ESPE Abstracts

Introduction: Approximately 25% of congenital hyperinsulinism (CHI) patients are unresponsive to medical therapy. These cases are usually associated with inactivating ABCC8/KCNJ11 genes mutations or rarely with dominant GCK variants. Activating dominant mutations in the CACNA1D gene were recently found to cause mild form of CHI, muscle hypotonia and autistic features.

Objectives: Herein we describe a clinical case of a patient with severe medically unresponsive CHI and global developmental delay due a novel CACNA1D mutation.

Results: A female baby from nonconsanguineous healthy parents was born large for gestational age at 34 weeks with low Apgar score. Persistent hypoglycaemia (0.7-1.9 mmol/l) was noticed with glucose requirement rate (GRR) of 18.3 mg/kg/min. Due to pulmonary hypertension, the patient was treated with IV Ca channel blockers. CHI was diagnosed at day 7 of life. Diazoxide and Octreotide treatment were ineffective. NGS panel for known CHI genes did not reveal mutations. Subtotal pancreatectomy was performed at the age of 2 months. Histological examination confirmed diffuse CHI. Hypoglycaemia persisted postoperatively. Octreotide was restarted with partial effect. Follow-up examination at 9 months revealed excessive weight gain, severe developmental delay and muscle hypotonia. Diazoxide and Chlorothiazide were restarted with partial effect and led to progressive weight loss. At 24 months, the patient was diagnosed with bilateral congenital glaucoma. At 30 months, investigations showed persistence of hyperinsulinaemic hypoglycaemia. There were no progression in patient’s psycho-motor development despite regular rehabilitation and absence of typical hypoglycaemic brain injury picture on MRI. The whole exome sequencing revealed a novel de novo variant (p.Phe767del) in the CACNA1D gene. The girl was started on Ca channel blockers therapy. After 6 months of treatment, there was no improvement neither in patient’s glucose control, nor in her mental and motor development.

Conclusions: Mutations in the CACNA1D gene were previously reported to cause mild CHI, muscle hypotonia and autistic features. We reported a case of severe Diazoxide-unresponsive CHI and global developmental delay due to a novel CACNA1D mutation, indicating the clinical variability of Cav1.3 defect associated CHI.