Disorders Of Sexual Differentiation Research Articles

SUN-205 A Case of 46XY Mixed Gonadal Dysgenesis Presenting with Unilateral Gonad and Hemiuterus: Family History Dictates Sex Assignment

Background: Disorders of sex differentiation (DSDs) result from an atypical congenital development of chromosomal, gonadal, or anatomical sex. Mixed gonadal dysgenesis, a rare DSD, is the presence of both ovarian and testicular tissue. Early sex assignment is challenging due to the variable clinical, cytogenetic, and histopathological presentations. Clinical Case: A 1-day-old born from an uncomplicated pregnancy at 36+4/7 weeks gestation (birth weight 3.7 kg) was noted to have ambiguous genitalia. Upon examination, external genitalia was a bifid scrotum with palpable right scrotal and non-palpable left gonad; no hyperpigmentation. Phallus length was 2.5 cm and width was 1.3 cm with chordee (Prader Stage 3 hypospadias) and a single proximal urogenital sinus (anogenital ratio 1.3). Family history included a paternal uncle and two paternal cousins with ambiguous genitalia requiring surgy. The paternal uncle had two healthy daughters without fertility interventions. Also, three paternal aunts are significantly taller and infertile. Father has gynecomastia. No consanguinity. The initial investigation found normal electrolytes, LH 2.1 mIU/ml, and FSH 3.1 mIU/ml. Anti-Mullerian hormone (AMH, 20.47 ng/mL) and testosterone levels (42.6 ng/dL) were low for a male. High-resolution karyotype showed 46, XY with no mosaicism and a positive FISH SRY. Chromosomal microarray analysis was unremarkable for small deletions or duplications. A high-dose (150 mcg) ACTH stimulation test ruled out adrenal steroid biosynthesis defects. Renin and aldosterone were unremarkable. An hCG stimulation test showed appropriate rise in testosterone (443.1 ng/dL), androstenedione (112 ng/dL), and 5-alpha-dihydrotestosterone (1027.2 pg/mL). Ultrasound showed a single right testicle (~3 mL volume) within the hemiscrotum, a left inguinal hernia containing mesentery, and a left hemiuterus with no ovaries. A genitogram showed a urogenital sinus with a normal-appearing vaginal canal and elongated female urethra. No vesicoureteral reflux or other perineal orifices. The low AMH with an appropriate rise in testosterone following hCG stimulation and the presence of male and female reproductive organs in an undervirulized XY suggests mixed gonadal dysgenesis. Sex assignment was deferred by the medical team until further evaluation, but the parents chose to raise as a male based on their family history. Extended family studies are in process. Conclusion: The wide clinical and molecular variation in mixed gonadal dysgenesis constitutes a challenge for sex assignment. A multi-disciplinary team approach before sex assignment is crucial, including accurate assessment of external and internal genitalia, biochemical gonadal function, and cytogenetic testing. Among the multiple genetic variants known to cause mixed gonadal dysgenesis, highest on our differential is DMRT1.

OR18-6 ADCY2 CNVs are Associated With Congenital Genitourinary Anomalies

Genitourinary (GU) anomalies are among the most common categories of birth defects and consist of disorders of sexual differentiation and congenital anomalies of kidney and urinary tract (CAKUT). Disorders of sexual differentiation include hypospadias (1 in 125 male births), cryptorchidism (3-6% of full term male births) and ambiguous genitalia (1:2000-1:4000 births). Though the prevalence of GU anomalies is high, their causes are poorly understood. A genetic change contributing to disease phenotypes is a copy number variant (CNV; a micro-deletion or micro-duplication of a small chromosomal region). When CNVs occur in dosage-sensitive genes, a disease phenotype can arise. Using array comparative genomic hybridization (aCGH), adenylyl cyclase 2 (ADCY2) CNVs were identified in a patient with hypospadias and a patient with ambiguous genitalia. ADCY2 is a member of the adenylyl cyclase class III family of genes that are responsible for converting ATP into cAMP. cAMP, is involved in several essential processes required for GU development and function including testicular descent and androgen production. Through a retrospective literature and database (DECIPHER, ICSA, ClinVar), nine patients with GU abnormalities and ADCY2 CNVs were identified. These GU anomalies consisted of upper and lower tract defects. The incidence of ADCY2 CNVs was determined by qPCR in a cohort of 378 GU abnormal patients and 45 control patients. ADCY2 CNVs (duplications) were present in 1.59% of patients with GU anomalies and 0% of control patients. The incidence of ADCY2 CNVs in the general population (Database of genomic variants) is 0.65%. Expression of ADCY2 in the GU tract was localized to renal tubules, bladder muscle, urethra, and interstitial cells of the testis with the highest expression in the testes. This expression pattern suggests a role for ADCY2 in steroid biosynthesis. When Adcy2 was overexpressed in the murine Leydig cell line MLTC-,1 cAMP compared to control MLTC-1 cells (4342.20 pmol/µl vs 2231.59 pmol/µl, two-way ANOVA <0.05), steroidogenic acute regulatory factor (StAR) expression and testosterone (52.33 ng/dL vs. undetectable, two-way ANOVA <0.05) were increased. Notably, the increase in testosterone production occurred independent of human chorionic gonadotropin (hCG) stimulation suggesting a ligand-independent, constitutively active system. In contrast to control cells transfected with an empty vector, hCG administration to ADCY2 overexpressing cells induced a slight additional increase in testosterone production. The lack of a robust response to hCG led to examination of the luteinizing hormone receptor (LHR). LHR was downregulated and internalized in Adcy2 overexpressing cells upon hCG stimulus. These findings suggest that microduplications in humans encompassing ADCY2 may contributed to lower tract genitourinary birth defects.

SAT-301 Mixed Gonadal Dysgenesis: A Case Report

INTRODUCTION: An ambiguous genitalia is a birth defect of the sex organs that makes it unclear whether an affected newborn is a girl or a boy. This condition occurs approximately 1 in every 4,500 births. Defects of the external genital organs (penis, testes, or clitoris) usually result from abnormal levels of sex hormones in the fetus before birth. Here we present a case report of an 18year old girl with ambiguous genitalia. CLINICAL CASE: An 18-year-old girl presented with complaints of primary amenorrhea along with lack of secondary sexual characters. Her mother also gave history of genital ambiguity. No history of recent change in sexual identity. Past history, family history, antenatal history, perinatal history and developmental history were non contributory. On examination, anthropometric measurements were appropriate for her age. She was normotensive. General and systemic examination were unremarkable and there were no Turner stigmata. Genital examination revealed phallic structure of 5cm length and two seperate perineal openings. Minimal posterior fusion of labial margins and a palpable mass were noted in left inguinal region. Prader staging was 3/5. Sexual maturity rating was A0P1B2. Her basal serum cortisol 14.53μg/dL,[5-25μg/dL], 17-OH-progesterone (17-OHP) 1.51ng/mL,[0.09-2.19ng/ml] and serum estradiol level 37 pg/ml [13.6-54.4pg/ml] were normal while basal androstenedione 2.23 ng/ml[0.29-1.44 ng/ml], serum testosterone 1ng/mL [ lt 0.6ng/ml]and gonadotrophins Pooled LH 22 IU/L [5-15IU/ml] and FSH 76.37 IU/L [5-20IU/ml] were elevated. Karyotype analysis was 46XY. MRI pelvis revealed absent mullerian structures and ovaries, presence of seminal vesicle and left inguinal subcutaneous sac, containing gonad, suggestive of testis was noted. Intra abdominal right gonad was detected on diagnostic laparoscopy. No vas deferens noted in entire deep inguinal ring. Left gonad noted in its entirety in left deep inguinal ring. Rudimentary uterus was also noted. Histopathological examination of gonadal biopsy revealed presence of testicular tissue showing atrophic seminiferous tubules with hyperplasia of Leydig cells. No ovarian tissue was seen. Based on these results a diagnosis of 46XY mixed gonadal dysgenesis was made, which is rare and is difficult to distinguish from 46XY ovotesticular disorder of sexual differentiation. The patient underwent feminizing genitopasty after discussion with the patient’s caregivers. CONCLUSION: Mixed Gonadal Dysgenesis represents an intermediate between pure gonadal dysgenesis and ovotesticular disorder of sexual differentiation (DSD). The external genitalia, internal genitalia, and gonadal phenotype are highly variable. The most common genotype in these patients is 46XO/XX, however 46XY genotype has also been described, which can be difficult to distinguish from 46XY ovotesticular DSD.

SAT-297 Mutation in SRY Gene Presenting as Syndromic 46XY Disorder of Sexual Differentiation (DSD)

Introduction Mutations in the SRY gene presenting as sex reversal is rare and not associated with problems in other organ systems. We report a case of a 46 XY adolescent with history of cleft lip and palate, phenotypically female, diagnosed with a mutation in the SRY gene causing sex reversal. Clinical Case A 14 year old phenotypically female patient was referred to our Endocrine clinic for evaluation of delayed puberty. She reported body odor for one year, without breast development, axillary or pubic hair. The family reported normal growth pattern growing at about 2 inches per year. She had a history of cleft lip and palate that had been repaired during infancy. They reported a history of recurrent 4-5 urinary tract infections in her lifetime. Her mother reported menarche at 12 years age, while her father had slightly delayed puberty. On physical examination her height was at z-score -0.63, weight z-score 0.42, BMI z-score 0.74. She had healed surgical scars on her right lip, with no other dysmorphic features. She had Tanner stage I breasts and no pubic or axillary hair. Examination of the external genitalia showed a normal vaginal and urethral opening with no clitoromegaly. Laboratory testing was significant for hypergonadotropic hypogonadism. Bone age was 10 years, therefore significantly delayed. Pelvic ultrasound showed a pre-pubertal uterus measuring 1.9 x 0.3 x 1.0 cm. The right gonad measured 1.5 x 1.0 x 1.1 cm. The left gonad was not visualized and there was no adnexal mass. MRI of the pelvis showed a prepubertal uterus measuring approximately 2 x 1 x 0.4 cm, and possible gonadal tissue measuring 1.2 cm on the left and 1.1 cm on the right, located antero-medial to the external iliac vessels. The urinary bladder was normal. Chromosomal analysis was consistent with 46,XY, ish(Y)(SRY+). Laparoscopic bilateral gonadectomy was performed without any complications. There was no indentifiable gonad on the right side but a formed fallopian tube with fimbria and an adjacent mesonephric duct remnant was identified. On the left side a small dysgenetic gonad with ovarian stroma, müllerian ductal epithelial remnant, ovarian hilar cell nests without germ cells, were identified. Genetic testing was done and was significant for a variant c.380A>G (p.Tyr127Cys), identified in her SRY gene. She was subsequently started on Estrogen supplement to which she is responding well. Conclusion - Mutations in the SRY gene presenting as sex reversal is rare and not reported to be associated with problems in other organ systems. Our patient with 46 XY sex reversal due to SRY mutation, had a history of cleft lip and palate, which has not been reported before to our knowledge. - Variants that disrupt the p.Tyr127Cys amino acid residue in SRYgene has been observed in affected individuals.

35. Case Series of Hormone Abnormalities in Term and Preterm Infants With Ambiguous Genitalia not Diagnosed With a Disorder of Sexual Differentiation

Work-up for diagnosing a disorder of sexual differentiation (DSD) in infancy is prompted by ambiguous genitalia seen at birth. But not all children born with ambiguous genitalia are ultimately diagnosed with a DSD, thus putting these neonates through needless testing. We present two cases of infants thought to have a DSD based on genital ambiguity and abnormal laboratory evaluation with subsequent resolution of both.

Pediatric endocrinology in Ukraine in 2018

The article provides information and analyzes the statistical indicators for 2018 regarding personnel provision of the pediatric endocrinology in Ukraine, in­patient care for children with endocrine diseases, their disability and oncological morbidity. Data are also provided for registers of children with certain endocrine diseases, namely, diabetes mellitus, including its various forms, pathological dwarfism, disorders of sexual differentiation (DSD). The problem issues of specialized care for children with diseases of the endocrine system are highlighted.It is noted that in 2018 there were 9,105 children with type 1 diabetes mellitus under the age of 18, which is 1.2 per 1,000 children 0—18 y. o. in Ukraine, with type 2 diabetes mellitus — 46 children, and 33 children with neonatal diabetes, with MODY — 32 patients, including 1 case of rare monogenic autoimmune diabetes. The Department of pediatric endocrinology of the Ukrainian Center for Endocrine Surgery, Transplantation of Endocrine organs and tissues of the MOH of Ukraine is conducting a genetic survey of children with rare forms of diabetes and children with DSD. Children undergo a detailed cytogenetic survey in leading genetic laboratories in the world. According to the survey, a database of such patients was created. The database of children with DSD included 95 patients: with chromosomal DSD — 17 children, 46, XY DSD — 46 patients, 46, ХХ — 13 pati­ents. It is reported that in 2018, Ukraine registered 1517 children with dwarfismunder the age of 18 who receive treatment with growth hormone funded from the state budget, including 1060 children with growth hormone deficiency, 312 children with Turner’s syndrome, 78 children with Russell­Silverse syndrome, 50 — with Prader—Willie syndrome, as well as 17 children with nanism due to chronic renal failure.The proposals concerning the improvement of care to children with endocrine system diseases were suggested.

Molecular investigation of mutations in androgen receptor and 5-alpha-reductase-2 genes in 46,XY Disorders of Sex Development with normal testicular development.

In this study, we aimed to determine androgen receptor (AR) and SRD5A2 gene mutations in 45 patients characterised by 46,XY Disorders of Sex Differentiation (DSD) signs with normal testicular development referred to the Children's Medical Center from February 2015 to September 2017. Karyotype and sex hormone analyses were performed. Cytogenetic investigation showed that seven patients were 46,XX DSD, six patients were chromosomal DSD and 32 patients were 46,XY DSD. Eight exons of the AR gene and five exons of the SRD5A2 gene were amplified. Two cases were affected with androgen insensitivity syndrome (AIS) (missense mutation on exon 7, position c.3637 G>A: p.R841H and position c.3610 G>A: p.R832Q), one case was affected with 5-alpha-reductase deficiency type 2 (missense mutation at c.578A>G: p.N193S on exon 4), and 22 cases (88%) did not demonstrate AIS or 5α-RD2 gene abnormality. Due to the great impact of these disorders on human lifestyle, evaluation of genes involved can improve genetic counselling and therapeutic management. We focused on the AR and SRD5A2 genes in patients with 46,XY DSDs with normal testicular development referred to the Children's Medical Center from all over the country to eventually culminate in a reliable prenatal diagnosis protocol at this major referral centre giving service to a great number of families with consanguineous marriages.

AMH and INSL3 in testicular and extragonadal pathophysiology: what do we know?

It is commonly accepted that testicular function is prevalently regulated by the hypothalamic-pituitary-gonadal axis: The pulsatile secretion of GnRH by the hypothalamus induces pituitary expression of the two gonadotropins FSH and LH, which then stimulate Sertoli and Leydig cells, respectively, therefore regulating steroidogenesis and spermatogenesis. However, a growing body of evidence has recently suggested that other hormones act on the reproductive tract since the early phases of fetal development. Anti-Müllerian hormone and INSL3 are still largely used only for research purposes despite being increasingly recognized as markers of Sertoli and Leydig cells function, respectively. Provide an up-to-date review of the role of anti-Müllerian hormone and INSL3 in human pathophysiology according to current evidence. A thorough literature review was performed on PubMed, OVID MEDLINE/EMBASE and Google Scholar for papers concerning anti-Müllerian hormone and INSL3 in human males. INSL3 is not acutely regulated by the hypothalamic-pituitary axis but is constitutively secreted by Leydig cells, therefore representing a valid marker for their number and status. Anti-Müllerian hormone expression, on the other hand, is downregulated by androgens, therefore occurring mostly at the early stages of testicular differentiation and before the onset of puberty. Several conditions affecting testicular development, such as male hypogonadotropic hypogonadism, and their treatment have been associated to specific pattern of INSL3 and anti-Müllerian hormone expression, proving a role for both hormones in the diagnostic and therapeutic management. Recent reports suggest a role for both anti-Müllerian hormone and INSL3 in extra gonadal physiology, such as cardiovascular and bone health. Anti-Müllerian hormone and INSL3 are markers of Sertoli and Leydig cells maturation, respectively, usually involved in the pathogenesis of disorders of sexual differentiation. However, their role in testicular pathology has only been hinted at in the last decades. Recent evidence supports an involvement of both anti-Müllerian hormone and INSL3 in extragonadal pathophysiology as well.

Sex assignment practice in disorders of sexual differentiation: survey results from paediatric endocrinologists in the Arab region.

Background Sex assignment is a major issue in disorders of sexual differentiation (DSD). Not all conditions of DSD have clear recommendations on assignment and timing of surgery. Reports about sex assignment practice and the influence of culture and religion in the Arab region are scarce. Methods A survey questionnaire was distributed to participants in a paediatric endocrinology conference. Four DSD cases were presented. Participants were asked to fill in their answers on sex assignment choice, reasons for the particular assignment, strength of own recommendation and timing of surgery based on their practice. The cases presented were severely virilised XX congenital adrenal hyperplasia (CAH), complete androgen insensitivity syndrome (CAIS), severely undervirilised 5α reductase deficiency (5α RD) and XX ovotesticular case. Results Eighty-five endocrinologists participated in the study. Eighty (97.5%) chose a female sex to assign for the XX CAH. For the CAIS, 64 (78%) chose a female sex. Seventy-one (86.5%) voted for a male sex for the XY case of 5α RD. Forty-seven (57%) and 35 (43%) chose a female and a male sex for the ovotesticular case, respectively. The majority indicated that their advice for sex assignment is based on strong recommendations for the CAH, CAIS and 5α RD patients but they were open to the parents' cultural and religious beliefs in their decision of the assignment for the ovotesticular case. Conclusions Practice in the Arab region appears to be in line with the international guidelines in the majority of DSD sex assignment and timing of surgery issues. However, culture and religious beliefs influence the practice in certain circumstances.

Swyer syndrome with heterotopic adrenal cortical tissue in streak gonads: A rare case and review of literature

Swyer syndrome is a 46 XY pure gonadal dysgenesis. Affected individuals are phenotypically female with external female genitalia, hypoplastic Mullerian structures, and the presence of streak gonads. Gonadectomy is indicated due to increased risk of development of malignancy in streak gonads. We hereby report a case of 15-year-old patient with Swyer syndrome who underwent laparoscopic gonadectomy. Histopathological examination showed streak gonads with the presence of accessory adrenal cortical tissue. The patient was put on hormonal replacement therapy postsurgery. Heterotopic adrenal rest may be an incidental finding in normal ovary and testis. Its presence in streak gonads has never been reported, and we propose a theory of increased risk of gonadal and adrenal tumors, possibly because of mutations in disorders of sex differentiation.

Testis Development.

Production of sperm and androgens is the main function of the testis. This depends on normal development of both testicular somatic cells and germ cells. A genetic program initiated from the Y chromosome gene sex-determining region Y (SRY) directs somatic cell specification to Sertoli cells that orchestrate further development. They first guide fetal germ cell differentiation toward spermatogenic destiny and then take care of the full service to spermatogenic cells during spermatogenesis. The number of Sertoli cells sets the limits of sperm production. Leydig cells secrete androgens that determine masculine development. Testis development does not depend on germ cells; that is, testicular somatic cells also develop in the absence of germ cells, and the testis can produce testosterone normally to induce full masculinization in these men. In contrast, spermatogenic cell development is totally dependent on somatic cells. We herein review germ cell differentiation from primordial germ cells to spermatogonia and development of the supporting somatic cells. Testicular descent to scrota is necessary for normal spermatogenesis, and cryptorchidism is the most common male birth defect. This is a mild form of a disorder of sex differentiation. Multiple genetic reasons for more severe forms of disorders of sex differentiation have been revealed during the last decades, and these are described along with the description of molecular regulation of testis development.

A retrospective population-based cohort study to evaluate the impact of an older sibling with undescended testis and hypospadias on the known maternal and fetal risk factors for undescended testis and hypospadias in Ontario, Canada, 1997–2007

There are several reported risk factors for undescended testis (UDT) and hypospadias (HYP). Also, a family history of UDT or HYP has not been accounted for in prior studies, and doing so may influence these independent risk estimates. A population-based retrospective cohort study was conducted using linked administrative databases in Ontario, Canada, to identify all live male newborns born between 1997 and 2007, and it was determined whether they underwent an orchidopexy or HYP repair within 5 years of birth. Baseline maternal and fetal risk factors were obtained using appropriate ICD codes. A statistical analysis using a generalized estimating equation with a logit link was performed, adjusting for clustering in mothers with a previous child born in the 5 years before the proband with UDT or HYP, to evaluate the adjusted risk factors of UDT and HYP. A total of 709,968 male infants were followed up from birth for 5 years, of which 5830 underwent an orchidopexy and 2722 had an HYP repair. On multivariable analysis, factors associated with a higher risk of UDT included prematurity, small for gestational age (SGA), associated HYP, gestational hypertension, use of assisted fertility techniques, increased maternal age, Cesarean section, previous sibling with UDT, and disorders of sexual differentiation (DSDs). After adjusting for clustering in mothers with a previous baby with UDT, DSD, associated HYP (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.0-4.1), and a previous sibling with UDT (OR, 3.6; 95% CI, 2.5-5.2) remained significant risk factors. The risk factors on multivariable analysis predicting the risk of HYP included SGA, prematurity, higher income families, and associated anomalies such as UDT. After adjusting for clustering in mothers with a previous sibling with HYP, SGA (OR, 1.8; 95% CI, 1.0-3.1), higher income families (OR, 1.5-1.6), associated UDT (OR, 7.1; 95% CI, 4.9-10.0), and a previous sibling with HYP (OR, 12.8; 95% CI, 9.1-18.1) remained significant risk factors. Studies estimating risk factors for UDT and HYP have used variable methodologies to identify index cases and perform statistical analysis. This study suggests that having an older sibling with UDT or HYP is a significant independent risk factor. Performing an analysis adjusting for clustering in mothers with a previous child with UDT or HYP leads to loss of statistical significance for other described risk factors. Underlying genetic or similar environmental exposures may be a key risk factor for UDT and HYP, which confounds known maternal and fetal risk factors for these anomalies.

XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage†.

The fertility of sex-reversed XY female mice is severely impaired by a massive loss of oocytes and failure of meiotic progression. This phenomenon remains an outstanding mystery. We sought to determine the molecular etiology of XY oocyte dysfunction by generating sex-reversed females that bear genetic ablation of Sry, a vital sex determination gene, on an inbred C57BL/6 background. These mutant mice, termed XYsry− mutants, showed severe attrition of germ cells during fetal development, resulting in the depletion of ovarian germ cells prior to sexual maturation. Comprehensive transcriptome analyses of primordial germ cells (PGCs) and postnatal oocytes demonstrated that XYsry− females had deviated significantly from normal developmental processes during the stages of mitotic proliferation. The impaired proliferation of XYsry− PGCs was associated with aberrant β-catenin signaling and the excessive expression of transposable elements. Upon entry to the meiotic stage, XYsry− oocytes demonstrated extensive defects, including the impairment of crossover formation, the failure of primordial follicle maintenance, and no capacity for embryo development. Together, these results suggest potential molecular causes for germ cell disruption in sex-reversed female mice, thereby providing insights into disorders of sex differentiation in humans, such as “Swyer syndrome,” in which patients with an XY karyotype present as typical females and are infertile.

Нарушения половой дифференцировки у детей: критический взгляд на нерешенные вопросы (часть I)

Management of children with disorders of sexual differentiation (DSD) continues to cause questions and receive criticism. This review discusses some contradictions concerning the newly proposed terminology, nomenclature, and classification. Congenital adrenal hyperplasia (CAH) is the most common cause of DSD, and its management also remains controversial. Therefore, in this part of the article, we critically analyze available literature on gender identity, the need and timing of surgery in children with DSD and 46, XX karyotype.

Нарушения половой дифференцировки у детей: критический взгляд на нерешенные вопросы (часть II)

Нарушения половой дифференцировки у детей: критический взгляд на нерешенные вопросы (часть II)

Sox9 regulation during sex determination

Sex Determination Sex determination is regulated by the Sox9 gene. During testis differentiation, this gene is directly targeted by the product of the Y chromosome–encoded gene Sry . The regulatory region of Sox9 is complex, which is typical of genes with multiple roles in development. Gonen et al. find that a single far-upstream 557–base pair element is critical for up-regulating Sox9 . Without it, XY mice develop as females instead of males. The 557–base pair enhancer is conserved, likely to be relevant to human disorders of sex differentiation, and probably essential because it acts early in a time-critical process, and any failure allows ovary-specific factors to dominate. Science , this issue p. [1469][1] [1]: /lookup/doi/10.1126/science.aas9408

Sex reversal following deletion of a single distal enhancer of Sox9.

Cell fate decisions require appropriate regulation of key genes. Sox9, a direct target of SRY, is pivotal in mammalian sex determination. In vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing revealed several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9 Although others are redundant, enhancer 13 (Enh13), a 557-base pair element located 565 kilobases 5' from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Our data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within a 32.5-kilobase region whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans.

Teleology and Defining Sex

Disorders of sexual differentiation lead to what is often referred to as an intersex state. This state has medical, as well as some legal, recognition. Nevertheless, the question remains whether intersex persons occupy a state in between maleness and femaleness or whether they are truly men or women. To answer this question, another important conundrum needs to be first solved: what defines sex? The answer seems rather simple to most people, yet when morphology does not coincide with haplotypes, and genetics might not correlate with physiology the issue becomes more complex. This paper tackles both issues by establishing where the essence of sex is located and by superimposing that framework onto the issue of the intersex. This is achieved through giving due consideration to the biology of sexual development, as well as through the use of a teleological framework of the meaning of sex. Using a range of examples, the paper establishes that sex cannot be pinpointed to one biological variable but is rather determined by how the totality of one’s biology is oriented towards biological reproduction. A brief consideration is also given to the way this situation could be comprehended from a Christian understanding of sex and suffering.

Duplication of SOX9 associated with 46,XX ovotesticular disorder of sex development.

The purpose of the present study was to investigate whether ten unrelated SRY-negative individuals with this sex differentiation disorder presented a double dose of SOX9 as the cause of their disease. Ten unrelated SRY-negative 46,XX ovotesticular disorder of sexual development (DSD) subjects were molecularly studied. Multiplex-ligation dependent probe amplification (MLPA) and quantitative real-time PCR analysis (qRT-PCR) for SOX9 were performed. The MLPA analysis demonstrated that one patient presented a heterozygous duplication of the entire SOX9 coding region (above 1.3 value of peak ratio), as well as at least a ~ 483 kb upstream duplication. Moreover, no duplication of other SOX9 probes was observed corresponding to the region between -1007 and -1500 kb upstream. A qRT-PCR analysis showed a duplication of at least -581 kb upstream and ~1.63 kb of the coding region that encompasses exon 3. The limits of the duplication were mapped approximately from ~71539762 to 72122741 of Chr17. No molecular abnormalities were found in the remaining nine patients. This study is thought to be the first report regarding a duplication of SOX9 that is associated with the presence of 46,XX ovotesticular DSD, encompassing at least -581 kb upstream, and the almost entire coding region of the gene.

Androgen insensitivity syndrome: a review.

Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype - phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.