title: A rare missense variant in RET exon 8 in a Portuguese family with atypical multiple endocrine neoplasia type 2A.
abstract: OBJECTIVE
  Multiple Endocrine Neoplasia type 2 (MEN2) is a rare genetic disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism. MEN2 is an autosomal dominant syndrome caused by mutations in the RET proto-oncogene. In the vast majority of patients, the mutations are localized in exons 10, 11 and 13-15 of the RET gene. Rare variants located in exon 8 were recently identified but their clinical significance remains unclear.
  
  
  METHODS
  We studied two sisters presenting with pheochromocytoma as the first tumor. One of the sisters was diagnosed with a right pheochromocytoma at the age of 44 and at age 53 she developed an invasive left pheochromocytoma with no other endocrine neoplasia. The other sister was diagnosed with a left pheochromocytoma at age 50 and at age 64 she had a right phemochromocytoma and MTC. Neither of the two sisters presented evidence of primary hyperparathyroidism. Mutations of the RET proto-oncogene were investigated by DNA sequencing.
  
  
  RESULTS
  We detected a germline missense variant in RET exon 8 (p.Cys531Arg) in both sisters. The p.Cys531Arg variant was not present in a third 50-year-old sister who has remained to date clinically unaffected.
  
  
  CONCLUSIONS
  This is the first case showing the p.Cys531Arg variant in RET exon 8 co-segregating with family members affected by a syndrome reminiscent of MEN2A. Our results suggest that this variant has a specific genotype-phenotype correlation as it is associated with the development of pheochromocytoma before the onset of MTC.
authors.affiliation: Serviço de Endocrinologia, Hospital de Santa Maria, Lisboa, Portugal. anafgmartins@gmail.com.
authors.forename: Ana Filipa
authors.initials: AF
authors.lastname: Martins
authors.affiliation: Serviço de Endocrinologia, Hospital de Santa Maria, Lisboa, Portugal.|Faculdade de Mediana, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: João Martin
authors.initials: JM
authors.lastname: Martins
authors.affiliation: Serviço de Endocrinologia, Hospital de Santa Maria, Lisboa, Portugal.|Faculdade de Mediana, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Sónia
authors.initials: S
authors.lastname: do Vale
authors.affiliation: Serviço de Endocrinologia, Hospital de Santa Maria, Lisboa, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Dias
authors.affiliation: Genomed, Instituto de Medicina Molecular, Centro Académico de Medicina de Lisboa, Lisboa, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Silveira
authors.affiliation: Genomed, Instituto de Medicina Molecular, Centro Académico de Medicina de Lisboa, Lisboa, Portugal.
authors.forename: Inês Rodrigues
authors.initials: IR
authors.lastname: da Silva
authors.affiliation: Faculdade de Mediana, Universidade de Lisboa, Lisboa, Portugal.|Genomed, Instituto de Medicina Molecular, Centro Académico de Medicina de Lisboa, Lisboa, Portugal.
authors.forename: Maria
authors.initials: M
authors.lastname: Carmo-Fonseca
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D000328:Adult; D018276:Carcinoma, Medullary / Q000151:congenital* / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010673:Pheochromocytoma / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D011174:Portugal; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000628:therapy
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human