Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License Page 1 Journal of Current Medical Research and Opinion 1:3 April (2018) Contents lists available at www.cmro.in JOURNAL OF CURRENT MEDICAL RESEARCH AND OPINION Journal homepage: http://cmro.in/index.php/jcmro Clinical Approach for Evaluation and Management of Disorders of Sex Development Najya A. Attia 1 1. King Abdulaziz Medical City.Pediatric Department. Endocrine unite King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia ARTICLE INFO ABSTRACT Corresponding Author: Najya A. Attia King Abdulaziz Medical City. Pediatric Department. Endocrine unite King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Keywords:genitalia; disorders of sex development; sex assignment. "It's a boy" and "It's a girl" are words that are heard every second of every day all around the world. However, it is very distressing when the birth attendants are unable to make such a pronouncement because of disorders of sex development (DSD). DSD are congenital conditions associated with an atypical development of chromosomal, gonadal or anatomical sex. Normal sex development progresses in steps from conception to the complete development of the fetal external genitalia; any disturbance in any of these steps can lead to DSD. Ambiguous genitalia are the most common type of DSD and it is a challenging clinical diagnosis for the pediatric endocrinologist. A newborn baby with ambiguous genitalia is often a surprise for both the medical team and the parents, frequently described as an emergency. The condition needs a special approach in terms of counseling the parents appropriately, evaluation and management. The Chicago Conference (2006) recommended new nomenclature and a classification for DSD, as the old nomenclature was confusing for doctors and parents, and sometimes pejorative. The new classification is based on karyotyping and gonadal structure, improving understanding of the underlying pathogenic mechanisms. The rapid progression of genetic diagnosis of DSD using advanced techniques such as next-generation sequencing (NGS) allows more appropriate diagnosis and genetic counseling for families. The focus of the article is a review of normal sex development, DSD classification, clinical approach, genetic assessment, sex assignment, surgical management and risk of germ cell tumor development. INTRODUCTION Normal sex development and differentiation Sex differentiation is a complex phenomenon that follows five steps: 1-Genetic sex, the conjugation of a sperm and the ovum gives rise to the fertilized egg, which has either a 46,XYor 46,XX chromosome (1). 2-Formation of undifferentiated structures, during the first six weeks of gestation the male and female fetus develops similar sex elements, which consist of the following potential structures: I) The gonadal ridge which develops in the testis or ovary. II) Germ cells, which eventually develop into spermatocytes or oocytes. III) Two sets of internal sex ducts (Wolffan ducts in males and Mullerian ducts in females). IV) External genitalia including the genital tubercle, urethral folds, labioscrotal folds and urogenital sinus. 3-Gonadal differentiation, the bipotential gonad develops into testis in the presence of a Y chromosome, which carries the SRY gene (Sex-determining Region Y) responsible for testicular formation. In the absence of a Y chromosome or SRY gene, the gonad develops into an ovary (2). 4-Gonadal hormones, at 7 weeks of gestation the testis secrete two hormones, testosterone and anti- Müllerian hormone (AMH). The testosteroneis produced by the Leydig cells of the fetal testes and plays an essential role in the differentiation of Wolffian ducts to the epididymis, vas deferens and seminal vesicle. The AMH, on the other hand, is secreted by the Sertoli cells of the fetal testes and is responsible for the regression of Müllerian ducts. In females, the Mü llerian ducts develop spontaneously into fallopian tubes, uterus and upper third of the vagina and the Wolffian ducts disappear (3). 5-Phenotypic sex differentiation, the cells of the external genitalia of the male fetus has the ability to metabolize testosterone to dihydrotestosteron (DHT), which is