BackgroundCutaneous lichen amyloidosis (CLA) has been reported in some multiple endocrine neoplasia type 2A (MEN 2A) families affected by specific germline RET mutations C634F/G/R/W/Y or V804M, as a characteristic of the clinical manifestation in ‘MEN 2A with CLA’, one of four variants of MEN 2A, which was strictly located in the scapular region of the upper back.Patient FindingsThis study reports a large south-eastern Chinese pedigree with 17 individuals carrying the MEN 2A-harboring germline C611Y (c.1832G>A) RET mutation by Sanger sequencing. One individual presented MEN 2A-related clinical features, including typical CLA in the interscapular region; another individual exhibited neurological pruritus and scratching in the upper back but lacked CLA skin lesions. Both subjects presented with CLA or pruritic symptoms several years before the onset of medullary thyroid carcinoma (MTC) and/or pheochromocytoma. The remaining 15 RET mutation carriers did not exhibit CLA; of these, one presented with MTC and pheochromocytoma, nine with MTC only, two with elevated serum calcitonin and three younger subjects with normal serum calcitonin levels. This family’s clinical data revealed a later diagnosis of MTC (mean age, 45.9 (range: 23–73) years), a lower penetrance of pheochromocytoma (2/17, 11.8%) and CLA (1/17, 5.9%). However, no hyperparathyroidism and Hirschsprung disease were reported in this family.Summary and ConclusionsThis is the first description of a family with MEN 2A-related CLA due to a germline RET C611Y mutation, which might exhibit a novel and diversified genotype–phenotype spectrum in MEN 2A.
Background Germline RET mutations and variants are involved in development of multiple endocrine neoplasia type 2 (MEN2). The present study investigated a spectrum of RET variants, analyzed genotype-phenotype relationships, and evaluated their effect on the MEN2 phenotype in Han Chinese patients. Methods Targeted sequencing detected germline RET variants in 697 individuals, including 245 MEN2, 120 sporadic medullary thyroid cancer (MTC), and 15 pheochromocytoma (PHEO) patients and their 493 relatives. In silico analyses and classifications following ACMG-2015 were performed. Demographic, clinical variant types, and endocrine neoplasia molecular diagnosis records were also analyzed. Results Nineteen different RET mutations (18 point and 1 del/ins mutations) in 214 patients with MEN2A (97.7%) or MEN2B (2.3%) were found, of which exon 11/10 mutations accounted for 79% (169/214). Nineteen compound mutations were found in 31 patients with MEN2A. Twenty-three variants (18 single and 5 double base substitution/compound variants) non-classification were also found. Of these, 17 (3 of pathogenic, 10 of uncertain significance, 2 of likely benign and 2 as benign) were found in 31 patients with MTC/PHEO. The remaining 6 variants (4 of uncertain significance and 2 of likely benign) found in 8 carriers had no evidence of MEN2. The entire cohort showed MEN2A-related PHEO, all occurring in exons 11/10, particularly at C634. Kaplan-Meier curves showed age-dependent penetration rates of MTC and PHEO, and occurrence rates of PHEO in patients with exon 11 mutations were all higher than those within exon 10; these bilateral PHEO were always associated with exon 11 mutations (all P < 0.05). While patient offspring had PHEO, parents with MEN2A had none, the frequency was approximately 10%. Interestingly, at least 6.8% of families were adoptive. Also, 3 non-hotspot RET variants (R114H, T278N, and D489N) appeared with high frequency. Conversely, polymorphism S836S was absent. Conclusions These data are largely consistent with current evidence-based recommendations in the clinical practice guidelines. Diversity of RET variants or carriers may involve a different natural disease course. Further large-scale targeted sequencing studies will serve as an accurate and cost-effective approach to investigating MEN2 genotype-phenotype correlations for discovery of rare or unknown variants of RET.
Background: laparoscopic or open cortical-sparing adrenalectomy (LCSA or OCSA; CSA) for treatment of bilateral pheochromocytomas (bPHEO) in multiple endocrine neoplasia type 2 (MEN2) offers a postoperative corticosteroid independence and is balanced against the risk of local recurrence. In this study, the optimal surgical approach and the value of the simultaneous bilateral LCSA/OCSA (SB-LCSA/ SB-OCSA) were further assessed.Methods: A total of 31 patients (54.8% women) were diagnosed with bPHEO in MEN2 at a median age at initial presentation of 38 years (range, 23–78). Twenty- seven patients (87.1%) presented with synchronous. With the exception two patients respectively presenting MEN2A died of MTC metastasis or MEN2B declined surgery, each of other 29 underwent initial CSA, and in 23 (79.3%), of whom 18 had SB-LCSA and 5 had SB-OCSA duration of the same anesthesia (synchronous surgery); whereas metachronous CSA was in 6 (20.7%), including 1 had metachronous bilateral LCSA, 2 had metachronous bilateral OCSA (metachronous surgery) and 3 had LCSA/OCSA (hybrid) surgery.Results: All 31 patients associated with RET-C634 mutations, as MEN2A (90.3%) and RET-M918T, as MEN2B (9.7%), respectively. No conversion and intraoperative or postoperative severe complications were necessary. There were less bleeding volume, and shorter hospitalizations between in SB-LCSA compared with those in SB-OCSA, as well as synchronous surgery versus metachronous (hybrid) surgery (all P < 0.05). An initial bilateral postoperative corticosteroid replacement was necessary in 14 patients (45.2%). During a median follow-up period of 7 years (range, 1.8–23), 3 of these patients (10.3%) showed a persistent/recurrent disease and needed reoperation.Conclusions: CSA for bPHEO in MEN2 has a relatively low recurrence and avoids lifelong corticosteroid replacement in well over half the patients. SB-LCSA for treatment of these synchronous bPHEO is safe and feasible, should be recommended as a prioritized surgical approach of choice.
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