Comprehensive genetic analyses of primary adrenal failure without enzymatic defects

Our objective is to estimate frequencies of mutations in STAR, CYP11A1, NR0B1, NR5A1, MC2R, and MRAP in a cohort of Japanese patients with primary adrenal failure without enzymatic defects. Twenty-one patients were included, who were diagnosed as having primary adrenal failure without enzymatic defect, namely 21-hydroxylase deficiency, 3bHSD deficiency, 11b-hydroxylase deficiency, and P450 oxidoreductase deficiency. Sixteen patients presented with primary adrenal failure before the age of 2 years. Fourteen patients had apparent mineralocorticoid deficiency. Fourteen patients were 46, XY and 7 patients 46, XX. Three had 46, XY disorders of sex development. Mutation analyses of STAR, NR0B1, NR5A1, MC2R, and MRAP were done by PCR-based sequencing and next generation sequencing. In case of no amplification of NR0B1 by PCR, we performed oligonucleotide array CGH. We descried clinical findings in each patients and determined possible genotype-phenotype correlation. Five patients were diagnosed as having DAX-1 deficiency. NR0B1 mutations were found hemizygously in 3 patients (c.116delG, c.846_865del, and p.Q283X). NR0B1 deletions were found in 2 patients (400kb deletion including NR0B1 and 2.4kb deletion of exon 1). Four patients presented with primary adrenal failure in newborn, and the other patient presented at the age of 6 years. STAR mutations were found in 3 patients. One patient was 46, XY, and 2 patients were 46, XX. One patient, who presented with primary adrenal failure in newborn, had c.712delA/p. Q258X. Two patients, who presented at preschool age, had p.Q258X/p.R272C and p.Q258X/p.R188H. No mutations were found in CYP11A1, NR5A1, MC2R, and MRAP. In conclusion, NR0B1 mutations and deletions are relatively common in 46, XY normal male phenotype patients (5/11). STAR mutations might be found in cases, being older than 2 years of age. 3. CYP11A1, NR5A1, MC2R, and MRAP mutations are rare.