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Von-Hippel-Lindau Syndrome - VHL
Clinical Features
Von
Hippel-Lindau (VHL)
syndrome is characterized by hemangioblastomas of the brain, spinal cord, and
retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma; and
endolymphatic sac tumors. Retinal hemangioblastomas may be the initial
manifestation of VHL syndrome and can cause complete vision loss. The
cerebellar hemangioblastomas may be associated with headache, vomiting, and
gait disturbances or ataxia. About 40% of patients with VHL syndrome develop
renal cell carcinoma. Pheochromocytomas are often asymptomatic but may cause
sustained or episodic hypertension due to abnormal production of hormones.
Endolymphatic sac tumors can cause hearing loss of varying severity, which can
be a presenting symptom.
Genetic Information
The
VHL-syndrom follows an autosomal dominant pattern of inheritance, approximately
80% of all patients have one affected parent, 20% of the mutations arise de
novo. In rare cases germline mosaics in healthy parents can be detected.
The responsible gene VHL is located at the chromosomal loci 3p26 and
consists of 3 exons. The encoded tumorsuppressorprotein VHL is part of a
proteincomplex exhibiting ubiquitin-ligase activity, which is involved in
degradation processes of certain transcription factors. If the clinical
diganosis of VHL is assured, mutations in the VHL-gene can be found more than
98% of patients (72% pointmutations and 27% partial/complete deletions of the VHL-gene).
The penetrance to show symptoms until 65 years of age is nearly 100%, the
incidence is described in the literature to be approximately 1:35.000.
Diagnostic
Indication
Patient
without known family history of VHL:
- two or
more hemangioblastomas of the brain or retina or
- one
hemangioblastomas in combination with visceral manifestation like kidney-
or pancreascysts, tumor of the kidney, pheochromocytoma and endolymphatic
sac tumors, papillary cystadenoma or endocrine tumor of the pancreas
Patient
with positive family history of VHL:
- angioma
of the retina
- hemangioblastomas
of the brain or spinal cord
- pheochromocytoma
- multiple
cysts of the pancreas or the kidney or
- renal
cell carcinoma under 60 years of age
Method
All 3 exons of the VHL-gene
as well as their flanking regions are analysed using DNA sequencing. A
MLPA-deletionscreening is performed to detect genomic deletions / duplications.
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