Nagaya Masahiro, Kato Junji, Niimi Norihiro, Tanaka Shuiti, Wakamatsu Nobuaki
Department of Pediatric Surgery, the Central Hospital, Aichi Prefectural Colony, Kasugai, Japan.
J Pediatr Surg. 2002 Aug;37(8):1117-22. doi: 10.1053/jpsu.2002.34455.
BACKGROUND/PURPOSE: The aim of this report is to describe the pattern of similarities among the patients, exemplifying a newly recognized form of Hirschsprung's disease (HSCR) caused by mutations of ZFHX1B encoding Smad interacting protein-1.
Fluorescence in situ hybridization (FISH) using several cDNAs and RP11-BAC clones and mutation gene scanning using direct nucleotide sequencing analysis of polymerase chain reaction (PCR) were conducted. Personal records of the patients also were analyzed retrospectively to confirm the clinical features.
All the patients represented isolated cases without any familial tendency. Aganglionic segments were limited to the recto-sigmoid colon in 3 cases and the rectum in one. Chromosomal screening found normal karyotypes in all cases except one, in whom a translocation between chromosomes 2 and 13 was detected. In addition to HSCR, characteristic facial appearance (hypertelorism with strabismus and wide nasal bridge), microcephaly with epilepsy, and severe physical and mental disabilities were found in all the patients. FISH for the patient having the chromosomal abnormality showed that about a 5-Mb cytogenetic deletion flanked at the 2q22 translocation breakpoint. Among 3 genes mapping to this deleted region, 2 nonsense mutations and a 4-base pair deletion were detected in ZFHX1B.
The clinical features of the patients have surprising resemblance and constitute a wide spectrum of neurocristopathies. These findings suggest that the ZFHX1B may be a very important gene for normal embryonic neural crest development. These also indicate that the HSCR can be regarded as a congenital malformation with a background of a multigenetic neurocristopathy. It is of great interest that mutations were located at the same spot (exon 8) of ZFHX1B in 3 of 4 cases, probably accounting for the unique clinical features of this newly recognized form of HSCR.
背景/目的：本报告旨在描述患者之间的相似模式，以例证由编码Smad相互作用蛋白-1的ZFHX1B突变引起的一种新认识的先天性巨结肠病（HSCR）形式。
使用几种cDNA和RP11-BAC克隆进行荧光原位杂交（FISH），并使用聚合酶链反应（PCR）的直接核苷酸测序分析进行突变基因扫描。还对患者的个人记录进行了回顾性分析以确认临床特征。
所有患者均为散发病例，无任何家族倾向。无神经节段在3例中局限于直肠乙状结肠，1例局限于直肠。染色体筛查发现除1例检测到2号和13号染色体之间的易位外，所有病例的核型均正常。除HSCR外，所有患者均有特征性面容（眼距过宽伴斜视和宽鼻梁）、小头畸形伴癫痫以及严重的身心残疾。对有染色体异常的患者进行FISH检测显示，在2q22易位断点两侧约有5-Mb的细胞遗传学缺失。在定位于该缺失区域的3个基因中，在ZFHX1B中检测到2个无义突变和1个4碱基对缺失。
患者的临床特征具有惊人的相似性，并构成了广泛的神经嵴病谱。这些发现表明ZFHX1B可能是正常胚胎神经嵴发育的一个非常重要的基因。这些还表明HSCR可被视为一种具有多基因神经嵴病背景的先天性畸形。有趣的是，4例中有3例的突变位于ZFHX1B的同一位点（外显子8），这可能解释了这种新认识的HSCR形式的独特临床特征。
