Background: Congenital hyperinsulinism of infancy (CHI) is the most common cause for persisting hypoglycaemia in infancy. Genetic causes are mutations in ABCC8 or KCNJ11 (coding for K+ATP-channel subunits), less frequently mutations in GCK or GLUD1. Further genetic examinations are usually performed only if phenotypic aspects point to other specific genes, such as the rare short chain 3-hydroxylacyl-CoA dehydrogenase (SCHAD, HADH) deficiency (worldwide <30 documented cases). It is characterized by an accumulation of 3-hydroxybutyrylcarnitine in blood and 3-hydroxyglutarate in urine which usually leads to initiation of specific genetic testing.
Objective and hypotheses: We report on two patients of Turkish origin with HADH (SCHAD) hyperinsulinism without detectable levels of 3-hydroxybutyrylcarnitine in blood as well as 3-hydroxyglutarate in urine.
Patients and methods: Patient 1: male, 17 years, postnatal macrosomy, recurrent hypoglycaemia, diazoxide responsive, older sister and grandmother also suffering from CHI. No mutations in ABCC8, KCNJ11. Patient 2: female, 9 years, recurrent hypoglycaemia since birth, diazoxide responsive. Grandfather and cousin as well suffering from CHI. No mutations in ABCC8, KCNJ11, GCK, GLUD1. In both of them: Analysis of acylcarnitine profiles by tandem-mass spectrometry in dry blood samples. GC-MS analysis of organic acids in urine. Next-generation sequencing (NGS) of further CHI genes.
Results: Patient 1: Homozygous HADH c.428T>A (p.Ile143Asn), new mutation. Patient 2: Homozygous HADH c.706C>T (p.Arg236*). In both patients 3-hydroxybutyrylcarnitine in blood as well as 3-hydroxyglutarate in urine were below the detection limit.
Conclusion: HADH deficiency should be considered in patients with CHI who are negative for ABCC8 and KCNJ11, even when its specific biochemical markers are not present. These data underline the broad clinical and genetic heterogeneity of CHI and other hypoglycaemia disorders, and the value of extensive sequencing, e.g. using NGS, to detect the molecular basis of the disease.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology