Acta Neuropathologica

, Volume 123, Issue 3, pp 349–367 | Cite as

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

  • Fausto J. Rodriguez
  • Constantine A. Stratakis
  • D. Gareth Evans


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 one-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.


Neurofibromatosis NF1 NF2 Schwannomatosis Carney complex Multiple endocrine neoplasia Neurofibroma Schwannoma 



The authors thank Drs Jaishri Blakeley, J. Aidan Carney, Caterina Giannini and Arie Perry who contributed pictures. They also thank Sharon Blackburn at the Johns Hopkins Pathology Photographic Arts Laboratory for graphical technical assistance.


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Fausto J. Rodriguez
    • 1
  • Constantine A. Stratakis
    • 2
  • D. Gareth Evans
    • 3
  1. 1.Division of Neuropathology, Department of PathologyJohns Hopkins UniversityBaltimoreUSA
  2. 2.Section on Endocrinology and Genetics Program on Developmental Endocrinology and GeneticsNICHD, NIHBethesdaUSA
  3. 3.Department of Genetic MedicineManchester Academic Health Science Centre, St Mary’s HospitalManchesterUK

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