DAX1 – X-linked Adrenal Hypoplasia Congenita

X-linked adrenal hypoplasia congenita (AHC) (MONDO:0010264) is a rare disorder of adrenal cortical development caused by pathogenic variants in NR0B1 (DAX1) (HGNC:7960). Affected males present in infancy with salt‐wasting primary adrenal insufficiency and subsequently develop hypogonadotropic hypogonadism in adolescence due to failure of hypothalamic–pituitary–gonadal axis maturation. Female carriers are typically asymptomatic but may transmit the disease in an X‐linked recessive pattern.

ClinGen classifies the DAX1–AHC association as Definitive based on over 200 unrelated probands across more than 25 years of reports, X‐linked segregation in multiple families, and concordant functional studies. The strength of evidence includes numerous loss‐of‐function variants (frameshift, nonsense) and missense alleles clustering in the ligand‐binding domain, all segregating with disease ([PMID:7609262], [PMID:9529340], [PMID:9508067]).

Inheritance is X-linked recessive. Segregation studies across at least 19 affected relatives confirm co‐segregation of NR0B1 variants with adrenal insufficiency and hypogonadotropic hypogonadism. Case series have reported recurrent and private variants, including the missense change c.1142T>C (p.Leu381Pro) identified in an asymptomatic 8-month-old at risk of AHC prior to crisis([PMID:11113848]).

The variant spectrum is dominated by loss‐of‐function alleles: frameshift and nonsense mutations leading to truncated DAX1 lacking its C-terminal repressor domain, and missense substitutions in conserved helices of the putative ligand‐binding domain. No common founder variants have been described, underscoring allelic heterogeneity. The representative variant in this summary is c.1142T>C (p.Leu381Pro).

Functional studies demonstrate that DAX1 normally represses SF-1–mediated transcription of steroidogenic genes. DAX1 missense and truncating mutants show impaired nuclear localization, loss of transcriptional repression, and aberrant activation of target promoters. Dax1 knockout mice recapitulate the human adrenal and gonadal phenotype, supporting haploinsufficiency as the mechanism([PMID:12519885], [PMID:26464492]).

In conclusion, NR0B1 mutation analysis is essential for early diagnosis of X-linked AHC, guiding life‐saving hormonal replacement and genetic counseling. Key take-home: Genetic testing for DAX1 enables presymptomatic identification, informed family planning, and tailored endocrine management.

References

• American journal of medical genetics • 1998 • Novel mutation of the DAX1 gene in a patient with X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. PMID:9508067
• JAMA • 1995 • Diagnosis of X-linked adrenal hypoplasia congenita by mutation analysis of the DAX1 gene. PMID:7609262
• American journal of human genetics • 1998 • DAX1 mutations map to putative structural domains in a deduced three-dimensional model. PMID:9529340
• The Journal of clinical endocrinology and metabolism • 2003 • An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita. PMID:12519885
• Human molecular genetics • 2015 • CRISPR/Cas9-mediated Dax1 knockout in the monkey recapitulates human AHC-HH. PMID:26464492

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