Disorders of Sex Development.

1. Alejandro Diaz, MD*,† 2. Elizabeth G. Lipman Diaz, PhD, ARNP, CPNP‡ 1. *Nicklaus Children’s Hospital, Miami, FL 2. †Herbert Wertheim College of Medicine, Florida International University, Miami, FL 3. ‡University of Miami School of Nursing and Health Studies, Coral Gables, FL * Abbreviations: AMH: : anti-mullerian hormone CAH: : congenital adrenal hyperplasia CAIS: : complete androgen insensitivity CYP21A2: : 21-hydroxylase CYP11B1: : 11β-hydroxylase type 1 DHEA: : dehydroepiandrosterone 5α-DHT: : 5α-dihydrotestosterone DSD: : disorder of sex development EMS: : external masculinization score FSH: : follicle-stimulating hormone HCG: : human chorionic gonadotropin 3β-HSD2: : 3β- hydroxysteroid dehydrogenase/isomerase type 2 17β-HSD3: : 17β-hydroxysteroid dehydrogenase type 3 LH: : luteinizing hormone NR5A1: : nuclear receptor subfamily 5 group A, member 1 17-OHP: : 17-hydroxyprogesterone PAIS: : partial androgen insensitivity 5α-RD2: : 5α-reductase type 2 WT1 : : Wilms tumor suppressor gene Traditionally, ambiguous genitalia have been defined as a “medical and social emergency”; however, it is not. It requires a systematic, team-oriented approach. Access to genetic testing and molecular diagnosis permits better understanding of conditions that produce ambiguous genitalia and allows better planning for gender assignment and further care. After completing this article, readers should be able to: 1. Identify the most common causes of ambiguous genitalia in infants. 2. Understand basic imaging and laboratory tests for diagnosis. 3. Recognize the complexity of gender assignment and the need to partner with other medical specialties and the family for decision-making. 4. Recognize conditions that need immediate pharmacologic treatment to avoid medical complications. Disorders of sex development (DSDs), a vastly heterogeneous array of innate conditions, are secondary to abnormal development of sex chromosomes, as well as atypical growth of the gonads and genital anatomy. Specifically, DSDs result from insufficient virilization of the genitalia in a 46,XY fetus due to disorders of gonadal development, abnormal androgen synthesis, or disorders of androgen action, or secondary to the masculinization of the genitals of a 46,XX fetus. There is broad phenotypic expression of DSDs, ranging from minor variations of gonadal function and genital appearance to severely atypical gonads and genitalia. The incidence of ambiguous genitalia at birth is estimated to be 1:4,500 to 1:5,500. (1) Among 46,XY individuals, the incidence of DSDs has been estimated to be 1:20,000 births; however, cryptorchidism and hypospadias are common congenital anomalies, occurring in 1:200 to 1:300 newborns. (1) Among 46,XX individuals, the most common cause of DSDs is congenital adrenal hyperplasia (CAH), which occurs in 1:14,000 to 1:15,000 live births. (1) Prenatal karyotype evaluation as part of cell-free DNA testing is now common. Conditions such as complete androgen insensitivity (CAIS) or complete gonadal dysgenesis were often missed at birth or during infancy and childhood, …