MARTINEZ-FRIAS SYNDROME DIABETES, NEONATAL, WITH PANCREATIC HYPOPLASIA, INTESTINAL ATRESIA, AND GALLBLADDER APLASIA OR HYPOPLASIA, INCLUDED
MITCHELL-RILEY SYNDROME, INCLUDED
The Martinez-Frias syndrome is characterized by pancreatic hypoplasia, intestinal atresia, and gallbladder aplasia or hypoplasia, with or without tracheoesophageal fistula. A possibly distinct syndrome, designated 'Mitchell-Riley,' is characterized by neonatal diabetes and the features of the Martinez-Frias syndrome ... The Martinez-Frias syndrome is characterized by pancreatic hypoplasia, intestinal atresia, and gallbladder aplasia or hypoplasia, with or without tracheoesophageal fistula. A possibly distinct syndrome, designated 'Mitchell-Riley,' is characterized by neonatal diabetes and the features of the Martinez-Frias syndrome without tracheoesophageal fistula (Smith et al., 2010).
- Pancreatic Hypoplasia, Intestinal Atresia, and Gallbladder Aplasia or Hypoplasia, With or Without Tracheoesophageal Fistula
Martinez-Frias et al. (1992) reported a seemingly distinct autosomal recessive syndrome in a brother and sister born to consanguineous Spanish Gypsy ... - Pancreatic Hypoplasia, Intestinal Atresia, and Gallbladder Aplasia or Hypoplasia, With or Without Tracheoesophageal Fistula Martinez-Frias et al. (1992) reported a seemingly distinct autosomal recessive syndrome in a brother and sister born to consanguineous Spanish Gypsy parents. The proband was a female infant with hypoplastic pancreas, duodenal atresia, and atresia of the extrahepatic biliary ducts, who died on day 2 of life. A male sib, born 3 years earlier, was reported to have had hypoplastic pancreas and gallbladder, duodenal atresia, hypoplastic intestines, tracheoesophageal fistula, and hypospadias; he died on day 5 of life. Anneren et al. (1998) described a brother and sister, born of healthy consanguineous parents, with a multiple congenital anomalies (MCA) syndrome that bore both similarities and differences to the syndrome described by Martinez-Frias et al. (1992). Features of the disorder in the sibs included low birth weight, intestinal malrotation, duodenal and esophageal atresia, intra- and extrahepatic biliary atresia, and hypoplastic pancreas. Both children died during infancy, at 25 days and 81 days. Gentile and Fiorente (1999) described a male infant, born to nonconsanguineous parents, who had tracheoesophageal fistula and duodenal atresia noted at birth. Laparotomy at 9 days of age revealed gastric hypoplasia, annular pancreas causing duodenal stenosis, agenesis of the gallbladder and extrahepatic biliary ducts, intestinal malrotation, and rectoanal atresia. Hypospadias was the only externally detected anomaly. An ostium secundum atrial septal defect was noted on 2-D echocardiography. The patient died of respiratory failure at 10 months of age due to recurrent bronchiolitis. - Neonatal Diabetes, Pancreatic Hypoplasia, Intestinal Atresia, and Gallbladder Aplasia or Hypoplasia 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); however, Chappell et al. (2008) reviewed all of those reports and suggested that they represent the same syndrome, comprised of 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.
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 ... 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. Smith et al. (2010) analyzed the candidate gene RFX6 (612659) 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 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.'