Disorders Of Sex Development Research Articles

Commentary to individualized care for patients with intersex (differences of sex development): Diagnosis and treatment of aphallia

Commentary to individualized care for patients with intersex (differences of sex development): Diagnosis and treatment of aphallia

DMRT1 is a testis-determining gene in rabbits and is also essential for female fertility

DMRT1 is the testis-determining factor in several species of vertebrates, but its involvement in mammalian testes differentiation, where SRY is the testis-determining gene, remains ambiguous. So far, DMRT1 loss-of-function has been described in two mammalian species and induces different phenotypes: Disorders of Sex Development (46, XY DSD) in men and male infertility in mice. We thus abolished DMRT1 expression by CRISPR/Cas9 in a third species of mammal, the rabbit. First, we observed that gonads from XY DMRT1−/− rabbit fetuses differentiated like ovaries, highlighting that DMRT1 is involved in testis determination. In addition to SRY, DMRT1 is required in the supporting cells to increase the expression of the SOX9 gene, which heads the testicular genetic cascade. Second, we highlighted another function of DMRT1 in the germline since XX and XY DMRT1−/− ovaries did not undergo meiosis and folliculogenesis. XX DMRT1−/− adult females were sterile, showing that DMRT1 is also crucial for female fertility. To conclude, these phenotypes indicate an evolutionary continuum between non-mammalian vertebrates such as birds and non-rodent mammals. Furthermore, our data support the potential involvement of DMRT1 mutations in different human pathologies, such as 46, XY DSD as well as male and female infertility.

DMRT1 is a testis-determining gene in rabbits and is also essential for female fertility.

DMRT1 is the testis-determining factor in several species of vertebrates, but its involvement in mammalian testes differentiation, where SRY is the testis-determining gene, remains ambiguous. So far, DMRT1 loss-of-function has been described in two mammalian species and induces different phenotypes: Disorders of Sex Development (46, XY DSD) in men and male infertility in mice. We thus abolished DMRT1 expression by CRISPR/Cas9 in a third species of mammal, the rabbit. First, we observed that gonads from XY DMRT1-/- rabbit fetuses differentiated like ovaries, highlighting that DMRT1 is involved in testis determination. In addition to SRY, DMRT1 is required in the supporting cells to increase the expression of the SOX9 gene, which heads the testicular genetic cascade. Second, we highlighted another function of DMRT1 in the germline since XX and XY DMRT1-/- ovaries did not undergo meiosis and folliculogenesis. XX DMRT1-/- adult females were sterile, showing that DMRT1 is also crucial for female fertility. To conclude, these phenotypes indicate an evolutionary continuum between non-mammalian vertebrates such as birds and non-rodent mammals. Furthermore, our data support the potential involvement of DMRT1 mutations in different human pathologies, such as 46, XY DSD as well as male and female infertility.

Disorders of sexual development: structured radiological reporting and practical approach.

Disorders of sexual development (DSD) comprise a complex group of conditions with varied clinical presentations, such as atypical genitalia, non-palpable testes, primary amenorrhea, or infertility. Besides being associated with other congenital anomalies, DSDs bear substantial ethical issues regarding assigning the sex of rearing to the child and future fertility options. Establishing the correct diagnosis is essential for the appropriate management of such cases. Various imaging modalities, such as ultrasonography, genitography, and MRI, when complemented with detailed clinical evaluation and karyotyping, are the key to diagnosing the condition. This article attempts to present a concise approach to various patterns of DSD, which will aid radiologists to solve these diagnostic dilemmas.

Primary Amenorrhea Due to Ovotesticular Disorder of Sexual Development

Primary amenorrhea with ambiguous genitalia is a diagnostic challenge to physicians. Ovotesticular disorder of sexual development is a one cause for that which need gonadectomy followed by histological assessment to confirm the diagnosis. This is a case of ovotesticular disorder of sexual development which presented with primary amenorrhea with ambiguous genitalia.

Virilization at puberty in adolescent girls may reveal a 46,XY disorder of sexual development.

Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

THU210 A Single-center Retrospective Study Of Brazilian Subjects With Differences In Sex Development (DSD) From Infancy To Adulthood

Abstract Disclosure: R.L. Batista: None. N.L. Gomes: None. T.A. Bachega: None. G. Madureira: None. M.C. Miranda: None. R.T. dallago: None. M.M. Ferrari: None. L.M. Lousada: None. F.L. Craveiro: None. J.P. Batatinha: None. R.D. Scalco: None. E.F. Costa: None. M.P. Sircili: None. F.T. Denes: None. M. Inacio: None. M.Y. Nishi: None. S. Domenice: None. B.B. Mendonca: None. Context: DSD represent a wide range of conditions presenting at different ages to many health professionals with several backgrounds. Establishing a correct diagnosis is essential for appropriate management. Objective: To amplify the understanding of the first clinical presentation, prevalence, and gender change of Brazilian DSD subjects. Design: A retrospective, observational cohort study of all DSD subjects referred to a DSD multi-professional team over 41 years (from 1980 to 2021). Participants: 696 subjects.Outcome Measures: Data included DSD diagnosis, sex assignment, age at diagnosis, gender change, clinical presentation, and phenotypic features. Results: Subjects presented at prepubertal, post-pubertal, and adult age, usually with atypical genitalia, undescended testes, or primary amenorrhea. Amongst the three major DSD categories, sex chromosome DSD was diagnosed in 264 subjects (135 with 45,X karyotype); 101 are mosaics (45,X/46,Xi(Xq) and three chimerism (all ovotesticular DSD). Among the 4 ovotesticular DSD subjects, 3 were raised as females and 1 as male, no gender changes occurred in this group. Thirteen chromosome DSD patients with Y material were assigned as male and two female-assigned patients changed their gender. 258 subjects have 46,XY DSD (69 unknown DSD, 64 gonadal dysgenesis, 36 5-αRD2 deficiency, 18 17β-HSD3 deficiency, 11 17α-hydroxylase deficiency, 9 Leydig cell hypoplasia, 25 CAIS, 18 PAIS, 8 AMH defects). Among the 192 XY subjects with atypical genitalia, the sex of rearing was female in 89 (46%) and gender change from female to male occurred in 13%, most in 5 αRD2 (45%) followed by 17β-HSD3 (33%) deficiency. Among those reared as male, only 2.9% changed their gender. 46,XX DSD was diagnosed in 178 patients. Congenital adrenal hyperplasia-CAH (most 21-hydroxylase deficiency) was diagnosed in 123 (115 female-assigned). Among CAH, gender change from female to male occurred in 6 cases, of which most have VS form (5/6; p=.004), a late beginning of treatment (>2 ys old), and poor compliance. In the remaining 55 with 46,XX DSD, 24 have ovotesticular DSD (all with atypical genitalia), 16 have 46,XX testicular DSD (seven with atypical genitalia). Among the ovotesticular subjects, 14 were reared as male and ten as female, and gender change occurred in 4 cases (3 from female to male). The diagnosis was not established in twelve 46,XX DSD patients (all with atypical genitalia, three with syndromic features). One patient has aromatase deficiency, one POR deficiency, and one glucocorticoid resistance syndrome. Conclusion: gender change from female to male mainly occurred among subjects with 46,XY DSD, particularly in those with 5 αRD2 and 17β-HSD3 deficiency, suggesting that male sex assignment is desirable in patients with these diagnoses. Among 46,XX DSD, the VS form of CAH, a late start of treatment, and poor compliance were implicated in female-to-male gender change. Presentation: Thursday, June 15, 2023

THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development

Abstract Disclosure: J. Kim: None. S. Park: None. S. Hwang: None. J. Yoon: None. G. Kim: None. H. Yoo: None. J. Choi: None. Background: Disorders of sexual development (DSDs) is a group of congenital conditions associated with discordant development of chromosomal, gonadal, and anatomical sex. Sex development is a complex process with a precise synergistic temporal-spatial transcriptional regulation of multiple genes. Advances in next-generation sequencing (NGS) techniques have achieved genetic diagnosis for up to 40 % of 46,XY DSDs. This study investigated the etiological distribution of DSDs identified by NGS. Methods: This study included 70 patients with DSDs (56 patients with 46,XY DSD and 14 patients with 46,XX DSD). Molecular genetic analysis was performed using targeted gene panel sequencing (n = 43) and whole-exome sequencing (WES, n = 26), including 25 patients for the first-line test and one without sequence variants by targeted gene panel sequencing. Whole-genome sequencing (WGS) was performed on 7 patients, including two patients for the first-line test and five patients without sequence variants by targeted gene panel sequencing or WES. Results: Patients with DSDs presented in infancy with ambiguous genitalia and at older children with aberrant pubertal development or discordance between karyotype and external genitalia. Twenty-four of 56 patients (42.9%) with 46,XY DSD were reared female, and 5 of 14 patients (35.7%) with 46,XX DSD were raised as a male. Pathogenic or likely pathogenic variants were identified in 21 of 56 patients with 46,XY DSD (37.5%); however, no rare sequence variants were found in patients with 46,XX DSD. The AR variants were the most common (8/70, 11.4%), followed by CYP17A1 (4/70, 5.7%), SRD5A2 (4/70, 5.7%), NR5A1 (2/70, 2.8%), GATA4 (1/70, 1.4%), MYRF (1/70, 1.4%), and deletion of DMRT1/2 (1/70, 1.4%). Mutation-positive patients with 46, XY DSD were assigned as female more frequently than mutation-negative patients (19/21 vs. 6/35, P-value <0.001). The lower diagnostic yield was observed in patients with a less severe phenotype, such as hypospadias or micropenis. Conclusions: This study demonstrated that genetic etiologies could be identified in 37.5% of patients with 46,XY DSD, whereas there were no genetic variants in patients with 46,XX DSD. Patients with a more severe phenotype were more likely to have a conclusive genetic diagnosis. NGS is a helpful technique to improve diagnostic efficiency in patients with DSD because of phenotypic and genetic heterogeneity. Presentation: Thursday, June 15, 2023

FRI446 A Case Of 46 XX Testicular Disorder Of Sex Development Presenting As Hypogonadism And Infertility

Abstract Disclosure: N. Balachandar: None. S. Agarwal: None. K.K. Soe: None. Introduction: Hypergonadotropic hypogonadism in males can be due to genetic, acquired or developmental causes. Common etiologies of testicular failure include trauma, systemic illnesses, radiotherapy, gonadotoxic drugs, and viral orchitis; in addition, genetic causes should be considered. Here, we present a case of primary hypogonadism and infertility due to 46 XX testicular disorder of sex development (DSD). Case Report: A male in his early fifties with history of obesity presented with fatigue to his PCP. A total testosterone level was 1.8 ng/mL (normal: 1.7 - 7.6 ng/mL) with a repeat value confirming the finding. Bioavailable testosterone was low at 85.1 ng/dL (normal: 110-575 ng/dL). FSH was elevated at 39.9 mIU/mL (normal: 1.3 - 19.3 mIU/mL), and LH was elevated at 16.6 mIU/mL (normal: 1.2 - 8.6 mIU/mL). In endocrinology clinic, he reported a year of fatigue, erectile dysfunction despite normal libido, and an inability to conceive despite three years of regular unprotected intercourse. He noted loss of muscle mass, bilateral breast tissue development, and reduction in testicular size. Physical exam revealed normal phallus, diffusely sparse body hair with atypical male distribution, bilateral gynecomastia, and bilateral reduction in testicular volume (right: 5 mL; left: 8 mL). Chromosomal analysis showed a mosaic pattern of 45 XO in 6% of cells and 46 XX in 94% of cells. Fluorescence in situ hybridization (FISH) analysis confirmed the presence of the sex-determining region (SRY) gene in 96% of cells. Metaphase FISH showed cryptic insertion of the SRY gene into the p arm of the X chromosome. Semen analysis showed azoospermia. He was diagnosed with 46 XX testicular DSD with abnormal mosaicism. He was prescribed testosterone gel and counseled on fertility options resulting in improvement of testosterone levels, sexual function, and subjective well-being. Discussion: The SRY gene, normally located on the p arm of the Y Chromosome, is responsible for development of primitive gonads into testicles during embryogenesis. Homologous recombination occurs between chromosomes during gametogenesis. It is hypothesized that in patients with 46 XX DSD, the SRY gene is translocated to the X chromosome, as demonstrated in this case. Its expression helps with selection of male sex in a growing fetus. Thus, in a 46 XX SRY positive male, the phenotypic presentation is male. Since the AZF gene on the q arm of the Y chromosome which is essential for spermatogenesis is not translocated, 46 XX males are infertile and undiagnosed until adulthood when azoospermia is noted during infertility workup. 46 XX SRY negative males develop ambiguous genitalia leading to earlier diagnosis. Eighty-percent of 46 XX males are SRY positive and twenty-percent are SRY negative. Thus, in adult males presenting with infertility and hypogonadism, genetic causes such as 46 XX DSD with SRY translocation should be considered. Presentation: Friday, June 16, 2023

SAT422 Gender Affirming Hormone Therapy in a Non-Binary Individual with Swyer Syndrome

Abstract Disclosure: J.M. Yohannan: None. T. Reisman: None. Background: Swyer syndrome is a rare genetic disorder of sexual development. Patients with Swyer syndrome require physiologic hormone replacement congruent with their gender identity in order to prevent bone loss. It is also important to screen for complications of this condition including osteopenia and dysgerminomas. Clinical Case: A 25 year old individual with a history of Swyer syndrome (46 XY gonadal dysgenesis) presents to clinic to discuss initiation of gender affirming hormone therapy. The patient identifies as non-binary and is interested in starting testosterone for masculinization. The patient was initially diagnosed with Swyer syndrome at age 23 during an evaluation for primary amenorrhea. At that time the patient had a laparoscopic gonadectomy and was found to have a dysgerminoma. Upon diagnosis the patient was started on hormone replacement therapy with norethindrone acetate-ethinyl estradiol 1 - 0.01 mg for bone loss prevention. They had a bone mineral density scan two years prior to presentation that was reportedly normal. To avoid the deleterious effects of hypogonadism they were started on estradiol-norethindrone 0.05 - 0.25 mg patch to provide bone protection. They were also provided testosterone gel for masculinization as part of their gender affirming care. Swyer syndrome is a disorder of sex development in which individuals with XY chromosomes develop phenotypically female Mullerian structures (uterus, fallopian tubes, and vaginal canal). Individuals with Swyer syndrome typically have non-functional “streak gonads” and are diagnosed during evaluation for primary amenorrhea. While some cases may be from a novel mutation, there are case reports showing that the condition can have an autosomal dominant, autosomal recessive, or even X-linked pattern of inheritance depending on the mutated gene. Patients with Swyer syndrome require physiologic doses of hormone replacement for maturation of secondary sex characteristics and bone health. For this patient in particular it is also important to provide appropriate hormone replacement congruent with their gender identity. Additionally, approximately 30% of patients with this condition may develop a gonadal tumor, including dysgerminomas. Because of this, patients frequently have their gonads removed upon diagnosis. Conclusion: Patient’s with Swyer syndrome should be on appropriate hormone replacement as they do not make endogenous sex steroids. Additional consideration of masculinizing hormone replacement should be made for patients that have a gender identity other than cisgender female. It is also important to screen patients for gonadal tumors as there is an increased incidence in this population.

THU574 Hsd17b1 Partially Compensates For The Lack Of Hsd17b3 In Testicular Testosterone Production In Fetal Mice, But Not In Adults

Abstract Disclosure: M. Poutanen: None. A. Junnila: None. P. Sipilä: None. I.T. Huhtaniemi: None. Hydroxysteroid (17β) dehydrogenase type 3 (Hsd17b3) is the primary enzyme converting androstenedione to testosterone in human testes. HSD17B3 deficiency is a known cause of a disorder of sex development (DSD), where XY individuals are born with a female appearance, but are virilized during puberty as testosterone starts to suddenly rise due to unknown compensatory mechanisms. We have previously established and characterized an Hsd17b3 knockout mouse line (HSD17B3KO). HSD17B3KO males were born phenotypically normal, but presented various signs of under-masculinization at later ages. However, although they have very high circulating androstenedione at adulthood, they also maintain normal-to-high concentrations of testosterone. Indeed, testosterone was only seen to be low during certain fetal and pubertal time points. We suspected that Hsd17b1, capable of catalyzing the same reaction and expressed in testes towards the end of the fetal development, could be responsible for the compensation in the testosterone production, especially in the presence of higher than normal concentrations of androstenedione. To test this, we created an Hsd17b1-Hsd17b3 double KO (DKO) mouse line. The loss of both Hsd17b1 and Hsd17b3 had a more drastic effect on the phenotype of the male animals than was observed in HSD17B3KO. The outward appearance of the DKO males was completely feminized both as newborns and at adulthood, with an anogenital distance comparable to females. The male internal genitalia were present, but compared to HSD17B3KO they were further reduced in size, as were several other androgen-sensitive tissues. However, the testes and epididymides of the DKO contained high number of mature spermatozoa. The loss of both enzymes had a clear effect on the testis steroidogenesis of the newborn animals, with a 2-fold increase in intra testis androstenedione and 6-fold decrease in testosterone concentration compared to WT and HSD17B3KO males. In contrast, at the age of 3 months, no difference in the circulating steroid concentrations was observed between the DKO and HSD17B3KO, and high concentrations of androstenedione and testosterone was present in both mice. This, along with the active spermatogenesis, imply that in a presence of high LH, a further compensatory mechanism of testosterone production is present in the adult testes. In conclusion, our results demonstrate that in the absence of Hsd17b3, Hsd17b1 is crucial for the remaining testosterone production capacity in fetal mouse testis. However, in adult animals, the compensatory role is taken over by other, so far unknown, enzymes. Compared to HSD17B3KO, the overall phenotype of the DKO male mice is more similar to that of the humans with HSD17B3 deficiency, while the phenotype of HSD17B3KO is less feminized. Presentation Date: Thursday, June 15, 2023

SAT395 Gender Dysphoria In A Patient With Ovotesticular Disorder Of Sex Development

Abstract Disclosure: T. Moreno: None. P. Rodrigues: None. S. Ribeiro: None. D.M. Carvalho: None. Introduction: Ovotesticular disorder of sex development (OT-DSD) is a rare condition characterized by the presence of both ovarian and testicular tissue in the gonads. Management and sex designation of these patients depend on several factors and an underlying potential for gender dysphoria should be acknowledged.Clinical Case: A 12-month-old patient from Guinea-Bissau, born from consanguineous parents, was referred to Pediatric Surgery due to atypical genitalia. Karyotype was 46,XX and SRY gene analysis was negative. Genitoscopy showed absence of a vagina and a uterus was not found on magnetic resonance imaging. An exploratory laparotomy and biopsy of the gonads was performed. The pathology report confirmed the presence of gonadal ovarian and testicular tissue, establishing the diagnosis of OT-DSD. Surgical removal of both gonads and clitoroplasty was performed and a female sex designation was attributed. Endocrinology follow-up was started at the age of 8 and the first physical examination revealed weight 48.6 kg (> P97), height 135.5 cm (P90–97); Tanner stage I (P1A1M0) and a blind vagina with normal clitoris size. Blood tests showed FSH 12.53 mUI/L, LH 1.07 mUI/L, estradiol 5.8 pg/mL and total testosterone 0.04 ng/mL. Reconstructive surgery for a neovagina was performed at 13-years-old and, two years later, the patient was started on hormone replacement therapy with transdermic estradiol. At the age of 16, the patient manifested gender dysphoria issues, decided to stop estradiol and was referred for psychiatric evaluation. Two years later, intramuscular testosterone enanthate was initiated but treatment was stopped after a six-month trial, as the patient claims to identify as male but is not interested in seeking hormone treatment at this point.Conclusion: OT-DSD is an uncommon condition, raising issues of gender assignment that are dependent on factors such as age at diagnosis, phenotype, internal structures and reproductive potential. Scarce data exists on long-term outcomes in OT-DSD, including the frequency of gender dysphoria in these patients. Gender identity is an important factor to consider on long-term follow-up of OT-DSD patients. Presentation: Saturday, June 17, 2023

THU184 Varying Presentations Of 46XX OTD

Abstract Disclosure: I. Mishra: None. S.K. Sahoo: None. A.K. Baliarsinha: None. Ovotesticular disorder of sex development (OT-DSD) is a condition associated with presence of both testicular and ovarian tissue in same individual, in which these tissues may co-exist either in the same gonad or independently. 46 XXOTD are most common. We describe 3 cases of 46 XXOTD presenting in their post pubertal years with varied presentation. Case 1: 19 year old reared as male presented with peripubertal gynaecomastia and cyclical pain abdomen. On examination there was symmetrical genitalia, non palpable gonads, microphallus, single genital opening below phallus (Prader 3), pubic hair stage 4, axillary hair stage 3 and breast stage 5. Biochemical evaluation revealed serum testosterone (19 ng/dl), 17-hydroxy progesterone (1.7ng/ml), LH (2.6IU/L), FSH (8.6IU/L) and E2(112pg/ml). Karyotype 46XX, FISH SRY negative. USG abdomen s/o uterus like structure with absent wollfian remnants. Post laproscopy histopathology s/o bilateral ovotestis, normal ovarian stroma with hyalinized seminiferous tubule, sertoli cells and leydig cells. Case 2: 18 year old reared as male presented with peripubertal gynaecomastia and genital ambiguity. On examination there was asymmetrical genitalia, palpable right scrotal gonads, phallus, single genital opening at base of phallus, pubic hair stage 4, axillary hair stage 3 and breast stage 5. Biochemical evaluation revealed serum testosterone (110ng/dl), LH (4.6IU/L), FSH (11.2IU/L) and E2(46pg/ml). Karyotype 46XX.USG abdomen s/o hypoplastic uterus like structure with possible ovary in left side of pelvis, hypoplastic testis in right scrotal sac. Post laproscopy histopathology was s/o left dysgenetic ovary, and hypoplastic uterus. Case 3: 17 year old reared as male presented with peripubertal gynaecomastia. On examination there was symmetrical genitalia, non palpable gonads, microphallus, single genital opening at the base of phallus (Prader 4), pubic hair stage 4, axillary hair stage 2 and breast stage 4. Biochemical evaluation revealed serum testosterone (98ng/dl), 17-hydroxyprogesterone (0.58ng/ml), LH (4.05IU/L), FSH (7.12IU/L) and E2 (96 pg/ml). Karyotype 46XX, FISH SRY positive. USG abdomen s/o uterus like structure with apparent left ovary and non visualization of right gonads. Post laproscopy histopathology s/o rudimentary uterus, left ovary with follicles and right gonads showing semineferous tubules with sertoli cells and few hyperplastic leydig cells. 46 XX OTDSD presents with wide phenotypic variability, which influences decisions about gender assignment and need of surgery. Conservative therapy, whenever feasible, is desirable to achieve fertility. Multidisciplinary team approach is required for healthy physical and psychological well-beings of these individuals. Presentation: Thursday, June 15, 2023

Predictors of surgical complications in boys with hypospadias: data from an international registry

BackgroundComplications are frequently reported after hypospadias repair and there is a need to understand the factors that influence their occurrence.MethodsData from boys with hypospadias born between 2000 and 2020 were...

Partial Androgen Insensitivity Syndrome: Incidentally Diagnosed in an Adolescent

Background: Androgen insensitivity syndrome is an X-linked genetic disease characterized by resistance to the actions of androgen in an individual with 46, XY karyotype. It is one of the most common causes of Disorders of sex development (DSD). Clinical Description: A 10-year-7-month-old child, reared as female, was incidentally detected with minor virilization of external genitalia. She had achieved thelarche and adrenarche with a Prader Stage 2. Management and Outcome: Routine investigations showed normal hemogram and kidney and liver functions, as also normal values of serum electrolytes. Ultrasonogram showed the absence of Mullerian structures and the presence of prostate- and testis-like structures. Karyotyping showed 46, XY. There were grossly elevated levels of testosterone and dihydrotestosterone, as well as raised follicle-stimulating hormone and luteinizing hormone levels. Diagnostic laparoscopy showed inguinal testis-like structures and biopsy from the same confirmed testicular tissue. Parents were counseled regarding the prognosis, need for gonadectomy, and hormone replacement. Conclusion: Our case creates awareness regarding the importance of early identification of minor virilizing features in a child, so as to avoid late revelation of an underlying DSD leading to undue anxiety and psychological trauma to parents and child.

Teacher studies students about intersex and transgender issues

The aim of the research was to diagnose the knowledge of students in the field of disorders of sex development, gender dysphoria and social functioning of intersex and transgender people, as well as to learn their opinions on the challenges related to intersex and transgender education. The research was carried out by focus interviews with 78 students of teaching specialties. It has been shown that students – future teachers – in Polish schools consider it necessary to include gender identity issues in the curricula, mainly in the biological and ethical aspect, but not everyone feels prepared to help intersex or transgender students.

Клінічні особливості порушень менструальної функції, асоційованих із психопатологією

The health of the younger generation is a public value. Today, the state of health of teenage girls is of particular concern due to its progressive deterioration. Purpose - to study the features of the clinical course of menstrual function disorders in adolescent girls with comorbid mental health disorders. Materials and methods. 154 girls aged 11-17 were examined with menstrual cycle disorders (77 with oligomenorrhea (OM) and 77 with abnormal uterine bleeding (AUB)). Assessment of physical and sexual development, age of menarche was carried out. Depending on the examination by a psychiatrist, all girls with OM and AUB were divided into groups: without deviations in mental status, with anxiety-phobic disorders and depressive states. Results. It was found that the average growth indicators were probably higher in girls with OM in relation to adolescents with AUB, especially in the presence of psychopathology. The use of BMI did not reveal a significant difference when comparing patients with OM and AUB. Abnormalities of sexual development were probably more often registered in patients with AUB, with its advance, this acquired a significant difference (p˂0.01) and depended on both body mass index (BMI) and psychopathology. If the percentage of patients with disorders of sexual development did not differ depending on psychopathology in girls with AUB, then in adolescents with OM, the specific weight of girls with abnormalities of sexual development increased with the appearance of psychopathology. The average age of menarche was significantly lower in patients with AUB compared to patients with OM (p˂0.003). Early menarche was more typical for AUB. Much more often in adolescents with AUB, it was registered with normative fluctuations of BMI and its excess, as well as with anxiety-phobic disorders both with AUB and OM. Conclusions. The analysis of the conducted studies indicates reliable differences regarding the clinical course of menstrual function disorders by the type of OM and AUB with comorbid psychopathology. It was established that there are significant differences in such indicators as growth, puberty, time of menarche, which depended on the type of menstrual disorders and comorbid psychopathology. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors.

The fundamentals of fibroblast growth factor 9

Fibroblast growth factor 9 (FGF9) was first identified during a screen for factors acting on cells of the central nervous system (CNS). Research over the subsequent two decades has revealed this protein to be a critically important and elegantly regulated growth factor. A hallmark control feature is reciprocal compartmentalization, particularly during development, with epithelium as a dominant source and mesenchyme a prime target. This mesenchyme selectivity is accomplished by the high affinity of FGF9 to the IIIc isoforms of FGFR1, 2, and 3. FGF9 is expressed widely in the embryo, including the developing heart and lungs, and more selectively in the adult, including the CNS and kidneys. Global Fgf9-null mice die shortly after birth due to respiratory failure from hypoplastic lungs. As well, their hearts are dilated and poorly vascularized, the skeleton is small, the intestine is shortened, and male-to-female sex reversal can be found. Conditional Fgf9-null mice have revealed CNS phenotypes, including ataxia and epilepsy. In humans, FGF9 variants have been found to underlie multiple synostoses syndrome 3, a syndrome characterized by multiple joint fusions. Aberrant FGF9 signaling has also been implicated in differences of sex development and cancer, whereas vascular stabilizing effects of FGF9 could benefit chronic diseases. This primer reviews the attributes of this vital growth factor.

Lessons Learned from 17 Years of Multidisciplinary Care for Differences of Sex Development Patients at a Single Indonesian Center

Background: Our multidisciplinary team (MDT) is a large specialized team based in Semarang, Indonesia, that cares for a wide variety of pediatric and adult individuals with differences of sex development (DSD) from across Indonesia. Here, we describe our work over the last 17 years. Methods: We analyzed phenotypic, hormonal, and genetic findings from clinical records for all patients referred to our MDT during the period 2004–2020. Results: Among 1,184 DSD patients, 10% had sex chromosome DSD, 67% had 46,XY DSD, and 23% had 46,XX DSD. The most common sex chromosome anomaly was Turner syndrome (45,X) (55 cases). For patients with 46,XY DSD under-masculinization was the most common diagnosis (311 cases), and for 46,XX DSD, a defect of Müllerian development was most common (131 cases) followed by congenital adrenal hyperplasia (CAH) (116 cases). Sanger sequencing, MLPA, and targeted gene sequencing of 257 patients with 46,XY DSD found likely causative variants in 21% (55 cases), with 13 diagnostic genes implicated. The most affected gene codes for the androgen receptor. Molecular analysis identified a diagnosis for 69 of 116 patients with CAH, with 62 carrying variants in CYP21A2 including four novel variants, and 7 patients carrying variants in CYP11B1. In many cases, these genetic diagnoses influenced the clinical management of patients and their families. Conclusions: Our work has highlighted the occurrence of different DSDs in Indonesia. By applying sequencing technologies as part of our clinical care, we have delivered a number of genetic diagnoses and identified novel pathogenic variants in some genes, which may be clinically specific to Indonesia. Genetics can inform many aspects of DSD clinical management, and while many of our patients remain undiagnosed, we hope that future testing may provide answers for even more.

Differences of Sexual Development (DSD) and Gender Incongruence (GI)

Differences of Sexual Development (DSD) and Gender Incongruence (GI)