[301] Pregnancy in von Hippel Lindau Disease.Grimbert P, Chauveau D, Richard S, Grünfeld JP. Service de Néphrologie et Laboratoire de Neuro-Oncologie EPHE, Hôpital Necker, Paris, France.
Anecdotal case reports suggest that pregnancy may adversely affect maternal issue in von Hippel Lindau (VHL) disease. Since no large study is available for accurate counseling, we evaluated maternal and fetal outcomes retrospectively in a series of VHL women.
Patients were recruited by mailing a questionnaire to 49 women randomly identified in the French VHL Register. Patients were questioned on age at each pregnancy, whether VHL-related symptoms occurred in pregnancy, birth term and weight. There was a 52% response rate (21 patients, 41 pregnancies). Similar parameters were studied in charts of 9 patients (15 pregnancies). Data were obtained for 56 pregnancies in 30 women.
VHL disease had been diagnosed before pregnancy in 10 women, including two at screening. Preconception involvement included hemangioblastoma of the retina (6) or CNS (4), renal (4) or pancreatic cysts (2) and phaeo-chromocytoma (1). Pregnancy started at mean age of 24 years (16-37). Gestational age, reported in 50 live births, was 38.2 weeks. Forty-six infants were born at term and 4 between 28 and 36 weeks. Maternal symptoms related to VHL occurred in 3/56 pregnancies (5%) (one cerebellar hemangioblastoma, one phaeochromocytoma, and one pancreatic cystadenoma respectively). These three cases required cesarean section; the mothers and infants recovered after specific treatment for VHL manifestations. There were 54 live births (96%) with 54 surviving infants. Two microcephalic stillbirths occurred to one patient. The newborn weight was reported in 42 live births and ranged from 2.5 to 4.6 kg (mean = 3.1).
In this unselected group of patients with VHL disease, most pregnancies had a favorable outcome with 96% survival rate for fetuses and a 5.4% VHL-specific morbidity rate in the pregnant women. If screening is negative, or adequate treatment of asymptomatic lesions has been performed, pregnancy should not be discouraged in VHL women. However, our data did not assess whether pregnancy accelerates development of asymptomatic or preexisting VHL-associated lesions.
[302] Hemorrhage into a Spinal Cord Tumor in a Pregnant Woman, at Risk for von Hippel Lindau Disease. Hirata G, Hsia YE. U. Hawai'i, Kapi'olani Medical Center for Women & Children, Honolulu, Hawai'i.
An 18 year-old woman, whose mother and many other relatives were known to be affected with VHL, was awakened by acute mid-back discomfort in the 35th week of her first pregnancy. By the time she arrived in an emergency room, she was paraplegic. Spinal cord imaging revealed two mid-dorsal spinal cord hemangioblastomata. Acute hemorrhage had occurred into one of these. Emergency decompression surgery was done, but the tumor was not excised until later.
Obstetric ultrasound revealed a space-occupying lesion in the right upper chest of the fetus. After careful consideration about the safest method for delivery, elective Cesarean section was done. The patient has since recovered most leg function, bowel and bladder control.
After birth, the baby was confirmed to have a space occupying lesion in the right upper chest. A large solid, well-encapsulated tumor was excised. The infant has recovered well. DNA analyses for the VHL mutation known to be in this family was done for the infant's tumor [by Dr. L. Schmidt], and blood from this woman, her presymptomatic brother and sister {by Dr. B. Zbar, T. Kishida, et al]; they were all found to be heterozygous.
We conclude that pregnant patients with VHL may develop unprovoked acute hemorrhage into a previously undiagnosed central nervous system tumor. The likelihood for this complication is unknown, but women affected with, or at risk for VHL, should be considered to have high risk for serious complications during pregnancy.
[303] Cancer and pregnancy. Hirata G. Fetal Diagnostic Center, Kapi'olani Medical Center, Honolulu, Hawai'i.
The occurrence of cancer is rare in pregnancy, with an estimated incidence of approximately 1/1,000. The most common sites of malignancies are breast, cervix, leukemia/ lymphoma, melanoma, thyroid, ovary and colon. Because of the physiologic, endocrinologic, and metabolic changes that occur during pregnancy, many questions have been raised regarding the natural progression of these tumors. Also at issue are the effects of anti-cancer treatments, i.e. radiation and chemotherapy, on the developing fetus.
Cervical cancer is the most common malignancy during pregnancy, and occurs in approximately 1 in 1,240 women. There is no direct evidence that survival and metastases are influenced by pregnancy. If discovered early in gestation, pregnancy termination with definitive surgical treatment seems to be the best option. If it occurs late in pregnancy, then delivery at or near term, followed by radical hysterectomy and radiation is most often recommended.
The second most common malignancy complicating pregnancy is breast cancer, occurring in 1 in 3,000 women, and representing approximately 3 percent of all breast cancers. There is no evidence that pregnancy, stage for stage, has any influence on the prognosis for this disease. Pregnant patients do tend to present at a more advanced stage as compared to the nonpregnant patient. Moreover, it is controversial as to what effect the hormonal changes of pregnancy have on its progression.
Lymphomas are relatively common, while leukemia is rare in pregnancy. Again, there seems to be no influence of pregnancy on the progression of this disease. However, many times staging and treatment are delayed because of concerns regarding effects on the fetus.
Melanomas have been found to contain estrogen receptor proteins and therefore are theoretically felt to be hormone-dependent. There have been anecdotal reports of exacerbations and recurrences during pregnancy. Unfor-tunately, most studies are based on a small number of patients, making interpretation difficult.
Because most chemotherapeutic medications act on rapidly dividing cells, they pose a tremendous risk to the developing fetus. Although largely dependent on the type of agent, exposure during the first trimester often results in fetal death. Fetuses that survive have a 10% risk for major malformations.
After embryogenesis is completed in the first trimester, exposure seems to have no major impact on development.
Fetal effects secondary to maternal exposure to diagnostic and therapeutic radiation is dependent on dosage. Fetal exposure to less than 0.05 Gy does not raise the teratogenic risk. However, higher doses have been associated with fetal damage such as microcephaly and developmental delay.
It is very rare for maternal cancers to metastasize to the developing fetus. Only 24 well-documented cases have been reported of spread to the products of conception. Even rarer are fetal tumors spreading to the mother.
[304] Establishing a Registry. Merz RD. Hawal'i Health Registries: Hawai'i Birth Defects Monitoring Program/ Hawai'i Tumor Registry, Honolulu, Hawai'i.
Since the 1950's, physicians, researchers, policy makers, health reporters, health activists and patients have drawn upon health registries as rich, reliable and accurate sources of information. Because leaders in the world of von Hippel-Lindau (VHL) disease are grappling with their expectations of how a registry can assist in a vast array of research, prevention, diagnosis, treatment and planning efforts, this presentation focuses on the important topics of;
1) issues to consider when initiating a registry,
2) the actual startup activities involved in establishing a registry, and
3) the specific benefits and uses of a registry and its data.
Examples from two Hawai'i Health Registries programs (the Hawai'i Birth Defects Monitoring Program and the Hawai'i Tumor Registry) are utilized as examples of possible questions that can be addressed using quality registry data (gender, age, ethnicity, geography, patterns of care, risk factors, and effect of migration differences).
[305] Screening Complexities and Costs: Insurance, Privacy, and Confidentiality. Collins DL. U. Kansas Medical Center, Kansas, MO.
Screening studies (such as radiographic imaging, DNA studies) for von Hippel Lindau syndrome in families allow early detection of some of the features, allowing early intervention. Genetic testing can establish the diagnosis and avoid needless referrals and extensive work-ups. Support systems and adequate health care should be available for everyone tested, but varies widely, frustrating patients and health care providers.
Studies which establish the diagnosis do not predict the prognosis with certainty. This is confusing to families, their insurance providers, and health care providers. Issues of privacy and confidentiality for presymptomatic DNA genetic test results are important to avoid discrimination and stigmatization. DNA testing raises issues affecting families, including the future health of relatives, testing minors, testing a child before their parent, as well as employment and insurance.
Variability
The variability of VHL symptoms (eye, brain/central nervous system, kidney, pancreas, adrenal gland, other) necessitates that screening, monitoring, and treatment be individualized. Numerous medical specialists involved Treatment, management, and screening studies vary with individual patients and families. Treatment varies Some individuals will be determined to have a mutant VHL gene, yet be asymptomatic or have only benign abdominal cysts. Some will have malignancy and other complications. Interpretation of tests Screening studies (imaging, DNA studies) need accurate interpretation. DNA studies will identify some individuals at high risk but does not indicate prognosis or age of onset of symptoms. Interpretation needs to emphasize that some individuals with a positive test result may never develop disease, and others will be mildly affected. If the individual is identified with a mutation in the VHL gene, and ongoing screening plan needs to be established.
Genetic Counseling for families involves numerous issues:
diagnosis of the condition
explanation of the inheritance
evaluation of symptoms/management/treatment
presymptomatic screening/coordination family member testing
development and updating family pedigree
explaining process of DNA testing and terms (direct test, linkage analysis, recombination)
The process of genetic counseling involves helping family with decision making about DNA studies including the benefits and limitations. Coordination of studies and other research may be involved as well.
Insurance coverage varies
There are numerous types of insurance and benefit programs potentially affected by VHL including life, disability-income, and health-care insurance. Because the symptoms vary, costs for managing VHL varies widely between individuals.
Health care providers and decisions about screening and management are complex because of the multiplicity of policies families may have (COBRA, accident only or disability income, Medicare supplemental health, Medicaid, liability, workers' compensation, specified disease or illness insurance, hospital or fixed indemnity, short-term limited duration, credit-only, or vision-only, long-term, nursing home, home health, and community-based care).
Insurance companies underwrite policies to provide protection against unexpected losses. The risk of loss is transferred from the individual to the insurance company, so that the group shares the loss.
For most patients with VHL or other genetic cancer family syndromes, insurance needs to be established before diagnostic/screening studies. In the U.S. many individual's insurance is through employment or they are self-insured. The new developments in DNA testing raise concerns about insurance discrimination, confidentiality and privacy of this information.
NABC NIH-DOE ELSI Working Group recommendations.
Recommendations for state and federal policy-makers to protect against genetic discrimination have been developed through the joint effort of NAPBC (National Action Plan on Breast Cancer) and NIH-DOE ELSI Working Group (National Institutes of Health/National Center for Human Genome Research - Department of Energy Ethical Legal and Social Implications of new advances in human genetics).
These recommendations include:
Insurance providers should be prohibited from using genetic information, or an individual's request for genetic services, or to deny or limit any coverage or establish eligibility, continuation, enrollment, or contribution requirement or to establish differential rates or premium payments based on genetic information or an individual's request for genetic services.
Provision of information to insurers is complicated
Families may be tested by various laboratory techniques. Early diagnosis can result in increased surveillance, detection of tumors, prevent death (e.g. renal cell carcinoma), and the availability of prenatal diagnosis. Insurance companies have a variety of approaches to deal with these issues.
In addition to insurance and discrimination concerns, family issues arise with presymptomatic DNA studies. There is controversy about testing minors, and complications when testing a child before the parent is tested. Psychological issues may arise when some relatives are found to be unaffected. Guilt, alienation from the rest of the family, loss of purpose or self-identification, and other difficulties may arise in a person who had always considered himself or herself to be at risk, and finds that they are unaffected.
S. 1028 Kasselbaum / Kennedy Health Care Portability
A potentially important bill currently being considered by the U.S. Congress advocates for access to health care benefits, portability of health care benefits, and security of health care benefits and increases the purchasing power of individuals / small employers.
The House of Representatives (H.R. 3103) is still discussing their version of the bill.
The Genetic Privacy Act is a proposal for federal legislation based on the premise that genetic information is different from other types of personal information in ways that require special protection.
These issues continue to be raised in public forums and in discussions in ELSI proposals, Family cancer syndromes and VHL can play a major role in these complex discussion, and family support groups can advocate effectively for individuals.
References
Annas G: The Genetic Privacy Act and Commentary. Health Law Department, Boston University School of Public Health, Boston, MA, 1995
ASHG Statement of the American Society of Human Genetics on genetic testing for breast and ovarian cancer predisposition. Summary of recommendations. Am J Hum Genet 1994, 56:327-331.
ASHG Points to consider: ethical, legal, and psychosocial implications of genetic testing on children and adolescents. Am J Hum Genet 1995, 57:1233-1241
Holtzman NA Johns Hopkins Medical Information Net-work: Interim principles of the task force on genetic testing of the NIH-DOE working group on ethical, legal and social implications of human genome research. Mar 1996
Ostrer H et al: Insurance and genetic testing: where are we now? Am J Hum Genet 1993, 52:565-5777.
Health Insurance Act of 1995. Kasselbaum/Kennedy Bill (S.1028 and H.R. 3103)
http://thomas.loc.gov/thomas.html/
Please note: this link no longer works since the passage of this bill. Please see http://www.yahoo.com, and search for Kennedy-Kassebaum to find related articles.
Privacy Commission of Canada: Genetic Testing and Privacy (1992) Ottawa, CANADA, ISBN 0-662-58966-1
Von Hippel Lindau Family Alliance Home Page (information for families, clinicians, researchers)
[306] Screening, Diagnosis, and Monitoring in VHL.Glenn G. National Cancer Institute, N.I.H, Bethesda, Maryland.
Screening and diagnosis of VHL now include DNA diagnostics that may resolve individual diagnostic dilemmas and is available for many families to determine which asymptomatic members inherited the VHL trait and may develop tumors. Also, a VHL classification of tumor types in families has been proposed, and germline mutations have been correlated with the phenotypes.
Screening of a kindred with clinically affected individuals needs to be carried out in all members, if no DNA diagnosis is available to identify asymptomatic carriers of the VHL trait. Multiple periodic imaging studies (MRI's, CT's and sonograms) and retinal examinations are carried out to detect VHL tumors and cysts commonly found in brain, spine, kidneys, pancreas, adrenal glands, and eyes. Progress in DNA diagnostics is decreasing the numbers in a kindred requiring clinical surveillance.
Diagnoses of the presence of specific benign or malignant tumors and cysts may occur before or after the onset of symptoms. Tumors in VHL include retinal, brain and spine hemangioblastomas, renal cell carcinomas, pancreatic islet cell tumors, pheochromocytomas, endo-lymphatic sac tumors, and epididymal cystadenomas. A diagnosis by DNA alone identifies an individual as a VHL trait carrier, who may or may not be found to have tumors on clinical examination.
Monitoring of existing VHL tumors and cysts by serial comparative imaging is indicated in managing small, stable tumors in an asymptomatic patient not scheduled for current treatment. With increasing tumor size, or development of symptoms, a recommendation for treatment is made, which for most tumor types will be surgical resection.
[307] Von Hippel-Lindau Disease: Ocular Manifestations, History, Management and Long Term Follow-Up. Welch RB. Dept Ophthalmology, Johns Hopkins U. Hospital, Baltimore, Maryland.
The historical background of von Hippel-Lindau disease is reviewed. The author's experience with this syndrome for over 30 years is discussed with special emphasis on the recognition of very early retinal lesions.
A classification of clinical stages of ocular involvement is presented to include the various forms of the early stage I lesions. Similarly, various types of angioma involving the optic nerve disc are illustrated.
Issues to be addressed include: technique for examination of the ocular fundus, growth and evolution of angiomas, and the development of de novo lesions.
Treatment modalities and long term follow-up will also be presented.
[308A] Conventional Treatment for Retinal Hemangioblastoma in VHL.Foerster MH1, Meter-Schwikerath2, Wessing2. 1AugenKlinik und Poliklinik, Freie Universitat Berlin, 2Essen, Germany.
[308B] Vitreoretinal Surgery and Radiation Therapy as Alternative Treatment Modalities in Advanced Capillary Hemangioma of the Retina.Kreusel KM, Bornfeld N, Lommatzsch A, Chauveau P, Friedrichs W, Wessing A, Foerster MH. Dept Ophthalmology, Berlin, Germany
Capillary hemangiomas of the retina are rare tumors which may occur either as solitary tumors or in von Hippel-Lindau (VHL) syndrome. Traditional treatment of capillary hemangiomas include photocoagulation. This cannot be performed on large hemangiomas as it may be complicated by extensive exudative retinal detachment and tractional detachment of the retina. Alternative treatment modalities include vitreoretinal surgery, external beam therapy using protons or photons, brachytherapy, or a combination of these methods.
Patients:
45 eyes in 44 patients with complicated hemangioma of the retina were treated with one of these treatment modalities. 33 of these patients were suffering from obvious VHL, as judged from the occurrence of multiple retinal angiomas, additional manifestations of the syndrome, or family history. 22 eyes were treated with brachytherapy using ruthenium plaques. In addition, a single vitrectomy was done in four of these eyes, while more than one vitrectomy were required in two eyes to manage tractional retinal detachment. External beam irradiation with protons was performed in 3 eyes and with photons in 2 eyes. Vitreoretinal surgery was performed in 15 eyes, in 5 of these eyes more than one vitrectomy was required.
Results:
Brachytherapy of solitary peripheral hemangiomas yielded the best functional results. In all of these treated eyes, the tumors could be completely destroyed, while an extensive exudative retinal detachment did not occur. Vitreoretinal surgery may preserve useful vision in half of the cases treated. Proton therapy is effective in controlling juxta- and intra-papillary tumors, but has limited success in the treatment of large tumors.
Conclusions:
Brachytherapy is the treatment of choice in large solitary peripheral hemangiomas, but sometimes requires additional vitreoretinal surgery to manage tractional retinal detachment. Other alternative treatment modalities are restricted to advanced complicated tumors with no therapeutic alternative.
[309] Diagnostic Imaging in VHL. Glenn G. National Cancer Institute, N.I.H, Bethesda, Maryland.
The advent of computed tomography (CT) and ultrasound (US) in 1970-1980 resulted in descriptions of von Hippel-Lindau disease (VHL) in several large families from around the world. Magnetic resonance imaging (MRI) followed as key to screening the cerebellum and spine. When researchers in the 1990's developed DNA markers for VHL, the correlative clinical diagnoses were made by diagnostic imaging with and without pathologic specimens. Despite advances in molecular genetics, imaging techniques will continue to play a major role in diagnosis, and management planning in VHL.
Radiologists may be the first to recognize VHL in an organ and initiate other examinations in patients and relatives; this may greatly increase the number of affected individuals found in a family. CT is essential for the diagnosis of renal involvement in VHL, and is more sensitive than US for detecting smaller lesions.
Pancreatic islet cell tumors, microcystic adenomas, and cysts are most commonly detected with CT and US. CT is excellent for evaluating adrenal glands, but most ectopic sites are better seen by MRI, or by testing with metaiodobenzylguanidine (MIBG). For children, however, US is used for routine screening of the abdomen. The best imaging technique available for hemangioblastomas of the brain and spinal cord is pre- and post-contrast enhanced imaging with a galadium chelate.
Endolymphatic sac tumor (ELST) imaging is perf-ormed with high resolution CT and MRI through the middle ear. Formal fluorescein angiography may be used for documenting small retinal hemangiomas.
For monitoring of established disease in VHL, periodic imaging schedules should be individualized.
