Special Medical Reports

AHA Assesses the Impact of Genotyping on Diagnosis of Genetic Cardiac Disease
Sharon Scott Morey

The American Heart Association (AHA) has issued a report on the impact of laboratory molecular diagnosis of three genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome and Marfan syndrome. The report notes that the present role for the DNA diagnosis of cardiovascular diseases is largely confined to research-oriented genotyping, with only limited access to laboratory genetic analysis.

The report, designated by the AHA as a "medical/scientific statement," was developed by the AHA Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science. It is published in the October 6, 1998, issue of Circulation.

According to the report, the need to examine the role of a molecular diagnosis in genetic cardiovascular disease relates to advances in the understanding of both the phenotypic and genotypic expressions of several genetically transmitted, nonatherosclerotic cardiovascular diseases. Although molecular laboratory techniques continue to be used primarily in research-oriented settings, such technologic advances have led to the identification of new subgroups of genetically affected individuals who do not exhibit the conventional manifestations of the cardiovascular disease. The AHA selected the three most common familial cardiovascular diseases for which gene defects have been identified: hypertrophic cardiomyopathy, long-QT syndrome and Marfan syndrome. All three of these diseases are associated with autosomal dominant inheritance and a risk of sudden cardiac death.

Discussed in the report are the clinical diagnosis (phenotype) and molecular diagnosis (genotype) of each of these diseases as well as conclusions that can be drawn from available data. Also discussed are some of the ethical questions that arise with genetic testing.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy has been found to be caused by mutation in any one of five genes that encode proteins of the cardiac sarcomere: beta-myosin heavy chain, cardiac troponin T, troponin I, alpha-tropomyosin and cardiac myosin-binding protein C. Data suggest that approximately 35 percent of cases of familial hypertrophic cardiomyopathy may be caused by mutations in the beta-myosin heavy chain gene. Genetic testing in selected pedigrees has shown that DNA-based diagnosis is capable of identifying a greater number of children and adults with a preclinical diagnosis of hypertrophic cardiomyopathy.

The report notes that hypertrophic cardiomyopathy is readily established by clinical examination, including two-dimensional echocardiography. The lack of left ventricular hypertrophy is uncommon in genetically affected individuals. According to the report, the lack of phenotypic expression is largely confined to individuals with nonmyosin mutations. Molecular studies may in the future be useful in ambiguous cases, such as in patients with a borderline or modest increase in left ventricular wall thickness, including some trained athletes with ventricular hypertrophy, and in patients with systemic hypertension who are suspected of having hypertrophic cardiomyopathy.

Criteria for the Diagnosis of Marfan Syndrome The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Long-QT Syndrome

Long-QT syndrome is characterized by abnormal prolongation of ventricular repolarization, which is manifested on electrocardiography (ECG) by lengthening of the QT interval. This abnormality is most easily identified in lead II or V₁, V₃ or V₅. While long-QT syndrome often remains unrecognized, it can be a cause of death in young persons, including competitive athletes. Genotypic studies have identified four mutant genes responsible for the development of long-QT syndrome. These genes encode proteins of the cardiac ion channels.

According to the report, the difficulties in identifying ECG evidence of long-QT syndrome suggest that there may be a significant role for DNA diagnosis in this disease. In addition, studies suggest that clinical diagnosis may be uncertain on the basis of the QTc measurement in as many as 50 percent of family members. However, the heterogeneity of the disease--four or more genes and many mutations--may hamper genetic screening for this disease.

Marfan Syndrome

The variabilities in how Marfan syndrome is expressed have led to the development of comprehensive diagnostic criteria for this disease (see the accompanying table). The primary genetic defect responsible for Marfan syndrome was first described in 1991. It resides in FBN1 gene, which is localized to the long arm of chromosome 15 encoding the connective tissue protein fibrillin-1. According to the AHA statement, phenotype­genotype correlations have not emerged in clinical studies, largely because of the array of mutations in the fibrillin gene. Genetic testing in Marfan syndrome is currently regarded as only an adjunct to diagnosis.

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AAP Updates Its Recommendations on Circumcision
Verna L. Rose

Although circumcision has potential benefits, the data "are not sufficient" to recommend neonatal male circumcision as a part of routine medical care, according to a new policy statement from the American Academy of Pediatrics (AAP) published in the March 1999 issue of Pediatrics. The AAP also recommends, for the first time, that it is essential to provide pain relief for infants undergoing circumcision. Members of the AAP Task Force on Circumcision reviewed nearly 40 years of medical research on circumcision before issuing the new recommendations. The task force was headed by Carole Lannon, M.D., M.P.H., University of North Carolina at Chapel Hill School of Medicine.

In 1971 the AAP concluded that no absolute medical indication existed for routine circumcision. However, an updated 1989 AAP statement concluded that, because of links between circumcision status and urinary tract infections and sexually transmitted diseases, newborn male circumcision does have potential medical benefits and advantages as well as risks. Because of continued debate over the past decade and with the publication of new studies on this subject, the AAP decided to reevaluate its 1989 policy.

The new policy statement discusses the epidemiology of newborn male circumcision; embryologic and anatomic considerations; penile problems; the role of hygiene; sexual practice, sensation and circumcision status; methods of circumcision; complications of the procedure; circumcision after the newborn period; analgesia and ethical issues. It also includes discussions on circumcision status and urinary tract infections (UTIs) in male infants, circumcision status and cancer of the penis, and circumcision status and sexually transmitted diseases including human immunodeficiency virus infection.

The AAP notes that, over the years, the practice of male circumcision has been advocated for reasons that vary from symbolic ritual to preventive health measure. The AAP recognizes that it is legitimate for parents to take into account cultural, religious and ethnic traditions in addition to medical factors when making the decision to circumcise their newborn males. Parents of all male infants should receive accurate information and should be provided with the opportunity to discuss this decision with their physician.

Methods of Circumcision

Three common methods of circumcision are discussed in the statement. These include use of the Gomco clamp, the Plastibell device and the Mogen clamp (or variations of each of these three devices). Use of each device involves estimation of the amount of external skin to be removed; dilation of the preputial orifice so that the glans can be seen; bluntly freeing the inner preputial epithelium from the epithelium of the glans; placing the device; leaving the device in situ long enough to produce hemostasis; and amputation of the foreskin.

The AAP emphasizes that physicians who perform circumcisions should become sufficiently skilled at the technical aspects of the procedures to minimize complications. Neonatal male circumcision is generally safe, but complications occur in one in 200 to one in 500 infants. These complications are generally minor and usually involve mild bleeding or local infection. The AAP states that circumcision should only be performed on stable, healthy infants.

Analgesia

Considerable new evidence shows that newborns circumcised without analgesia experience pain and physiologic stress measured by changes in their heart rate, blood pressure, oxygen saturation and cortisol levels. The AAP, therefore, recommends that analgesia be provided if the procedure is performed. Several methods to provide pain relief have been evaluated. Analgesic methods include eutectic mixture of local anesthetics cream (2.5 percent lidocaine and 2.5 percent prilocaine), the dorsal penile nerve block and the subcutaneous ring block. The AAP notes that the subcutaneous ring block may provide the most effective analgesia.

Urinary Tract Infections

A number of recent studies have addressed the association between circumcision status and UTIs. Although these studies show that the relative risk of developing a UTI in the first year of life is higher for infants who are uncircumcised, the AAP policy concludes that the absolute risk of developing a UTI is low--at most approximately 1 percent. Research indicates that, during the first year of life, an uncircumcised male infant has at most about a one in 100 chance of contracting a UTI, compared with a one in 1,000 chance of a UTI in a circumcised male infant.

Penile Cancer

The report notes that the literature on the relationship between circumcision status and risk of penile cancer is difficult to evaluate. Studies conclude that the risk of an uncircumcised man developing cancer of the penis is more than threefold that of a circumcised man. Phimosis, a condition that exists only in uncircumcised men, increases this risk even more. However, the AAP policy notes that in the United States only nine to 10 cases of penile cancer are diagnosed each year per 1 million men, indicating that while the risk is higher for uncircumcised men, the overall risk is extremely low.

Sexually Transmitted Diseases

Evidence regarding the relationship of circumcision to sexually transmitted diseases in general is conflicting, according to the report. Some research suggests that circumcised men may be at a reduced risk for acquiring syphilis and human immunodeficiency virus infections. However, the AAP policy states that behavioral factors continue to be far more important in determining a person's risk of contracting sexually transmitted diseases than circumcision status.

Copyright © 1999 by the American Academy of Family Physicians.
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