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103 NUCLEOTIDE SUBSTITUTION OF INTRON 1 OF MATURITY-ONSET DIABETES OF YOUTH (MODY)-3 ASSOCIATED WITH SITUS INVERSUS AND ABNORMAL PANCREATIC ANATOMY
  1. J. K. Byrd,
  2. R. F. Stanfield,
  3. I. D. Schwartz
  1. University of South Carolina School of Medicine and Palmetto Health, Columbia

Abstract

Purpose To present the clinical presentation and evaluation of a patient with uncontrolled diabetes mellitus (DM), possible MODY-3, and a protuberant abdomen.

Methods Case report.

Results This black female presented with DM at age 12.6 years with a history of polydipsia. Her mother had diabetes “requiring insulin” and the paternal grandmother had probable type 2 diabetes. The patient had obesity (BMI = 32.9 kg/m2), elevated fasting insulin level of 36 μIU/mL (with concomitant glucose of 184 mg/dL), and negative pancreatic antibodies. She was diagnosed with type 2 DM and metformin, 500 mg twice daily, was started. There was sporadic follow-up. The HbA1c ranged from 5.4-6.6% during the first 26 months after diagnosis but had increased to 12.2% six months later. A thiazoladinedione was added but HbA1c remained elevated. Insulin was added. There was poor compliance with all medications and inconsistent adult supervision. She had oligomenorrhea with increased abdominal girth; β-hCG—was negative. CT of the abdomen and small bowel barium study confirmed abdominal situs inversus (right-sided: stomach, small bowel, and multiple splenic masses; left-sided: liver and gallbladder; midline: ascending colon and cecum) and a globular pancreas with a truncated body and tail. Oral glucose tolerance testing (OGTT; 1.75 g/kg to a maximum of 75 g) showed peak glucose and insulin levels of 361 mg/dL and 20.2 μIU/mL, respectively. MODY-3 genetic analysis (Esoterix Laboratory Service, Inc.) demonstrated a novel, heterozygous nucleotide cytosine to adenine substitution at position +20 of intron 1. In addition, she had two other previously described variants in exons 1 and 4 of the hepatocyte nuclear factor 1-α gene, but which are thought not to have clinical significance.

Discussion While certainly measurable, the insulin level during the OGTT seemed inappropriately low for the degree of hyperglycemia, which suggests limited β cell function. Negative pancreatic antibodies mitigate against type 1A diabetes.

Conclusion We present an unusual case of type 2 DM with a novel mutation at +20 of intron 1of the MODY-3 gene associated with abdominal situs inversus, polysplenism, and truncated pancreatic anatomy. While there may not be a causal link, mutations within introns, such as the one we identified in the MODY-3 gene, can lead to alterations in mRNA splicing that affect gene function. Gene product analysis has not yet been performed. Complete MODY-3 analysis on the mother remains pending.

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