Division of Paediatric Surgery, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa.
J Pediatr Surg. 2010 Feb;45(2):393-6. doi: 10.1016/j.jpedsurg.2009.10.080.
Hirschsprung disease (HSCR) is associated with the later development of multiple endocrine neoplasia (MEN2), because RET gene variations are associated with both conditions. Specifically, HSCR-MEN2 cosegregation mostly relates to the cysteine-rich area at the RET-620 (the "Janus gene").
The aim of this study was to explore the clinical and genetic associations of HSCR-MEN2 in a cohort of HSCR patients.
RET gene variation was evaluated by heteroduplex single-strand conformational polymorphism analysis and validated with automated sequencing techniques in HSCR patients (including 18 kindreds). Those with RET C620 variations were subjected to familial evaluation for coexisting HSCR-MEN2.
A cohort of 118 patients with HSCR (n = 89) or medullary thyroid carcinoma (n = 29) were studied, including 3 families where a RET-620 point mutation was identified. No C618, C609, or C611 variations were detected. In 1 remarkable 6-generational family (family 3), HSCR in early generations seemed to be later replaced by MEN2A. In the other 2 families with total colonic aganglionosis, a relative with a medullary thyroid carcinoma was identified.
Gene mutation in the RET-620 position carries significant risk and may be part of a targeted investigation of high-risk areas in HSCR. We propose an alternative hypothesis of endoplasmic reticulum control to explain the changing phenotypic expression.
先天性巨结肠（HSCR）与多发性内分泌肿瘤（MEN2）的后期发展有关，因为 RET 基因突变与这两种情况都有关。具体来说，HSCR-MEN2 的共分离主要与 RET-620 处富含半胱氨酸的区域（“双生子基因”）有关。
本研究旨在探讨一组 HSCR 患者中 HSCR-MEN2 的临床和遗传相关性。
通过异源双链单链构象多态性分析评估 RET 基因突变，并在 HSCR 患者（包括 18 个家系）中使用自动测序技术进行验证。对具有 RET C620 变异的患者进行共患 HSCR-MEN2 的家族评估。
研究了 118 例 HSCR 患者（n=89）或甲状腺髓样癌患者（n=29）的队列，其中 3 个家系中发现了 RET-620 点突变。未检测到 C618、C609 或 C611 变异。在一个显著的 6 代家族（家族 3）中，早期的 HSCR 似乎后来被 MEN2A 所取代。在另外 2 个全结肠无神经节细胞的家系中，发现了一个患有甲状腺髓样癌的亲属。
RET-620 位置的基因突变具有显著风险，可能是 HSCR 高危区域靶向调查的一部分。我们提出了内质网控制的替代假说来解释表型表达的变化。
