AUTHOR=Passone Caroline de Gouveia Buff , Vermillac Gaëlle , Staels Willem , Besancon Alix , Kariyawasam Dulanjalee , Godot Cécile , Lambe Cécile , Talbotec Cécile , Girard Muriel , Chardot Christophe , Berteloot Laureline , Hachem Taymme , Lapillonne Alexandre , Poidvin Amélie , Storey Caroline , Neve Mathieu , Stan Cosmina , Dugelay Emmanuelle , Fauret-Amsellem Anne-Laure , Capri Yline , Cavé Hélène , Ybarra Marina , Chandra Vikash , Scharfmann Raphaël , Bismuth Elise , Polak Michel , Carel Jean Claude , Pigneur Bénédicte , Beltrand Jacques TITLE=Mitchell–Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations JOURNAL=Frontiers in Endocrinology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.802351 DOI=10.3389/fendo.2022.802351 ISSN=1664-2392 ABSTRACT=Aims/Hypothesis

Caused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell–Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function.

Methods

Clinical records were analyzed and described in detail. The functional impact of two RFX6R181W and RFX6V506G variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function.

Results

All four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6V506G and RFX6R181W mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function.

Conclusions/Interpretation

Multidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.