ESPE Abstracts

Introduction: Congenital hyperinsulinism (CHI) is a rare condition often caused by variants in genes that regulate insulin production. Among the 30 genes identified, CACNA1D, which encodes L-type calcium channels in various cells, is a rare cause. Variants in CACNA1D lead to a multisystem disorder characterized by developmental delay, intellectual disability, autism, hypotonia, seizures, primary aldosteronism, CHI, hearing loss, visual issues, and cardiac defects. Some variants alter channel function, increasing Cav1.3 activity, suggesting potential management with Cav1.3 inhibitors. However, evidence is limited, and mixed results have been observed in patients treated with calcium channel blockers (CCBs). Here, we report an infant with CHI due to a de novo gain-of-function CACNA1D variant who showed a promising response to CCB treatment.

Case Presentation: A male infant, born at 36+6 weeks weighing 3.39 kg, developed hypoglycemia on his first day, requiring high glucose infusion. Tests confirmed hyperinsulinism, and diazoxide treatment was initiated, yielding a positive response. Genetic testing revealed a de novo pathogenic gain-of-function CACNA1D variant (NM_000720.3:c.1208G>A,p.(Gly403Asp). In view of his CACNA1D variant, multidisciplinary review was arranged. Medical issues identified included:cortical visual impairment, hypermetropia, moderate to severe hearing loss, cardiac defects, central and limb hypertonia, dystonia (frequent back arching, limb posturing), global developmental delay and excessive sleepiness. MRI brain and electroencephalogram were normal. A trial of CCB (slow release Nifedipine), was initiated at 9 months to improve neurological outcomes. The dosage gradually increased to 2.5 mg/kg/day without signs of hypotension or other side effects. Four days post-treatment, diazoxide discontinued, and the infant tolerated a 12-hour fast without hypoglycaemia. Six months later, improvements were seen in muscle tone, significant reduction in dystonia, increase in alertness and wakefulness time. He has intermittent fixing and following and reacts to sounds. His head circumference continues to grow on the 80^th centile. However, at 14 months, he remains significantly delayed, unable to roll or make purposeful hand movements. The infant remains on nifedipine treatment.

Conclusion: This case highlights the importance of genetic diagnosis in CHI cases. Early identification of CACNA1D -related CHI is essential for implementing a multidisciplinary approach and targeted treatment strategies. Our case provides further evidence that early intervention with CCBs, like nifedipine, may improve neurodevelopmental symptoms in infants with CHI due to CACNA1D variants. We recommend considering a trial of CCBs in such cases.