title: Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis.
abstract: OBJECTIVE
  The aim of this study was first to investigate whether early total thyroidectomy (ETT; 1-5 years of age) can prevent medullary thyroid carcinoma with persistent or recurrent disease (PRD) in pediatric patients with multiple endocrine neoplasia type 2A (MEN-2A) and second, to evaluate the strength of codon analysis in children with MEN-2A as prognostic parameter.
  
  
  METHODS
  Case reports and review of the literature for pediatric patients with MEN-2A were conducted. Inclusion criteria were age (0-20 years) and histologic degree of C-cell disease (normal = N, C-cell hyperplasia = CCH, medullary thyroid carcinoma = MTC, metastatic MTC = MMTC). To evaluate therapeutic results of ETT (1-5 years) versus late total thyroidectomy (LTT; 6-20 years), age-dependent histologic stages of C-cell disease and postoperative occurrence of PRD were compared. Prognostic value of specific codons, age-dependent histologic distribution, and long-term outcome were analyzed.
  
  
  RESULTS
  In a total of 260 cases, 42 (16%) underwent ETT, and 218 (84%) underwent LTT. Histologic analysis showed significant difference between ETT versus LTT (57% vs 76%) regarding malignant stage of C-cell disease (of combined rate of MTC and MMTC). Long-term outcome was documented in 74 patients (28%). During a median follow-up period of 2 years (range: 0-15 years), 21 of 65 of the LTT group versus 0 of 9 of the ETT group suffered PRD. Information about codon analysis was available in 150 patients (58%). Mutated codons were c634 (63%), c618 (19%), c620 (9%), and c804 (6%). Codon-related histologic analysis resulted in prognostic differences: 81% of patients with c634-mutation had MCT or MMTC in contrast to c804 (44%), c618 (34%), and c620 (7%). Fifteen of 17 MMTC and 7 of 9 PRD occurred in patients with c634-mutation.
  
  
  CONCLUSIONS
  1) ETT until 5 years of age in MEN-2A gene carriers results in significant reduction of MTC and MMTC in favor of CCH and improved disease-free long-term outcome. 2) Codon analysis is an important prognostic factor. Timing of TT could be individualized based on codon-specific prognosis. Until more detailed knowledge is available, consequent genetic and biochemical screening is mandatory for appropriate individual timing of ETT before age of 5 years.
authors.affiliation: Department of Pediatric Endocrinology, University Children's Hospital, Basel, Switzerland.
authors.forename: Gabor
authors.initials: G
authors.lastname: Szinnai
authors.forename: Christian
authors.initials: C
authors.lastname: Meier
authors.forename: Paul
authors.initials: P
authors.lastname: Komminoth
authors.forename: Urs W
authors.initials: UW
authors.lastname: Zumsteg
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D018276:Carcinoma, Medullary / Q000235:genetics / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000235:genetics*; D029721:Drosophila Proteins; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006961:Hyperparathyroidism / Q000453:epidemiology / Q000235:genetics; D007223:Infant; D018813:Multiple Endocrine Neoplasia Type 2a / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009367:Neoplasm Staging; D018299:Neoplasms, Ductal, Lobular, and Medullary / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D010673:Pheochromocytoma / Q000453:epidemiology / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D013965:Thyroidectomy / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D003062:Codon; D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila