World J Pediatr, Vol 5 No 2 . May 15, 2009 . www.wjpch.com 93 Update on disorders of sex development Review article Author Affiliations: Department of Pediatrics, Division of Pediatric Endocrinology, University Hospital Gent, De Pintelaan 185, 9000 Gent, Belgium (Cools M); Department of Pathology, Erasmus Medical Center, Josephine Nefkens Institute, Daniel Den Hoed Cancer Clinic, Postbus 2040, 3000 DR Rotterdam, The Netherlands (Looijenga LHJ); Department of Urology (Wolffenbuttel KP) and Department of Pediatrics (Drop SLS), Sofia Children's Hospital, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands Corresponding Author: Martine Cools, Department of Pediatrics, Division of Pediatric Endocrinology, University Hospital Gent, Building 5K6, De Pintelaan 185, 9000 Gent, Belgium (Tel: +32 93324728; Email: martine. cools@ugent.be) doi:10.1007/s12519-009-0020-7 ©2009, World J Pediatr. All rights reserved. Background: Considerable progress has been made on genetic mechanisms involved in disorders of sex development and on tumor formation in dysgenetic gonads. Clinical and psychological outcome of patients are, as far as evaluated, unsatisfactory at present. Guidelines are emerging in order to optimize long-term outcome in the future. Data sources: The information obtained in this review is based on recent original publications and on the experience of our multidisciplinary clinical and research group. Results: This review offers an update on our knowledge concerning gene mutations involving in disorders of sex development, on the renewed nomenclature and classification system, and on the mechanisms of tumor development in patients. Conclusions: The consensus meeting on disorders of sex development has renewed our interest in clinical studies and long-term outcome of patients. Psychological research emphasizes the importance to consider male gender identity wherever possible in cases of severe undervirilization. Patient advocacy groups demand a more conservative approach regarding gonadectomy. Medical doctors, scientists and governmental instances are increasingly interested in the set-up of international research collaborations. As a consequence, it is expected that new guidelines for the optimal care of patients will be proposed in the coming years. World J Pediatr 2009;5(2):93-102 Key words: consensus; germ cell tumor; nomenclature; risk; sex development Introduction D isorders of sex development (DSD) is regarded as an umbrella term, referring to a group of congenital conditions in which the development of the chromosomal, gonadal or anatomical sex has been atypical. [1,2] DSD has replaced the formerly used term "intersex". DSD represents a markedly heterogeneous group of conditions. On one hand, identical genetic defects may result in various clinical presentations; on the other hand, a similar phenotype may be the end point of different genetic pathways. A detailed insight in the stepwise normal process of sex development and the different genes involved is essential to understand the mechanisms eventually leading to DSD. Specific subgroups of DSD patients are prone to the development of a germ cell tumor (GCT). Their individual risk profile can be estimated by combining knowledge on the specific gonadal differentiation patterns present in patients, and detailed histological and genetic diagnostic investigations. The process of normal sex development The embryonic precursors of the gonads and genital structures are bipotential, in other words, they have the potential to differentiate either into the male or female direction, depending on the correct and timely expression of specific genes. In mammals, male sex Martine Cools, Leendert HJ Looijenga, Katja P Wolffenbuttel, Sten LS Drop Ghent, Belgium and Rotterdam, The Netherlands Disorders of sex development: update on the genetic background, terminology and risk for the development of germ cell tumors