Clinical Endocrinology (2009) 70, 173–187 doi: 10.1111/j.1365-2265.2008.03392.x © 2009 The Authors Journal compilation © 2009 Blackwell Publishing Ltd 173 CLINICAL PRACTICE UPDATE Blackwell Publishing Ltd 46,XY disorders of sex development (DSD) Berenice Bilharinho Mendonca, Sorahia Domenice, Ivo J. P. Arnhold and Elaine M. F. Costa *Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular, LIM 42, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil Summary The term disorders of sex development (DSD) includes congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. Mutations in genes present in X, Y or autosomal chromosomes can cause abnormalities of testis determination or disorders of sex differentiation leading to 46,XY DSD. Detailed clinical phenotypes allow the identification of new factors that can alter the expression or function of mutated proteins helping to understand new undisclosed biochemical pathways. In this review we present an update on 46,XY DSD aetiology, diagnosis and treatment based on extensive review of the literature and our three decades of experience with these patients. (Received 15 January 2008; returned for revision 16 February 2008; finally revised 4 May 2008; accepted 4 August 2008) Introduction Male phenotypic development can be viewed as a two-step process: (i) testis formation from the primitive gonad (sex determination) and (ii) internal and external genitalia differentiation due to factors secreted by the testis (sex differentiation). The first step is very complex and involves interplay of several transcription factors. 1–3 (Fig. 1). The second step, male sex differentiation, is a more straightforward process (Fig. 2). The term disorders of sex development (DSD) includes congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. The terms ‘male pseudohermaphroditism’, ‘intersex’, ‘sex reversal’, that previously described the DSD, were potentially derogatory to the patients and the consensus on the management of intersex disorders recommended a new nomenclature that will be followed in this review. 4,5 The 46,XY DSD are characterized by ambiguous or female external genitalia, caused by incomplete intrauterine masculinization, and the presence or absence of Mullerian structures. Complete absence of virilization results in normal female external genitalia and these patients generally seek medical attention at pubertal age, due to the absence of breast development and/or primary amenorrhoea. A classification of 46,XY DSD based on the disorder’s aetiology is proposed in Table 1. 46,XY DSD due to abnormalities of gonadal development Gonadal agenesis Total absence of gonadal tissue or gonadal streak has rarely been described in 46,XY subjects with female external and internal geni- talia indicating the absence of testicular determination. The origin of this disorder remains to be determined. A defect in genes essential for bipotential gonad development is likely the cause of this disorder. 46,XY DSD due to gonadal dysgenesis Complete and partial 46,XY gonadal dysgenesis 46,XY gonadal dysgenesis consist of a variety of clinical conditions in which the foetal gonad development is abnormal and encompasses both complete and a partial forms. The complete form is characterized by female external and internal genitalia, lack of secondary sexual characteristics, normal or tall stature without somatic stigmata of Turner syndrome and the presence of bilateral dysgenetic gonads. The partial form of this syndrome is characterized by impaired testicular development that results in patients with ambiguous external genitalia with or without Mullerian structures. Similar phenotypes can also result from a 45,X/46,XY karyotype. 46,XY gonadal dysgenesis is a heterogeneous disorder that results from SRY deletions or point mutations, dosage sensitive sex (DSS) locus duplication on X chromosome or mutations in autosomal genes. Mutations in SRY were found in < 20% of the patients with complete 46,XY gonadal dysgenesis. To date, more than 53 mutations have been identified within the SRY, and most of them (43 mutations), are located in the HMG box. Most of the mutations described in SRY are predominantly de novo mutations. However, some cases of fertile fathers and their XY affected children, sharing the same altered SRY sequence, have been reported. 6,7 In few of these cases, the father’s somatic mosaicism for the normal and mutant SRY have been demonstrated. Correspondence: Berenice B Mendonca, MD, Hospital das Clínicas, FMUSP, Divisão de Endocrinologia, Caixa Postal 3671, São Paulo, 01060-970, Brazil. Tel.: +55 11 30697512; Fax: +55 11 3083 7519; E-mails: beremen@usp.br; sorahia@ipt.br; iarnhold@usp.br; elaine@emfcosta.med.br