title: The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A.
abstract: BACKGROUND
  Germline missense mutations of the RET protooncogene cause a clinical spectrum called multiple endocrine neoplasia (MEN) type 2. A strong genotype-phenotype correlation results in major implications for the clinical approach. More information on less common mutations is needed to advance specific guidance.
  
  
  METHODS
  We report individualized patient information on 36 carriers of the intracellular RET gene mutation S891A from three centers and clustered data of 38 former patients reported in the literature in nine additional studies.
  
  
  RESULTS
  S891A mutation accounts for up to 5% of all patients to date reported with RET mutations and 16% of those hitherto reported with intracellular mutations. S891A mutation caused medullary thyroid cancer (MTC) in 69.4%, pheochromocytoma in 2.8%, and parathyroid hyperplasia in 8.3% of the 36 patients of this case series and in 63.5, 4.1, and 4.1%, respectively, for the entire groups of 74 patients. The youngest age of onset for MTC in this group was 17 yr (median, 46 yr; range, 17-80 yr), for pheochromocytoma 46 yr (median, 46 yr), and for parathyroid hyperplasia 17 yr (median, 20 yr, range, 17-46 yr). Persistence of MTC was described in 14.3% of patients with available follow-up. Additional findings included corneal nerve thickening in three of 74 patients (4.1%).
  
  
  CONCLUSIONS
  This intracellular mutation can initiate the full spectrum of MEN2a, initiates MTC at an early age, and causes recurrence and death if undertreated. We recommend stringent adherence to established guidance in MEN2a in this rare mutation.
authors.affiliation: Department of Endocrine Surgery, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. klaus-martin.schulte@nhs.net
authors.forename: Klaus-Martin
authors.initials: KM
authors.lastname: Schulte
authors.forename: Andreas
authors.initials: A
authors.lastname: Machens
authors.forename: Laura
authors.initials: L
authors.lastname: Fugazzola
authors.forename: Alan
authors.initials: A
authors.lastname: McGregor
authors.forename: Salvador
authors.initials: S
authors.lastname: Diaz-Cano
authors.forename: Louise
authors.initials: L
authors.lastname: Izatt
authors.forename: Simon
authors.initials: S
authors.lastname: Aylwin
authors.forename: Nadia
authors.initials: N
authors.lastname: Talat
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Henning
authors.initials: H
authors.lastname: Dralle
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D018276:Carcinoma, Medullary / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000150:complications / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D010673:Pheochromocytoma / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D017354:Point Mutation / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012694:Serine / Q000235:genetics; D013964:Thyroid Neoplasms / Q000150:complications / Q000235:genetics*; D055815:Young Adult
chemical_list: D012694:Serine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D000409:Alanine