Endocrine Abstracts

JOINT3386

Background: The DAX1 (NR0B1) gene, located at Xp21.2, encodes a nuclear receptor critical for adrenal and reproductive system development. Its dosage sensitivity is documented, with duplications causing 46,XY disorder of sexual development (DSD) through testicular dysgenesis. This case report expands the phenotypic spectrum of Xp21 duplication syndrome and reinforces DAX1’s role in sex determination pathways.

Clinical Case: A pediatric patient presented with syndromic features including hypertelorism, epicanthic folds, low-set ears, broad nasal bridge, and global developmental delay. Genital examination revealed ambiguous external genitalia (Prader stage II). Chromosomal microarray analysis identified two pathogenic copy number variations: a 37.2 Mb duplication at Xp22p21 (chrX:168,546-37,348,545) encompassing DAX1, and a 3.5 Mb duplication at Yp11.2 (chrY:24,985,261-28,458,663). Karyotype confirmation demonstrated 46,XY, dup(X)(p22p21). Endocrine evaluation showed elevated gonadotropins (FSH 18.7 IU/l, LH 12.3 IU/l) with low anti-Müllerian hormone (1.2 ng/mL), consistent with testicular insufficiency.

Conclusion: This case provides definitive evidence that DAX1 duplication alone suffices to cause 46,XY DSD, independent of Y chromosome anomalies. The identified Xp22p21 duplication (containing 63 OMIM genes including IL1RAPL1 and ARX) may explain the neurodevelopmental comorbidities. We propose that DAX1 copy number analysis should be integrated into first-tier genetic testing for 46,XY DSD, particularly in syndromic cases. These findings underscore the necessity of comprehensive genomic characterization to unravel complex genotype-phenotype correlations in sexual differentiation disorders.