VHL Disease in France

For generations in France, as in other countries, von Hippel-Lindau disease was seen as a rare condition of cerebellar and retinal tumors. Visceral manifestations, when they were considered at all, were thought of as curiosities, without significance in the course of the disease. Today, due to progress in brain imaging, microsurgery, and post-operative care, neurosurgical manifestations of the disease are comparatively easy to manage. Persons affected with VHL disease tend to live longer, and diagnosis is more accurate. This has led to the realization that VHL is more prevalent than previously thought, and has brought into focus many previously underrated manifestations, especially kidney tumors.

In 1990 we started an extensive survey of VHL disease cases among a number of French physicians, representative of the various medical specialties involved in the care of people with VHL. This is a continuation and extension of the survey conducted by Dr. François Resche in 1983 among neuro-surgeons. Its ultimate aim is to collect all French cases of VHL disease. In addition, we studied the records of numerous departments of neurosurgery, ophthalmology, pathology, and especially neuro-pathology, dating back in some instances more than sixty years. This proved invaluable for the next step, a formal genetic study involving a thorough, record-based genealogical survey, which enabled us in a number of instances to tie up so-called "sporadic" cases to previously known VHL families.

This project is sponsored by the Association Française contre les Myopathies (the French "Téléthon", to combat muscle diseases) and the Ligue National contre le Cancer (National Cancer Society). The main aim of the project is to promote better knowledge of the natural history, radiology, and pathology, criteria of diagnosis, and management of the health of people with VHL disease.

The multidisciplinary staff is composed of F. Resche (neurology), M. Hurth (neurosurgery), A. Gaudric (ophthalmology), P. F. Plouin (internal medicine), C. Proye (endocrine surgery), J. P. Grunfeld, D. Chauveau (nephrology), Y. Chrétien (urology), P. Hammel (gastroenterology), C. Beigelman, O. Hélénon (radiology), S. Olschwang and G. Thomas (molecular genetics) and S. Richard (clinical genetics). We have contributors to the study in all medical specialties in most French hospitals. Patients are referred to us by physicians who have been alerted by our papers in French professional journals and by the lectures we have been asked to give to various scientific and professional societies.

People with VHL and their at-risk relatives are referred to us at La Salpêtrière Hospital. Basic check-up with neurological examination, ophthalmoscope, and family history is completed along with cerebral and spinal MRI, abdominal ultrasound or CT scan, and 24-hour urine collection for detection of lesions which may not yet have symptoms. Patients are then referred to any required specialist. For the time being, genetic investigation and counseling are done free of charge as part of the research project. Clinical investigation and treatment are paid for by the French state medical insurance system (Sécurité sociale) on an 80% basis for most people, and on a 100% basis if the patient is deemed "affected by a cancerous disease." Today we know 380 affected people and 85 VHL families in France. Seventeen families have six or more (as many as 26) members with characteristic features of VHL.

Our particular interest is the formal genetics of the disease, that is, the precise way the disease runs in families. The genealogy of each family is studied several centuries back in order to unravel a possible common ancestor who might link various apparently independent families. Large kindreds are a powerful tool for genetic studies, and have led to breakthroughs in other diseases. We have consulted parish and municipal registers of births, marriages, and deaths. Access to recent records for living persons is usually prohibited by law, but permission has been granted to us in view of the scientific and practical importance of this research.

Here is one example of the value of systematic genetic inquiry in daily practice. (See Figure below.) Patient #654 is a woman, age 27. In 1990 she was operated on for cerebellar hemangioblastoma and treated for retinal hemangioblastomas. Family history was recorded as negative at that time; the patient declined to undergo the investigations that had been suggested by the neurosurgeon. In April 1992 systematic inquiries enabled us to link this patient to a large VHL kindred with 18 known affected members, resulting in fusion of four previously unrelated pedigrees, the "Sancerre" family, originating from a famous vineyard region in the center of France. The father of the patient (#1399) died at age 32, reportedly from malignant melanoma [a cancer not connected with VHL]. He had complained of loss of vision in one eye, dizziness, and headache. Her grandfather (#1398) died in 1970. The relevant entry in the hospital records mentions kidney cancer as the cause of death.

At that point, members of the family gave their consent for systematic investigations. Her brother, age 24 (#2994), had complained for three years of headaches and vomiting, with considerable weight loss, that had been diagnosed at another hospital as a psycho-somatic illness. In May 1992, following the demonstration of a link with a VHL kindred, he underwent tests which revealed a large hemangioblastoma of the medulla oblongata which was successfully removed in July 1992. Check-up of their sister, age 34 (#2993), who had no symptoms, revealed bilateral retinal hemangioblastoma and bilateral renal tumors, that were treated with conservative surgery.

Genetic diagnosis is at present available in France through linked markers when several affected family members have been sampled. It was developed by G. Thomas and S. Olschwang. It is going to transform the outlook for VHL gene carriers, since most of the manifestations of VHL are amenable to effective treatment if diagnosed early. In the future, knowing the characterization of mutations, molecular diagnosis is going to be possible even in the absence of a documented family history.

Drs. Richard and Resche are affiliated with La Salpêtrière Hospital in Paris. Their study is reported in greater detail in a number of professional publications, most recently S. Richard et al, "Renal Lesions and Pheochromocytoma in von Hippel-Lindau Disease," Advances in Nephrology, 23 (1994) Mosby-Year Book, Chicago.   [Editor's note 12/97: Dr. Richard is now at the Necker Hospital.]

To assist you in drawing up your own family tree, ask for the booklet Your Family Health Tree, available from the VHL Family Alliance. q

As published in the VHL Family Forum 1:4, December 1993. For permission to reprint, please contact the VHL Family Alliance at editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.