter suggested that the key question is, "Who is going to get diabetes?" Dr. Rotter is working on answering this question, but for now, suggests that there is no easy answer.

Diabetes, both type 1 and type 2, has serious implications for the management of pregnancy. Early diagnosis and implementation of treatment is essential for ob/gyns who may be able to identify at-risk women and diagnose them before they become pregnant. This can decrease the risk to pregnancy and allow women to make informed decisions about pregnancy.

Type 1 diabetes incidence varies throughout the world, with the highest incidence in Finland and Sardinia. Native American populations have a low type 1 incidence but a very high type 2 incidence. Contrary to general belief, type 2 has been shown to have a strong genetic contribution.

When undertaking genetic counseling in idiopathic diabetes mellitus (IDDM), or type 1 diabetes, Dr. Rotter suggested we consider the following risks. There is an increased risk to first-degree relatives as follows:

  • Monozygotic twins: 35%

  • Siblings: 5% to 10%

  • Offspring: 2% to 5%

    • If the mother has IDDM: 2%

    • If the father has IDDM: 6%

It is also important for clinicians to realize that individuals with IDDM and their first-degree relatives are at increased risk for thyroid disease (screening via thyrotropin [TSH]), atrophic gastritis/pernicious anemia (screening via B12 level), and Addison's disease. Dr. Rotter suggests that physicians screen diabetic patients and their first-degree relatives, as well. The screening tests can be quite simple, such as measuring TSH and B12 levels, as noted above.

Insulin resistance as well as mutant insulin are causes of adult onset (type 2) diabetes. Patients with type 2 diabetes are not prone to ketoacidosis. The risk factor with the most serious consequences for those with type 2 diabetes is obesity. Type 2 diabetes is influenced by genes and the environment. A popular belief is that type 2 is entirely caused by environmental factors; in fact, it has a large genetic component. Individuals who are first-degree relatives of patients with type 2 diabetes face a 10% to 15% risk for overt type 2 diabetes and an even higher risk for insulin resistance.

Ms. Susan Hahn (Duke University Medical Center, Durham, North Carolina) discussed genetic counseling for Alzheimer's disease (AD).[5] Ms. Hahn introduced AD by describing the clinical symptoms, which include progressive impairment of behavioral, cognitive, and motor functions. AD was first described in 1907 and affects 4 million people in the United States today.

Risk factors for AD include: (1) family history of AD -- strongest association in first-degree relatives; (2) genetics; and (3) factors that modify genetic risk, including age, gender, ethnicity, and environmental factors such as head trauma and diet.

Early-onset familial AD, which usually has its onset before age 60 years, has been shown to be caused by 1 of 3 genes:

  • Presenilin 1 (PS1)

  • Presenilin 2 (PS2)

  • Amyloid precursor protein (APP)

Together, these genes account for approximately 2% of all AD cases.

Familial late-onset AD can be affected by apolipoprotein E (APOE) alleles. APOE protein is involved in cholesterol storage, transport, and metabolism. The APOE4 allele acts in a dose-dependent fashion and increases the risk of AD. As many as 50% of clinically diagnosed AD patients carry at least 1 E4 allele.

Genetic testing for asymptomatic individuals is currently warranted only for families with a history of autosomal dominant early-onset AD. Risk information based on family history and empiric data can be provided to all interested at-risk individuals.

Concerns regarding AD may come to the attention of ob/gyns through patients who are pregnant and have an older relative who is affected with AD. A patient may hear something in the popular press about the contribution of genetics to AD and inquire as to the risk for her pregnancy. Ob/gyns can reassure patients that genetic testing for asymptomatic individuals is currently warranted only in families with a history of autosomal dominant early-onset AD. Any individuals with such a family history should be offered genetic counseling.


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