Up to 10% of all pathogenic variants in the NF1 gene are present in the form of somatic mosaics. The highest proportion of mosaics occurs in type 2 microdeletions and atypical microdeletions.
Mosaic neurofibromatosis type 1 (MNF) is caused by a postzygotic genetic modification during embryonic development. Depending on the time of the mutation event and the affected cell population, isolated pigmentation disorders (café au lait spots with or without freckling), neurofibromas or plexiform neurofibromas can develop, each of which often occur unilaterally. If the NF1-characteristic manifestations are restricted to specific body regions, this is also called segmental NF1. The prevalence of mosaic neurofibromatosis is estimated at 1:36,000. In mosaic neurofibromatosis type 1, a genetic change in the NF1 gene is either not detectable in DNA from peripheral leukocytes or detectable only in small amounts (<5%). For isolated pigmentation disorders, a genetic change can be detected in cultured melanocytes from the affected region. In isolated neurofibromas, a genetic alteration can only be detected in Schwann cells from the corresponding tumor and possibly in the overlying skin.
Pathogenic variants in the introns and regulatory variants account for 1-3% of all NF1 changes. Variants in the non-coding regions could be detected by NGS of the entire genomic region of the NF1 gene and by RNA analyses, although these analyses are not currently part of routine diagnostics.
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Von Hippel-Lindau syndrome (VHL syndrome) is a rare hereditary tumor disease (prevalence 1:50,000), which is associated with the development of mostly benign tumors and follows an autosomal dominant inheritance pattern. Affected persons mainly develop hemangiomas or hemangioblastomas in the retina or the CNS. Furthermore, patients are diagnosed with kidney and/or pancreatic cysts, renal cell carcinomas, pheochromocytomas, neuroendocrine tumors (NET) or endolymphatic sac tumors (ELST).
Von Hippel-Lindau syndrome is caused by pathogenic variants in the tumor suppressor gene VHL. The VHL gene is located on chromosome 3, consists of three exons, and encodes the VHL protein (pVHL), which is part of a protein complex that plays an important role in the regulation of gene expression in response to oxygen. Germline variants in VHL do not lead directly to degeneration. Only after failure of the second intact VHL allele by spontaneous somatic variants can uncontrolled division and degeneration of the affected cells occur (Knudson's two-hit hypothesis). However, the penetrance of pathogenic VHL variants is estimated to be nearly 100% until the age of 65.
Phenotypically, a distinction can be made between VHL type I and VHL type II: VHL type I is characterized by the occurrence of hemangiomas in the retina and/or CNS, renal cell carcinomas and/or neuroendocrine tumors. However, the risk for pheochromocytomas is very low. VHL type I is associated with nonsense variants or deletions of larger gene segments. In contrast, VHL type II has a very high risk of developing pheochromocytomas, and missense variants are often detected in VHL in affected individuals.
Homozygous or combined heterozygous variants can cause a rare form of familial erythrocytosis (Chuvash polycythemia, OMIM 263400). Clinically, increased erythrocyte numbers and an elevated erythropoietin serum level with normal oxygen content in the tissues are shown in these cases.
If a causative variant is detected, an annual systematic screening program is recommended for carriers consisting of a general clinical examination, an ophthalmological examination and a catecholamine determination, as well as MRI images of the head, spine and abdomen. There is a 50% risk that offspring will inherit the variant. Children of carriers should be specifically tested for the familial variant before the age of 5, and if the variant is detected, they should participate in the screening program from the age of 5. The predictive genetic examination of persons considered at risk with known familial variants can be carried out after genetic counselling.
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