Von Hippel Lindau disease is an autosomal dominant gene pathology that causes the development of a number of polymorphic tumors in the body. Most often these are retinal angiomas, CNS hemangioblastomas, pheochromocytomas, neoplasms of the kidneys and pancreas. Sometimes a single tumor process acts as a manifestation of the disease. The diagnosis is verified after neurological and ophthalmological examinations, CT or MRI of the brain and spine, ultrasound or CT of the kidneys, pancreas, adrenal glands, genetic diagnosis. Treatment consists in early detection and removal of emerging tumors.
ICD 10
Q85.8 Other phacomatoses not classified elsewhere
General information
The disease occurs with a frequency of 1 case per 36 thousand people. It is characterized by a large polymorphism and different localization of emerging tumors. The most common sign is retinal angiomatosis, which accompanies up to 75% of cases of the disease. It often acts as a diagnostic marker of this pathology. Cerebellar hemangioblastomas, according to various data, are observed in 35-70% of cases, neoplasms and kidney cysts — in 25% of patients, pancreatic lesions — in 24%, pheochromocytoma – in 7%. Due to the large variability of neoplasms, patients with Von Hippel Lindau disease need joint supervision of specialists in the field of ophthalmology, neurology, oncology, urology, gastroenterology, endocrinology.
Causes
Von Hippel Lindau disease is a genetic pathology. In about 80% of cases, it is inherited in an autosomal dominant way with incomplete gene penetration. In another 20% of cases, Von Hippel Lindau disease occurs due to new mutations. Aberrations affect the p25-26 region located in the 3rd chromosome, namely the VHL gene, which plays the role of a suppressor suppressing the growth of neoplasms. To date, about 140 mutations of this gene are known.
As a result of insufficient oncosuppression, neoplasms grow, mainly angioreticulum and hemangioblast. Tumors affect the cerebellum and retina of the eye, intracerebral tumors of the hemispheres, neoplasms of subcortical structures and the medulla oblongata are less common, tumors of the spinal cord and peripheral nerves are even less common. Due to the incomplete manifestation of genetic aberrations, some patients may have only one clinical sign of the disease.
According to the classification, Von Hippel Lindau disease has 2 types: without pheochromocytoma and with its presence. The second type is divided into variants: 2A — with a low risk of kidney adenocarcinoma, 2B — with a high risk of carcinoma, 2C — only pheochromocytoma is observed. In all variants of the disease, except 2C, the presence of CNS hemangioblastomas and retinal angiomas is possible.
Symptoms
The debut of neurological manifestations usually occurs in the 3-4 decades of life. In childhood, Von Hippel Lindau disease is characterized by the appearance of neurological symptoms against the background of already existing visual disorders. In some cases, the disease manifests in children with subarachnoid hemorrhage.
Defeat of the central nervous system. The most common source of primary symptoms are cerebellar cysts (cerebellar cysts). They manifest as general cerebral symptoms (diffuse headaches, nausea without food intake, vomiting, tinnitus) caused by increased intracranial pressure. The first signs also include epiprimes, they can be generalized or focal. Over time, signs of damage to the cerebellum appear, forming a symptom complex of cerebellar ataxia: static and dynamic discoordination, adiadochokinesis, hypermetria and asinergia, intentional tremor, myodistonia. As the cerebellar neoplasm grows, displacement and compression of the brain stem occurs, accompanied by stem symptoms, primarily swallowing disorder, diplopia, dysarthria. Spinal tumors (more often angioretticulomas) are manifested by radicular syndromes, loss of deep types of sensitivity, lack of tendon reflexes. In 80% of cases of spinal pathology, there is a clinic similar to syringomyelia. A picture of a complete lesion of the spinal cord diameter is possible.
Eye damage in the early stages is diagnosed only with ophthalmoscopy. After 8 years, there are complaints about the nebula of the image and its distortion (metamorphopsies). In half of the patients, damage to both eyes is detected. Retinal angiomas that increase over time lead to circulatory disorders in its vessels, ischemia and cystic degeneration. In the late stage, uveitis, cataract, retinal detachment, glaucoma, hemophthalmos are possible.
Kidney damage in 60-90% of cases is represented by cysts, in 45% of cases — renal cell carcinoma. As a rule, renal carcinoma makes its clinical debut at the age of 40 to 50 years in patients who have previously been treated for neoplasms. In half of the cases, at the time of diagnosis of carcinoma, its metastases are detected. The combination of polycystic kidney disease with retinal angiomatosis is more characteristic than its combination with cerebral angiomas. In 35% of patients with Von Hippel Lindau disease, polycystic disease is diagnosed posthumously. In childhood, with the familial type of the disease, polycystic kidney disease is often its only manifestation.
Pheochromocytoma is bilateral in almost half of cases. It may be the only clinical manifestation of the disease. In combination with renal carcinoma, it is quite rare.
The pancreas is affected from 30 to 72% by its cysts. Pancreatic cysts are benign in nature and rarely lead to clinically significant enzymatic insufficiency of the pancreas. Although there are cases of complete cyst replacement of normal gland tissues with the development of diabetes mellitus.
Diagnostics
Full verification of the diagnosis is carried out collectively by a neurologist, ophthalmologist and geneticist with the participation of other doctors: oncologist, endocrinologist, urologist, gastroenterologist.
At the initial stage, a complete neurological and ophthalmological examination is performed. In order to identify cerebellar formations, CT or MRI of the brain is prescribed. To detect tumors of other localization, ultrasound or CT of the kidneys, ultrasound of the pancreas or its MRI, MRI of the spine, CT of the adrenal glands are necessary. The level of catecholamines and pancreatic enzymes is analyzed. DNA diagnostics is aimed at detecting mutations in the VHL gene.
Von Hippel Lindau disease should be assumed and excluded in every case of detection of retinal angiomatosis during ophthalmoscopy, especially in the presence of a burdened family history. In the initial stage, ophthalmoscopy can determine a single retinal angioma with dilation of the vessels feeding it, subsequently angiomas become multiple, aneurysms and serpentine tortuosity of the vessels are characteristic. Fluorescence angiography of the retina allows to diagnose the earliest changes in retinal vessels and erased forms. With its help, it is possible to differentiate the retinal changes accompanying Von Hippel Lindau disease from other ophthalmological pathologies: retinopathy, ritinitis, retinoblastoma, optic neuropathy, etc. Clarification of the diagnosis is possible with the help of retinal laser tomography.
Treatment and prognosis
Today, Von Hippel Lindau disease has only symptomatic treatment. It is aimed at eliminating the emerging tumor formations. For the earliest possible detection of tumors, follow-up and annual examination of patients are recommended.
The early stages of retinal angiomatosis are an indication for focal radiation therapy, however, a year after its implementation, radiation retinopathy may occur. Laser coagulation, diathermocoagulation is possible with respect to small angiomas, with large formations — transcleral cryopexy. If Von Hippel Lindau disease is accompanied by neoplasms of the central nervous system, a consultation with a neurosurgeon is necessary.
Surgical removal of tumors of the cerebellum, cerebral hemispheres, and optic nerve is possible. Cases of application of stereotactic surgery are described. When diagnosing renal carcinoma, partial nephrectomy is performed, and when pheochromocytoma is detected, its removal is performed. Surgical treatment of benign neoplasms of the pancreas is indicated with an increase in their size over 2-3 cm.
Without treatment, the disease leads to blindness due to progressive retinal angiomatosis and to death due to the development of tumors of cerebral and somatic localization. With observation and treatment, patients live on average to 40-50 years of age. Half of the deaths are caused by hemangioblastomas of the central nervous system. In the early stages, radical removal of these tumors is possible in most patients, but neoplasms tend to recur on average 6 years after their removal.