MNX1 mutations causing neonatal diabetes: Review of the literature and report of a case with extra‐pancreatic congenital defects presenting in severe diabetic ketoacidosis.

The MNX1 gene encodes a homeobox transcription factor found to be important for pancreatic beta cell differentiation and development. Mutations of the MNX1 gene that cause permanent neonatal diabetes mellitus (PNDM) are rare and have been reported in only two cases. Both cases presented with hyperglycemia, with one case having isolated PNDM while the other had PNDM and multiple neurologic, skeletal, lung, and urologic congenital anomalies resulting in death in early infancy. We describe the genetic and clinical features of a preterm male infant with a homozygous [c.816C > A p.(Phe272Leu)] MNX1 mutation. Our proband is the first case to present in severe diabetic ketoacidosis (DKA), indicating severe insulin deficiency. Unlike the previously reported female case who had the same mutation and presented with isolated PNDM, our proband had hypospadias and congenital umbilical hernia and showed poor growth on follow up. Our case suggests that MNX1 mutations causing NDM can result in a range of extra‐pancreatic features and a variable phenotype, similar to other transcription factors causing NDM such as GATA6 and GATA4 mutations. We also cannot exclude the possibility of sex‐biased expression of MNX1 gene (which was recently reported for other monogenic/neonatal diabetes genes such as the NEUROD1 and HNF4A in humans) since the two male cases had associated multiple anomalies while the female case had isolated PNDM. Our report further defines the phenotype caused by recessive homozygous MNX1 mutations and explores potential new mechanisms regulating MNX1 gene expression which should be further explored. Our manuscript describes a male newborn with the rare MNX1 mutation with a novel presentation/phenotype of not only hyperglycemia but also severe diabetic ketoacidosis, hypospadias and congenital umbilical hernia. Thus, we expand on the phenotype presentation of MNX1 mutations associated with permanent neonatal diabetes. Since the two males who had MNX1 mutation and diabetes (our case and another previously reported case with a different mutation), had multiple congenital anomalies, whereas the female who had the same mutation as our patient had isolated diabetes, our report also raises the possibility of sex‐biased gene expression, which was recently reported for several monogenic diabetes genes. This is worth exploring further in the future especially as more cases are reported. [ABSTRACT FROM AUTHOR]