Frontiers in Endocrinology (Jun 2022)

Mitchell–Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations

  • Caroline de Gouveia Buff Passone,
  • Caroline de Gouveia Buff Passone,
  • Gaëlle Vermillac,
  • Willem Staels,
  • Willem Staels,
  • Willem Staels,
  • Alix Besancon,
  • Dulanjalee Kariyawasam,
  • Dulanjalee Kariyawasam,
  • Cécile Godot,
  • Cécile Lambe,
  • Cécile Talbotec,
  • Cécile Talbotec,
  • Muriel Girard,
  • Christophe Chardot,
  • Laureline Berteloot,
  • Taymme Hachem,
  • Alexandre Lapillonne,
  • Amélie Poidvin,
  • Caroline Storey,
  • Mathieu Neve,
  • Cosmina Stan,
  • Emmanuelle Dugelay,
  • Anne-Laure Fauret-Amsellem,
  • Yline Capri,
  • Hélène Cavé,
  • Marina Ybarra,
  • Vikash Chandra,
  • Vikash Chandra,
  • Raphaël Scharfmann,
  • Elise Bismuth,
  • Michel Polak,
  • Jean Claude Carel,
  • Bénédicte Pigneur,
  • Jacques Beltrand,
  • Jacques Beltrand,
  • Jacques Beltrand

DOI
https://doi.org/10.3389/fendo.2022.802351
Journal volume & issue
Vol. 13

Abstract

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Aims/HypothesisCaused 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.MethodsClinical 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.ResultsAll 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/InterpretationMultidisciplinary 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.

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