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 14–13). 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).
|A||Aspirin for primary prevention of cardiovascularevents4||Discuss aspirin chemoprevention with adults who are at increased risk of coronary heart disease.||Risk assessment should include questions about age, sex, diabetes, elevated total cholesterol levels, low high-density lipoprotein cholesterol levels, elevated blood pressure, family history, and smoking.|
|A||Screening for colorectal cancer5||Screen men and women 50 years and older for colorectal cancer.||Initiating screening at an earlier age is reasonable in persons at higher risk (e.g., those with a first-degree relative who receives a diagnosis before 60 years of age).|
|Expert guidelines exist for screening very high-risk patients, including those with a history suggestive of familial polyposis or hereditary nonpolyposis colorectal cancer.|
|B||Behavioral counseling in primary care to promote a healthy diet6||Counsel adult patients with hyperlipidemia and other known risk factors for cardiovascular and diet-related chronic disease.||—|
|B||Chemoprevention of breast cancer7||Discuss chemoprevention with women at high risk for breast cancer and at low risk for adverse effects of chemoprevention.||Older age, a family history of breast cancer, and a history of atypical hyperplasia on breast biopsy are the strongest risk factors for breast cancer.|
|B||Screening for abdominal aortic aneurysm8||Perform one-time ultrasound screening in men 65 to 75 years of age who have ever smoked.||Major risk factors include age (65 years or older), male sex, and a history of smoking (at least 100 cigarettes in a person’s lifetime). A first-degree family history of abdominal aortic aneurysm that required surgical repair also increases men’s risk.|
|B||Screening for breast cancer9||Perform screening mammography, with or without clinical breast examination, every one to two years in women 40 years of age and older.||Women at increased risk for breast cancer (e.g., those with a family history of breast cancer in a mother or sister, a previous breast biopsy revealing atypical hyperplasia, first childbirth after age 30) are more likely to benefit from regular mammography than women at lower risk.|
|B||Screening for lipid disorders in adults10||Screen men 20 to 35 years of age and women 20 to 45 years of age with diabetes, a family history of cardiovascular disease before age 50 in male relatives or age 60 in female relatives, or a family history suggestive of familial hyperlipidemia.||—|
|D||Screening for pancreatic cancer11||Do not screen routinely for pancreatic cancer in asymptomatic adults using abdominal palpation, ultrasonography, or serologic markers.||Persons with hereditary pancreatitis may have a higher lifetime risk for developing pancreatic cancer.|
|I||Screening for prostate cancer12||Evidence is insufficient to recommend for or against routine screening for prostate cancer using prostate-specific antigen testing or digital rectal examination.||Men older than 45 years of age who are at increased risk (e.g., black men, men with a family history of prostate cancer in a first degree relative) are most likely to benefitfrom screening.|
|I||Newborn hearing screening13||Evidence is insufficient to recommend for or against routine screening of newborns for hearing loss during postpartum hospitalization.||The screening yield and proportion of true-positive results will be substantially higher when screening is targeted at high-risk infants (e.g., those admitted to the neonatal intensive care unit for two days or more, infants with syndromes known to include hearing loss or a family history of childhood sensorineural hearing loss, congenital infections, and craniofacial abnormalities).|
|Primary symptom||Family history||Disease||Gene|
|Fatigue or arthralgias||Diabetes or cirrhosis||Hereditary hemochromatosis||HFE|
|Nonfebrile seizure||Seizures, developmental delay, mental retardation, tumors||Tuberous sclerosis||TS1, TS2|
|Recurrent UTI or hematuria||Hypertension, nephrolithiasis, cerebral aneurysm, or renal failure||Autosomal-dominant PKD||ADPKD1, ADPKD2|
|Shortness of breath||Epistaxis, telangiectasias||Hereditary hemorrhagic telangiectasia||ENG, ACVRL1|
|Shortness of breath||Heart failure (cor pulmonale)||Idiopathic pulmonary hypertension||BMPR2|
|Syncope||Syncope, sudden death||Long QT syndrome||Multiple|
|Diagnosis||Family history||Disease etiology||Gene|
|DVT||DVT, pulmonary embolism||Hereditary thrombophilia||Multiple; F5|
|Most common: activated protein resistance-factor V Leiden|
|Emphysema||Emphysema||α-1 antitrypsin deficiency||SERPINA|
|Glaucoma (primary open-angle)||Glaucoma||Hereditary glaucoma||MYOC|
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 athttp://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 Initiative17 is available online athttp://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.
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 119). 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.
|First-degree relative (50% shared genes)||Second-degree relative (25% shared genes)||Third-degree relative (12.5% shared genes)|
|Children||Aunts and uncles||Cousins|
|Nieces and nephews|
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 riskof α-1 antitrypsin deficiency increases if there is a family history of emphysema or bronchiectasis. If airf low 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.
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.