ABSTRACT

The 46,XY differences of sex development (46,XY DSD) can result either from decreased synthesis of testosterone and/or DHT or from impairment of androgen action. 46,XY DSD are characterized by micropenis, atypical or female external genitalia, caused by incomplete intrauterine masculinization with or without the presence of Müllerian structures. Male gonads are identified in the majority of 46,XY DSD patients, but in some of them no gonadal tissue is found. 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 amenorrhea. A careful clinical evaluation of the neonate is essential because most DSD patients could be recognized in this period and prompt diagnosis allows a better therapeutic approach. Family and prenatal history, complete physical examination and assessment of genital anatomy are the first steps for a correct diagnosis. The diagnostic evaluation of DSD includes hormone measurements (assessment of Leydig and Sertoli cell function), imaging (ultrasonography is always the first and often the most valuable imaging modality in DSD patients’ investigation), cytogenetic, and molecular studies. Endoscopic and laparoscopic exploitation and/or gonadal biopsy are required in very few cases. Psychological evaluation is of crucial importance to treat DSD patients. Every couple that has a child with atypical genitalia must be assessed and receive counseling by an experienced psychologist, specialized in gender identity, who must act as soon as the diagnosis is suspected, and then follow the family periodically, more frequently during the periods before and after genitoplasty. Parents must be well informed by the physician and psychologist about normal sexual development. A simple, detailed, and comprehensive explanation about what to expect regarding integration in social life, sexual activity, need of hormonal and surgical treatment and the likely possibility or not of fertility according to the sex of rearing, should also be discussed with the parents before the assignment of final social sex. Optimal care of DSD patients begins in the newborn period and sometimes in prenatal life and requires a multidisciplinary team. Most of the well-treated DSD patients present a normal quality of life in adulthood. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Male phenotypic development is a 2-step process: 1) testis formation from the primitive gonad (sexual determination) and 2) internal and external genitalia differentiation by action of factors secreted by the fetal testis (sexual differentiation). The first step is very complex and involves interplay of several transcription factors and signaling cells (1-3). Dosage imbalances in genes involved in DSD (deletions or duplication) have also been identified as a cause of these developmental differences (Fig. 1).

Figure 1.

Summary of the molecular events in sex determination indicating the genes in which molecular defects can cause gonadal disorders in animal models. Some of these disorders were confirmed in humans. Nr5a1, Wnt4 and Wt1 are expressed in the urogenital ridge whose development results in formation of the gonads, kidneys, and adrenal cortex. Several genes, Wt1, Nr5a1, M33 (CBX2 mouse homologue), Lhx9, Lim1, Gata4/Fog2, Dmrt1, Emx2 and Cited are expressed in the bipotential gonad. Nr5a1 up-regulates Cbx2 expression that is required for upregulation of the Sry gene. Nr5a1 and Wt1 up-regulate Sry expression in pre-Sertoli cells and Sry initiates male gonad development. Sry strongly up-regulates Sox9 in Sertoli cells. Sox9 up-regulates Fgf9 and Fgf9 maintains Sox9 expression, forming a positive feed-forward loop in XY gonads. The balance between Fgf9 and Rspo1/Wnt4 signals is shifted in favor of Fgf9, establishing the male pathway. If Wnt4/Rspo1 is overexpressed activating the β-catenin pathway, this system blocks Fgf9 and disrupts the feed-forward loop between Sox9 and Fgf9. Pdg2 signaling up-regulates Sox9 and Sox9 activate Ptgds. Sox9 establishes a feed-forward loop with the Pgd2. Sox9 inhibits beta-catenin-mediated Wnt signaling. Overexpression in either Dax1 (locus DSS) or Rspo1/Wnt4 antagonizes testis formation. On the other hand, Dax1 regulates the development of peritubular myoid cells and the formation of testicular cords. Dmrt1 has recently been shown to be required for the maintenance of gonadal sex and to prevent female reprogramming in postnatal testis, Cbx2 directly or indirectly repress ovarian development. Dhx37 has critical roles in early human testis determination and also in the maintenance of testicular tissue.

The second step, male sex differentiation, is a more straightforward process. Mesonephric (Wolffian) and paramesonephric (Mullerian) ducts are present in both, male and female fetuses, and originate from the anterolateral epithelium of the urogenital ridge. Anti Müllerian hormone (AMH) secreted by the testicular Sertoli cells acts on its receptor in the Müllerian ducts to cause their regression. Testosterone secreted by the testicular Leydig cells acts on the androgen receptor in the Wolffian ducts to induce the formation of epididymis, deferent ducts and seminal vesicles (Fig. 2) (4). The external genitalia of the fetus derive from mesenchyme cells from the primitive streak. Under androgen stimuli male fetal urethral folds, genital tubercle and genital swellings give rise to corpus spongiosum and primitive urethra, phallus, and scrotal swellings respectively. This process is mediated by testosterone and its further reduced dihydrotestosterone (DHT), which acts on the androgen receptor of the prostate and external genitalia leading to their masculinization (5,6) (Figs. 3 - 8).

Figure 2.

Summary of the molecular events in sex differentiation indicating the genes in which molecular defects cause 46,XY DSD in humans. After testis determination, hormones produced by the male gonad induce the differentiation of internal and external genitalia acting on their specific receptor. The regulation of AMH gene requires cooperative interaction between SOX9 and NR5A1, WT1, GATA4 and HSP70 at the AMH promoter. Combined expression of DHH, MAMLD1 and NR5A1 is required for Leydig cell development. NR5A1 regulates gonadal steroidogenesis. The Leydig cells also produce INSL3, which causes the testes to descend to the scrotum.

Figure 3.

The development of male internal genitalia in the human embryo. The 6-wk-end embryo is equipped with both male and female genital ducts derived from the mesonephrons.

Figure 4.

The development of male internal genitalia in the human embryo. The regression of the Müllerian ducts is mediated by the action of AMH secreted by the fetal Sertoli cells.

Figure 5.

The development of male internal genitalia in the human embryo. The stabilization and differentiation of the Wolffian ducts are mediated by testosterone synthesized by the fetal Leydig cells. The enzyme 5α-reductase 2 converts testosterone to dihydrotestosterone (DHT). The Wolffian ducts differentiate into epididymis, vas deferens and seminal vesicles. DHT contributes to prostate differentiation.

Figure 6.

Development of male external genitalia in the human embryo. At the 8-wk-end embryo the external genitalia of both sexes are identical and have the capacity to differentiate in both directions: male or female. DHT stimulates growth of the genital tubercle and induces fusion of urethral folds and labioscrotal swellings. It also inhibits growth of the vesicovaginal septum, preventing development of the vagina.

Figure 7.

Development of male external genitalia in the human embryo. At the 12-week-end embryo the male external genitalia are entirely formed.

Figure 8.

Development of male internal and external genitalia in the human embryo. At the 12-week-end embryo both internal and external genitalia are completely formed.

The term differences of sex development (DSD) include- congenital conditions in which development of chromosomal, or gonadal or anatomical sex is atypical. This nomenclature has been proposed to replace terms such as intersex, pseudo-hermaphroditism and sex reversal (6,7). These terms, previously used to describe the differences of sex development, are potentially offensive to the patients and the consensus on the management of intersex disorders recommends a new nomenclature that will be followed in this chapter (6). The proposed changes in terminology aim to integrate upcoming advances in molecular genetics in the most recent DSD classification (8).

The 46,XY DSDs are characterized by micro-penis, atypical or female external genitalia, caused by incomplete intrauterine masculinization with or without the presence of Müllerian structures. Male gonads are identified in the majority of 46,XY DSD patients, but in some of them no gonadal tissue is found. 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 amenorrhea. 46,XY DSD can result either from decreased synthesis of testosterone or DHT or from impairment of androgen action (9,10). Our proposal classification of 46,XY DSD is displayed in Table 1.

INVESTIGATION OF DSD PATIENTS

Optimal care of patients with DSD requires a multidisciplinary team and begins in the newborn period. A careful clinical evaluation of the neonate is essential because most DSD patients could be recognized in this period and prompt diagnosis allows a better therapeutic approach. Family and prenatal history, complete physical examination and assessment of genital anatomy are the first steps for a correct diagnosis. The diagnostic evaluation of DSD includes hormone measurements, imaging, cytogenetic, and molecular studies (11). In very few cases, endoscopic and laparoscopic exploitation and/or gonadal biopsy are required (12).

The endocrinological evaluation of 46,XY DSD infants includes assessment of testicular function by basal measurements of LH, FSH, inhibin B, anti-Mullerian hormone (AMH), and steroids.

AMH and inhibin B are useful markers of the presence of Sertoli cells and their assessment could help in the diagnosis of testis determination disorders. In boys with bilateral cryptorchidism serum AMH and inhibin B correlate with the presence of testicular tissue and undetectable values are highly suggestive of absence of testicular tissue (13,14).

In minipuberty and in postpubertal patients with testosterone synthesis defects, the diagnosis is made through basal steroid levels. Testosterone levels are low and steroids upstream from the enzymatic blockage are elevated. This pattern can be confirmed by an hCG stimulation test, which increases the accumulation of steroids before the enzymatic blockage, with a slight elevation of testosterone. In prepubertal individuals, an hCG stimulation test is essential for the diagnosis, since basal levels are not altered.

There are several hCG stimulation protocols and normative data must be established for each of them. We established a normal testosterone response 72 and 96 hours after the last of 4 doses of hCG, 50-100 U/kg body weight, given via intramuscular every 4 days in boys with cryptorchidism but otherwise normal external genitalia: testosterone peak levels reached 391 ± 129 ng/dL and we consider a subnormal response a value <130 ng/dL (equivalent to -2 SD) (15).

Imaging evaluation is indicated in the neonatal period when atypical genitalia are identified. If apparent female genitalia with clitoral hypertrophy, posterior labial fusion, foreshortened vulva with single opening or inguinal/labial mass is present, imaging studies may also be performed. A family history of DSD and later presentations as abnormal puberty or primary amenorrhea, cyclic hematuria in a male, and inguinal hernia in a female also require an imaging evaluation.

Ultrasonography is always the first and often the most valuable imaging modality in DSD patients’ investigation. Ultrasound shows the presence or absence of Müllerian structures at all ages and can locate the gonads and characterize their echo texture. This exam can also identify associated malformations such as kidney abnormalities (16).

Genitography and cystourethrography can display the type of urethra, the presence of vagina, cervix, and urogenital sinus. MRI contributes to accurate morphologic evaluation of Mullerian duct structures, the gonads, and the development of the phallus, all of which are essential for appropriate gender assignment and planning of surgical reconstruction (17).

CYTOGENETIC AND MOLECULAR INVESTIGATION

The routine use of genetic testing for reaching a diagnosis in XY DSD is increasingly playing an important role in the diagnostic process. A wide range of techniques may be used, each one having a different investigative application and genetic resolution (18,19).

More than 75 genes involved in gonadal development and/or sex hormone biosynthesis/action are known causes of DSDs and the molecular methodologies have contributed to identify already known as well as novel causes of DSD. These results have led to the adoption of molecular tests into clinical practice for diagnosis and genetic counseling, reducing the need of hormonal and imaging tests to reach the correct diagnosis (20). Advances in molecular biological techniques for diagnosing DSD are reviewed in recent publications (18,19).

Sequencing Analysis

Among the genetic tests, many use a candidate-gene approach (Sanger sequencing), while targeted DSD gene panels, wider whole-exome (WES) and whole-genome (WGS) scale are high-throughput screening technologies, in which multiple short DNA target sequences are analyzed to identified the presence of allelic variants (29).

Sanger sequencing is often the method of choice if a specific genetic condition is highly suspected by an established clinical and hormonal diagnosis. AR and SRD5A2, in addition to almost all testosterone synthesis defects, are the most requested genes in 46,XY DSD to be sequenced using this approach (20).

The superiority of targeted DSD gene panel tests, that can evaluate simultaneously several and non-standard sets of genes, over single-gene testing approaches is well established, especially considering time and cost-effectiveness (26,30).

Whole-Exome Sequencing (WES) and Whole-Genome Sequencing (WGS) are also based on short-read sequencing. They present a clear improvement over single-gene testing in providing clinical diagnosis for DSD. The advantage of WES/WGS is the potential to identify new DSD-related genes in the research setting. On the other hand, WGS has more consistent coverage of gene sequences throughout the genome, including the non-coding regions and so it has the potential to provide a much higher diagnostic yield than WES (25,31).

Nevertheless, WES and WGS require significant bioinformatic resources and are expensive strategies; consequently, their application for first-line diagnostic investigation in many clinical settings are still limited (18,32).

The target DNA can also be read in longer fragments (several kb). The main advantage of using long-reads during the process is that repetitive elements and complex structural variants can often be resolved to a greater extent than in assemblies generated from short-read sequencing (18). Long-read sequencing offers a potential solution to genome-wide short tandem repeats analysis, which are highly variable elements, which play a pivotal role in the regulation of gene expression.

Studies in animal models have suggested the involvement of epigenetic regulation in the process of gonadal formation, reinforcing a probable role of epigenetic variation in the etiology of DSD (33).

Careful selection of the genetic test indicated for each condition remains important for a good clinical practice (Figure 9).

Figure 9.

Algorithm for 46,XY DSD diagnosis

46,XY DSD DUE TO ABNORMALITIES IN GONADAL DEVELOPMENT

Uncountable allelic variants identified in several genes involved in the process of human gonadal determination have been associated with 46,XY gonadal dysgenesis. They will be described according to the period of gene expression in gonadal determination.

46,XY DSD ASSOCIATED WITH CHOLESTEROL SYNTHESIS DEFECTS

46,XY DSD DUE TO TESTOSTERONE PRODUCTION DEFECTS

46,XY DSD Due to Enzymatic Defects in Testosterone Synthesis

Six enzymatic defects that alter the normal synthesis of testosterone have been described to date (Figure 10). Three of them are associated with defects in cortisol synthesis leading to congenital adrenal hyperplasia. All of them present an autosomal recessive mode of inheritance and genetic counseling is mandatory since the chance of recurring synthesis defects among siblings is 25%.

Figure 10.

Standard steroidogenesis and alternative pathway to DHT synthesis.

DEFECTS IN ADRENAL AND TESTICULAR STEROIDOGENESIS

Adrenal hyperplasia syndromes are examples of hypoadrenocorticism or mixed hypo- and hyper cortico-adrenal steroid secretion. Synthesis of cortisol or both cortisol and aldosterone are impaired. When cortisol production is impaired, there is a compensatory increase in ACTH secretion. If mineralocorticoid production is impeded, there is a compensatory increase in renin-angiotensin production. These compensatory mechanisms may return cortisol or aldosterone production to normal or near normal levels, but at the expense of excessive production of precursors that can cause undesirable hormonal effects.

Lipoid Congenital Adrenal Hyperplasia due to Deficiency of the Steroidogenic Acute Regulatory Protein (StAR)

StAR is a mitochondrial phosphoprotein which facilitates the influx of cholesterol from the outer to the inner mitochondrial membrane for the subsequent action of the P450scc enzyme (212).

StAR is encoded by the STAR gene and its deficiency leads to congenital lipoid adrenal hyperplasia (CLAH), the most severe form of congenital adrenal hyperplasia (213) . Lipoid adrenal hyperplasia is rare in Europe and America, but it is thought to be the second most common form of adrenal hyperplasia in Japan where 1 in 300 individuals carries the p.Q258X variant (214).

Affected subjects are phenotypic females irrespective of gonadal sex or sometimes have slightly virilized external genitalia with or without cryptorchidism, underdeveloped internal male organs and an enlarged adrenal cortex, engorged with cholesterol and cholesterol esters (215). Adrenal steroidogenesis deficiency leads to salt wasting, hyponatremia, hyperkalemia, hypovolemia, acidosis, and death in infancy, although patients can survive to adulthood with appropriate mineralocorticoid- and glucocorticoid-replacement therapy (215).

Hormonal diagnosis is based on high ACTH and renin levels and the presence of low levels of all glucocorticoids, mineralocorticoids, and androgens.

The disease was firstly attributed to P450scc deficiency, but most of the cases studied through molecular analysis showed an intact P45011A gene and its RNA (216). Since StAR is also required for the conversion of cholesterol to pregnenolone, molecular studies were performed in StAR gene and variants were found in most of the affected patients (217) Congenital lipoid adrenal hyperplasia (LCAH) in most Palestinian cases is caused by a founder c.201_202delCT variant causing premature termination of the StAR protein (217) Histopathological findings of excised XY gonads included accumulation of fat in Leydig cells since 1 yr. of age, positive placental alkaline phosphatase and octamer binding transcription factor (OCT4) staining indicating a neoplastic potential (217).

A two-hit model has been proposed by Bose et al. (216) as the pathophysiological explanation for LCAH. In response to a stimulus (e.g., ACTH), the normal steroidogenic cell recruits cholesterol from endogenous synthesis, stored lipid droplets or low-density lipoprotein-receptor mediated endocytosis.

Subsequently StAR promotes the cholesterol transport from the outer to the inner mitochondrial membrane in which cholesterol is further processed to pregnenolone. In cells with mutant StAR (first hit), there is no rapid steroid synthesis, but still some StAR-independent cholesterol flows into the mitochondria, resulting in a low level of steroidogenesis. Due to increased steroidogenic stimuli in response to inadequately low steroid levels, additional cholesterol accumulates. Massive cholesterol storage and resulting biochemical reactions eventually destroy all steroidogenic capacity (second hit) (217). This two-hit model has been confirmed by clinical studies (218) as well as StAR knockout mice research (219).

The human STAR gene is localized on chromosome 8p11.2 and consists of seven exons (220). It is translated as a 285-amino acid protein including a mitochondrial target sequence (N terminal 62 amino acids), which guides StAR to the outer mitochondrial membrane and a cholesterol binding site, which is located at the C-terminal region. In vitro studies revealed that StAR protein lacking the N terminal targeting sequence (N-62 StAR) can still stimulate steroidogenesis in transfected COS-1 cells, whereas variants in the C-terminal region led to severely diminished or absent function (221-223). Most of the STAR gene variants associated with LCAH are located in the C-terminal coding region between exons 5 and 7 StAR related lipid transfer (START) domain (224). Mild phenotype of lipoid CAH is a recognized disorder caused by StAR variants that retain partial activity (225). Affected males can present with adrenal insufficiency resembling autoimmune Addison disease with micropenis or normal development with hypergonadotropic hypogonadism (224,225). More than 40 StAR variants causing classic lipoid CAH have been described (217,226,227), but very few partial loss-of-function variants have been reported (224-226). Therefore, there is a broad clinical spectrum of StAR variants, however, the StAR activities in vitro correlate well with clinical phenotypes (228).

Three 46,XY patients with the homozygous p.R188C STAR variant causing primary adrenocortical insufficiency without atypical genitalia were reported (229). Patients with nonclassical lipoid CAH may present with male genitalia and preserved testicular function (230).

Table 8.

_{Phenotype of 46,XY Subjects with StAR Deficiency}

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Inheritance	Autosomal recessive
External genitalia	Female Micropenis (mild form)
Müllerian duct derivatives	Absent
Wolffian duct derivatives	Absent -> hypoplastic
Testes	Small size
Clinical Features	Early adrenal insufficiency; no pubertal development; hypergonadotropic hypogonadism
Hormonal diagnosis	Elevated ACTH and renin levels; low levels of all glucocorticoids, mineralocorticoids, and androgens
Gender role	Female Male (mild form)
STAR gene location	8p11.2
Molecular defect	Inactivating variants in STAR
Treatment	Early gluco- and mineralocorticoid replacement; estrogen replacement at pubertal age
Outcome	Infertile, female or male gender role and behavior

Deficiency of P450 Side Chain Cleavage Enzyme (P450scc) Due to Variants in CYP11A1

The first step in the conversion of cholesterol to hormonal steroids is hydroxylation at carbon 20, with subsequent cleavage of the 20-22 side chain to form pregnenolone. In steroidogenic tissues, such as adrenal cortex, testis, ovary, and placenta, this is the initial and rate-limiting step in steroidogenesis. This reaction, known as cholesterol side-chain cleavage, is catalyzed by a specific cytochrome P450 called P450scc or CYP11A1 encoded by the CYP11A1 gene (231).

A number of patients with CYP11A1 variants have now been described (232-235), including late-onset non-classical forms secondary to variants that retain partial enzyme activity (236,237). Clinically, these patients are indistinguishable from those with lipoid CAH, but none of them present enlarged adrenals that characterize lipoid CAH.

Analyzing infants with adrenal failure and disorder of sexual differentiation compound heterozygous variants in CYP11A1 have been identified, recognizing that this disorder may be more frequent than originally thought. The phenotypic spectrum of P450scc deficiency ranges from severe loss-of-function variants associated with prematurity, complete under androgenization, and severe early-onset adrenal failure, to partial deficiencies found in children born at term with mild masculinization and later-onset adrenal failure (236,237).

3β-Hydroxysteroid Dehydrogenase type II Deficiency

3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency is a rare form of congenital adrenal hyperplasia (CAH), with fewer than 200 cases reported in the world literature.

3β-HSD converts 3β-hydroxy 5 steroids to 3-keto 4 steroids and is essential for the biosynthesis of mineralocorticoids, glucocorticoids and sex steroids Two forms of the enzyme have been described in man: the type I enzyme which is expressed in placenta and peripheral tissues such as the liver and skin, and type II that is the major form expressed in the adrenals and gonads (238). The two forms are very closely related in structure and substrate specificity, though the type I enzyme has higher substrate affinities and a 5-fold greater enzymatic activity than type II (238).

Male patients with 3β-HSD type II deficiency present with atypical external genitalia, characterized by microphallus, proximal hypospadias, bifid scrotum and a blind vaginal pouch associated or not with salt loss (239,240). Precocious pubarche and gynecomastia at pubertal stage is a common phenotype in 3β-HSD type II deficiency (241).

Serum levels of Δ-5 steroids such as pregnenolone, 17OHpregnenolone (17OHPreg), DHEA, DHEAS are elevated and basal levels of 17OHPreg and 17OHPreg/17OHP ratio are the best markers of this deficiency in both prepubertal and postpubertal stage. Δ-4 steroids are slightly increased due to the peripheral action of 3β-HSD type I enzyme but the ratio of Δ-5/Δ-4 steroids is elevated. Cortisol secretion is reduced but the response to exogenous ACTH stimulation varies from decreased (more severe deficiency) to normal. At adult age, affected males can reach normal or almost normal levels of testosterone due to the peripheral conversion of elevated Δ-5 steroids by 3β-HSD type I enzyme and also due to testicular stimulation by the high LH levels (242).

The human genome encodes two functional 3βHSD genes on chromosome 1p13.1. The HSD3B2 gene is expressed in adrenal and gonads and consists of four exons coding for a 372 amino acid protein (243). To date, around 40 variants in the HSD3B2 gene have been described. Most of them are base substitutions, and they are located especially at the N-terminal region of the protein. The amino acids A10, A82, P222 and T259 could be considered a hotspot since different variants were reported in these HSD3B2 positions.

Variants abolishing 3β-HSD type II activity lead to congenital adrenal hyperplasia (CAH) with severe salt-loss (244). Variants that reduce, but do not abolish type II activity ( > 5% of wild type 3βHSD2 activity in vitro) lead to CAH with mild or no salt-loss, which in males is associated with 46,XY DSD due to the reduction in androgen synthesis (241,242,245,246). Male subjects with 46,XY DSD due 3β-HSD type II deficiency without salt loss showed clinical features in common with the deficiencies of 17β-HSD3 and 5α-reductase 2.

Most of the patients were raised as males and kept the male social sex at puberty. In one Brazilian family, two cousins with 46,XY DSD due to 3β-HSD type II deficiency were reared as females; one of them was underwent orchiectomy in childhood and kept the female social sex; the other did not undergo orchiectomy at childhood and changed to male social sex at puberty (246).

There is little data on the outcomes of 3β-HSD type II deficiency. A mixed longitudinal and cross-sectional study from a single Algerian center reported 14 affected subjects (8 females) with pathogenic variants in HSD3B2 gene (247). Premature pubarche was observed in four patients (3F:1M). Six patients (5F:1M) entered puberty spontaneously, aged 11 (5-13) years in 5 girls and 11.5 years in one boy. Testicular adrenal rest tumors were found in three boys. Four girls reached menarche at 14.3 (11-14.5) years, with three developing adrenal masses and polycystic ovary syndrome (PCOS), with radiological evidence of ovarian adrenal rest tumor in one. The median IQ was 90 (43-105), >100 in only two patients and <70 in three of them (247).

Table 9.

_{Phenotype of 46,XY Subjects with 3β-HSD Type II Deficiency}

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Inheritance	Autosomal recessive
External genitalia	Atypical (proximal hypospadias, bifid scrotum, urogenital sinus), precocious pubarche
Müllerian derivatives	Absent
Wolffian duct derivatives	Normal
Testes	Well developed; generally topic
Clinical features	Adrenal insufficiency or not in infancy; virilization at puberty with or without gynecomastia
Hormonal diagnosis	Elevated basal and ACTH-stimulated 17OHPreg and 17OHPreg/17OHP ratio
Gender role	Male; female to male
HSD3B2 gene location	1p13.1
Molecular defect	Inactivating variants in HSD3B2
Treatment	Glucocorticoid replacement along with mineralocorticoids in salt-losing form; at puberty variable necessity for testosterone replacement
Outcome	Variable spermatogenesis; fertility possible by in vitro fertilization

Combined 17-Hydroxylase and C-17-20 lyase deficiency

CYP17 is a steroidogenic enzyme that has dual functions: hydroxylation and lyase. It is located in the fasciculata and reticularis zone of the adrenal cortex and gonadal tissues. The first activity results in hydroxylation of pregnenolone and progesterone at the C(17) position to generate 17α-hydroxypregnenolone and 17α-hydroxyprogesterone, while the second enzyme activity cleaves the C(17)-C(20) bond of 17α-hydroxypregnenolone and 17α-hydroxyprogesterone to form dehydroepiandrosterone and androstenedione, respectively. The modulation of these two activities occurs through cytochrome b5, necessary for lyase activity (248).

Deficiency of adrenal 17-hydroxylation activity was first demonstrated by Biglieri et al. (249). The phenotype of 17-hydroxylase deficiency in most of the male patients described is a female-like or slightly virilized external genitalia with blind vaginal pouch, cryptorchidism and high blood pressure, usually associated with hypokalemia. New in 1970, reported the first affected patient with atypical genitalia which was assigned to the male sex (250). The 17-hydroxylase deficiency is the second most common cause of CAH in Brazil (251).

At puberty, patients usually present sparse axillary and pubic hair. Male internal genitalia are hypoplastic and gynecomastia can appear at puberty. Most of the male patients were reared as females and sought treatment due to primary amenorrhea or lack of breast development. Genetic female patients may also be affected and present normal development of internal and external genitalia at birth and hypergonadotropic hypogonadism and amenorrhea at post pubertal age; enlarged ovaries at adult age and infarction from twisting can occur (252,253). These patients do not present signs of glucocorticoid insufficiency, due to the elevated levels of corticosterone, which has a glucocorticoid effect. The phenotype is similar to 46,XX or 46,XY complete gonadal dysgenesis and the presence of systemic hypertension and absence of pubic hair in post pubertal patients suggests the diagnosis of 17-hydroxylase deficiency (254).

Serum levels of progesterone, corticosterone, and 18-OH-corticosterone are elevated, while aldosterone, 17-OH-progesterone, cortisol, androgens and estrogens are decreased. Martin et al, performed a clinical, hormonal, and molecular study of 11 patients from 6 Brazilian families with the combined 17-alpha-hydroxylase/17,20-lyase deficiency phenotype (255). All patients had elevated basal serum levels of progesterone and suppressed plasma renin activity. The authors concluded that basal progesterone measurement is a useful marker of P450c17 deficiency and suggest that its use should reduce the misdiagnosis of this deficiency in patients presenting with male DSD, primary or secondary amenorrhea, and mineralocorticoid excess syndrome.

Excessive production of deoxycorticosterone and corticosterone results in systemic hypertension, suppression of renin levels and inhibition of aldosterone synthesis. The CYP17A1 gene, which encodes the enzymes 17-hydroxylase and 17-20 lyase, is a member of a gene family within the P450 supergene family and is mapped at 10q24.3 (254) (256). Several variants in the CYP17A1 gene have been identified in patients with both 17-hydroxylase and 17,20 lyase deficiencies (252,253,257). Four homozygous variants, p.A302P, p.K327del, p.E331del and p.R416H, were identified by direct sequencing of the CYP17A1 gene. Both P450c17 activities were abolished in all the mutant proteins but the mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of P450c17 proteins (257).

Glucocorticoid replacement for hypertension management, gonadectomy and estrogen replacement at puberty for patients reared in the female social sex are indicated. In male patients, androgen replacement is usually necessary since they present very low levels of testosterone. These patients are very sensitive to glucocorticoids and low doses of dexamethasone (0.125-0.5 mg at night) are sufficient to control blood pressure. In some patients, however, estrogens might aggravate hypertension. The control of blood pressure can be initially achieved by salt restriction although mineralocorticoid antagonists might be necessary (257).

Table 10.

_{Phenotype of 46,XY Subjects with 17a-Hydroxylase and 17,20-Lyase Deficiency}

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Inheritance	Autosomal recessive
External genitalia	Female like --> atypical
Müllerian duct derivatives	Absent
Wolffian duct derivatives	Hypoplastic --> normal
Testes	Intra-abdominal or inguinal
Clinical features	Low renin hypertension; absent or slight virilization at puberty; gynecomastia
Hormonal diagnosis	Elevated progesterone, DOC, corticosterone; low plasma renin activity low cortisol not stimulated by ACTH
Gender role	Female in most patients
CYP17 gene location	10q24.3
Molecular defect	Variants in CYP17A1 gene
Treatment	Repair of sexual ambiguity; glucocorticoid and estrogen or testosterone replacement according to social sex
Outcome	Female behavior, infertility

Cytochrome P450 Reductase (POR) Deficiency (Electron Transfer Disruption)

The apparent combined P450C17 and P450C21 deficiency is a rare variant of congenital adrenal hyperplasia, first reported by Peterson et al in 1985 (258). Affected girls and boys are born with atypical genitalia, indicating intrauterine androgen excess in females and androgen deficiency in males. Boys and girls can also present with skeletal malformations, which in some cases resemble a pattern seen in patients with Antley-Bixler syndrome. Findings of biochemical investigations of urinary steroid excretion in affected patients have shown accumulation of steroid metabolites, indicating impaired C17 and C21 hydroxylation, suggesting concurrent partial deficiencies of the 2 steroidogenic enzymes, P450C17 and P450C21. However, sequencing of the genes encoding these enzymes showed no variants, suggesting a defect in a cofactor that interacts with both enzymes. POR is a flavoprotein that donates electrons to all microsomal P450 enzymes, including the steroidogenic enzymes P450c17, P450c21 and P450aro (259). Shephard et al. (1989) isolated and sequenced cDNA clones that encode the rat and human NADPH-dependent cytochrome P-450 reductase and located the human gene at 7q11.2 (260).

The underlying molecular basis of congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency was defined in 3 patients, who were compound heterozygotes for variants in POR (259,260). Antley-Bixler syndrome is characterized by craniosynostosis, severe midface hypoplasia, proptosis, choanal atresia/stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, radio-humeral synostosis, long bone fractures, femoral bowing, phalangeal malformation (arachno-/campto-/clinodactyly, brachy-tele-phalanges, rocker bottom feet) and urogenital abnormalities (259). The occurrence of genital abnormalities in patients with Antley-Bixler syndrome, especially females was reported in 2000 (261). In a recent large survey of patients with Antley-Bixler syndrome, it was demonstrated that individuals with an Antley-Bixler-like phenotype and normal steroidogenesis have FGFR2 variants, whereas those with atypical genitalia and altered steroidogenesis have POR deficiency (262). The skeletal malformations observed in many, but not all patients with POR deficiency, are thought to be due to disruption of enzymes involved in sterol synthesis, 14α-lanosterol demethylase (CYP51A1) and squalene epoxidase, and disruption of retinoic acid metabolism catalyzed by CYP26 isoenzymes that depend on electron transfer from POR (263).

Pubertal presentations in females with congenital POR deficiency were described. Incomplete pubertal development and large ovarian cysts prone to spontaneous rupture were the predominant findings in females (264).The ovarian cysts may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR. In the two boys evaluated, pubertal development was more mildly affected, with some spontaneous progression. These findings may suggest that testicular steroidogenesis may be less dependent on POR than adrenal and ovarian steroidogenesis (265).

Table 11.

_{Phenotype of 46,XY Patients with POR Deficiency}

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Inheritance	Autosomal recessive
External genitalia	Atypical
Müllerian duct derivatives	Normally developed
Wolffian duct derivatives	Normally developed
Testes	Well developed, frequent cryptorchidism
Hormonal diagnosis	Low T and cortisol and elevated basal ACTH, Prog and 17OHP
POR gene location	7q11.2
Molecular defect	Inactivating variants of POR gene
Puberty	Spontaneous pubertal development in males
Gender role	Male
Treatment	Repair of sexual ambiguity; glucocorticoid replacement and estrogen or testosterone replacement according to social sex
Outcome	Puberty development, fertility?

DEFECTS IN TESTICULAR STEROIDOGENESIS

Three defects in testosterone synthesis that are not associated with adrenal insufficiency have been described: CYP17A1 deficiency, cytochrome B5 deficiency and 17-β-HSD3 deficiency.

CYP17A1 Deficiency

Human male sexual differentiation requires production of fetal testicular testosterone, whose biosynthesis requires steroid 17,20-lyase activity. The existence of true isolated 17,20-lyase deficiency has been questioned because 17-α-hydroxylase and 17,20-lyase activities are catalyzed by a single enzyme and because combined deficiencies of both activities were found in functional studies of the variant found in a patient thought to have had isolated 17,20-lyase deficiency (266,267). Later, clear molecular evidence of the existence of isolated 17,20 desmolase deficiency was demonstrated (268).

The patients present atypical genitalia with micropenis, proximal hypospadias and cryptorchidism. Gynecomastia Tanner stage V can occur at puberty (268). Elevated serum levels of 17-OHP and 17-OHPreg, with low levels of androstenedione, dehydroepiandrosterone and testosterone, are described. The hCG stimulation test results in a slight stimulation in androstenedione and testosterone secretion with an accumulation of 17-OHP and 17-OHPreg.

The CYP17A1 gene of two Brazilian 46,XY DSD patients with clinical and hormonal findings indicative of isolated 17,20-lyase deficiency, since they produce cortisol normally, were studied. Both were homozygous for missense variants in CYP17A1 (268). When expressed in COS-1 cells, the mutants retained 17α-hydroxylase activity and had minimal 17,20-lyase activity. Both variants alter the electrostatic charge distribution in the redox-partner binding site, so that the electron transfer for the 17,20-lyase reaction is selectively lost (268).

Table 12.

_{Phenotype of 46,XY Subjects with 17,20 Lyase Deficiency}

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Inheritance	Autosomal recessive
External genitalia	Atypical (proximal hypospadias, bifid scrotum, urogenital sinus)
Müllerian derivatives	Absent
Wolffian ducts derivatives	Hypoplastic --> normal
Testes	In the inguinal region, small size
Clinical features	Gynecomastia variable; poor virilization at puberty
Hormonal diagnosis	Elevated 17OHP and 17OHP/A ratio after hCG stimulation and decreased A and T levels;
Gender role	Male or female
CYP17 gene location	10q24.3
Molecular defect	Variants in the redox partner binding site of CYP17A1 enzyme
Treatment	Repair of hypospadias and gynecomastia; testosterone replacement at pubertal age
Outcome	Male or female behavior

Cytochrome B5 deficiency (Allosteric Factor for P450c17 and POR Interaction)

In 1986, Hegesh et al described a 46,XY DSD patient with type IV hereditary methemoglobinemia (269). The patient had a 16-bp deletion in the cytochrome b5 mRNA leading to a new in-frame termination codon and a truncated protein. The etiology of 46,XY DSD in this patient was attributed to the cytochrome b5 defect since cytochrome b5 acts as an allosteric factor, promoting the interaction of. P450c17 and POR favoring 17,20 lyase reactions (270).

Two homozygous variants in CYB5 in 46,XY DSD patients with elevated methemoglobin levels but without clinical phenotype of methemoglobinemia were reported (269).

46,XY DSD due to 17β-HSD 3 Deficiency

This disorder consists of a defect in the last phase of steroidogenesis when androstenedione is converted to testosterone and estrone to estradiol. This disorder was described by Saez and his colleagues (271) and is the most common disorder of androgen synthesis, reported from several parts of the world (272,273).

There are 5 steroid 17β-HSD enzymes that catalyze this reaction (274) and 46,XY DSD results from variants in the gene encoding the 17β-HSD3 isoenzyme (275). Patients present female-like or atypical genitalia at birth, with the presence of a blind vaginal pouch, intra-abdominal or inguinal testes and epididymis, vasa deferentia, seminal vesicles and ejaculatory ducts. Most affected males are raised as females (276,277), but some have less severe defects in virilization and are raised as males (274). Virilization in subjects with 17β-HSD3 deficiency occurs at the time of expected puberty. This late virilization is usually a consequence of the presence of testosterone in the circulation because of the conversion of androstenedione to testosterone by some other 17β-HSD isoenzyme (presumably 17β-HSD 5) in extra-gonadal tissue and, occasionally, of the secretion of testosterone by the testes when levels of LH are elevated in subjects with some residual 17β-HSD3 function (274,277). However, the discrepancy between the failure of intrauterine masculinization and the virilization that occurs at the time of expected puberty is poorly understood. A limited capacity to convert androstenedione into testosterone in the fetal extragonadal tissues may explain the impairment of virilization of the external genitalia in the newborn. Bilateral orchiectomy resulted in a clear reduction of androstenedione levels indicating that the main origin of this androgen is the testis (278). 46,XY DSD phenotype is sufficiently variable in 17β-HSD3 deficiency to cause problems in accurate diagnosis, particularly in distinguishing it from partial androgen insensitivity syndrome (276,279).

Laboratory diagnosis is based on elevated serum levels of androstenedione and estrone and low levels of testosterone and estradiol resulting in elevated androstenedione/testosterone and estrone/ estradiol ratios or low (or low testosterone/androstenedione and estradiol/estrone ratios) indicating impairment in the conversion of 17-keto into 17-hydroxysteroids. Testosterone/Androstenedione ratio of 0.4±0.2 was found in prepubertal patients with 17β-HSD3 deficiency after hCG stimulation. Based on these data, a T/A ratio below <0.8 is suggestive of 17β-HSD3 deficiency (272). At the time of expected puberty, serum LH and testosterone levels rise in all affected males and testosterone levels may reach the normal adult male range (277,278).

Pitfalls in the hormonal diagnosis of 17β-HSD3 deficiency had been reported in the literature. Two of the fourteen cases of 17β-HSD3 deficiency reported from the UK database had a T/A ratio > 0.8 (276). Both patients were from a consanguineous pedigree, with two affected sisters (both assigned in the female gender) and one nephew. The former patient had atypical genitalia with proximal hypospadias and was assigned as male. The hCG test was performed at 2 years and 2 months of age, respectively, resulting in a T/A ratio of 3.4 and 1.5. Two other patients with atypical genitalia, who were also assigned in the female social sex, were evaluated at 5 months and 9.2 year of age, respectively (280). After the hCG stimulation test, there was a clear elevation of serum testosterone (measured by HPLC tandem mass spectrometry) with a small increase of the androstenedione levels resulting in a high T/A ratio (2.47 and 2.27 respectively). Sequencing of the HSD17B3 gene identified deleterious molecular defects in both alleles in both patients. The possible explanation for the normal T/A ratio in these 4 children is the individual and temporal variability in the HSD17B isoenzymes activity (280).

The disorder is due to homozygous or compound heterozygous variants in the HSD17B3 gene which encodes the 17β-HSD3 isoenzyme. Up to now, almost 40 variants in the HSD17B3 gene have been reported. These include missense, nonsense, exonic deletion, duplication and intronic splice site variants (274,277). Although allelic variants have been described throughout HSD17B3, a variant cluster region was identified in the exon 9. The 17β-HSD3 activity was completely eliminated in the majority of the HSD17B3 variants (276). Outside exon 9, the most frequent site of variant in HSD17B3 gene is the R80 in exon 3, which primarily disrupts the binding of the NADPH cofactor to the protein. The p.R80Q variant has been found in Palestinian, Brazilian, and Turkish families (281).

Most patients are raised as girls during childhood. Change to male gender role behavior at puberty has been frequently described in individuals with this disorder who were reared as females (282-285), including members of a large consanguineous family in the Gaza strip (286). In a review of all adult patients with 46,XY DSD due to 17β-HSD3 deficiency reared as female and not castrated during childhood reported until now, we found that 30 of them (61%) kept the female gender and 19 of them (39%) changed to male gender (277).

After a histological analysis of testicular tissue stained with hematoxylin-eosin from 40 reported cases of 46,XY patients with 17β-HSD3 deficiency, the prevalence of germ cell tumor was 5%, which is lower than the estimated GCT risk for some 46,XY DSD etiologies (287-289). However, the maintenance of the testes in male patients is safe if the testes can be positioned into the scrotum (277,290).

Table 13.

_{Phenotype of 46,XY Patients with 17β-HSD 3 Deficiency}

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Inheritance	Autosomal recessive
External genitalia	Atypical, frequently female-like at birth
Müllerian duct derivatives	Absent
Wolffian duct derivatives	Normally developed
Testes	Well developed, frequent cryptorchidism
Hormonal diagnosis	Low T and elevated basal and hCG-stimulated A and A/T ratio
HSD17B3 gene location	9q22
Molecular defect	Inactivating variants of HSD17B3
Puberty	Virilization at puberty; variable gynecomastia
Gender role	Most patients keep the female social sex; some change to male social sex
Treatment	Repair of sexual ambiguity; estrogen or testosterone replacement according to social sex
Outcome	Male or female gender identity; in males’ fertility possible by in vitro fertilization

ALTERNATIVE PATHWAY TO DHT SYNTHESIS

46,XY DSD Due to 3α-Hydroxysteroid Dehydrogenase Deficiency (AKR1C2 and AKR1C4 Defects)

Back in 1972, the molecular analysis of 46,XY DSD due to isolated 17,20-lyase deficiency patients failed to find variants in the CYP17A1 (248). However, the hormonal data was inconsistent with other adrenal enzymatic deficiencies. Therefore, the alternative or backdoor pathway was considered to explain the etiology of the DSD in these patients. The backdoor pathway was firstly described in marsupials and is remarkable for having both reductive and oxidative 3α-HSD steps: the reductive reaction converts 17-OH-dihydroprogesterone (17OH-DHP) into 17OH-allopregnanolone (17OH-Allo), and the oxidative reaction converts androstanediol into DHT (291,292) (Figure 6). Therefore, synthesis of dihydrotestosterone (DHT) occurs without the intermediacy of DHEA, androstenedione or testosterone (291). All the human genes participating in the backdoor pathway have not been identified, however it has been thought that the reductive 3α-HSD activity can be catalyzed by an aldo-keto reductase called AKR1C2 (293), as well as by other enzyme, such as the oxidative 3α-HSD activity by 17β-HSD6, also called as RoDH (294) and possibly by AKR1C4 (295).

The first reported cases with isolated 17,20 lyase deficiency from 1972 (266) were found to carry variants in two aldo-keto reductases, AKR1C2 and AKR1C4 which catalyze 3α-hydroxysteroid dehydrogenase activity. The two affected 46,XY females were compound heterozygotes for AKR1C2 variants, the p.I79V/H90Q and p.I79V/N300T. However, the mutant AKR1C2 enzymes retained 22-82% of wild-type activity in vitro analysis suggesting that another gene might be involved (248). Analysis of AKR1C cDNA found that AKR1C4 was spliced incorrectly and gene sequencing displayed an intronic variant 106 bases upstream from exon 2 that caused this exon skipping. So, in this family, a digenetic inheritance was found to impair testicular synthesis of DHT during prenatal life (296).

AKR1C2 is abundantly expressed in the fetal testis, but minimally expressed in the adult testis; on the other hand, the AKR1C4 was found in fetal and adult testes at lower levels (293). Therefore, it appears that both AKR1C2 and AKR1C4 participate in the backdoor pathway to DHT in the fetal testis, and that molecular defects in these genes appear to cause incomplete male genital development (297). However, the relative roles of these two AKR1C enzymes remain unclear and testosterone levels at adult age are not available in these patients (298).

All findings described above, which substantially advanced our understanding of the underlying mechanisms of male sexual differentiation, illustrate the importance of detailed studies of rare 17,20 lyase deficiency patients.

46,XY DSD DUE TO DEFECTS IN TESTOSTERONE METABOLISM

46,XY DSD DUE TO DEFECTS IN ANDROGEN ACTION

46,XY DSD DUE TO PERSISTENT MÜLLERIAN DUCT

CONGENITAL NON-GENETIC 46,XY DSD

46,XY OVOTESTICULAR DSD

There are rare descriptions of 46,XY DSD patients with well characterized ovarian tissue with primordial follicles and testicular tissue, a condition that is histologically characterized 46,XY ovo-testicular DSD (386). The differential diagnosis of 46,XY ovo-testicular DSD with partial 46,XY gonadal dysgenesis should be performed considering that in the latter condition there are descriptions of dysgenetic testes with disorganized seminiferous tubules and ovarian stroma with occasional primordial follicles in the first years of life (46). To our knowledge there are no descriptions of an adult patient with 46,XY ovo-testicular DSD with functioning ovarian tissue, as occurs in all 46,XX ovo-testicular DSD. Therefore, the diagnosis of 46,XY ovo-testicular DSD is debatable.

NON-CLASSIFIED FORMS

GONADAL TUMOR DEVELOPMENT IN 46,XY DSD PATIENTS

Any disturbance in the gonadal development, including testicular descent, increases the risk of developing gonadal malignancies (288). For inherited disturbances in gonadal development or endocrine alterations, patients with 46,XY DSD are at increased risk of developing type II germ cell tumors (GCT) (289). In testicular tissues, GCTs comprise both premalignant conditions, such as germ cell neoplasia in situ (GCNIS) and malignant invasive germ cell tumors, including seminomas and non-seminomas (393).

The term GCNIS was introduced in the 2016 WHO classification of urological tumors to define precursor lesions of invasive GCTs, since GCNIS has the potential to develop into several types of GCTs (394,395). GCNIS cells are fetal gonocytes present in the seminiferous tubules arrested during gonadal development that failed to mature into spermatogonia (396). GCNIS are often detected in testicular tissues from 46,XY DSD subjects (397). It is estimated that 50% of GCNIS progress to an invasive GCT in five years (396,398,399).

A high risk of GCT is found when sex determination is disrupted at an early stage of Sertoli cell differentiation (due to abnormalities in SRY, WT1, SOX9) (289,397,400). For that reason, specific etiologies of 46,XY DSD (401) have a significant risk factor for GCT development (393). Early Sertoli cell development is also disturbed in patients with 45X/46,XY mosaicism (402). The presence of the well-defined Y chromosome region, known as the gonadoblastoma Y locus (GBY), is a prerequisite for malignant transformation. Among the genes located in the GBY region the testis-specific protein Y (TSPY) seems to be the most significant candidate gene for the tumor-promoting process (288,403). The presence of undifferentiated gonadal tissue containing germ cells that abundantly express TSPY has also been identified as a gonadal differentiation pattern bearing a high risk for GCT development (404). Prolonged expression of OCT3/4 (POU5F1) and the stem cell factor KITL after one year of age are also estimated to play a role in GCNIS/GCT development. Other factors implicated in that risk include MAP3K1 variants in 46,XY patients with gonadal dysgenesis due to MAPK signaling pathway upregulation and loss of androgen receptor function in patients with androgen insensitivity syndrome (289,405). Additionally, gonads at the abdominal region are at higher risk of GCNIS/GCT development than those appropriately positioned (393,406).

Unfortunately, GCNIS/GCT screening is challenging due to a lack of a predictive factor or a biomarker with adequate sensitivity and specificity (407). As far as imaging is concerned, ultrasound (US) is more sensitive than MRI at identifying dysgenetic gonads, but MRI showed better sensitivity and specificity than US at localizing non-palpable gonads (408). However, both imaging techniques are poor at identifying GCNIS/GCT, since MRI failed to identify GCNIS in patients with CAIS and the US only identified one out of ten malignant lesions in 46,XY DSD people (409). There are serum markers that are associated with GCT in non-DSD people, such as alpha-fetoprotein, beta-hCG, and lactate dehydrogenase, but there is poor evidence about how useful they are for GCT screening in 46,XY DSD individuals (410). An interesting perspective for GCT screening are microRNAs (miRNA), since some miRNA clusters are expressed in the presence of GCT (411). For non-DSD people, microRNAs are more sensitive than serum markers and imaging to detect GCT. Noteworthy, GCNIS also expresses some embryonic-type miRNAs (miR-371-3, miR-302, and miR-367) that are also expressed by GCTs (410,412). Therefore, they have the potential to serve as a biomarker even for GCNIS(407).

Overall, neoplastic transformation of germ cells in dysgenetic gonads (gonadoblastoma and/or an invasive germ cell tumor) occurs in 20-30% of 46,XY DSD individuals, but the risk varies among 46,XY DSD etiologies (413). Individuals with Denys-Drash syndrome (40%), Frasier syndrome (60%), and gonadal dysgenesis (15 - 35%) have the highest risk of GCNIS/GCT among 46,XY DSD etiologies (413). On the other hand, individuals with CAIS (at prepubertal age) and ovotestis DSD have lower risk of GCNIS/GCT (414). The age matters in the estimation of GCNIS/GCT risk. For example, it is as low as 1.3% in CAIS individuals before puberty, but it can reach 33% thereafter (287,415).

For 46,XY DSD subjects, gonadectomy is classically recommended to avoid GCNIS/GCT development, preventing additional therapies and related risks (290). Despite a very effective strategy to avoid GCNIS/GCT, gonadectomy leads to hypogonadism and infertility.

Regarding the time for gonadectomy, bilateral gonadectomy should be performed in early childhood in 46,XY DSD patients with gonadal dysgenesis, females with Y chromosome material, and patients with androgen biosynthesis defect, unless the gonad is functional and easily accessible to palpation and imaging studies, which should be performed yearly (11,289). Although data are limited, in the androgen insensitivity syndrome the risk seems to be markedly lower in the complete form before puberty than in the other 46,XY DSD (416). Therefore, gonadectomy can be postponed until puberty is complete in CAIS individuals (417). Unfortunately, the GCNIS/GCT risk for other causes of 46,XY DSD patients, such as Leydig Cell Hypoplasia and 5 alpha reductase type 2 deficiency has not been estimated yet.

Rarely, gonadal tumors can produce sexual steroids (418). In those cases that are able to produce estrogens, spontaneous breast development may be a clinical sign that suggests the presence of an estrogen-secreting gonadal tumor, and bilateral gonadectomy is indicated even at early childhood, regardless of the 46,XY DSD etiology.

Overall, 46,XY DSD patients are at increased risk for gonadal malignancy which seems to be related to 46,XY DSD etiology. While it is clear that prepubertal CAIS patients are at low risk for GCT and 46,XY DSD individuals harboring WT1 variants present a high risk for GCT development, the real GCT risk for other 46,XY DSD etiologies is not that clear (413). In the absence of a reliable predictive factor or biomarker of GCNIS/GCT as well as appropriate recommendations for GCT screening, bilateral gonadectomy will still be recommended for most 46,XY DSD etiologies.

FERTILITY IN PATIENTS WITH 46,XY DSD

Most 46,XY DSD individuals face infertility due to abnormal gonadal development, endocrine disturbances, anatomical issues, or prophylactic gonadectomy for malignancy risk (419). However, there has been growing evidence showing that fertility is relevant for several 46, XY DSD people, in addition to the possibility of delaying gonadectomy in some 46,XY DSD etiologies (420). In parallel, fertility preservation technologies have been improved in recent years along with a better social perception of non-traditional family structures (421,422).

In 46,XY DSD, the fertility potential varies depending on the underlying etiology as well as the severity of the condition (421). In this sense, all options for fertility should be discussed considering the 46,XY DSD etiology or the gonadal structure and internal genitalia in those in whom the 46,XY etiology is unknown (420).

For example, individuals with complete gonadal dysgenesis possess uterus, despite lacking gametes (423). Therefore, pregnancy by oocyte donation is an alternative for these patients. On the other hand, male individuals with partial and mild androgen insensitivity often present oligospermia, but biological fertility is possible (334,338).

Overall, there is limited literature about fertility potential among 46,XY DSD people. Successful biological fertility was obtained in a man with PAIS after prolonged high-dose testosterone therapy followed by intracytoplasmic sperm injection (424). The possibility of fertility seems to be more frequent among MAIS since there are six cases of successful fertility (338). There are few reported cases of successful pregnancies and live births in men with 5RD2 deficiency, both spontaneous and with assisted reproductive technology (319,425-427). Biological fertility has also been documented in individuals with nonclassical congenital lipoid adrenal hyperplasia, 3b-HSD2 deficiency, and LHCG receptor defect (420). Conversely, there are no reported cases of biological fertility in individuals with classic congenital lipoid adrenal hyperplasia, cytochrome p450 oxidoreductase deficiency, complete CYP17A1 deficiency, 17b-HSD3 deficiency, and CAIS (419,428).

To estimate fertility potential, a pilot study evaluated the presence of germ cells and the germ cell density in individuals with several 46,XY DSD etiologies (429). In six patients with CAIS, all presented Sertoli Cell nodules and hyperplasia, but germ cells were detected in areas between nodules. All six patients with mixed gonadal dysgenesis and two with ovo-testicular DSD presented germ cells, and ten out of twelve 46,XY DSD patients with unknown etiology presented germ cells in their gonads. On the other hand, germ cells were not found in any of the patients with either complete or partial gonadal dysgenesis. However, the number of germ cells was inversely correlated with age, suggesting that the gonadectomy delay may decrease fertility potential. It needs to be confirmed by more extensive studies, but it indicates that 46,XY DSD fertility potential may be greater than previously thought.

As far as desire for fertility is concerned, a large follow-up study included 1,040 DSD individuals to investigate their fertility preferences (430). The authors reported that 55% of patients expressed a desire to have had fertility treatments in the past or have it in the future, and 40% mentioned that they would like to try new fertility treatment techniques. Additionally, CAIS women reported the possibility of future fertility as one of the reasons to keep their gonads (362).

Indeed, fertility preservation has been primarily assessed in oncology to preserve patients' fertility under gonadotoxic treatments (431). In this sense, cryopreservation of postpubertal testicular tissue is helpful to keep fertility potential in patients having gonadectomy or those before gonadotoxic treatment. As an alternative, cryopreservation of immature testicular tissue containing spermatogonial cells or spermatogonial stem cells can be offered to prepubertal patients (432). These techniques could also be considered for 46,XY DSD patients.

In summary, addressing fertility is essential in 46,XY DSD management. The fertility potential must be discussed considering the 46,XY DSD etiology and the patient’s desire. As assisted fertility and preservation techniques improve, these advancements should be offered and accessible to all 46,XY individuals.

46,XY GENDER IDENTITY DISORDERS

Transgender Women are characterized by the wish to live as members of the female sex with conviction and consistently and progressively efforts to achieve such state. 46,XY gender identity disorders are more frequent among the male sex, although it also occurs in the female sex. Its first manifestations usually start during childhood. If it has a biological basis is still unknown, but some hormonal alterations during intrauterine life and familial factors before and after birth cannot be ruled out (433).

The term used to name men and women who live a relevant incongruence between their gender identity and their inborn physical phenotype has changed over time. The term “trans-sexualism” was coined by Hirschfeld in 1923 and was adopted by the International Classification of Diseases – version 10 (ICD-10). The American Psychiatric Association, in its 4^th edition, adopted “gender identity disorder” to define persons who are not satisfied with their biological gender (Association, American Psychiatric. "Diagnostic and statistical manual of mental disorders (2000).

Finally, the current classification system of the American Psychiatric Association (DSM-5) replaced the term “gender identity disorder” with “gender dysphoria” and the upcoming version of International Classification of Diseases – version 11 (ICD-11) has proposed the term “gender incongruence” (434).

In this chapter we will use the current DSM-5 term, “gender dysphoria”. To refer to male to female gender-dysphoric persons we will use the term transgender woman (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition - DSM-5; 2013). Therefore, the term “transgender woman” refers to all 46, XY individuals with typical male phenotype who wish to live and be accepted as a female.

Higher prevalence of addictions and suicidal thoughts or suicide attempt than those observed in the general population, revealed the need for early care of these patients by health professionals. Among transgender women, total mortality was 51% higher than in the general population, mainly from increased mortality rates due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse, and unknown cause (435). Based on these data, supervised gender-affirming treatment for gender dysphoric persons is crucial because they are at increased risk of committing suicide and self-harm (436).

MANAGEMENT OF PATIENTS WITH 46,XY DSD

It is important to stress that the treatment of 46,XY DSD patients requires an appropriately trained multi-disciplinary team. Early diagnosis is important for better outcomes and should start with a careful examination of the newborn’s genitalia at birth (445-447).

ACKNOWLEDGMENT

The authors would like to thank the postgraduate students Nathalia Lisboa Gomes and Jose Antonio D Faria Junior for their help in the update of this chapter.

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