SAT-237 - X-Linked Adrenal Hypoplasia Congenita Due to A Pathogenic DAX1 Mutation: Hypogonadotropic Hypogonadism with Adrenal Insufficiency

Background: Adrenal hypoplasia congenita (AHC) is a rare disorder of adrenal development most commonly caused by X-linked mutations in DAX1 (NR0B1)1. Impaired formation of the permanent adult adrenal cortex results in glucocorticoid and mineralocorticoid deficiency, often presenting as life-threatening salt-wasting in infancy without early treatment (1). DAX1 is expressed in the adrenal cortex, hypothalamus, pituitary, and gonads, regulating both the hypothalamic-pituitary-adrenal and gonadal axes (1). Hypogonadotropic hypogonadism (HH) with impaired fertility is a hallmark feature, typically recognized at puberty and frequently resistant to gonadotropin therapy, suggesting intrinsic gonadal dysfunction (1).

Case Presentation: We report a 21-year-old male with X-linked AHC due to a pathogenic frameshift mutation in NR0B1 (DAX1), p.Arg117GlufsX135. He presented at one week of life with hypotension, vomiting, and hyperkalemia consistent with salt-wasting adrenal crisis. Congenital adrenal hyperplasia was excluded, and genetic testing confirmed DAX1-related AHC; FISH analysis showed no Xp21 deletion. He was initiated on lifelong glucocorticoid and mineralocorticoid replacement. In infancy, he was found to have bilateral inguinal hernias and cryptorchidism, requiring orchiopexy and right orchiectomy. Pathology demonstrated prepubertal testicular tissue with reduced germ cell presence. During adolescence, he exhibited absent pubertal progression and a dysplastic solitary testis, confirming HH, and testosterone replacement therapy was initiated.

This case demonstrates the classic phenotype of X-linked AHC with neonatal-onset adrenal insufficiency followed by HH. Cryptorchidism, streak gonad, dysplastic testicular tissue, and impaired pubertal development highlight the multisystem effects of DAX1 dysfunction, involving both central hypogonadism and primary gonadal defects. These findings are consistent with prior reports of poor spermatogenic response to gonadotropin therapy in DAX1-related disease, supporting an intrinsic testicular abnormality.

Conclusion: This case emphasizes the importance of early recognition and genetic confirmation of X-linked AHC to distinguish it from other causes of neonatal adrenal insufficiency. It highlights the lifelong endocrine and reproductive consequences of pathogenic DAX1 mutations and underscores the need for multidisciplinary management, fertility counseling, and genetic counseling.


References:
1. Reutens A.T., Achermann J.C., Ito M., Ito M., Gu W., Habiby R.L., Donohoue P.A., Pang S., Hindmarsh P.C., Jameson J.L. (1999). Clinical and Functional Effects of Mutations in the DAX-1 Gene in Patients with Adrenal Hypoplasia Congenita. The Journal of Clinical Endocrinology & Metabolism, 84(2), 504–511. https://doi.org/10.1210/jcem.84.2.5468

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