Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa

Abstract Mitchell-Riley syndrome, an autosomal recessive disorder caused by mutations in the RFX6 gene, is defined as a combination of neonatal diabetes mellitus and serious congenital gastrointestinal defects. We describe Mitchell-Riley syndrome in two sisters with two novel compound heterozygous variants in the RFX6 gene: c.1154G > A, p.(Arg385Gln), and c.1316_1319delTCTA, p.(Ile439Thrfs*13). Both sisters present milder forms of the syndrome, likely due to possible residual activity of the p.Arg385Gln variant, which is localized in a dimerization domain of the RFX6 transcription factor. We propose that the prognosis is dependent on patient RFX6 genotype and possible residual activity of RFX6 transcription factor. Both sisters had atypical later onset of diabetes, at 2 years and 10 months and 2 years and 7 months, respectively. This supports the need of extending the definition of diabetes in Mitchell-Riley syndrome from neonatal to childhood onset and regular glyceamia check in patients with gastrointestinal tract malformations typical for Mitchell-Riley syndrome. The clinical course in both sisters improved significantly after surgical removal of parts of the small intestine with heterotopic gastric mucosa. We suggest that gastric mucosa heterotopy is an important actionable part of Mitchell-Riley syndrome and could have been responsible for the malabsorption, failure to thrive and severe anemia present in previously reported patients with Mitchell-Riley syndrome.