Total colonic aganglionosis and cleft palate in a newborn with Janus-cysteine 618 mutation of RET proto-oncogene: a case report.

Publisher: BioMed Central Country of Publication: England NLM ID: 101510759 Publication Model: Electronic Cited Medium: Internet ISSN: 1824-7288 (Electronic) Linking ISSN: 17208424 NLM ISO Abbreviation: Ital J Pediatr Subsets: MEDLINE

Original Publication: London : BioMed Central

Cleft Palate/*genetics ; Cysteine/*genetics ; Hirschsprung Disease/*genetics ; Janus Kinases/*genetics ; Proto-Oncogene Proteins c-ret/*genetics; Germ-Line Mutation ; Humans ; Infant, Newborn ; Italy ; Male ; Proto-Oncogene Mas

Background: 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.
Case Presentation: 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.
Conclusions: 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.

J Neonatal Surg. 2014 Jul 10;3(3):28. (PMID: 26023499)
Lancet. 2002 Apr 6;359(9313):1200-5. (PMID: 11955539)
J Med Genet. 2018 Jul;55(7):449-458. (PMID: 29500247)
Pediatr Surg Int. 2012 Feb;28(2):123-8. (PMID: 21986619)
Thyroid. 2015 Jun;25(6):567-610. (PMID: 25810047)
Hum Mutat. 2007 Aug;28(8):790-6. (PMID: 17397038)
Cleft Palate Craniofac J. 2020 Jun;57(6):778-781. (PMID: 31876173)
Mol Endocrinol. 2004 Apr;18(4):1004-17. (PMID: 14715928)
Int J Mol Sci. 2017 Mar 10;18(3):. (PMID: 28287439)
Endocr J. 2014;61(1):19-23. (PMID: 24152999)
Birth Defects Res. 2020 Feb 1;112(3):234-244. (PMID: 31825181)
Nat Rev Gastroenterol Hepatol. 2018 Mar;15(3):152-167. (PMID: 29300049)
J Clin Lab Anal. 2018 Jul;32(6):e22428. (PMID: 29512191)
BMC Oral Health. 2019 Dec 23;19(1):290. (PMID: 31870360)
Pediatr Surg Int. 2006 Apr;22(4):305-15. (PMID: 16518596)
J Endocrinol Invest. 2011 Nov;34(10):764-9. (PMID: 21422799)
Pediatr Res. 2017 Jan;81(1-2):177-191. (PMID: 27682968)
Nat Rev Genet. 2011 Mar;12(3):167-78. (PMID: 21331089)
J Med Genet. 2008 Jan;45(1):1-14. (PMID: 17965226)

Keywords: Case-report; Congenital digestive system abnormalities; Hirschsprung disease; Neurocristopathy; REarranged during Transfection

0 (MAS1 protein, human)
0 (Proto-Oncogene Mas)
EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
EC 2.7.10.2 (Janus Kinases)
K848JZ4886 (Cysteine)

Date Created: 20200919 Date Completed: 20210823 Latest Revision: 20211204

20250114

PMC7501675

10.1186/s13052-020-00901-9

32948239