Birth weight and diazoxide unresponsiveness strongly predict the likelihood of congenital hyperinsulinism due to a mutation in ABCC8 or KCNJ11

Abstract

Objective Mutations in the KATP channel genes, ABCC8 and KCNJ11, are the most common cause of congenital hyperinsulinism. The diagnosis of KATP-hyperinsulinism is important for the clinical management of the condition. We aimed to determine the clinical features that help to identify KATP-hyperinsulinism at diagnosis. Design We studied 761 individuals with KATP-hyperinsulinism and 862 probands with hyperinsulinism of unknown aetiology diagnosed before 6 months of age. All were referred as part of routine clinical care. Methods We compared the clinical features of KATP-hyperinsulinism and unknown hyperinsulinism cases. We performed logistic regression and ROC analysis to identify the features that predict KATP-hyperinsulinism. Results Higher birth weight, diazoxide unresponsiveness and diagnosis in the first week of life were independently associated with KATP-hyperinsulinism (adjusted Odds Ratio 4.5 (95% CI, 3.4-5.9), 0.09 (0.06-0.13) and 3.3 (2.0- 5.0) respectively). Birth weight and diazoxide unresponsiveness were additive and highly discriminatory for identifying KATP-hyperinsulinism (ROC area under the curve for birth weight 0.80, diazoxide responsiveness 0.77, and together 0.88, 95% CI 0.85-0.90). 86% born large for gestation and 78% born appropriate for gestation who did not respond to diazoxide treatment had KATP-hyperinsulinism. In contrast, of those individuals born small for gestation, none who were diazoxide responsive and only 4% of those who were diazoxide unresponsive had KATP-hyperinsulinism. Conclusions Individuals with hyperinsulinism born appropriate or large for gestation and unresponsive to diazoxide treatment are most likely to have an ABCC8 or KCNJ11 mutation. These patients should be prioritised for genetic testing for KATP channel genes.

Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease

“…These constraints force laboratories to screen genes sequentially in descending order of prior probability based on clinical characteristics and how commonly disease-causing variants in the gene are identified. Whilst this phenotype-driven approach works well in many scenarios [for example in the rapid screening of KATP channel genes in individuals with diazoxide-unresponsive disease ( 68 , 69 )], the reliance of clinical features to guide testing can delay a genetic diagnosis for individuals with an atypical presentation. This is an important consideration for HI, as phenotypic variability is described within most genetic subgroups, for example the presence of normal ammonia levels in some children with GLUD1 -HI ( 70 , 71 ).…”

Clinical management of diazoxide-unresponsive congenital hyperinsulinism: A single-center experience

“…Early genetic diagnosis of focal CHI due to a paternally inherited recessive ABCC8 or KCNJ11 pathogenic variant may lead to cure via lesionectomy and become treatment-free, as in patient 3. Heavy birth weight for gestational age and DZX unresponsiveness were the most discriminative, independent, and additive factors for identifying children with KATP-associated CHI ( 11 ). Thus, individuals with DZX-unresponsive CHI born at a normal or large gestational age should be prioritized for earlier testing of KATP-associated genes.…”

Congenital hyperinsulinism in a Nigerian infant: A case report and review of literature

“…Making a molecular diagnosis of CHI is not possible in most of Africa, so samples need to be transported to specialized research laboratories in Europe and America. [19][20][21] is was relatively easy with our patient after successfully completing the procedures for transport of biological samples. After signing a material transport authorization with the ministry of health and obtaining permission from the parents, the courier to London arrived within a day and results were made available within 3 weeks.…”