Von Hippel-Lindau syndrome

Von Hippel-Lindau syndrome. It is a genetic disease caused by the mutation of a gene and that causes a person’s predisposition to acquire tumors in some organs , especially the kidneys , the central nervous system , most commonly the cerebellum . It is also characterized by affecting the retina .

Summary

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  • 1 Story
  • 2 Causes
  • 3 Epidemiology
  • 4 Etiology
  • 5 Symptoms and development
  • 6 Prevalence
  • 7 Diagnosis
    • 1 Clinical diagnosis
    • 2 Differential diagnosis
  • 8 Treatment
  • 9 Forecast
  • 10 Sources

History

The disease was described by two independent groups, led by Eugen von Hippel (in 1894 ) and Arvid Lindau (in 1926 ). The cause of the disease is the mutation of both alleles of the VHL group, caused in one by genetic factors and in the second after a de novo mutation. The syndrome is characterized by increasing the predisposition to tumors of the kidney , of the central nervous system – particularly the cerebellum – and by affecting the retina . At the moment there is no medical treatmentcure, but knowledge of its symptoms and genetic research make it possible today to establish early diagnoses before the onset of complications from tumor proliferation .

Causes

The syndrome can cause the growth of several tumors: hemangioblastomas in the central nervous system while in the retina it can cause angiomas. These are some but it can also cause kidney cancer and even cysts . The cause of the syndrome is the mutation of the VHL group genes . There is no cure for the syndrome, so tumors can continue to come out, but a treatment can be used for these tumors.

epidemiology

A study carried out in England puts the frequency of this heterozygous alteration at around 1: 53,000, that is to say 1: 36,000 births. Other research in Germany estimated the frequency of the disease at 1: 38,000. It is estimated that around 1000 people living with Hippel-Lindau syndrome live in Poland .

Etiology

The disease manifests itself through an autosomal dominant pattern. It is related to a genetic mutation in the synthesis of the von Hippel-Lindau tumor suppressor gene (VHL), located on chromosome 3. According to Knudson’s hypothesis , for the phenotype to be expressed , it is necessary that the individual be previously a carrier of the mutation in one of the alleles, and later the somatic mutation of the second. This mechanism is called loss of heterozygosity (LOH abbreviated, for its acronym in English : the of heterozygosity).

In the majority of those affected by the syndrome (80%), the constitutive mutation of the VHL gene is inherited from the parent, and the de novo mutation is responsible for 20% of cases of von Hippel-Lindau disease. Cases of parental mosaicism have been described, but its incidence is not known. The offspring of an individual with VHL has a 50% risk of inheriting the disease- causing mutation . Prenatal testing in risky pregnancy is possible if the disease- causing mutation has been previously identified in a family member.

Very rarely, the mutation originates from the embryonic stage. At that time, the presence of the gene is only partial in the embryo not yet formed (mosaicism). It has been proven that the polymorphism in the gene of cyclin D1 (CCND1) in 11q13 locus may be modified in the phenotype affected by the mutation of the gene VHL.

Rare cell carcinoma associated with this syndrome.

Symptoms and development

The proliferation of tumors is observed in patients with von Hippel-Lindau syndrome , of which the most essential – from a clinical point of view – is their location in the brain , spinal cord , retina and kidneys . Apart from this, many other clinical disorders can affect other organs and systems . The tumors that respond to the Von Hippel-Lindau disease are characterized generally by their multiple foci, and the same way multiply faster in a young patient in the population older.

Prevalence

It is estimated at 1 / 53,000 and the incidence at birth at 1 / 36,000. The disease affects men and women equally . The average age at diagnosis is 26 years, but the disease can be detected from childhood to 70 years.

The first manifestation may be the appearance of retinal hemangioblastomas, which are usually asymptomatic, but can cause retinal detachment , macular edema , glaucoma, and vision loss. Hemangioblastomas of the central nervous system (CNS) usually appear in the cerebellum , but can also affect the brain stem or spinal cord , and can be associated with headaches , vomiting, and gait disturbances or ataxia .

Multiple renal cysts can also develop and are associated, in many cases, with an increased risk of developing CRC. In some cases, patients present with pheochromocytoma , which may be asymptomatic but can cause hypertension . The cysts and cistoadenomas epididymal and multiple cysts of the pancreas may also appear. In about 10% of cases, endolymphatic sac tumors have been observed , causing loss of hearing ability. The VHL is caused by mutations in the gene suppressor tumors: VHL (3p25.3). Transmission is autosomal dominant with high penetrance. Most cases are diagnosed by identification of the VHL germline mutation.

Diagnosis

Clinical diagnosis

The diagnosis clinician is possible only in the presence of a tumor characteristic (eg: tumor of the retina , hemangioblastoma of the CNS or CCR) and family history. In the absence of a family history (20% of cases are due to de novo mutations), more tumors (eg, two hemangioblastomas or one hemangioblastoma and one CRC) are required to make a diagnosis . A complete blood count, a measurement of urinary catecholamines, a urinalysis, and urinary cytology identify: polycythemia , pheochromocytoma , renal abnormality, or RCC. Imaging studies (IRM,scanner , ultrasound) allow to detect: tumors of the central nervous system, pheochromocytoma, endolymphatic sac tumors, renal tumors and renal and pancreatic cysts.

Differential diagnosis

Differential diagnosis includes: multiple endocrine neoplasia , neurofibromatosis , polycystic kidney disease , tuberous sclerosis, Birt-Hogg-Dube syndrome, and mutations of succinate dehydrogenase subunits (SDHB, SDHC, SDHD). Prenatal diagnosis is possible by molecular analysis of amniocytes or chorionic villi cells , if the causal mutation has been previously identified in any member of the family. Genetic counseling should be proposed to patients and their families. The surgery is the most effective treatment and management should include ongoing monitoring.

Treatment

Treatment involves surgical removal of the tumors before they become dangerous in size, plus life-long follow-up to prevent the tumors from growing back. The prognosis can be poor if the tumors are large.

However, because a large percentage of cases have a history of the same disease , an early diagnosis can be made taking into account the family’s genetic history.

Deaths from the disease are usually due to a vascular complication of the brain . A study carried out shows that life expectancy in people with this syndrome is 41 years.

Forecast

The prognosis depends on the occurrence of multiple tumors . RCC is the leading cause of death in VHL patients, followed by CNS hemangioblastomas. Average life expectancy is estimated at 49 years, however, regular monitoring and prompt management of tumors reduces morbidity and mortality.

 

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