RFX6 – Hypoplastic Pancreas-Intestinal Atresia-Hypoplastic Gallbladder Syndrome (Mitchell-Riley Syndrome)

Mitchell-Riley syndrome (MRS) is a rare, autosomal recessive disorder characterised by neonatal diabetes, pancreatic hypoplasia, intestinal atresia or malrotation, biliary abnormalities, and chronic diarrhea. MRS overlaps phenotypically with Martinez-Frías syndrome but is distinguished by biallelic pathogenic variants in the RFX6 gene, encoding a transcriptional regulator of pancreatic and gut endocrine development. To date, over 16 probands have been described with homozygous or compound heterozygous RFX6 mutations, supporting a definitive gene–disease relationship (Definitive; 16 probands [PMID:35813646], multi-family segregation, concordant functional data [PMID:33033118]).

Genetic evidence includes at least six distinct recessive RFX6 variants reported across unrelated families, including c.1129C>T (p.Arg377Ter) and c.1316_1319del (p.Ile439ThrfsTer13), identified in both homozygous and compound het configurations with complete penetrance of key features (Strong; 2 siblings segregation [PMID:27523286]). Segregation analyses in multiplex sibships further confirm autosomal recessive inheritance. The variant spectrum comprises nonsense, frameshift, and missense changes disrupting RFX6 DNA-binding or dimerization domains.

Functional assays in Xenopus demonstrate that morpholino knockdown of rfx6 abolishes early endoderm and pancreatic marker expression, rescueable only by wild-type rfx6 mRNA (Moderate; PMID:21215266). Human iPSC models homozygous for c.1129C>T exhibit a marked reduction in pancreatic endoderm differentiation and loss of PDX1+/NKX6.1+ progenitors, recapitulating pancreatic hypoplasia (Moderate; PMID:33033118).

Additional functional studies in patient-derived MRS iPSCs and hiPSC knockouts show that RFX6 deficiency downregulates endocrine differentiation genes and increases apoptosis in islet organoids, linking RFX6 loss to endocrine cell scarcity and hypoplasia (Moderate; PMID:39080045). In vitro transactivation assays of RFX6R181W and RFX6V506G variants confirm impaired insulin promoter activation and defective L-type Ca2+ channel gene expression, explaining neonatal diabetes and intestinal endocrine cell deficits (Moderate; PMID:35813646).

Although rare, the high correlation of genotype with phenotype and multiple concordant experimental models establish RFX6 as definitively causal for hypoplastic pancreas-intestinal atresia-hypoplastic gallbladder syndrome. Early genetic diagnosis enables anticipatory management of endocrine and gastrointestinal complications. Key take-home: Biallelic RFX6 mutations cause a monogenic malformation syndrome with actionable features in both the pancreas and gut, underscoring the value of genetic testing for personalized care.

References

• Journal of perinatology • 2014 • Clinical and genetic complexity of Mitchell-Riley/Martinez-Frías syndrome PMID:25421130
• Case Reports in Genetics • 2015 • Mitchell-Riley Syndrome: A Novel Mutation in RFX6 Gene PMID:26770845
• European Journal of Medical Genetics • 2016 • Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa PMID:27523286
• Development (Cambridge, England) • 2020 • Mitchell-Riley syndrome iPSCs exhibit reduced pancreatic endoderm differentiation due to a mutation in RFX6 PMID:33033118
• Frontiers in Endocrinology • 2022 • Mitchell-Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations PMID:35813646
• Developmental Biology • 2011 • Functional analysis of Rfx6 and mutant variants associated with neonatal diabetes PMID:21215266

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