Identification of a diffuse form of hyperinsulinemic hypoglycemia by 18-fluoro-l-3,4 dihydroxyphenylalanine positron emission tomography/CT in a patient carrying a novel mutation of the HADH gene

Abstract

Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infancy (HI), leading to severe neurologic disabilities if not promptly treated. The recent application of positron emission tomography (PET)/computed tomography (CT) scanning with 18-fluoro-l-3,4 dihydroxyphenylalanine improved the ability to distinguish the two histopathologic forms of HI (focal and diffuse), whose differentiation heavily influences the therapeutic management of the patient. We describe the case of a patient presenting with severe hypoglycemia from infancy. High concentration of insulin suggested the diagnosis of congenital hyperinsulinism. No metabolic disorders related to amino acid, organic acids or fatty acid oxidation were detected. Medical treatment was able to obtain a satisfactory metabolic response. The patient underwent PET/CT scanning, revealing a diffuse form of the disease. The absence of mutations in KCNJ11 and ABCC8 genes (responsible for 50% of HI cases), and whole genome single nucleotide polymorphisms analysis by microarray suggested the HADH gene as a likely candidate. Sequence analysis revealed a novel homozygous nonsense mutation (R236X) in HADH gene. This case indicates that mutations of the HADH gene should be sought in hyperinsulinemic patients in whom diffuse form of HI and autosomal recessive inheritance can be presumed when KCNJ11 and ABCC8 genes mutational screening is negative, even in the absence of altered organic acids and acylcarnitines concentration.