Alternative titles; symbols
ORPHA: 293864;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q22.1 | Mitchell-Riley syndrome | 615710 | Autosomal recessive | 3 | RFX6 | 612659 |
A number sign (#) is used with this entry because of evidence that Mitchell-Riley syndrome (MTCHRS) is caused by homozygous or compound heterozygous mutation in the RFX6 gene (612659) on chromosome 6q22.
Mitchell-Riley syndrome (MTCHRS) is characterized by neonatal diabetes, pancreatic hypoplasia, intestinal atresia, and gallbladder aplasia or hypoplasia. There is considerable phenotypic overlap between Mitchell-Riley syndrome and Martinez-Frias syndrome (601346), the latter being characterized by the features of the Mitchell-Riley syndrome except for neonatal diabetes, and including tracheoesophageal fistula in some patients (Smith et al., 2010).
Mitchell et al. (2004) described 5 infants, including a brother and sister born of first-cousin Pakistani parents (family 1), a brother and sister born of nonconsanguineous Asian parents (family 2), and an unrelated girl conceived by in vitro fertilization with a donated egg, who presented with neonatal diabetes, hypoplastic or annular pancreas, duodenal and jejunal atresia, and absent gallbladder. There were no dysmorphic features. Both pairs of sibs died in the first year of life despite aggressive medical management, but the unrelated girl had a milder form and was surviving free of insulin at 1 year of age, with a corrected duodenal web. Pancreatic immunohistochemistry revealed a few scattered chromogranin-A-positive cell clusters but complete absence of insulin, glucagon, and somatostatin. Exocrine histology was variable. Mitchell et al. (2004) concluded that this combination of multiple congenital anomalies represented a distinct autosomal recessive syndrome involving a genetic abnormality that interferes with normal islet development.
Galan-Gomez et al. (2007) reported a girl with neonatal diabetes, acholia, and hyperbilirubinemia, born of consanguineous Spanish Gypsy parents. On laparotomy she was found to have type C duodenal atresia, hypoplastic pancreas, and intestinal malrotation; the gallbladder and extrahepatic biliary ducts were not observed, and technetium scintigraphy confirmed the absence of extrahepatic biliary ducts. She died at 60 days of age; the parents did not permit an autopsy.
Chappell et al. (2008) reported a Pakistani girl, born to first-cousin parents, who had neonatal diabetes, duodenal atresia, gallbladder agenesis, and an anteriorly placed anus. No pancreatic abnormality was found on abdominal ultrasound. In the first year of life, she underwent surgical repair of her intestinal anomalies, and at age 1 year her development was considered to be normal. Because their patient had neonatal diabetes without a demonstrable structural pancreatic abnormality, Chappell et al. (2008) concluded that a deficit in pancreatic function is involved. The authors noted that Mitchell et al. (2004) considered the phenotype of their cases to be distinct from that of the cases described by Martinez-Frias et al. (1992), Anneren et al. (1998), and Gentile and Fiorente (1999) (see 601346); however, Chappell et al. (2008) reviewed all of those reports and suggested that they represent the same syndrome with 6 key features: neonatal diabetes mellitus, intestinal atresia, malrotation, biliary atresia, gallbladder hypoplasia, and absent or abnormal pancreas.
Martinovici et al. (2010) reported a male infant, born of first-cousin parents, who had severe intrauterine growth retardation (IUGR), congenital hemochromatosis, neonatal diabetes, and duodenal atresia. There were no dysmorphic features. Laparotomy on day 2 of life confirmed duodenal atresia with apple peel-type jejunal atresia and intestinal malrotation as well as agenesis of the gallbladder; cholangiography was suggestive of biliary atresia, and liver biopsy confirmed severe siderosis of the hepatocytes without parenchymal loss or fibrosis. At 2 months of age, cholangio-MRI showed hypoplasia of the pancreas. Upon repeat laparotomy, cholangiography demonstrated cystic dilation of the extrahepatic bile ducts, with permeability of both biliary and pancreatic ducts, precluding surgical correction. The infant died shortly thereafter; autopsy was declined. Family history was remarkable for many cases of diabetes mellitus, including the mother, suggestive of monogenic diabetes; the father had impaired fasting glucose. Martinovici et al. (2010) noted that diabetes was reported in 1 of the consanguineous families with 2 affected children described by Mitchell et al. (2004).
Smith et al. (2010) reported 2 unrelated patients with IUGR and duodenal atresia: one was a male infant, born to nonconsanguineous French parents, in whom neonatal diabetes was diagnosed at day 2. His course was complicated by refractory ascites, sepsis, and gastrointestinal hemorrhage, from which he died at 2.5 months of age. Family history was relevant for gestational diabetes in the mother and type I diabetes in the father. The other patient was a female infant, born to nonconsanguineous Irish parents, who was diagnosed with neonatal diabetes requiring insulin treatment following surgery to repair her duodenal atresia.
Sansbury et al. (2015) studied a Turkish family in which 2 double first cousins had intestinal atresia consistent with a diagnosis of Mitchell-Riley syndrome, but did not develop diabetes until the ages of 3 years and 6 years. The first patient was a 9-year-old girl who was born at 32 weeks' gestation with duodenal atresia, jejunal web, and Meckel diverticulum. At age 2 years, hyperglycemia was noted but no further investigation or treatment was pursued. She presented at 3 years of age with diabetic ketoacidosis, which was then treated with daily insulin injections. Further evaluation at 5 years of age revealed absent gallbladder. She had an identical twin who was diagnosed with duodenal atresia but died of complication of prematurity and surgery at age 1 month. The second patient was her 9-year-old male cousin who was born at 34 weeks' gestation with duodenal atresia and mid-gut rotation. He was noted to have asymptomatic fasting hyperglycemia at age 5 years, at which time no treatment was initiated; he was diagnosed with diabetes after presenting with hyperglycemia at age 6 years, and treated with daily insulin. He also had chronic iron deficiency anemia of unknown etiology; he had no structural abnormality of the hepatobiliary tract, and liver function tests were always within normal limits. Family history included 4 relatives with adult-onset diabetes; all 4 were nonobese and treated with oral hypoglycemic agents.
Smith et al. (2010) performed high-resolution homozygosity mapping in the proband with neonatal diabetes, duodenal and jejunal atresia, annular pancreas, and gallbladder agenesis from Pakistani 'family 1,' previously reported by Mitchell et al. (2004), and a Pakistani girl with neonatal diabetes, duodenal atresia, gallbladder agenesis, and an anteriorly placed anus, previously reported by Chappell et al. (2008). Smith et al. (2010) identified 3 homozygosity-by-descent regions that were common in the 2 probands, totaling 24 Mb. Among the genes in this region, only RFX6 (612659) on chromosome 6q21-q22 had pancreas-enriched expression in the TiGER database (Liu et al., 2008) and also showed increased expression in human pancreas concordant with the appearance of endocrine cells.
Mitchell-Riley syndrome is an autosomal recessive disorder (Smith et al., 2010).
Smith et al. (2010) analyzed the candidate gene RFX6 and identified homozygosity or compound heterozygosity for RFX6 mutations in 5 of 6 probands with neonatal diabetes, hypoplastic or annular pancreas, intestinal atresia and/or malrotation, and gallbladder hypoplasia or agenesis, including splice site mutations in 2 patients previously reported by Mitchell et al. (2004) (612659.0001-612659.0003, respectively) and missense mutations in the 2 patients previously reported by Chappell et al. (2008) (S271P; 612659.0004) and Martinovici et al. (2010) (R181Q; 612659.0005), respectively, as well as an out-of-frame deletion in a new proband (612659.0006). No DNA was available from a sixth proband with neonatal diabetes and duodenal atresia, but analysis of the nonconsanguineous Irish parents revealed no mutation; similarly, no mutation was detected in the parents of the patient with Martinez-Frias syndrome (601346) previously described by Gentile and Fiorente (1999). Noting that some Martinez-Frias syndrome patients were reported to have esophageal atresia and hypospadias and none had neonatal diabetes, Smith et al. (2010) proposed that the apparently distinct phenotype of RFX6 mutation-positive patients be designated 'Mitchell-Riley syndrome.'
In 2 Turkish double first cousins, who had features consistent with Mitchell-Riley syndrome except for childhood-onset rather than neonatal diabetes, Sansbury et al. (2015) identified compound heterozygosity for 2 nonsense mutations in the RFX6 gene (R726X, 612659.0007; R866X, 612659.0008). The parents were each heterozygous for 1 of the mutations, each of which had been inherited from the respective grandmother. Noting that the 2 affected cousins exhibited a relatively milder phenotype than previously reported patients, including later onset of diabetes, no liver pathology apart from absent gallbladder in 1 patient, and a greater age of survival, Sansbury et al. (2015) suggested that their mutations might result in incomplete inactivation of RFX6.
Exclusion Studies
Mitchell et al. (2004) performed genetic analysis of a Pakistani girl, born of consanguineous parents ('family 1'), who had neonatal diabetes, distal duodenal atresia and type IIIA jejunal atresia, annular pancreas, and absent gallbladder, but found no duplication or uniparental isodisomy of PLAGL1 (603044) on chromosome 6q24, no contiguous gene deletion involving the glucokinase gene (GCK; 138079), and no mutation in the coding sequences or splice sites of IPF1 (600733).
In a Pakistani girl, born of consanguineous parents, who had neonatal diabetes, duodenal atresia, absent gallbladder, and an anteriorly placed anus, Chappell et al. (2008) excluded methylation defects, duplication of 6q24, and parental isodisomy of chromosome 6. Sequencing of 7 genes with a recognized role in monogenic forms of diabetes as well as a novel candidate gene, HNF6 (604164), known to be involved in hepatobiliary and pancreatic development, did not reveal any mutations.
Anneren, G., Meurling, S., Lilja, H., Wallander, J., von Dobeln, U. Lethal autosomal recessive syndrome with intrauterine growth retardation, intra- and extrahepatic biliary atresia, and esophageal and duodenal atresia. (Letter) Am. J. Med. Genet. 78: 306-307, 1998. [PubMed: 9677074] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980707)78:3<306::aid-ajmg22>3.0.co;2-i]
Chappell, L., Gorman, S., Campbell, F., Ellard, S., Rice, G., Dobbie, A., Crow, Y. A further example of a distinctive autosomal recessive syndrome comprising neonatal diabetes mellitus, intestinal atresias and gall bladder agenesis. Am. J. Med. Genet. 146A: 1713-1717, 2008. [PubMed: 18512226] [Full Text: https://doi.org/10.1002/ajmg.a.32304]
Galan-Gomez, E., Sanchez, E. B., Arias-Castro, S., Cardesa-Garcia, J. J. Intrauterine growth retardation, duodenal and extrahepatic biliary atresia, hypoplastic pancreas and other intestinal anomalies: further evidence of the Martinez-Frias syndrome. Europ. J. Med. Genet. 50: 144-148, 2007. [PubMed: 17321227] [Full Text: https://doi.org/10.1016/j.ejmg.2006.12.001]
Gentile, M., Fiorente, P. Esophageal, duodenal, rectoanal and biliary atresia, intestinal malrotation, malformed/hypoplastic pancreas, and hypospadias: further evidence of a new distinct syndrome. (Letter) Am. J. Med. Genet. 87: 82-83, 1999. [PubMed: 10528254]
Liu, X., Yu, X., Zack, D. J., Zhu, H., Qian, J. TiGER: a database for tissue-specific gene expression and regulation. BMC Bioinformatics 9: 271, 2008. Note: Electronic Article. [PubMed: 18541026] [Full Text: https://doi.org/10.1186/1471-2105-9-271]
Martinez-Frias, M.-L., Frias, J. L., Galan, E., Domingo, R., Paisan, L., Blanco, M. Tracheoesophageal fistula, gastrointestinal abnormalities, hypospadias, and prenatal growth deficiency. Am. J. Med. Genet. 44: 352-355, 1992. [PubMed: 1488984] [Full Text: https://doi.org/10.1002/ajmg.1320440316]
Martinovici, D., Ransy, V., Eijnden, S. V., Ridremont, C., Pardou, A., Cassart, M., Avni, F., Donner, C., Lingier, P., Mathieu, A., Gulbis, B., De Brouckere, V., Cnop, M., Abramowicz, M., Desir, J. Neonatal hemochromatosis and Martinez-Frias syndrome of intestinal atresia and diabetes mellitus in a consanguineous newborn. Europ. J. Med. Genet. 53: 25-28, 2010. [PubMed: 19887127] [Full Text: https://doi.org/10.1016/j.ejmg.2009.10.004]
Mitchell, J., Punthakee, Z., Lo, B., Bernard, C., Chong, K., Newman, C., Cartier, L., Desilets, V., Cutz, E., Hansen, I. L., Riley, P., Polychronakos, C. Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome. Diabetologia 47: 2160-2167, 2004. [PubMed: 15592663] [Full Text: https://doi.org/10.1007/s00125-004-1576-3]
Sansbury, F. H., Kirel, B., Caswell, R., Allen, H. L., Flanagan, S. E., Hattersley, A. T., Ellard, S., Shaw-Smith, C. J. Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus. Europ. J. Hum. Genet. 23: 1744-1748, 2015. Note: Erratum: Europ. J. Hum. Genet. 23: 1750 only, 2015. [PubMed: 26264437] [Full Text: https://doi.org/10.1038/ejhg.2015.161]
Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. Rfx6 directs islet formation and insulin production in mice and humans. Nature 463: 775-780, 2010. [PubMed: 20148032] [Full Text: https://doi.org/10.1038/nature08748]