Von hippel-lindau syndrome Q85.8

Von Hippel-Lindau disease (VHS) is an autosomal-dominant inherited neuro-cutaneous systemic disease with nevus flammeus, various malignant and benign neoplasms, most commonly retinal, cerebellar and spinal hemangioblastomas, renal cell carcinomas (RCC) and pheochromocytomas.

Prevalence: 1-9 / 100 000

Highly penetrant mutations (mostly germline mutations) have been detected in the VHL gene (3p25.3), a classic tumor suppressor gene that codes for the protein of the same name "Von Hippel-Lindau Tumor Suppressor" (pVHL). A total of 42 different rare VHL gene variants were detected in 166 patients (Reich M et al. 2021). The VHL tumor suppressor protein plays a key role in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation.

Infancy, childhood, adolescence, adulthood up to the 7th decade of life; the mean age of diagnosis is 24 years (Reich M et al. 2021).

Skin: Nevus flammeus (rare)

Eye: Retinal hemangioblastomas are the most common first sign (multiple and bilateral in 50% of cases). They are usually asymptomatic but may cause retinal detachment, macular edema, glaucoma and loss of vision.

CNS: Hemangioblastomas of the central nervous system (CNS) are the first symptom in about 40% of cases and occur in 60-80% of patients. They are most frequently located in the cerebellum, but also in the brain stem and spinal cord. They are benign, but cause symptoms due to pressure on neighboring nerve tissue. The most common symptoms of tumors in the cerebellum are increased intracranial pressure, headaches, vomiting and ataxia of the limbs or trunk.

Cyst formation: Multiple renal cystsare very frequently detected. Cysts are also found in the pancreas and liver.

Tumor formations in: Kidney (hypernephroma), adrenal glands(pheochromocytoma) liver (cavernomas) and pancreas (islet cell tumors in about 10% of patients).

Other:

• Epididymal cysts and cystadenomas occur in 60% of male patients.
• Tumors of the endolymphatic sac (ELST) are found in up to 10% of patients and may be the cause of hearing loss.
• Paragangliomas of the head and neck are rare (0.5%). The mean age of diagnosis of these tumors is considerably younger in VHL than in sporadic cases.

Considerable intrafamilial variability has been reported.

The diagnosis can be made using as little as a single typical tumor (retinal or CNS hemangioblastoma or renal cell carcinoma) and a positive family history of VHL. In the absence of a family history (approximately 20% are new mutations), the presence of multiple tumors (eg, 2 hemangioblastomas or 1 hemangioblastoma and 1 RCC) is required for diagnosis.

Imaging techniques are used to detect CNS tumors, pheochromocytoma, tumors of the endolymphatic sac, renal tumors, and renal and pancreatic cysts.

Multiple Endocrine Neoplasia (MEN)

Neurofibromatosis

Polycystic kidney disease

Tuberous sclerosis

Birt-Hogg-Dubé Syndrome

Hereditary pheochromocytoma-paraganglioma syndromes.

Interdisciplinary ophthalmological, neurological and surgical therapy approach.

1. Cushing H, Bailey P (1928) Hemangiomas of cerebellum and retina (Lindau's disease), with the report of a case. Arch Ophthal 57: 447-463

2. Reich M et al (2021) Genotype-phenotype correlation in von Hippel-Lindau disease. Acta Ophthalmol 99(8):e1492-e1500.

3. Lindau A (1926) Studies on cerebellar cysts. Structure, pathogenesis and relations to angiomatosis retinae. Doctoral thesis. Acta pathologica et microbiologica Scandinavica (Copenhagen) 3 (supplement): 1-128

4. von Hippel E (1895) Presentation of a patient with a very unusual retinal or choroidal disease. Report of the 24th meeting of the Ophthalmologic Society in Heidelberg 24: 269