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Nourah Alruqaie et al, 2018;1(2):87–92.

Mitchell-Riley syndrome report of novel mutation and review of the literature

Nourah Alruqaie1, Majid Alfadhel1,2*

Correspondence to: Majid Alfadhel

*Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.

Email: dralfadhelm [at] gmail.com

Full list of author information is available at the end of the article.

Received: 04 May 2018 | Accepted: 10 June 2018


ABSTRACT

Background:

Mitchell-Riley syndrome (OMIM # 615710) is a rare autosomal recessive disorder, characterized by a genetic mutation in the RFX6 gene. Clinically, it is presented with a triad of neonatal diabetes, gallbladder agenesis/hypoplasia, and intestinal atresia.

Case Presentation:

We reported a female Saudi twin of consanguineous parents presented with neonatal diabetes, gallbladder agenesis/hypoplasia, and intestinal atresia since birth who deceased at 5 months of age due to sepsis. Molecular genetic testing of the RFX6 gene showed novel homozygous missense mutation; NM_173560.3: (c.983A > T; p.Asp328Val). We compared the current patient to previously reported cases.

Conclusion:

We alert the clinicians to consider this syndrome in any neonate presenting with diabetes, gallbladder agenesis, and intestinal atresia.


Keywords:

Diabetes, RFX6 gene, Mitchell-Riley syndrome, gallbladder agenesis, intestinal atresia, pancreatic insufficiency.

Introduction

Mitchell-Riley syndrome (OMIM # 615710) is a rare autosomal recessive disorder characterized by a genetic mutation in the RFX6 gene. The syndrome consists of neonatal diabetes mellitus with congenital digestive system defects including biliary atresia, pancreatic hypoplasia, duodenal and/or jejunal atresia, intestinal malrotation, gallbladder aplasia, and cholestasis (1,2). In addition, less common features were reported such as severe neonatal anemia (28), hypothyroidism (1,4,7), hemochromatosis (3,4,7), and anteriorly placed anus (8,9). Khan et al. (7) reported one case with atypical features of cerebral calcification, hypospadias, and rhabdomyomas. Furthermore, heterotopic gastric mucosa in the small bowel and heterotopic pancreatic tissue were reported (2,6,8). Sansbury et al. and Skopkova et al. have described two siblings with the diagnosis of Mitchell-Riley syndrome with a milder phenotype. They had childhood onset diabetes and have survived post-infancy. The oldest child was reported alive at the age of 9 years compared with the usual poor prognosis of death within the first year of life in half of the cases (13,6,10,11). To date, there have been only 15 genetically confirmed cases reported with Mitchell-Riley syndrome (111). In this report, we describe a case with a novel mutation not described previously in the RFX6 gene of an infant with Mitchell-Riley syndrome. The child presented with typical features including failure to thrive, neonatal diabetes, gallbladder agenesis, and intestinal atresia and deceased at 5 months of life due to sepsis. We compared the current case with the previously reported cases in the literature.

Case Presentation

Twin infants were a product of in vitro fertilization, second gravidity of a 33-year old woman with dizygotic (dichorionic, diamniotic) pregnancy, delivered to a consanguineous Saudi couple. The mother was diagnosed with diabetes mellitus at the age of 24, on oral medication, and was shifted to insulin therapy during her pregnancy. Antenatal ultrasound (US) showed normal Twin A, while Twin B had an abnormal gross anatomy of dilated bowel loop and polyhydramnios. They were born at 30 weeks of gestation by cesarean section due to premature labor and breech presentation. Twin A, a male infant born with APGAR scores of 8 and 9 at 1 and 5 minutes, respectively. He has normal growth parameters and physical examination was normal with no dysmorphic features. He had a smooth hospital course. He was discharged home with no complications noted after 20 days, mainly from his prematurity and low birth weight.

On the other hand, Twin B is a female infant scored an APGAR of 6 and 8 at 1 and 5 minutes, respectively. Weight at birth 1,100 g (10th–25th percentile), length 38 cm (50th percentile), and head circumference (HC) 28.5 cm (50th–75th percentile). No dysmorphic features were noted. She was shifted to the neonatal intensive care unit as she was initially requiring non-invasive mechanical ventilation; soon after she was intubated due to severe abdominal distention. Initial abdominal X-ray showed dilated bowel loop. X-ray with contrast was performed later which revealed a dilated stomach and first part of the duodenum with severe duodenal stenosis while the US reported an unvisualized gallbladder with collapsed distal bowel loops and rectum. Surgery was scheduled on the second day of life, but it was postponed as the patient was unstable due to severe coagulopathy, pulmonary hemorrhage, and uncontrolled hyperglycemia. Her hyperglycemia was noted from day 1. Four hours after birth blood glucose was 9.5 mmol/l (3.9–7.7mmol/l then started to increase reaching 23.7 mmol/l at 6 hours of life. She was requiring insulin infusion due to persistent hyperglycemia along with episodes of hypoglycemia. Her coagulopathy was completely resolved at the age of 4 days. During a hyperglycemic episode, insulin level was <2.0 μIU/ml (3.2–16.3 μIU/ml) and C-peptide 0.1 ng/ml (0.8–4.2 ng/ml) which were both low. Furthermore, there was no mutation in neither the ABCC8 and KCJN11 genes. Laparotomy was performed on day 17, confirmed duodenal and jejunal atresia along with Meckel’s diverticulum. Additionally, a cyst-like lesion in the duodenum was resected and its histological study revealed the presence of heterotopic gastric mucosa. Feeding was initiated 10 days after surgery, but she was dependent on parenteral feeding as she failed to gain weight with a clay-colored watery stool. Medium chain triglyceride oil and trials of different formulas showed no improvement. Later on, cholestasis progressed with severe conjugated hyperbilirubinemia and was started on ursodiol. A hepatobiliary iminodiacetic acid (HIDA) scan reported non-visualized biliary channels. She had liver failure along with high ferritin levels 5,508 ng/l (4.6–204 ng/l) and transferrin saturation >48% suggesting a picture of hemochromatosis. At 2 months of age, her growth parameters showed a failure to thrive as follows: her weight 1.40 kg (<3rd percentile), her length 38 cm (<3rd percentile), and HC 30 cm (<3rd percentile). The repeated brain US showed a small right choroid plexus cyst while the echocardiogram study was normal. She underwent genetic analysis for the RFX6 gene, which confirmed a novel homozygous missense variant not reported previously in the RFX6 gene; NM_173560.3 (c.983A > T; p.Asp328Val), which causes amino acid, changes from aspartic acid to valine at position 328. The mutation was confirmed to be heterozygous in both parents and healthy sister while the wild type in a male twin.

Cholangiography and liver biopsy could not be performed as the patient condition was critical and deteriorated due to sepsis and passed away at the age of 5 months.

Discussion

The current patient is the 16th case ever reported of Mitchell-Riley syndrome in the literature, and the first case to be reported from Saudi Arabia and third from Arab ethnicity. The proband has the same classic phenotype features of Mitchell-Riley syndrome (Table 1), starting with classic features in-utero of intrauterine growth restriction, polyhydramnios, and duodenal atresia as well as the presence of key diagnostic features including neonatal diabetes, gallbladder agenesis, and intestinal atresia. However, the current patient lacked two major features, which are intestinal malrotation and abnormal pancreas. On the other hand, biliary atresia was suggestive by HIDA scan but could not be confirmed as she was not stabilized to undergo liver biopsy or cholangiography. Additionally, the current patient had malabsorption with chronic watery acholic stool, and exocrine pancreatic supplements were never given. Many reported cases with this mutation received a trial of exocrine pancreatic supplements but with no significant improvement (1–4,7–9,11). Similar to other cases, she had chronic anemia requiring multiple transfusions. Interestingly, heterozygous mutation in the RFX6 gene was recently associated with maturity-onset diabetes of the young with reduced penetrance, which may have associations with the mother’s diabetes as the mother was diagnosed with diabetes mellitus at the age of 24 years, on oral medication and, later on, shifted to insulin therapy during her pregnancy [12].

In 2015, Sansbury et al. (6) were the first to point out a new abnormal histological novel feature, where he reported the presence of heterotopic gastric mucosa in the small intestine. Later, Skopkova et al. (2) also described two cases with the same abnormal histological findings. All reported cases had a gastrointestinal bleed that improved after resection. Interestingly, this feature was found in the current case but she had no intestinal bleed. Amorim et al. (8), on the other hand, reported the presence of heterotopic pancreatic tissue.

Moreover, hemochromatosis reported in previous cases were found in the current patient (3,4,7). An additional feature that was never reported before, which could be an incidental finding in the current case was a small right choroid plexus cyst seen by head US. Pointing out, among all reported cases, brain pathology was only reported by Khan et al. (7), with periventricular calcification finding by brain magnetic resonance imaging (MRI).

For the first time in the literature, we reported a novel mutation that has not been previously reported (c.983A > T; p.Asp328Val) in the RFX6 gene. The pathogenicity of this variant supported by segregation with other family members and the variant is rare and not described in the Exome Aggregation Consortium, Exome Sequencing Project, 1,000 genomes browser as well as a database of 2,000 in-house ethnically matched exomes. Additionally, computational analysis tools including polyphen, SIFT, and mutation tester predict this variant to be probably damaging. The molecular spectrum of the RFX6 gene defect is heterogeneous. The most common type of mutation is missense accounting for 37.5%; however, other types of mutations including intronic, non-sense and deletion were reported. The genotype-phenotype correlation is unclear.

Table 1. Summary of the clinical phenotype of previously reported cases compared to the current patient

Table 2. Prognosis and types of mutation in the previously reported cases compared to the current patient

The prognosis of Mitchell-Riley syndrome is relatively poor with six cases (37.5%) having died in the first year of life (Table 2).

Conclusion

In conclusion, we report a case of Mitchell-Riley syndrome with a novel homozygous missense mutation. We alert the clinicians to consider this syndrome in any neonate presenting with diabetes, gallbladder agenesis, and intestinal atresia.

Acknowledgment

We are grateful to the patient and his family reported in this article for their genuine support.

Declaration of conflicting interests

The authors of this report have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Funding

None.

Consent for publication

Written consent was obtained from the parents.

Ethical approval

This study was approved by the Institutional review board office at King Abdullah International Medical Research Centre (KIMARC) (Study number: RC16/113/R).

Author details

Nourah Alruqaie1, Majid Alfadhel1,2

  1. College of Medicine, King Saud bin Abdul-Aziz University for Health science, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia
  2. King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Genetic Division, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia

References

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