Genetic predisposition to peripheral nerve neoplasia: diagnostic criteria and pathogenesis of neurofibromatoses, Carney complex, and related syndromes

Abstract

Neoplasms of the peripheral nerve sheath represent essential clinical manifestations of the syndromes known as the neurofibromatoses. Although involvement of multiple organ systems, including skin, central nervous system and skeleton, may also be conspicuous, peripheral nerve neoplasia is often the most important and frequent cause of morbidity in these patients. Clinical characteristics of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) have been extensively described and studied during the last century, and the identification of mutations in the NF1 and NF2 genes by contemporary molecular techniques have created a separate multidisciplinary field in genetic medicine. In schwannomatosis, the most recent addition to the neurofibromatosis group, peripheral nervous system involvement is the exclusive (or almost exclusive) clinical manifestation. Although the majority of cases of schwannomatosis are sporadic, approximately a third occur in families and a subset of these has recently been associated with germline mutations in the tumor suppressor gene SMARCB1/INI1. Other curious syndromes that involve the peripheral nervous system are associated with predominant endocrine manifestations, and include Carney Complex and MEN2b, secondary to inactivating mutations in the PRKAR1A gene in a subset, and activating mutations in RET respectively. In this review, we provide a concise update on the diagnostic criteria, pathology and molecular pathogenesis of these enigmatic syndromes in relation to peripheral nerve sheath neoplasia.

INF2 mutations in Charcot‐Marie‐Tooth disease complicated with focal segmental glomerulosclerosis

“…It was also reported that formin (mDia) family proteins might mediate the disease progression role of the adenomatous polyposis coli familial colon cancer tumor suppressor gene (Wen et al, 2004). We analyzed NF2 and or SMARCB1 in case 3, but we could not find any mutation leading to schwannomatosis (DeWard et al, 2010;Rodriguez et al, 2012). Schwannomatosis should be remarked as a complication in further case carrying INF2 mutation.…”

Tumors of Central and Peripheral Nervous System Associated with Inherited Genetic Syndromes

“…Plexiform and cellular variants of schwannomas are also observed in NF2 patients, while melanotic schwannoma is not observed in NF2 and its psammomatous variant is correlated with the Carney complex [26]. Cellular schwannoma, commonly affecting paraspinal sites, is encapsulated entirely composed of Antoni A areas without Verocay bodies, with preserved pericellular reticulin.…”

An unusual case of schwannomatosis with bilateral maxillary sinus schwannomas and a novel SMARCB1 gene mutation

“…She was also noted to have no new lesions at that time. discussion Schwannomatosis is a rare disease characterized by the development of multiple schwannomas 11,18,22 and meningiomas. 14 The present case is a particularly aggressive case and is associated with a novel mutation in the SMARCB1 gene.…”