A Newly-Discovered Mutation in the RFX6 Gene of the Rare Mitchell-Riley Syndrome.
The Mitchell Riley Syndrome is a recently diagnosed genetic disorder characterised by neonatal diabetes, pancreatic hypoplasia, intestinal atresia, malrotation, biliary atresia, and gallbladder aplasia or hypoplasia. A novel genetic mutation in the RFX6 gene (regulatory factor X on chromosome 6) was detected in babies with neonatal diabetes.
What this study adds?
We report a case with neonatal diabetes, pancreatic hypoplasia gall bladder agenesis, duodenal atresia, haemochromatosis, hypospadias and intrauterine growth restriction with some additional features along with a different mutation in the RFX6 gene which has not been reported before.
The Mitchell-Riley syndrome (1) is a recently diagnosed genetic disorder characterized by neonatal diabetes, pancreatic hypoplasia, intestinal atresia and/or malrotation, biliary atresia, and gallbladder aplasia or hypoplasia (2). It was initially considered as a variant of Martinez-Frias syndrome, diagnosed in 1992, with similar phenotypic characteristics (3). However, the two syndromes differ in that neonatal diabetes is present in Mitchell-Riley, while tracheoesophageal fistula is found in the Martinez-Frias syndrome (4). Over the years, many cases were reported with the same phenotypes, but additional features have also been discovered such as haemochromatosis, thyroid dysfunction, auditory canal defects, hypospadias in males and anteriorly-placed anus in females (5,6). Infants with neonatal diabetes have also been investigated for gene defects for diabetes, such as PLAGL-1 (ZAC), glucokinase and PDX-1 (IPF-1) genes, with negative results (6). In 2010, Smith et al (7) detected a novel genetic mutation in the RFX6 gene (regulatory factor X on chromosome 6) in 6 babies, all of whom had neonatal diabetes. This defect could not be found in babies who had same phenotypic features but did not have neonatal diabetes (8). After that, two further cases were reported, an Israeli Arab patient reported by Spiegel et al (9) and another patient from a Vietnamese family in 2014 reported by Concepcion et al (10). Sansbury et al (11) 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.
Here, we report a case with neonatal diabetes, pancreatic hypoplasia, gall bladder agenesis, duodenal atresia, haemochromatosis, hypospadias, and intrauterine growth retardation (IUGR) with some additional features along with a different mutation in the RFX6 gene which has not been reported before.
This male baby was born, at term, by normal delivery to a consanguineous (third degree) couple from the United Arabian Emirates (UAE) with a prenatal diagnosis of duodenal atresia. The infant had severe IUGR with a birth weight of 1.3 kilograms and practically no subcutaneous fat. Hypospadias was also present. No facial dysmorphism was noted. During the first week of life, the patient developed hyperbilirubinemia with mildly elevated liver enzymes, hyperammonemia, and hyperglycaemia which required insulin. He also tested positive for the direct agglutination test (DAT positive), had renal dysfunction, microangiopathic haemolytic anaemia, and coagulopathy with prolonged activated partial thromboplastin time (APTT). With these problems, he was initially diagnosed and managed as a patient with an inborn error of metabolism. Although the surgery for duodenal atresia was delayed because of thrombocytopenia and severe coagulopathy, these issues were later found to be related to the factor IX deficiency At the same time, the Doppler test showed a congenital large portosystemic shunt in the liver with a ratio less than 30%. An echocardiogram revealed multiple echogenic masses in the ventricles which were consistent with cardiac rhabdomyoma. An ultrasound of the brain revealed periventricular calcification. TORCH infections and tuberous sclerosis were ruled out by viral and genetic studies.
Once the clotting profile and anaemia had been stabilised by multiple transfusions of fresh frozen plasma (FFP), cryoprecipitate, packed red-blood cells (PRBC), platelets and Factor IX, a laparotomy was performed for duodenal atresia and for a duodenostomy when the baby was 4 weeks of age. The surgery also revealed absence of the gall bladder. A liver biopsy and an endoscopic retrograde cholangiopancreatography (ERCP) could not be performed due to the patient's poor condition. He had developed severe peritonitis and sepsis, requiring antibiotic and ventilator support for a prolonged period of time. Later on, a hepatobiliary scan (HIDA) revealed poor uptake by the liver and delayed excretion of bile with no visualisation of the gall bladder.
The patient had persistent hyperglycemia, requiring insulin in high doses, followed by hypoglycaemia at intervals. These findings were labelled as neonatal diabetes. Thyroid function tests were slightly abnormal on multiple occasions so a small dose of levothyroxine was started. The ferritin level was also checked and was found to be >6000 [micro]g/L, suggesting hemochromatosis. At the age of nine weeks, severe hypertension developed, which was controlled by antihypertensive medication. Renal Doppler and renal functions were normal at this time.
The baby started tolerating small amounts of expressed breast milk (EBM) two weeks after the surgery. Ingested amounts increased slowly, but soon, he started passing loose, sticky and green-coloured stool. The work-up for malabsorption showed minute levels of stool elastase (<50 [micro]g/g of stool) and low serum lipase which was consistent with severe exocrine insufficiency of the pancreas and possible pancreatic hypoplasia.
Magnetic resonance imaging (MRI) of the abdomen confirmed aplasia of the gall bladder and hypoplasia of pancreas, while the brain MRI showed periventricular calcification. The genetic studies done for Mitchell-Riley syndrome (RFX6 gene locus) confirmed presence of a homozygous mutation in the RFX6 gene (c.1153C>T p.Arg385*), a previously unreported homozygous mutation in exon 11 of the RFX6 gene. Therefore, this was a confirmed case of Mitchell-Riley syndrome with additional features. The parents were not studied for a carrier state.
This is the second case of Mitchell-Riley syndrome diagnosed in a population of Arab ethnicity, the first case ever reported from the Arab peninsula and the ninth case overall (9,10). Although this infant had the classical features of the Mitchell-Riley syndrome including neonatal diabetes, pancreatic hypoplasia, duodenal atresia, gall bladder aplasia, he did not have malrotation or biliary atresia. The infant also had chronic diarrhoea/malabsorption due to severe exocrine pancreatic insufficiency and cholestatic jaundice, findings which have been reported in most of the published cases (5,6,9,10,12). He even had hemochromatosis, reported only by Martinovici et al (5). However, similar to other patients, this infant also had several features overlapping with the Martinez-Frias syndrome such as hypothyroidism (4,12,13,14), severe IUGR, and hypospadias (4,15). In most of the previously known patients, severe hypoplasia or aplasia of the gall bladder and biliary atresia with acholia were the main features and the Kasai procedure was successfully carried out in one of these patients (2,10,12,13,14). Although the gall bladder could not be visualized on the HIDA scan, in the MRI scan nor per-operatively, our patient never had acholic stools. He had mild direct hyperbilirubinemia and elevated liver enzymes and unfortunately, we could not carry out an ERCP or a liver biopsy to confirm a diagnosis of biliary atresia. Our patient also had anaemia during his first week and tested DAT positive; since he had thrombocytopenia, microangiopathic anaemia was considered. Anaemia was also found in one of the previously reported cases and a blood transfusion was given. However, a cause for anaemia was not mentioned and thrombocytopenia was never reported in any patient (10).
This patient had various other previously unreported features such as cerebral calcification and cardiac rhabdomyomas. A cardiac lesion was reported previously, but that patient had a septal defect. Cerebral lesions were most likely never detected, due to most of the infants dying in their first few days of life with no reports of post-mortem findings. Our patient had coagulopathy with factor IX deficiency which has also not been reported in any other patient. Gastrointestinal bleeding was noted in some patients, but the cause had not been identified. The portosystemic shunt and hyperammonemia in our patient can be considered an incidental finding or possibly a developmental defect along with the intestinal atresia. The shunt in our baby closed spontaneously and the ammonia level returned to normal. A minimal shunt was shown afterwards. The systemic hypertension requiring antihypertensive medicine was another finding not reported before and unfortunately, its cause could not be identified; either it was a part of the syndrome due to the distinctive genetic mutation or just an additional finding. The genetic mutation was also different from previously reported patterns, which consisted of c.649T4C homozygous (6), c.781-2_787delAGGTT-GATAinsG homozygous (9) and c.779A4C homozygous (10), while this patient had a previously unreported mutation: c.1153C>T p.Arg385*.
In conclusion, we have reported a confirmed case of Mitchell-Riley syndrome with a previously unreported homozygous mutation in exon 11 of the RFX6 gene. To our knowledge, this is the first ever reported case from the Arab peninsula. Furthermore, the patient had atypical additional features which could be related to a new mutation which needs to be further explored.
Informed Consent: It was taken.
Peer-review: External and Internal peer-reviewed.
Concept: Nusrat Khan, Waleed Dandan, Design: Nusrat Khan, Data Collection and/or Processing: Nusrat Khan, Suha Hadi, Noura Al Hassani, Waleed Dandan, Analysis and/or Interpretation: Suha Hadi, Noura Al Hassani, Literature Research: Nusrat Khan, Suha Hadi, Noura Al Hassani, Writing: Nusrat Khan, Waleed Dandan.
Financial Disclosure: The authors declared that this study has received no financial support.
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Nusrat Khan (1), Waleed Dandan (2), Noura Al Hassani (1), Suha Hadi (2)
(1) Tawam Hospital, Clinic of Pediatrics and Neonatology, Al Ain, United Arab Emirates
(2) Tawam Hospital, Clinic of Pediatrics and Endocrinology, Al Ain, United Arab Emirates
Address for Correspondence
Nusrat Khan MD, Tawam Hospital, Clinic of Pediatrics and Neonatology, Al Ain, United Arab Emirates
Phone: +971 (0) 50 845 62 67 E-mail: email@example.com
[c]Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.
Conflict of interest: None declared
Table 1, Reported cases of Mitchell-Riley syndrome No. BW GA Diabetes GI atresia/ Hepatobiliary (g) (weeks) onset malrotation defects (age) 1 1540 36 1 day DA, JA GBA 2 1310 34 2 days DA, JA GBA 3 2295 39 2 days Duodenal GBA web and malrotation 4 1700 35 8 days DA, GBA malrotation 5 1340 38 Soon after DA, JA GBA birth (apple peel type), intestinal malrotation 6 <10th 35 2 days DA No anomaly centile reported 7 1490 38 1 day DA, JA, GBA intestinal malrotation 8 1375 34 1 day DA, intestinal GBA malrotation 9 1650 32 3 years DA, jejunal GBA web, Meckel's diverticulum 10 1700 34 6 years DA, mid-gut No anomaly malrotation reported 11 1300 38 2 days DA without GBA malrotation No. Pancreas Other 1 AP Malabsorption unresponsive to pancreatic supplements/bile acids; cholestasis 2 AP Duodenal biopsy: partial villous atrophy. Intrahepatic cholestasis. 3 Small Intrahepatic cholestasis; bilateral Pancreas inguinal hernias 4 Undetectable Intrahepatic cholestasis; faecal elastase anteriorly placed anus 5 Pancreatic Intrahepatic cholestasis; hypoplasia malabsorption unresponsive to pancreatic supplements /bile acids; neonatal haemochromatosis 6 No anomaly Ascites, sepsis, gastro-intestinal reported haemorrhage 7 AP Intrahepatic cholestasis; red cell aplasia confirmed on bone marrow biopsy; malabsoprtion unresponsive to pancreatic supplements/bile acids 8 AP Intrahepatic cholestasis; malabsoprtion unresponsive to pancreatic supplements/bile acids 9 No anomaly No abnormality reported reported 10 No anomaly No abnormality reported reported 11 Pancreatic Malabsorption, unresponsive hypoplasia to pancreatic supplements /bile acids; cholestasis, neonatal haemochromatosis, sepsis, DAT+ive, Factor IX, periventricular calcification, cardiac rhabdomyomas, hypertension, hypothyroidism, hypospadias No. RFX6 RFX6 Reference mutation-nucleotide mutation-protein 1 C.380+2T4C p.? Mitchell homozygous et al(2) 2 C.380+2T4C p.? Mitchell homozygous et al(2) 3 C.672+2T4G/ P.?/P.? Mitchell C.224-12A4G et al(2) compound heterozygote 4 C.649T4C p.Ser217Pro Chappel homozygous et al(6) 5 C.542G4A pArg181Gly Martinovici homozygous et al(5) 6 c.776 780 p.? Smith et +8del13 al (7) homozygous 7 c.781- p.? Spiegel 2_787delAGGTT- et al(9) GATAinsG homozygous 8 C.779A4C p.Lys260Thr Concepcion homozygous et al(10) 9 C.2176C4T p.Arg726X Sansbury et homozygous al(11) 10 C.2176C4T p.Arg726X Sansbury et homozygous al(11) 11 c.1153C>T p.Arg385 This report homozygous BW: body weight, GA: gestational age, Gl: gastro intestinal, DA: duodenal atresia, JA: jejunal atresia, AP: aplasia of pancreas, GBA: gall bladder aplasia
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|Title Annotation:||Case Report|
|Author:||Khan, Nusrat; Dandan, Waleed; Al Hassani, Noura; Hadi, Suha|
|Publication:||Journal of Clinical Research in Pediatric Endocrinology|
|Article Type:||Case study|
|Date:||Jun 1, 2016|
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