Background: X-linked adrenal hypoplasia congenita (AHC) is a rare genetic cause of early-onset primary adrenal insufficiency (PAI) in males resulting from pathogenic variants in the NR0B1 gene (DAX1). The disorder typically presents in infancy with adrenal crisis, markedly elevated ACTH levels, and mineralocorticoid deficiency. While most reported NR0B1 pathogenic variants are truncating mutations, non-truncating variants affecting critical functional domains of DAX1 may also impair adrenal development but remain difficult to classify under current American College of Medical Genetics and Genomics (ACMG) variant classification criteria. Clinical
Case: A male patient presented at 12 months of age with symptoms compatible with PAI, including salt-wasting adrenal crisis, requiring hospitalization. Initial biochemical evaluation revealed elevated ACTH level 1102 pg/mL (9-52 pg/mL) and low cortisol level 0.2 mcg/dL (10-20 mcg/dL). Serum electrolytes showed borderline hyponatremia with preserved potassium level, and anti-adrenal antibodies were negative. Imaging of the adrenal glands was reported as normal. The patient was started on lifelong glucocorticoid and mineralocorticoid replacement therapy, including hydrocortisone (9–15 mg/m²/day) and fludrocortisone (60–75 mcg/day) with stable clinical course and no further adrenal crises reported during follow-up. To investigate the underlying genetic etiology, whole-exome sequencing was performed and identified a novel hemizygous in-frame indel in the NR0B1 gene (NM_000475.5:c.1108_1120delinsC; p.Ser370_Ser374delinsArg), absent from population databases (gnomAD frequency = 0%) and not reported in ClinVar. This variant is predicted to alter the C-terminal ligand-binding-like domain of DAX1, essential for transcriptional repression and normal adrenal development. According to ACMG criteria, this is a variant of uncertain significance (PM2_supporting, PM4). However, whole-exome sequencing did not identify any alternative genetic explanation for the patient’s phenotype, which was consistent with X-linked AHC.
Conclusion: The case described a boy with early-onset PAI associated with a previously undescribed NR0B1 in-frame indel. Although currently classified as a variant of uncertain significance, multiple lines of evidence — including hemizygosity in an affected male, absence from population databases, involvement of a critical functional domain of DAX1, and a phenotype highly consistent with classical X-linked AHC — strongly support its likely pathogenic role. To our knowledge, this is the first report of the NR0B1 variant associated with adrenal insufficiency. This case expands the mutational spectrum of NR0B1-associated AHC and highlights the importance of integrating genomic findings with detailed clinical phenotyping for interpretation of rare variants in endocrine disorders.
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