The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD): I) Physiology, classification, approach, and methodologyII) Biochemical and genetic markers in 46,XX DSD.

Maria Luisa Granada,Laura Audí

doi:10.1515/almed-2021-0042

Abstract

The development of female or male sex characteristics occurs during fetal life, when the genetic, gonadal, and internal and external genital sex is determined (female or male). Any discordance among sex determination and differentiation stages results in differences/disorders of sex development (DSD), which are classified based on the sex chromosomes found on the karyotype. This chapter addresses the physiological mechanisms that determine the development of female or male sex characteristics during fetal life, provides a general classification of DSD, and offers guidance for clinical, biochemical, and genetic diagnosis, which must be established by a multidisciplinary team. Biochemical studies should include general biochemistry, steroid and peptide hormone testing either at baseline or by stimulation testing. The genetic study should start with the determination of the karyotype, followed by a molecular study of the 46,XX or 46,XY karyotypes for the identification of candidate genes. 46,XX DSD include an abnormal gonadal development (dysgenesis, ovotestes, or testes), an androgen excess (the most frequent) of fetal, fetoplacental, or maternal origin and an abnormal development of the internal genitalia. Biochemical and genetic markers are specific for each group. Diagnosis of DSD requires the involvement of a multidisciplinary team coordinated by a clinician, including a service of biochemistry, clinical, and molecular genetic testing, radiology and imaging, and a service of pathological anatomy.

Highlights

Any discordance among sex determination and differentiation stages results in differences/disorders of sex development (DSD), which are classified based on the sex chromosomes found on the karyotype
Content: This chapter addresses the physiological mechanisms that determine the development of female or male sex characteristics during fetal life, provides a general classification of DSD, and offers guidance for clinical, biochemical, and genetic diagnosis, which must be established by a multidisciplinary team
C-2) Genetic testing The most frequent monogenic causes of DSD were identified in the late 20th century with the cloning of the genes codifying proteins that were known to be altered in the clinical and biochemical phenotype

Summary

This work is licensed under the Creative Commons

Granada and Audí: Differences/disorders of sex development (DSD) 46,XX development into an ovary [1, 3, 5, 6]. International scientific societies recommend the use of mass spectrometry-based methods (LC–MS/MS and gas chromatography–mass spectrometry [GC–MS/MS]) for measuring sex steroids and their precursors in the diagnosis of DSD, especially, in neonates [24] These methods measure different steroids in the same sample, including metabolites that cannot be determined by specific immunoassays [25]. C-2) Genetic testing The most frequent monogenic causes of DSD were identified in the late 20th century with the cloning of the genes codifying proteins that were known to be altered in the clinical and biochemical phenotype This was especially useful for determination of enzyme deficiencies in adrenal and gonadal steroidogenesis (Figure 2), both in 46,XX and 46,XY DSD, and in complete androgen insensitivity. Table : Clinical diagnoses and genes involved in disorders or differences of sex development (DSD) of monogenic etiology

Ovotesticular DSD

Findings

Müllerian aplasia and hyperandrogenism