Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes

Gene. 2014 Feb 25;536(2):332-5. doi: 10.1016/j.gene.2013.12.003. Epub 2013 Dec 21.


Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease with an estimated incidence of 1 in 3000/3500 live births. NF1 is caused by a mutation in a gene which encodes a protein known as neurofibromin. In up to 5% of cases, NF1 is associated with pheochromocytomas. RET proto-oncogene encodes a member of the receptor tyrosine kinase family involved in the normal development or the neoplastic growth of neural crest cell lineages. Germ-line RET mutations account for cases of Multiple Endocrine Neoplasia type 2 (MEN2), an autosomal dominant genetic syndrome where medullary thyroid carcinoma (MTC) is the major and more clinically severe feature, with nearly complete penetrance. C-cell hyperplasia (CCH) is described in MEN2 patients, and it has been implicated as the precursor of in situ MTC. Patients with RET mutations develop pheochromocytomas in 50% of cases. Rarely, patients with NF1 have been found to present, in addition to the NF1 clinical picture, other lesions, such as parathyroid hyperplasia/adenoma and/or medullary thyroid carcinoma. In spite of the presence of these MEN2 lesions, in none of these patients mutations of gene RET have been found so far. In this report, we describe the first case of a patient affected by a germ-line mutation in both NF1 and RET genes.

Keywords: C-cell hyperplasia; C-cells; CCH; CT; MEN2; MTC; Multiple Endocrine Neoplasia type 2; NF1; NF1 gene; Neurofibromatosis type 1; PKA; RET gene; Thyroid C-cell hyperplasia; calcitonin; medullary thyroid carcinoma; neurofibromatosis type 1; parafollicular cells; protein kinase A.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Neuroendocrine
  • Female
  • Genes, Neurofibromatosis 1*
  • Germ-Line Mutation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Neurofibromatosis 1 / genetics*
  • Neurofibromatosis 1 / pathology
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-ret / genetics*
  • Thyroid Dysgenesis / genetics*
  • Thyroid Dysgenesis / pathology
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology


  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Supplementary concepts

  • Thyroid cancer, medullary