IMPE Abstracts

Introduction: Neurogenin-3 (NEUROG3) is a key transcription factor expressed in endocrine progenitor cells and is necessary for the development of endocrine cells in the pancreas and intestine. Its homozygous pathogenic variants cause an autosomal recessive disorder characterized by congenital malabsorptive diarrhea due to paucity of enteroendocrine cells and diabetes which occurs from the neonatal stage to school age.

Objectives: To report 2 patients with diabetes and chronic diarrhea due NEUROG3 pathogenic variants. Patient 1). A 9.5-year-old male, carrier of congenital malabsorptive diarrhea and recent diabetes onset. He is the first child of non-consanguineous parents born at 40 wks. His BW 2665 g and BL 47 cm been SGA. His on TPN at home, MDI insulin, carbohydrates restriction and oral supplements of Zn, iron, folic acid, and bicarbonate. PE: weight 27.7 kg, height 122.1 cm (T/E -2.39 SD), BMI 18.6 (0.88 SD); he is prepubertal without dysmorphic features. Labs: IAb GAD, IA-2, ICA, Anti-ZnT8 were negatives. Genetic analysis shows a homozygous pathogenic variant of NEUROG3 c.404T>C p. (Leu135Pro). Patient 2) A 12.5-year-old female carrier of congenital malabsorptive diarrhea, developed diabetes mellitus at 9-year-old. She was born at term. BW 2370 gr and BL 47 cm being SGA. The consanguinity status of the parents is unknown. Immunostaining of a large intestine biopsy for chromogranin A demonstrated the complete absence of neuroendocrine cells. She was managed with total parenteral nutrition until 18 months, then enteral nutrition and oral supplements of electrolytes, vitamins, and Zn. She is on basal-bolus insulin treatment with good metabolic control Somatropin treatment was recently started to optimize her growth. PE: weight 22.7 kg, height 112.7 cm (T/E -5.0 Z), BMI 17.7 (0.14 Z). She has mild cognitive delay, mild dysmorphic facial features and breast Tanner 2. No other physical findings were observed. A genetic analysis revealed a homozygous pathogenic variant of NEUROG3 g.320G>C p.R107P.

Commentaries: NEUROG3 homozygous pathogenic variants result in loss of function of the protein. It causes disruption of the pathway that determines the differentiation of enterocytes and enteroendocrine cells and has severe effects on the capacity of the small intestine to absorb nutrients. This defect has been named “enteric anendocrinosis” and manifests with congenital malabsorptive diarrhea and early-onset diabetes. To date, there is no specific treatment.

Conclusion: The association of severe malabsorptive diarrhea at an early age associated with Diabetes Mellitus should suggest mutations in NEUROG3 and a specific genetic study should be requested.