Clinical characteristics and phenotype–genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations

Abstract

Objective: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients. Design and methods: A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected. Results: Diazoxide unresponsiveness was observed in nearly half of the patients (nZ17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (nZ18), mutations were identified in two patients (11%). Genotype-phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P!0.0001). Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydraterich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients. Conclusions: This is the largest study to report genotype-phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.

Clinical and Genetic Characteristics, Management and Long-Term Follow-Up of Turkish Patients with Congenital Hyperinsulinism

“…Besides, in one of these reports, the diagnosis is based only on clinical and laboratory findings (37). In another multicenter study, clinical findings and genetic analyses of patients with CHI treated in four different centers were demonstrated, yet long-term follow-up was not reported (38). …”

A novel mutation ofABCC8gene in a patient with diazoxide-unresponsive congenital hyperinsulinism

“…Up to now, there have been many nation-wide studies about ABCC8 and KCNJ11 mutations in patients with CHI3678) and more than 150 mutations have been reported in the ABCC8 gene9). Twelve different mutations of the ABCC8 gene have been reported in Korean patients2).…”

Current Status of Childhood Hyperinsulinemic Hypoglycemia in Turkey

“…ABCC8 gene mutations have been reported as the commonest cause of CHI by Demirbilek et al (24) in the largest cohort consisting of Turkish CHI patients. They estimated the frequency of ABCC8 mutation in the CHI patients as 40% (14/35).…”

“…Three of them were reported in a cohort (24). The authors of this review detected three patients with KCNJ11 mutation.…”

“…In Turkey, there is a high rate of consanguinity, thus the incidence of CHI is expected to be high (12,13). Until now, there are no nationwide data regarding this disorder, and only some individual case reports and studies including a total of 141 patients had been published (6,13,14,15,16,17,18, 19,20,21,22,23,24,25,26,27,28,29,30,31,32). Determining the characteristics of Turkish patients with CHI may gain a different perspective to this rare disorder.…”