Genetic defects in pediatric-onset adrenal insufficiency in Japan.

CONTEXT

Most patients with pediatric-onset primary adrenal insufficiency (PAI), such as 21-hydroxylase deficiency, can be diagnosed by measuring the urine or serum levels of steroid metabolites. However, the etiology is often difficult to determine in a subset of patients lacking characteristic biochemical findings.

OBJECTIVE

To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients.

METHODS

We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. The pathogenicities of rare variants were assessed based on analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics.

RESULTS

We identified genetic defects in 50 (85%) families: in 19, in 18, in seven, in two, in two, in one and in one. defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency.

CONCLUSIONS

Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as defects are presumed based on phenotypes, while others with broad phenotypic variability, such as defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients.