Brauckhoff Michael, Gimm Oliver, Weiss Carl-Ludwig, Ukkat Jörg, Sekulla Carsten, Brauckhoff Katrin, Thanh Phuong Nguyen, Dralle Henning
Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, D-0609 Halle/Saale, Germany.
World J Surg. 2004 Dec;28(12):1305-11. doi: 10.1007/s00268-004-7637-4. Epub 2004 Nov 4.
More than 50% of patients with typical MEN-2B have a de novo M918T germline mutation of the RET protooncogene. However, even in typical MEN-2B, extrathyroidal manifestations of MEN-2B can be found to be differently expressed. We analyzed the clinical manifestation and course in 21 patients harboring a de novo RET M918T mutation. Mean age at MEN-2B diagnosis was 14.2 years (range: 1-31 years). All patients had medullary thyroid carcinoma (MTC). At the time of syndrome diagnosis, oral manifestations (bumpy lips, ganglioneuroma), ocular manifestations (corneal fibers, conjunctivitis sicca), intestinal dysfunctions, musculoskeletal manifestations, and pheochromocytoma were found in 86%, 90%, 74%, 79%, and 19% of the patients, respectively. At the time of follow-up examination, the symptoms were found at higher frequency. Severe intestinal manifestation was predominantly found in patients with prepubertal onset (< or = 12 years) of MTC (n = 4/10) compared with patients with late onset (> 12 years) of MTC (n = 0/11) (40% versus 0%; p = 0.019). Although biochemical cure was found only in four patients with early onset of MTC, the long-term prognosis for patients with early onset of MTC was poorer than for patients presenting with late onset of MTC (p = 0.005). During mean follow-up of 55.8 months (range: 3-161 months), seven patients (33%) died from MTC. In conclusion, whereas most typical MEN-2B symptoms were found to be age-related, severe intestinal manifestation was found to be predominantly expressed in patients with early onset of MTC. Furthermore, in patients with early onset of MTC who could not be biochemically cured, the long-term prognosis was found to be worse than that of non-cured patients with late onset of MTC, suggesting an additional pathological process in the younger subgroup reinforcing the very high transforming in vitro activity of the M918T RET mutation.
超过50%的典型MEN-2B患者存在RET原癌基因的新发M918T种系突变。然而，即使在典型MEN-2B中，也可发现MEN-2B的甲状腺外表现存在不同程度的表达差异。我们分析了21例携带新发RET M918T突变患者的临床表现及病程。MEN-2B诊断时的平均年龄为14.2岁（范围：1 - 31岁）。所有患者均患有甲状腺髓样癌（MTC）。在综合征诊断时，分别有86%、90%、74%、79%和19%的患者出现口腔表现（嘴唇粗糙、神经节瘤）、眼部表现（角膜纤维、干眼症）、肠道功能障碍、肌肉骨骼表现和嗜铬细胞瘤。在随访检查时，这些症状出现的频率更高。与MTC发病较晚（>12岁）的患者（n = 0/11）相比，MTC青春期前发病（≤12岁）的患者（n = 4/10）中严重肠道表现更为常见（40%对0%；p = 0.019）。尽管仅在4例MTC发病早的患者中实现了生化治愈，但MTC发病早的患者的长期预后比发病晚的患者更差（p = 0.005）。在平均55.8个月（范围：3 - 161个月）的随访期间，7例患者（33%）死于MTC。总之，虽然大多数典型MEN-2B症状与年龄相关，但严重肠道表现主要出现在MTC发病早的患者中。此外，在无法实现生化治愈的MTC发病早的患者中，发现其长期预后比MTC发病晚且未治愈的患者更差，这表明较年轻亚组中存在额外的病理过程，强化了M918T RET突变在体外非常高的转化活性。
