Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6. Issue 1 (5th August 2013)

• Record Type: Journal Article
• Authors: Concepcion, Jennifer P; Reh, Christina S; Daniels, Mark; Liu, Xiaoming; Paz, Veronica P; Ye, Honggang; Highland, Heather M; Hanis, Craig L; Greeley, Siri Atma W
• Is Part Of: Pediatric diabetes. Volume 15:Issue 1(2014:Feb.)
• Page Start: 67
• Page End: 72
• Publication Date: 2013-08-05
• Subjects: Diabetes in children -- Periodicals; 616.462
• DOI: 10.1111/pedi.12063
• Languages: English
• ISSNs: 1399-543X

Abstract

<abstract abstract-type="main" id="pedi12063-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="pedi12063-para-0001">Recently, bi‐allelic mutations in the transcription factor <italic>RFX6</italic> were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446 mg/dL) within 24 h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to <italic>RFX6</italic> as the causative gene; indeed, whole exome sequencing revealed a novel homozygous <italic>RFX6</italic> mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5′ splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost‐effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with <italic>RFX6</italic> mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case.</p> </abstract>