Neonatal Intensive Care Unit, Department of Health Promotion, Mother-Child Care, Internal Medicine and Medical Specialties "G. D'Alessandro", University Hospital "P. Giaccone", Via Alfonso Giordano n. 3, 90127, Palermo, Italy.
Pediatric Surgery Unit, Department of Health Promotion, Mother-Child Care, Internal Medicine and Medical Specialties "G. D'Alessandro", University Hospital "P. Giaccone", Via Alfonso Giordano n. 3, 90127, Palermo, Italy.
Ital J Pediatr. 2020 Sep 18;46(1):135. doi: 10.1186/s13052-020-00901-9.
Hirschsprung disease, the most important congenital colonic dysmotility in children results from neural crest migration, differentiation, proliferation, or apoptosis defects where the rearranged during transfection (RET)-Protooncogene pathway has a central role. Although palatal and retinal anomalies in the context of chromosomopathies and some mono-/oligogenic syndromes are reported associated with Hirschsprung disease the role of inactivating RET mutations in these cases is not clarified.
We report on a dysmorphic newborn with cleft palate and palatal synechia, who showed intestinal obstruction after 24 h of life. Transient ileostomy and surgical biopsies were performed to diagnose aganglionosis of the colon and last ileal loop. No chromosomal anomalies or copy number variations were found. We identified a paternal heterozygous germline mutation c.1852 T > C, which results in the substitution of cysteine by arginine in the RET-receptor tyrosine kinase (p.C618R mutation). There was no family history of Hirschsprung disease, but the father underwent surgery for medullary thyroid carcinoma and was affected by retinal dystrophy.
The occurrence of Hirschsprung disease and carcinoma shows how a single mutation may be responsible for adverse effects: gain and loss of function of the same receptor. Furthermore, it would be interesting to study its dual role in face and retina embryology, and to extend targeted investigations of RET hotspots in these developmental abnormalities to facilitate counselling, follow-up, and tumor prevention. Complex surgical procedures and genetic testing as well as socio-economic impact are a challenge for familiar compliance.
先天性巨结肠症是儿童中最重要的结肠动力障碍，源于神经嵴迁移、分化、增殖或凋亡缺陷，而转染过程中重排（RET）原癌基因通路起着核心作用。虽然腭和视网膜异常与染色体病和一些单基因/寡基因综合征有关，但这些情况下 RET 失活突变的作用尚未阐明。
我们报告了一名有腭裂和腭粘连畸形的发育不良的新生儿，他在出生后 24 小时出现肠梗阻。进行了暂时性回肠造口术和外科活检，以诊断结肠无神经节细胞和最后回肠袢。未发现染色体异常或拷贝数变异。我们鉴定出了一个来自父亲的杂合性胚系突变 c.1852T>C，导致 RET 受体酪氨酸激酶（p.C618R 突变）中的半胱氨酸被精氨酸取代。家族中没有先天性巨结肠病的病史，但父亲曾因甲状腺髓样癌接受过手术，并有视网膜营养不良。
先天性巨结肠病和癌的发生表明，单个突变可能导致不良影响：同一受体的功能获得和丧失。此外，研究其在面部和视网膜胚胎发生中的双重作用将很有趣，并将 RET 热点的靶向研究扩展到这些发育异常中，以促进咨询、随访和肿瘤预防。复杂的手术程序和基因检测以及社会经济影响是家庭依从性的挑战。
