Getting The Diagnosis Right

At first look, a family has a simple request regarding their family history of medical disease. "I have an uncle with hemophilia. I want to be checked to see if I am a carrier." Or "I have three daughters and had a son that died from hemophilia. Please test each of my daughters." One must be careful which bleeding disorder we are talking about.

A quick check of bleeding disorders shows that there are at least 40 types of hemophilia. Increased bleeding tendency is seen in about 150 disorders. Out of these bleeding conditions about 36 are x-linked. The most common condition said to be hemophilia, or x-linked bleeding disorder, is Factor 8 deficiency. The second is Factor 9 deficiency (also x-linked.) The most common x-linked condition causing increased bleeding is von Willebrand deficiency. The severity of hemophilia is usually greater than a bleeding condition like von Willebrand deficiency, but not always. One must be very specific when talking about clotting deficiencies.

Recommendations:

• Get the family information documented; who is who?
• Prove the diagnosis! — the actual test report is best.
• Sort out who is at risk for being a carrier.
• Give empiric recurrence risk estimate.
• Give family time to think over their decision.
• Order the test from the same lab whenever possible; indicate the previous family member's name and date of birth.
• Only test consenting adults.
• Refer to Genetics — if family has multiple individuals, children, and pre-symptomatic individuals. Although tests are available — is doing the test appropriate for this individual, and the family. What information is the family wanting to get?

Concerns About The Unpredictable Nature
Of A Genetic Condition

A family has two daughters and is expecting a third child. The oldest daughter has many birth marks. The mother was told not to worry about it after they ran some tests on the child when she was 3 years old. Mother never understood fully what the fuss was about. The 3 year old had had several complex seizures with fever, but is developmentally within normal limits. The father has a new onset of seizures and a few skin lumps taken off. The neurologist tells the father that he has neurofibromatosis (NF). The family reads about neurofibromatosis on the Internet. The mother goes to her OB/GYN and tells them that she does not want to have a severely affected child with neurofibromatosis. Realizing the gestation is already 18 weeks the obstetrician does an amniocentesis. and then calls the lab to ask where to send the cells for DNA testing for neurofibromatosis.

The gene for NF is known, but the genetics is complex. The gene is testable, but it is false negative in 30% of those affected. The gene shows different mutations somatically, and one can not accurately predict the severity. Further this family was divided about doing the NF test. The mother wanted to abort the pregnancy if the child had the gene. The father said he would want the pregnancy to continue adding that caring for a child with NF is not a big deal. Should this family have been told what the 3 year old was being checked for with the birthmarks? What would you do if you were their family doctor? Their neurologist? Their pediatrician?

Genetic Screening

One of the most useful and sensitive tools of geneticists is the pedigree, or "family history." Many medical disciplines use a questionnaire which patients complete with family health history for common disorders and major health problems. A three- X generation pedigree can often yield additional information, as it is common for patients to recall additional information as detailed pedigree construction proceeds. Mis-information, such as assuming Down syndrome is a term for mental retardation or admission of consanguinity, is often revealed during the taking of a pedigree. A detailed pedigree may take 15 to 30 minutes to complete, but the time and information may prove to be invaluable.

When taking a pedigree, the following pieces of information are most useful:

1. medical information on the patient (and partner if pregnant or planning a pregnancy);
2. medical histories of children, biologic parents, siblings, grandparents, aunts and uncles, and first cousins. Note any significant problems, age of onset, and age and cause of death;
3. mentally retarded biologically related individuals;
4. individuals with birth defects;
5. pregnancy losses or stillbirths;
6. consanguineous relationships; and
7. ethnicity.

To confirm carrier status, DNA or enzymatic carrier testing can be performed for a number of conditions such as Tay Sachs disease, cystic fibrosis, Fragile X syndrome, sickle cell disease, and others. Patients at risk for other conditions such as neurofibromatosis, Marfan syndrome, and other undiagnosed conditions may benefit from an evaluation by a medical geneticist.

Patient information may not be complete or reliable, so it is always wise to confirm possibly significant problems by obtaining medical records, pathology reports, photographs, or death certificates.

When the pedigree is positive and further evaluation is necessary, the patient might benefit from a formal risk assessment. Some examples might included repeated pregnancy loss, consanguinity, advanced maternal or paternal age if pregnancy is involved, disorders with obvious patterns of inheritance, or personal or family history of birth defects, mental retardation, or genetic disorders. Referral for genetic counseling might be offered.

Patients with certain ethnic backgrounds may be at risk for specific disorders such as Tay Sachs or Canavan diseases in Ashkenazi Jewish patients where 1 in 30 are carriers for these autosomal recessive disorders. Among African Americans, 1 in 10 carries the gene for sickle cell disease and individuals of southern European or Asian ancestry may be at risk for the thalassemias.

Human Genome Project

The Human Genome Project is a 15 year effort coordinated by the U.S. Department of Energy and the National Institutes of Health to: "identify all the estimated 80,000 genes in human DNA, and to determine the sequences of the 3 billion chemical bases that make up DNA, store this information in databases, and develop tools for data analysis."²

Medical practice is likely to be radically altered once the genome project has been completed and interpreted. We certainly are able to envision some wonderful future benefits, but it is equally likely we have little concept of all the benefits and issues, which may emerge. It is likely medicine will become more prevention focused, there will be the ability to recognize predisposed individuals, and new classes of drugs will emerge. Gene therapy may become more widely available, and biotechnology will explode.

Ethical, Legal, And Social Issues

As more and more technology becomes available, issues of confidentiality and privacy as well as public education are raised. The Human Genome Project is devoting 3 to 5% of its annual budget to these issues.² Such information accumulated in large databanks has the potential to become available and may cause issues regarding employer or insurance accessibility. How should such information be stored? Do employers or insurers have entitlement to such information, and should hiring or costs for insurance be based on this information? These are difficult questions, which are important to all of us. This technology will require informed consent _ how will we properly educate individuals so they are aware of all the implications this testing may raise? Do individuals really want to know about their medical futures pre-symptomatically? Is the response different from person to person, or should pre-symptomatic testing be offered only if treatment is available? What kind of counseling is available before and after such testing is performed? Are there enough properly trained individuals to provide all the necessary counseling? Who should benefit financially from commercialization of genome research products? If this technology is able to greatly extend live expectancy, what would the social costs be? Who would have access to requesting various tests? Who would have access to results and under what circumstances?

As we all need to realize, this technology, while very exciting and powerful, needs to be evaluated and addressed very carefully. The next 10 years and beyond are likely to bring many changes. What an exciting and challenging time we live in!

REFERENCES

1. Hall JG, Powers EK, IcIlvaine RT, Ean VH. The frequency and financial burden of genetic disease in a pediatric hospital. American Journal of Medical Genetics. 1978; 1: 417-436.
2. The Human Genome Project. <<http://www.ornl.gov/TechResources/Human_Genome/faq/faqsl.html >>
3. Gardner RJ, Sutherland GR. Chromosome Abnormalities and Genetic Counseling. Oxford University Press, NY, NY, 1989.

February, 1999/ Jacksonville Medicine

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