Case Presentation: A 44-year-old man with history of uncontrolled diabetes mellitus, gastroparesis, chronic malnutrition, and cognitive impairment presented to the emergency room with two weeks of nausea, vomiting, and inability to tolerate oral intake. Given chronic malnutrition and inability to control symptoms with anti-emetics, enteral access was obtained and both tube feeds and motility agents were initiated. His hospital course was complicated by persistent hypomagnesemia and development of pyelonephritis; a CT scan incidentally showed that he had a solitary cystic kidney. After reestablishing adequate oral intake, he was discharged on glargine and sitagliptin for diabetes management in addition to motility agents. Given his unusual constellation of findings, genetic testing was sent and returned after discharge showing hepatocyte nuclear factor-1 beta (HNF1B) heterozygous deletion, consistent with a diagnosis of Maturity-Onset Diabetes of the Young type 5 (MODY5).
Discussion: MODY5 is caused by deletion or mutation in the gene encoding HNF1B, a transcription factor key to the development of several embryonic structures and results in diffuse abnormalities. MODY5 is characterized by early-onset diabetes, pancreatic atrophy, abnormal renal development, progressive renal insufficiency, and other manifestations including hypomagnesemia, elevated aminotransferases, and genitourinary abnormalities. HNF1B gene abnormalities have also been suggested to affect brain development and be related to neurodegenerative disease [1]. As a group, MODY accounts for at least 1% of all diabetes cases but nearly 95% of them are misdiagnosed [2]. MODY5 comprises 5-6% of all MODY diagnoses [3] and is passed in an autosomal dominant pattern. Due to the variability of phenotypes, it can be difficult to diagnose this condition; genetic gene panel testing should be sent once diagnosis is suspected. Correct diagnosis of MODY5 is important in order to guide treatment options for diabetes as well as monitor closely for associated complications. As HNF1B gene abnormalities affect pancreatic beta cell function leading to impaired glucose sensing and insulin secretion, insulin therapy is of high importance. Sulfonylureas and meglitinides are less effective due to hepatic insulin resistance, and metformin even less so [1]. Some case reports suggest that SGLT2-inhibitors may also be of use in treating MODY5, especially in cases of refractory hypomagnesemia [4]. Complications associated with MODY5 that require close monitoring include progression of chronic kidney disease.
Conclusions: MODY5 is often misclassified as a different form of diabetes. The diagnosis should be suspected in patients found to have new diabetes in young adulthood and abnormal renal development; these patients may also have abnormal genitourinary development, liver abnormalities, cognitive impairment, and hypomagnesemia. Establishing the correct diagnosis is important in order to optimize diabetes treatment and prevent recurrent hospitalizations, monitor closely for progressive renal dysfunction, and perform genetic counseling to guide family planning.