399- How does VHL gene mutation result in tumorigenesis?
VHL is a tumor suppressor gene that encodes a protein which in normoxic state
leads to ubiquitylation of hypoxia-inducible factor (HIF), thereby resulting in
its proteasomal degradation and prevents cell growth and proliferation. Loss-
of-function mutation of VHL gene results in stabilization of HIF which acti-
vates downstream signaling pathways including VEGF, PDGF, and TGF-α and
thereby promoting angiogenesis, cell growth, and proliferation leading to
tumorigenesis. The clinical implication of this knowledge is the use of tyrosine
kinase inhibitors (such as sorafenib and sunitinib) in patients with VHL syn-
drome, as these drugs inhibit the VEGF and PDGF receptor tyrosine kinase and
consequent tumorigenesis.- When to suspect a diagnosis of neurofibromatosis type 1?
Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome characterized
by constellation of following features, and the presence of two of these features
is required to establish the diagnosis.- Six or more café au lait macules >5 mm in longest diameter in prepubertal
and >15 mm in longest diameter in postpubertal individuals - The presence of neurofibromas ≥2 or plexiform neurofibroma ≥ 1
- Freckling in the axillary or inguinal area
- Optic glioma
- Lisch nodules ≥ 2
- Skeletal dysplasia (sphenoid wing) and pseudoarthrosis
- A first-degree relative with NF1
- What are the endocrine manifestations of NF1?
Endocrine neoplasias associated with NF1 include pheochromocytoma, hypo-
thalamic/optic nerve glioma, PHPT, duodenal carcinoids, and rarely
MTC. Approximately, 15 % of children with NF1 may harbor optic nerve gli-
oma which may present as gonadotropin-dependent precocious puberty, and
2 % of patients with NF1 have concurrent pheochromocytoma.- What is the molecular basis for tumors associated with neurofibromatosis type 1?
Neurofibromatosis type 1 is associated with mutations of NF1 gene, a tumor
suppressor gene, which is located on chromosome 17q11.2. NF1 gene encodes
a protein neurofibromin, which is expressed in many tissues including the brain,
neural crest-derived tissues, kidney, and spleen. Neurofibromin stimulates
intrinsic GTPase activity which in turn inhibits the ras p21 family. Normally,11 Multiple Endocrine Neoplasia