European Review for Medical and Pharmacological Sciences 2018; 22: 3873-3887 Androgen insensitivity syndrome C. GULÍA1, S. BALDASSARRA2, A. ZANGARI1, V. BRIGANTI1, S. GIGLI3, M. GAFFI4, F. SIGNORE5, C. VALLONE5, R. NUCCIOTTI6, F.M. COSTANTINI6, A. PIZZUTI7, S. BERNARDO7, A. PORRELLO8, R. PIERGENTILI9 1Department of Pediatric Surgery and Urology Unit, San Camillo-Forlanini Hospital, Rome, Italy 2Physical Medicine and Rehabilitation, Policlinico Umberto I Hospital, Sapienza University, Rome, Italy 3Department of Radiology, Anatomo-pathology and Oncology, Policlinico Umberto I Hospital, Sapienza University, Rome, Italy 4Department of Urology, San Camillo-Forlanini Hospital, Rome, Italy 5Department of Obstetrics and Gynecologics, Misericordia Hospital, Grosseto, Italy 6Department of Urology, Misericordia Hospital, Grosseto, Italy 7Department of Medical Genetics, Policlinico Umberto I Hospital, Sapienza University, Rome, Italy 8Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 9Institute of Molecular Biology and Pathology, Italian National Research Council (CNR-IBPM), Rome, Italy Abstract. – OBJECTIVE: We provide a review Introduction of the literature about the Androgen Insensitivity Syndrome (AIS), its onset and associated devel- In animals, the development of a new indi- opmental anomalies and the genetic alterations vidual organism starts with fertilization, the causing it. MATERIALS AND METHODS: fusion of an ovum and a sperm, to create the We searched diploid zygote. Subsequent mitotic divisions al- PubMed with a larger emphasis on the physiol- ogy, genetics and current management of AIS. low the formation of the specific, recognizable RESULTS: AIS is an X-linked recessive Disor- stages of blastula, gastrula, and then organo- der of Sex Development (DSD). It is caused by genesis, finally resulting in the development of mutations of the Androgen Receptor, and their an embryo. The fusion of gametes defines the large amount and heterogeneity (missense and genetic pattern of the individual, sex determi- nonsense mutations, splicing variants, deletions, nation included. If the embryo presents a 46 XY and insertions) are responsible for the wide spec- karyotype, under normal circumstances it heads trum of possible phenotypes of patients, divided into Partial AIS (PAIS) and Complete AIS (CAIS). toward the formation of a male foetus because Once the clinical and laboratory investigations of the presence of the testis determining factor 1 have laid the foundation for a diagnostic hypothe- (TDF) on the Y chromosome . sis, it is important to identify the actual karyotype of the individual and search for the mutation in The Genetics of Foetus Development the Androgen Receptor to diagnose with certain- The initiation of male sex characterization in ty the syndrome. Alternatively, in the absence of humans is regulated by the Sex-determining Re- such evidence, the diagnosis should more prop- gion Y gene (SRY, situated on Yp11.2). This gene erly be an AIS-like condition, which we describe as well in our report. encodes a transcription factor that is a member CONCLUSIONS: The management of this DSD of the high mobility group (HMG) box family of is based on pharmacotherapies, surgery and DNA-binding proteins. The encoded protein is psychological support: all of them must be di- the Testis-Determining Factor (TDF), which ini- rected to facilitate the patient’s life, considering tiates male sex determination (Figure 1). Muta- his/her sexual identity. tions impairing SRY function cause sex reversal, with females with an XY karyotype and affected Key Words: by the gonadal dysgenesis syndrome2. Transpo- AIS, PAIS, CAIS, AIS-like, Androgen Receptor, Disor- ders of Sex Development (DSD). sition of part of the Y chromosome containing this gene to an X chromosome, either by unequal Corresponding Author: Alessandro Porrello, Ph.D; e-mail: [email protected] Roberto Piergentili, Ph.D; e-mail: [email protected] 3873 C. Gulía, S. Baldassarra, A. Zangari, V. Briganti, S. Gigli, M. Gaffi, et al. X-Y crossing over during male meiosis or by SOX9 and SF1 proteins allow the embryonic chromosome translocation, causes the birth of cells of the primordial gonads to start their dif- males with an XX karyotype and affected by the ferentiation into Sertoli cells at around day 50 XX male syndrome (also called de la Chapelle after fertilization, determining the making of a syndrome)3 (Figure 1). A summary of the main primordial testis. Simultaneously, SOX9 and SF1 genetic events regulating the early steps of sex suppress sexual female characteristics, through determination is illustrated in Figure 2. The fun- the regulation of the production of the anti-Mülle- damental and specific task of the TDF consists rian hormone (AMH, produced by Sertoli cells), in the activation of a male-specific transcription a member of the transforming growth factor-beta factor, belonging to the family of DNA-binding gene family, which mediates male sexual differ- proteins, called SRY box 9 (SOX9, encoded by a entiation (Figure 2). This hormone has the abil- member of the SRY box gene family on 17q24)4 ity to inhibit the development of the Müllerian and the Steroidogenic Factor I (SF1, encoded by ducts (which would otherwise differentiate into the NR5A1 gene on 9q33)5. SOX9 is a protein the uterus and fallopian tubes) in male embryos, coding gene that directs the male pathway in the promoting instead the making of Wolffian ducts. foetus and plays an important role also in the Sertoli cells contribute to testicular embryo- normal skeletal development. Therefore, muta- genesis also by producing a protein called Desert tions of this gene are often associated with skel- Hedgehog (DHH, located on 12q13), whose role etal dysplasia, with campomelic dysplasia, and is to promote the maturation of Leydig cells in the with genital ambiguity6. making of primordial testes (Figure 2). DHH is a The gene NR5A1 (Nuclear Receptor Subfamily member of the Hedgehog gene family encoding 5 Group A Member 1) encodes for the Steroidogen- signalling molecules that play an important role in ic Factor 1, a transcriptional activator essential for regulating morphogenesis. Defects in this protein sexual differentiation and formation of the prima- have been associated with 46,XY partial gonadal ry steroidogenic tissues. Mutations involving this dysgenesis8. gene are largely considered a major cause of hu- Another gene involved in the male reproduc- man Disorder of Sex Development (DSD)7. tive system’s development is Fibroblast Growth Figure 1. Sex determination in Homo sapiens depends on the dominant effect of the Sex-determining Region Y (SRY) gene, coding for the Testis Determining Factor (TDF) mapping in the short arm of the Y chromosome. A, The Y chromosome has two regions of homology with the X chromosome (dark grey; pseudoautosomal region) and a male-specific region (white, light grey) containing, among the others, the SRY gene. B, As a consequence of an aberrant crossing over (thin crossed lines) involving the male specific region, the SRY gene may translocate to the X chromosome. Thus, the translocated X chromosome (XSRY) may in- duce a male phenotype in a person with a 46,XX karyotype, while the translocated Y chromosome (YΔSRY) may cause a female phenotype in a person with a 46,XY karyotype. 3874 Androgen insensitivity syndrome Figure 2. Summary of the main genetic events regulating the early steps of sex determination. The dominant effect of TDF is sufficient to drive the bipotential gonad towards a male differentiation. See the text for detailed explanations. Factor 9 (FGF9, located on 13q11-12) (Figure 2) Androgen Insensitivity Syndrome - AIS encoding a protein, which is member of the fibro- AIS is one of the most commonly diagnosed blast growth factor (FGF) family. FGF9 carries XY DSD, with an estimated prevalence of out many biological processes, including embryo 2:100.000 to 5:100.00013 and an incidence of development, cell growth and testicular embryo- 1:20.00014 to 1:99.00015. It consists in the partial genesis9; therefore, FGF9 is activated by the pres- or complete inability of the cell to respond to an- ence of SOX9 and simultaneously increases the drogens16: this cellular inability can lead to the expression of both genes, determining a positive wrong development of primary and secondary feedback with SOX9 itself10. Presumably, FGF9 sexual characteristics. Historically, AIS is known performs basic processes in human testicular em- with several different names; here we remem- bryogenesis; indeed, mice lacking this gene dis- ber for example Reifenstein syndrome17, Gold- play a male-to-female sex reversal phenotype11. berg-Maxwell syndrome18, Morris’ syndrome19, Instead, an embryo with a 46,XX karyotype Gilbert-Dreyfus syndrome20, Lubs’ syndrome21, has a typical female development (Figure 2). The incomplete testicular feminization22, Rosewater absence of the Y chromosome implies the lack syndrome23, and Aiman’s syndrome24. The differ- of the SRY gene and, consequently, of the TDF; ent names reflected differences in patients’ phe- for this reason, the bipotential cells of embryonic notypes, thus inducing scientists and physicians gonads develop into ovaries, the Wolffian ducts to believe that they were due to different etiol- atrophy, and the Müllerian ducts develop into the ogies. Only later, the analysis of families with uterus, Fallopian tubes, cervix and upper portion recurrent pathologies but different phenotypes of