Next-Generation Sequencing as First-Line Diagnostic Test in Patients With Disorders of Sex Development?

Disorders of sex development (DSD) are a group of highly heterogeneous disorders presenting mainly at birth or at pubertal age, characterized by discordance between chromosomal, gonadal, and/or genital sex. Newborns usually present with ambiguous genitalia while adolescents present with atypical or downright absent pubertal development (1). The underlying pathogenesis may rely on gonadal differentiation or on sex hormone biosynthesis or action. Indeed, the pioneering experiments performed by Alfred Jost in the 1940s demonstrated that the actions of 2 testicular hormones—androgens and the subsequently characterized anti-Müllerian hormone (AMH)—are essential for the virilization of the fetus, while in the absence of testicular hormones the fetal genitalia undertake the female pathway (2). The primordia of the external genitalia are identical in all embryos before gonadal differentiation, and their degree of virilization during fetal life depends on the extent of androgen action. This can be clinically assessed using the external genitalia score, based on a standardized description of the external genitalia, which applies a graded scale from female (score 0) to male (score 10.5-12), with intermediate values in patients with ambiguous genitalia (3). Disorders of gonadal differentiation occur in individuals with atypical sex chromosomes but may also present as a consequence of single gene variants, particularly in 46,XY patients. Isolated impaired testosterone or dihydrotestosterone (DHT) biosynthesis and target-organ insensitivity to androgens are other endocrine etiologies of DSD, usually resulting from gene mutations in 46,XY individuals (4). Atypical, rather than ambiguous, genitalia are characteristic of complex dysmorphic syndromes that are not endocrine-related and prompt a different diagnostic approach (5).