Mitchell-Riley Syndrome Due to a Novel Mutation in RFX6

Kambal, Mohammed A; Al-Harbi, Doha Ayed; Al-Sunaid, Areej; Al-Atawi, Mohsen Suliaman

doi:10.3389/fped.2019.00243

Cited by 12 publications

(12 citation statements)

References 15 publications

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“…We report the disease course of four genetically confirmed cases of MRS. In line with previous studies, neonatal diabetes was the key to making the diagnosis in a newborn with duodenal atresia ( 1 , 8 , 9 , 14 – 17 ).…”

Section: Discussionsupporting

confidence: 82%

“…Pancreatic enzyme replacement therapy is still controversial in the literature. Some authors support that despite the reduced pancreatic size, there is no pancreatic enzyme deficiency, and therefore patients would be unresponsive to supplementation ( 2 , 8 , 9 , 14 , 15 ). Evidence also includes two autopsies, revealing normal-appearing exocrine pancreas with clusters of chromogranin-A-positive cells and adequate gene expression by knockout mice ( 2 , 8 ).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, pancreatic abnormalities are heterogeneous depending on the type of mutation involved. Pearl and collaborators described in 2011 a loss of exocrine gene expression in an in vitro experiment using a Xenopus RFX6 ( 5 , 14 ). All our patients received pancreatic enzyme replacement therapy at some point in their care, with partial response.…”

Section: Discussionmentioning

confidence: 99%

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

Passone

Vermillac²,

Staels³

et al. 2022

Front. Endocrinol.

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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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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Passone

Vermillac²,

Staels³

et al. 2022

Front. Endocrinol.

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“…31,32 Biallelic loss of function mutations in RFX6 (including missense, frameshift and mutations predicted to affect splicing) were first identified in five individuals with suspected Mitchell-Riley syndrome, a condition characterised by neonatal diabetes, bowel atresia and gallbladder agenesis/hypoplasia. 32 Eleven further cases have been reported in the literature since, 33 including four cases from two families with diabetes onset in infancy rather than in the neonatal period. In both families, the disease was caused by compound heterozygous mutations, with one allele being predicted to preserve some degree of activity.…”

Section: Neonatal Diabetes Caused By Autosomal Recessive Rfx6 Mutations (Mitchell-riley Syndrome)mentioning

confidence: 99%

Neonatal diabetes caused by disrupted pancreatic and β‐cell development

Franco

2021

Diabet Med

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Neonatal diabetes is diagnosed before the age of 6 months and is usually caused by single-gene mutations. More than 30 genetic causes of neonatal diabetes have been described to date, resulting in severely reduced βcell number or function.Seven of these genes are known to cause neonatal diabetes through disrupted development of the whole pancreas, resulting in diabetes and exocrine pancreatic insufficiency. Pathogenic variants in five transcription factors essential for βcell development cause neonatal diabetes without other pancreatic phenotypes. However, additional extra-pancreatic features are common. This review will focus on the genes causing neonatal diabetes through disrupted βcell development, discussing what is currently known about the genetic and phenotypic features of these genetic conditions, and what discoveries may come in the future.

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“…Mitchell–Riley syndrome (MRS) is an autosomal recessive disorder caused by mutations in the RFX6 gene in which a combination of neonatal diabetes mellitus and congenital gastrointestinal defects—such as atresia, stenosis or malrotation of the small intestine, gallbladder hypoplasia or agenesis, intrahepatic or extrahepatic ductal atresia, or hypoplastic or annular pancreas—occur [ 1 – 6 ]. In a limited number of patients with MRS, heterotopic jejunal gastric mucosa, including in the duodenal and jejunal tract, has been described [ 2 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Determining oncogenic patterns and cancer predisposition through the transcriptomic profile in Mitchell–Riley syndrome with heterotopic gastric mucosa and duodenal atresia: a case report

Calcaterra

Chiricosta

Mazzon

et al. 2021

Orphanet J Rare Dis

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Background Homozygous mutations in the transcription factor RFX6 are the cause of the Mitchell–Riley syndrome (MRS) associating neonatal diabetes, congenital digestive system, such as biliary atresia, pancreatic hypoplasia, duodenal and/or jejunal atresia, intestinal malrotation, gallbladder aplasia, cholestasis. A constitutive inactivation of RFX6 leads also to gastric heterotopia. Application of RNA-seq in human diseases may help to better understand pathogenic mechanism of diseases and to predict the risk of developing chronic disorders and personalizing their prevention and treatment. We evaluated oncogenic patterns and cancer predisposition using the transcriptomic profile in a case of MRS with neonatal diabetes, duodenal atresia, and extensive intestinal tract gastric heterotopia. Results We signalled the interactors of RFX6 with other up and downregulated genes, that may be interested in severity of diabetic condition, in multi-organs impairment and cancer predisposition. Furthermore, several dysregulated genes are involved in biological processes that can lead to promote cancer including “Evading apoptosis” (BAD, BBC3, EGF, FGFR2, FLT3LG, HMOX1, HRAS, IFNAR2, IGF1R, IL12RB1, IL13RA1, IL15, IL2RB, IL2RG, IL6R, KEAP1, MGST1, PDGFA, PDGFRB, PIK3R3, RALB, RALGDS, RASSF1, SOS1, TGFA, TXNRD3), “Proliferation” (APC, BRAF, CCND2, CCND3, CCNE2, FGFR2, FLT3LG, FZD1, FZD6, HMOX1, HRAS, IGF1R, KEAP1, LRP6, MAPK3, MGST1, PDGFA, PDGFB, PDGFRB, RB1, SOS1, TGFA, TXNRD3, WNT10B), “Sustained angiogenesis” (BRAF, FGFR2, FLT3LG, HRAS, IGF1R, JAG1, MAPK3, NOTCH2, PDGFA, PDGFB, PDGFRB, SOS1, TGFA, TGFB1), “Genomic instability” (BAD, BBC3) and “Insensitivity to anti-growth signals” (SMAD2, TGFB1). We also inspected the signalings and their related genes in cancer, such as “PI3K signaling”, “ERK signaling”, “JAK-STAT signaling”, “Calcium signaling”, “Other RAS signaling”, “WNT signaling”. Conclusions In our MRS patient, we signaled the interactors of RFX6 with other up- and downregulated genes that may be related to severe diabetic condition, multi-organ impairment, and cancer predisposition. Notably, many dysregulated genes may lead to triggering carcinogenesis. The possibility of the patient developing cancer degeneration in heterotopic gastric mucosa and/or additional long-term tumoral sequelae is not excluded. Personalized prevention and treatment strategies should be proposed.

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Mitchell-Riley Syndrome Due to a Novel Mutation in RFX6

Cited by 12 publications

References 15 publications

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

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

Neonatal diabetes caused by disrupted pancreatic and β‐cell development

Determining oncogenic patterns and cancer predisposition through the transcriptomic profile in Mitchell–Riley syndrome with heterotopic gastric mucosa and duodenal atresia: a case report

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