Successful Liver, Pancreas and Intestinal Transplantation for Neonatal Diabetes (Martinez-Frias) Syndrome Causes by RFX6

A Khanna,M Fujiki,K Hashimoto,D Allende,R Spiegel,S Ellard,K Radhakrishnan,K Abu-ElMagd

OBJECTIVES AND INTRODUCTION

MATERIALS AND METHODS

RESULTSHe was discharged with normal liver functions, full nutritional autonomy and insulin free. C peptide levels were normal. He is currently 20 months post-transplant with excellent graft function, and quality of life.

CONCLUSIONSTo our knowledge, this is the first report of successful liver, duodenum, pancreas and small bowel transplant in a patient with RFX6 mutation.Liver , duodenum, pancreas and small bowel transplant is life-saving and can restore nutritional autonomy, replace diseased liver and provide freedom from insulin

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A 3 year old with Martinez-Frias syndrome was referred with nutritional failure. Laparotomy at 2 weeks of age showed duodenal and jejunal atresia, annular pancreas, and agenesis of gallbladder. Liver biopsy showed severe intra-hepatic cholestasis, grade IV siderosis. He was TPN and insulin dependent, had cholestatic liver disease, hypothyroidism, thalassemia, and nephrocalcinosi. He had homozygosity for RFX6 mutation (a deletion/insertion mutation (c.781-2_787delinsG) in intron7/exon 8 of the RFX6 gene. Sequence chromatograms showed the presence of a homozygous deletion in the proband (Figure 1) and a carrier state in paternal and maternal grandfathers. He was listed for multivisceral transplantation after appropriate workup. He received liver, duodenum, pancreas and small bowel transplantation from a 2 year deceased donor. Portocaval shunt was constructed. Donor to recipient suprahepatic caval anastomosis was done piggy-back to the recipient middle and left hepatic veins. Arterial anastomosis was done between infrarenal arterial conduit to donor common Carrel patch of the SMA and celiac trunk. GI tract was reconstructed by recipient duodenum to donor jejunal anastomosis. Recipient sigmoid colon to distal ileal allograft anastomosis was done in a side-to-side fashion with a 20 cm chimney ileostomy. A feeding jejunostomy tube was placed. No antibody pretreatment was given. Tacrolimus and solumedrol immunosuppression was used. Postoperative Course: Jejunal feeding was advanced to 24 calorie per oz of Elecare junior while TPN was cycled and weaned off by POD 34. He was off insulin with normal C-peptide levels. Episodes of acute cellular rejection on POD 11 and 22 were treated with 500 mg of methylprednisone and 2 mg/kg of thymoglobulin respectively. Histopathology of explant showed preserved villi and gastric heterotopia (Figure 2A &B), follicular hyperplasia (Figure 2C), and marked hemosiderin deposition in liver (Figure 2D).

Regulatory factor x 6 (RFX6) is encoded by the RFX6 gene and is located on chromosome 6q22.1 This gene is specifically required for the differentiation of islet cells Mutations in RFX6 gene lead to neonatal diabetes from pancreatic hypoplasia, hepatobiliary abnormalities, hemochromatosis, cholestatsis and intestinal atresias.

This report describes successful outcome from liver, uodenum, pancreas and small bowel transplantation in a patient born with RFX6 mutation associated with neonatal diabetes, cholestatic liver disease, duodenal and jejunal atresia, and nutritional failure from intestinal malabsorption and total parenteral nutrition dependence.