title: Bilateral Pheochromocytomas in MEN2A Syndrome: A Two-Institution Experience.
abstract: BACKGROUND
  Bilateral pheochromocytoma (PHEO) is more frequently found in patients with multiple endocrine neoplasia 2A carrying a RET germline mutation located in codon 634 (C634). However, it is unclear whether different amino acid substitutions within C634 cause differences in bilateral PHEOs expression. We aimed to answer this by pooling data from two Asian institutions.
  
  
  METHODS
  Sixty-seven patients had confirmed C634 germline mutation. Age-dependent penetrance of bilateral PHEO was calculated from date of birth to the date when bilateral PHEO was first diagnosed or when the contralateral gland became a PHEO (if the patient already had one adrenal gland removed). Age-dependent penetrance was estimated by the Kaplan-Meier method and compared by log-rank test.
  
  
  RESULTS
  The 4 different amino acid substitutions included C634R (arginine) (n = 19, 28.4 %), C634Y (tyrosine) (n = 36, 38.8 %), C634G (glycine) (n = 4, 6.0 %), and C634W (tryptophan) (n = 8, 11.9 %). The age-related penetrance of PHEO was similar between C634R, C634Y, C634G, and C634W (by age 40, 69.8, 55.2, 25.0, and 56.2 %, respectively) (p = 0.529). However, the age-related penetrance of bilateral PHEO in C634R was significantly higher than C634Y (by age of 40, 59.3 % vs. 25.2 %, p = 0.046) or C634Y, C634G, and C634W combined (59.3 % vs. 21.5 %, p = 0.024). Nevertheless, the accumulative risk of bilateral PHEOs across all four C634 mutations almost approached 100 % over time.
  
  
  CONCLUSIONS
  The accumulative risk of bilateral PHEOs almost reached 100 % but its onset was significantly earlier in C634R mutation. These findings implied that those with C634R mutation might benefit from earlier screening of contralateral PHEO than other C634 mutations after an unilateral adrenalectomy.
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, SAR, China, blang@hkucc.hku.hk.
authors.forename: Brian Hung-Hin
authors.initials: BH
authors.lastname: Lang
authors.forename: Hyeong Won
authors.initials: HW
authors.lastname: Yu
authors.forename: Chung-Yau
authors.initials: CY
authors.lastname: Lo
authors.forename: Kyu Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Maria-Mercedes
authors.initials: MM
authors.lastname: Garcia-Barcelo
authors.forename: Yu Cho
authors.initials: YC
authors.lastname: Woo
authors.forename: Paul C H
authors.initials: PC
authors.lastname: Lee
authors.forename: Kai Pun
authors.initials: KP
authors.lastname: Wong
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000601:surgery; D000315:Adrenalectomy; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine; D002648:Child; D002675:Child, Preschool; D003062:Codon; D005260:Female; D018095:Germ-Line Mutation; D005998:Glycine; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D019683:Penetrance; D010673:Pheochromocytoma / Q000235:genetics* / Q000601:surgery; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D014364:Tryptophan; D014443:Tyrosine; D055815:Young Adult
chemical_list: D003062:Codon; D014443:Tyrosine; D014364:Tryptophan; D001120:Arginine; D051096:Proto-Oncogene Proteins c-ret; D005998:Glycine