https://orcid.org/0009-0000-4061-8700
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Sofía Suco Valle, Rodolfo A Rey, The Importance of Clinical Categorization for a Successful Etiologic Diagnosis of Monogenic Disorders in 46,XY DSD, The Journal of Clinical Endocrinology & Metabolism, 2025;, dgaf054, https://doi.org/10.1210/clinem/dgaf054
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Disorders of sex development (DSD) encompass conditions that alter chromosomal, gonadal, or genital sex and include a large spectrum of overlapping phenotypes and an equally wide array of etiologies. The diagnosis of DSD is suspected at birth or on ultrasound evaluations during pregnancy, when ambiguous genitalia are seen. Less commonly, the appearance of the external genitalia is typically female or male, and the diagnosis may be delayed until the age of puberty. DSD is usually classified according to karyotype into 3 major groups: 1) sex chromosome DSD, which occurs when the arrangement of sex chromosomes is different from the XX or XY pair; 2) 46,XX DSD, and 3) 46,XY DSD.
46,XY DSD are characterized by incomplete masculinization of the genitalia. Typically, during the first trimester of gestation, Leydig cells of the testes secrete testosterone and Sertoli cells produce antimüllerian hormone (AMH). Testosterone, acting on the androgen receptor (AR), leads to the differentiation of the Wolffian ducts into the epididymides, vasa deferentia, and seminal vesicles. In the urogenital sinus and the external genitalia, testosterone is transformed into the more portent androgen dihydrotestosterone (DHT) by the enzyme 5α-reductase type 2, encoded by SRD5A2. DHT drives the development of the prostate, the closure of the urethral folds driving the meatus to the tip of the penis, and the fusion of the labioscrotal folds to form the scrotum. AMH, acting on its specific receptor AMHR2, provokes the regression of the müllerian ducts, which otherwise give rise to the fallopian tubes, the uterus, and the upper part of the vagina. 46,XY DSD include gonadal development disorders, disorders of androgen synthesis or action, disorders of AMH synthesis or action, complex malformative syndromes affecting the development of the genitourinary and digestive system, and severe early-onset intrauterine growth retardation, which is associated with hypospadias (1).
