Familial Mediterranean fever

The collection of a family history ranges from simply asking patients if family members have the same presenting illness to diagramming complex medical and psychosocial relationships as part of a family genogram. The three-generation pedigree provides a pictorial representation of diseases within a family and is the most efficient way to assess hereditary influences on disease. Two recent events have made family history assessment more important than ever: the completion of the Human Genome Project with resultant identification of the inherited causes of many diseases, and the establishment of national clinical practice guidelines based on systematic reviews of preventive interventions. The family history is useful in stratifying a patient's risk for rare single-gene disorders and more common diseases with multiple genetic and environmental contributions. Major organizations have endorsed using standardized symbols in pedigrees to identify inherited contributions to disease.

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A three-generation pedigree has been used for diagnostic consideration or risk assessment of rare single-gene or chromosomal disorders. However, the utility of family history in the assessment of risk for common diseases is becoming increasingly recognized. (1-3) Most common diseases result from a combination of environmental factors and variations in multiple genes. Inherited variations within these genes confer individual risks that can differ greatly from the population-based average. Assessment of family history is useful to detect increased risks for diseases that have modifiable risk factors or preventable exposures. Clinical preventive measures for asymptomatic patients recommended by the U.S. Preventive Services Task Force involve a consideration of relevant family history (Table 1 (4-13)). Family history assessment also can help identify relatively rare conditions that may not be considered in a differential diagnosis (Table 2). Alternatively, when a relatively common disease is caused by an inherited mutation in a single gene, family history assessment may lead to early diagnosis and more aggressive management (Table 3).

Prevention efforts are enhanced by family discussions that shed light on lifestyles or family behaviors that have adverse health consequences. Prevention also is achieved by identifying patients with a higher risk than the population average because of shared inherited factors associated with disease. In some cases, standard screening may be supplanted by targeted genetic testing and a change in clinical intervention for persons at high risk for disease, such as those with a strong family history of cancer.

Office Collection of Family History

Physicians can use several approaches to collect family information and construct a pedigree. The most traditional approach is physician-directed questioning of the patient or family informant. Nurses, physician assistants, and other trained clinical staff also may complete this process. This approach typically takes 15 to 30 minutes. Alternatively, patients can be provided with questionnaires about their family history information before an office visit. This method still requires a health professional to review the information and create a pedigree.

Unfortunately, a health maintenance visit does not allow for this amount of time to devote to family history collection. (14) In reality, the average office visit lasts 16 minutes, and family history discussion has been observed to last less than three minutes. (15,16) Many physicians compensate for this time limitation by collecting family history information piecemeal over several visits. Checklists may be used in an attempt to speed data collection, but the usefulness of this approach may be limited by patient recall. Checklists also may not distinguish which relatives are affected or their degree of relatedness to the patient. Additionally, unknown family medical information, a patient's focus on an acute problem, and fear of discrimination may impede collection of a complete and accurate family history.

Patient Collection of Family History

With guidance, patients may construct their own pedigrees, which should be reviewed by the physician to assure their accuracy. The American Medical Association has developed a pocket guide that provides instructions and examples for patients on how to generate a pedigree. It is available online at http://www. ama-assn.org/ama/pub/category/2380.html.

A print and Web-based tool developed as part of the U.S. Surgeon General's Family History Initiative (17) is available online at http://www.hhs.gov/familyhistory. This tool, which is available in English and Spanish, guides the collection of family history, which is then transferred to a printable, standardized, three-generation pedigree. Specific questions target six adult diseases: heart disease; diabetes; stroke; and breast, ovarian, and colon cancers. These diseases are highlighted because they are common and require a change in clinical evaluation or intervention based on family history. Families are encouraged to seek specific information directly from family members, their physician, and medical records.

Assessment

Regardless of whether family history was collected in the physician's office or the patient's home, assessment should occur at the initial patient evaluation and be updated periodically to identify newly diagnosed medical or developmental conditions within the family. Physicians should begin with recording the current age and age at onset of symptoms or diagnosis of the patient and first-, second-, and third-degree relatives on each side of the family. The age and cause of death for deceased family members also should be recorded. The accuracy of information generally decreases as the degree of relatedness decreases. Therefore, physicians should note when information is from a medical source instead of a family report.

The most useful family history includes medical, developmental, and pregnancy outcome information on first-, second-, and third-degree relatives. (18) The degree of relatedness indicates the percentage of shared genes (Table 4). For example, the half-sibling and the uncle of a patient inherit the same proportion of genes (25 percent) identical to the patient's. Standard symbols and diagrams allow rapid attribution of diseases to particular branches of the family (Figure 1 (19)). Having two relatives from the same side of the family affected with cancer (one with endometrial cancer and the other with colon cancer) increases suspicion for hereditary nonpolyposis colon cancer (an inherited form of colon cancer) more than if one relative was from the paternal side of the family and the other from the maternal side.

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Medical information often is not known because of generational, cultural, or health literacy issues. For example, older relatives mistakenly may believe that discussion of a cancer diagnosis is futile, because in the past there was not effective treatment. A couple planning to have children may not know the relevance of inquiring about previous miscarriages in the family, and family members may not volunteer this emotionally sensitive information. Conditions that are thought to occur sporadically actually could be inherited. For example, a family history of multiple relatives with Down syndrome suggests an inherited translocation, not sporadic non-disjunction. A woman may not realize that her paternal grandmother's and aunt's breast cancer diagnoses confer the same risk to her as if they were maternal relatives. Therefore, encouraging ascertainment of health information for three generations of relatives is warranted.

Consanguinity, the shared relationship of a common ancestor, is frequent in many cultures and should be considered in the evaluation of a patient with unusual symptoms or those suggestive of a rare disease. Persons from cultures within which intermarriage remains common share a greater proportion of genes. In Iraq, for example, 29.2 percent of marriages are between first cousins, and 57 percent of marriages demonstrate some amount of consanguinity. (20) An autosomal-recessive disease is more likely to occur in a consanguineous family because of the increased probability of a person having two copies of the same mutation in a gene. (21) Recurrence of common complex diseases also may be increased in the children of consanguineous parents because of a greater proportion of shared genes.

Physicians should identify patients' ancestries and, if known, the countries of origin of their grandparents. A single gene may have genetic variations whose frequencies differ depending on ancestral origin. A low mean corpuscular volume and normal iron studies in a patient without chronic disease signals a diagnosis of thalassemia trait. If a patient and partner with these findings are certain that their ancestors were from Africa, they have a very low likelihood of having a clinically affected child. But if the patient or partner has an ancestor from southeast Asia, there is an increased chance of thalassemia H or even fatal hydrops in their child. Many diseases are more prevalent in certain ancestral groups. For example, persons of Ashkenazi Jewish or Muslim Arabic origin share odds of one in four for carrying a defective gene for familial Mediterranean fever. (22) In these patients, awareness of their disease risk is important because early diagnosis avoids prolonged evaluation for other disorders and makes effective treatment possible.

The recall of spontaneous abortions, stillbirths, illnesses, and deaths of family members may evoke strong emotional responses in patients. Feelings of guilt and blame are not unusual in families in which several relatives are affected by the same condition. Visualizing the family history in pictorial form may clarify risks to a patient that had not been appreciated previously. Establishing a relationship with a geneticist or genetic counselor may be helpful, although genetics professionals are not widely available. Extra clinic time and the assistance of mental health professionals may be required.

Relatives sometimes may be identified who have significant risk for a disease and in whom early intervention may improve outcomes. The patient should be encouraged to notify these family members of their risk and refer them to a physician. In these cases, the physician's obligation to warn other family members directly is not clear. (23) There have been successful claims of negligence against physicians for failure to warn patients that their family members were at increased risk for colon and breast cancers. (24)

The exact duty of the physician in these instances often is untested, particularly given the restrictions of the Health Insurance Portability and Accountability Act, and is subject to individual state court interpretation. Therefore, disclosure to other family members must be considered carefully with respect to privacy and weighed against a duty to warn.

When Family History Suggests a Genetic Condition

In some patients, the family history may be significant enough (e.g., multiple affected relatives with early onset of a disease) to consider genetic testing for an identified or suspected mutation in a single gene. If the tested gene is a component of a complex disease, a found mutation offers susceptibility or predictive, but not confirmatory, information. The degree of risk attributable to variations or mutations in a single gene can range from a modest contribution in complex disease to near 100 percent certainty. For example, a variation in the APC gene found in the Ashkenazi Jewish population confers a modest risk of colorectal cancer. (25) Other mutations in the same gene cause familial adenomatous polyposis with a near 100 percent lifetime risk of colorectal cancer.

Susceptibility or predictive testing for familial cancers may significantly decrease morbidity or mortality by changing the management of the disease. Alternative screening with lower specificity but higher sensitivity may be sought (e.g., magnetic resonance imaging for early breast cancer detection), and chemoprophylaxis may be offered (e.g., tamoxifen [Nolvadex] for breast cancer prevention). Aggressive screening and surgical prophylaxis may be initiated (e.g., colonoscopy for detection and removal of precancerous lesions in patients with hereditary nonpolyposis colon cancer). Early surgical intervention may be recommended as preventive measures (e.g., in family members of a patient with a mutation of the MEN2A gene who inherit a mutation in the RET gene and are virtually certain to develop medullary thyroid carcinoma) or offered (e.g., mastectomy or oophorectomy may be chosen by patients with an unidentified BRCA1/2 mutation). Predictive testing for noncancerous conditions also may be initiated. In an adult who has asthma that cannot be improved with bronchodilators, the risk of [alpha]-1 antitrypsin deficiency increases if there is a family history of emphysema or bronchiectasis. If airflow obstruction is found to be incompletely reversible on pulmonary function testing, the patient is a candidate for genetic testing. (26)

Family history also may guide diagnosis even when DNA-based genetic testing is not available for an inherited condition. In a child presenting with a syncopal episode, a family history of syncope prompts consideration of long QT syndrome. (27) In an adult presenting with fatigue or arthralgias, a family history of diabetes and cirrhosis should signal measurement of transferrin saturation and consideration of hereditary hemochromatosis. (28)

New guidelines incorporating genomic principles into family history assessment are increasing the utility of this powerful clinical tool. Taking a traditional "targeted" family history may be necessary in an emergency or when time is limited, but it should not be a substitute for maintaining a three-generation pedigree for every patient.

Genomics Glossary

Complex disease: The presence of disease is not matched by a specific variation in a single gene. Multiple genetic and environmental factors act collectively to cause complex disease; however, variations in one or several genes may dramatically alter the likelihood of a disease and its severity.

Consanguinity: A genetic relationship between persons descended from a common ancestor. Consanguinity increases the likelihood of inheriting identical versions of a given gene.

Consultand: Person who seeks genetic counseling for knowledge about a disease or condition in the family.

Predictive genetic testing: Determination of genetic variation in an asymptomatic person to ascertain whether the probability for a given disease or condition is greater than the population-based average.

Proband: The person in a family affected with a disease or condition that raises suspicion that other family members may have an increased propensity for the same disease or condition.

The authors thank Alan E. Guttmacher, M.D., for assistance with the preparation of the manuscript.

REFERENCES

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DANIEL J. WATTENDORF, MAJ, MC, USAF, is a family physician and clinical geneticist. He is assistant professor in the Department of Family Medicine at the Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Md., clinical geneticist at the Armed Forces Institute of Pathology, Washington, D.C., and attending clinical geneticist at the National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda.

DONALD W. HADLEY, M.S., C.G.C., is a certified genetic counselor and associate investigator in the social and behavioral research branch of the NHGRI. He received his master's degree in health and medical sciences with a concentration in genetic counseling at the University of California, Berkeley.

Address correspondence to Daniel J. Wattendorf, MAJ, MC, USAF, National Institutes of Health, National Human Genome Research Institute, Building 31, Room 4B09, Bethesda, MD 20892-2152 (e-mail: dwatten@mail.nih.gov). Reprints are not available from the authors.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Air Force Medical Service, the U.S. Air Force at large, the National Human Genome Research Institute, or the National Institutes of Health.

This article is one in a series coordinated by the National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. Guest editor of the series is Daniel J. Wattendorf, MAJ, MC, USAF.

This is one article in a series coordinated by Kenneth Lin, M.D.

Author disclosure: Nothing to disclose.

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