Endocrine Abstracts

Introduction: Activating mutations of Glucokinase (GCK) gene are described as a rare genetic aetiology of Congenital Hyperinsulinism (CHI), which can cause variable disease severity. However, cardiac anomalies such as aortic valve disease have not been reported as a feature of this genetic form of CHI. We describe two patients diagnosed with GCK-CHI and aortic valve disease.

Case 1: A twelve-month-old female presented at the neonatal period with hypoglycaemia due to hyperinsulinism. Genetic testing showed a novel missense de novo variant in the GCK gene (c.644A>C; p.Tyr215Ser). 18F-DOPA PET/CT scan confirmed diffuse form of CHI. The infant failed to respond to diazoxide or octreotide monotherapy. Subsequently, a conservative approach was chosen and managed with combination of diazoxide (maximum dose 8 mg/kg per day) and Lanreotide (60 mg/4weekly) which has maintained her blood glucose stable while tolerating 8 hours overnight fast. Echocardiogram showed bicuspid aortic valve with moderate aortic valve stenosis (4.0 m/s, mean gradient 35 mmHg) which was surgically treated.

Case 2: A twelve-year-old female diagnosed in the neonatal period with CHI due a GCK gene missense variant (c.641A>G; p.Tyr214Cys). She was diazoxide partially responsive (maximum dose 15 mg/kg per day) and failed to respond to Sirolimus. Due to ongoing hypoglycaemic episodes surgical treatment was decided and the patient had near-total pancreatectomy at the age of 17 months, with histopathology confirming diffuse form of CHI. Post-surgery, she had persistent hyperinsulinism which was managed with diazoxide, until 9 years of age when she developed insulin depended diabetes mellitus. She also developed pancreatic exocrine insufficiency 9 months after surgery and started pancreatic enzymes replacement treatment. Echocardiogram showed sub-aortic ridge attached to septum anteriorly and extending around towards right coronary cusp (4.4 m/s, mean gradient 48 mmHg), treated surgically with complete resection of thick circumferential subaortic fibromuscular ridge.

Conclusion: CHI due to activating GCK gene variants usually presents at the neonatal period, show variable severity and can be challenging to manage requiring combination of medications or even near total pancreatectomy. Aortic valve disease can be an additional feature as our cases illustrate, although the underlying mechanism is undefined. Thus, screening for aortic valve disease via echocardiogram should be considered for patients diagnosed with GCK-CHI.