Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6

Pediatr Diabetes. 2014 Feb;15(1):67-72. doi: 10.1111/pedi.12063. Epub 2013 Aug 5.


Recently, bi-allelic mutations in the transcription factor RFX6 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 RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 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 RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case.

Keywords: Mitchell-Riley Syndrome; RFX6; neonatal diabetes.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Congenital Abnormalities
  • DNA-Binding Proteins / genetics*
  • Diabetes Mellitus, Type 1 / congenital*
  • Digestive System Abnormalities
  • Duodenal Obstruction
  • Fatal Outcome
  • Gallbladder / abnormalities
  • Humans
  • Infant
  • Infant, Newborn
  • Infant, Newborn, Diseases / genetics*
  • Intestinal Atresia
  • Intestinal Volvulus
  • Male
  • Pancreas / abnormalities
  • Pancreatic Diseases
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / genetics*


  • DNA-Binding Proteins
  • Regulatory Factor X Transcription Factors
  • Rfx6 protein, human
  • Transcription Factors

Supplementary concepts

  • Annular pancreas
  • Familial duodenal atresia
  • Gallbladder, Agenesis Of
  • Volvulus Of Midgut