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Background Previous studies have suggested that sexual function may be compromised in women born with differences of sex development (DSD) or early loss of gonadal function. Aim To describe sexual function and sexual wellbeing in women with complete androgen insensitivity syndrome (CAIS), complete gonadal dysgenesis (GD) and premature ovarian insufficiency (POI) in relation to gynecological measures and in comparison with unaffected women. Methods A cross sectional study including 20 women with CAIS, 8 women with 46,XY GD, 8 women with 46,XX GD, 21 women with POI, and 62 population-derived controls. Study participants underwent gynecological examination for anatomical measurements and evaluation of tactile sensitivity. They responded to the validated Sexual Activity Log (SAL), Profile of Female Sexual Function (PFSF), and the Personal Distress Scale (PDS). Results The women with CAIS, XY GD, XX GD and POI showed overall satisfying sexual function in comparison to unaffected age-matched population female controls with a median of 1 to 2 satisfying sexual episodes per week among both the patients and the controls depending on available partner. Women with CAIS had shorter vagina and smaller clitoris and women with XY GD had a significantly shallower vagina in comparison to controls. Clitoral width was also significantly smaller among women with XX GD compared to controls. However, results showed overall good genital touch sensitivity with no significant differences between groups. Clinical Implications Women with DSD or POI can be informed on overall satisfactory sexual function and normal genital touch sensitivity. Strengths & Limitations The strength is the use of age-matched population-based controls to these rare conditions of DSD and POI. Limitations are the nonresponder rate of recruited controls, as well as the small groups of women with DSD. Conclusion Women with differences of sex development or early loss of gonadal function show overall good sexual well-being, however clinicians have to make efforts to optimize caretaking and treatment to ensure good sexual quality of life for all patients.

A female phenotype with strip-like gonads, 46, XY pure gonadal dysgenesis (PGD) has a high tendency to develop into gonadal germ cell tumors. We described one patient with 46, XY PGD, who had a gonadal mixed germ cell tumor (GCT) and acute lymphoblastic leukemia (ALL). This is a unique case because two malignancies developed and relapsed in one person with chromosome abnormality, and the patient is the youngest reported so far. There is an association between her GCT and ALL, as the two malignancies may share a common clonal origin and the

Introduction The bell-clapper deformity (BCD) predisposes to intravaginal torsion (IVT) and is classically bilateral. The precise pathological definition of what constitutes a BCD is not clear. The current study aims to clarify the specific anatomic details of this anomaly. Methods A systematic review was performed utilizing the PRISMA principles. Studies are presented chronologically based on their level of evidence. They are further divided into study types: autopsy and operative studies of acute torsion, intermittent torsion and studies of the contralateral testis in vanishing testis. Results The bell-clapper deformity is best defined by complete investment of the testis, epididymis and a length of the spermatic cord by the tunica vaginalis. Based on autopsy studies the rate of BCD in scrotal testis varied from 4.9% to 16%; with bilaterality in 66%–100%. In cases of acute IVT bilaterality was noted in 54%–100%. The most disparate results were in cases of testicular regression syndrome where contralateral BCD was noted in 0%–87% of cases. Conclusion We suggest future studies employ the strict anatomical definition above. As there is evidence of age-dependent investment of the testes, it will be important to develop age-standardized measurements of intravaginal length of spermatic cord. This critical morphometric measurement will allow a better understanding of the risk of IVT. Level of evidence Systematic review of diagnostic studies: lowest level of evidence of included manuscripts Level IV (case–control studies with a poor reference standard).

Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular regression syndrome (TRS), or anorchia. All affected children have non-syndromic forms of disorders/differences of sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains of the protein, are predicted by in silico tools to have a deleterious effect on helicase function. DHX37 is required for ribosome biogenesis in eukaryotes, and how these variants cause DSD is unclear. The relationship between DHX37 and human congenital disorders is complex as compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies. Here, we will give a brief overview of ribosome biogenesis and the role of DHX37 in this process. We will discuss variants in DHX37, their contribution to human disease in the general context of human ribosomopathies, and the possible disease mechanisms that may be involved.

Male sex determination in mammals is initiated by SRY, a Y-encoded transcription factor. The protein contains a high-mobility-group (HMG) box mediating sequence-specific DNA bending. Mutations causing XY gonadal dysgenesis (Swyer syndrome) cluster in the box and ordinarily arisede novo. Rare inherited variants lead to male development in one genetic background (the father) but not another (his sterile XY daughter).De novoand inherited mutations occur at an invariant Tyr adjoining the motif’s basic tail (box position 72; Y127 in SRY). In SRY-responsive cell lines CH34 and LNCaP,de novomutations Y127H and Y127C reduced SRY activity (as assessed by transcriptional activation of principal target geneSox9) by 5- and 8-fold, respectively. Whereas Y127H impaired testis-specific enhancer assembly, Y127C caused accelerated proteasomal proteolysis; activity was in part rescued by proteasome inhibition. Inherited variant Y127F was better tolerated: its expression was unperturbed, and activity was reduced by only twofold, a threshold similar to other inherited variants. Biochemical studies of wild-type (WT) and variant HMG boxes demonstrated similar specific DNA affinities (within a twofold range), with only subtle differences in sharp DNA bending as probed by permutation gel electrophoresis and fluorescence resonance-energy transfer (FRET); thermodynamic stabilities of the free boxes were essentially identical. Such modest perturbations are within the range of species variation. Whereas our cell-based findings rationalize thede novogenotype-phenotype relationships, a molecular understanding of inherited mutation Y127F remains elusive. Our companion study uncovers cryptic biophysical perturbations suggesting that thepara-OH group of Y127 anchors a novel water-mediated DNA clamp.

Male reproductive functions are governed by hypothalamic pituitary testicular axis. If any component of this axis malfunctions, then hypogonadism will develop which is characterized by ill-defined secondary sexual features and low serum testosterone. The common patterns seen are primary and secondary testicular failure in the young; and late onset hypogonadism in the elderly. All such cases can be virilized and managed by androgen supplementation. Spermatogenesis can be induced by use of appropriate gonadotropins in selected cases. The aim of the study was to find out the pattern, management and outcome of male hypogonadism.It was a prospective questionnaire based observational study, carried out on infertile hypogonadic males, attending medicine outdoor at medical college hospital from January 2015 to December 2020. There were 50 males with hypogonadic features, cases of late onset of hypogonadism were excluded. Sexual maturity rating, semen analysis, serum testosterone and FSH level were estimated in all patients at baseline and at 6 months duration of treatment. Testicular biopsy, Karyotyping and MRI brain were performed in selected cases. Azoospermic patients having hypogonadotropic hypogonadism were treated with long-acting testosterones and gonadotropins.The study subjects were infertile azoospermic males. On the basis of serum FSH and testosterone levels, they were classified into two groups. Group A (n=42) cases were hypergonadotropic hypogonadism or primary testicular failure; of these 32 were Klinefelter syndrome (XXY), 7 chronic orchitis and 3 empty scrotal syndrome including one case of anorchia. These patients also developed other systemic illnesses in addition to hypogonadism. Group B (n=8) hypogonadotropic hypogonadism or secondary testicular failure; of these 2 were Kallman syndrome and the rest were idiopathic. After testosterone replacement all patients were virilized and there was marked improvement in libido and androgenization.The study brings out that primary testicular failure is more common than secondary testicular failure. Both pattern of hypogonadism should receive lifelong androgen replacement therapy; otherwise, they will be a basket of multiple systemic disorders. Presently testosterone undecanoate once in every three months is the agent of choice.

Objectives For women with Swyer Syndrome, a 46,XY gonadal dysgenesis, full term pregnancies are possible after oocyte donation. According to literature, mode of delivery is almost always by Caesarean section for various reasons. Medical indications are multiple pregnancies and related complications, preeclampsia, an androgynous shaped pelvis and failed induction of labor. Elective Caesarean sections were performed based on maternal request and medical recommendation. Methods Following careful examination and shared decision making, we planned a spontaneous delivery with a patient with Swyer syndrome and tested the different hypotheses regarding anatomical and functional features according to literature. In addition, deliveries of women with Swyer Syndrome were analyzed in a German multicenter case series. Results A total of seven women with Swyer syndrome with a total of 10 pregnancies were identified, who later gave birth to twelve live-born children. Seven out of 10 births were performed by elective and non-elective Caesarean section, three births took place vaginally. Conclusions In summary, the risk of Caesarean section delivery has increased, but spontaneous delivery can be attempted in the event of inconspicuous findings.

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

A disorder of sex development (DSD) is defined as a congenital condition in which development of chromosomal, gonadal, or anatomical sex is atypical. Swyer syndrome is an example of 46,XY DSD with a female phenotype. It usually becomes apparent in adolescence with delayed puberty and amenorrhoea. Spontaneous breast development is very rare. A 15-year-old girl was presented due to primary amenorrhoea with breast development compatible with Tanner stage V. Hormonal tests revealed hypergonadotropic hypogonadism with low level of oestradiol. Pelvic ultrasound and magnetic resonance imaging revealed a small uterus, and no ovaries were found. In the right lower abdomen, a structure of unknown origin was visible. The chromosome analysis revealed a 46,XY karyotype. The patient was qualified for a laparoscopic bilateral gonadectomy. Postoperative histopathological examination revealed gonadoblastoma. We underline the need to consider DSD 46,XY in the presence of primary amenorrhoea, even when pubertal development is present. Germ cell tumors have a tendency to grow and metastasize rapidly. Delayed diagnosis may increase the risk of malignant transformation and cause a poor diagnosis.Zaburzenia różnicowania płci polegają na niezgodności płci genetycznej i gonadalnej z fenotypem zewnętrznych narządów płciowych. Zespół Swyera jest przykładem DSD z kariotypem 46,XY i żeńskim fenotypem. Rozpoznanie jest ustalane głównie w wieku nastoletnim w związku z diagnostyką pierwotnego braku miesiączki i opóźnionego pokwitania. Prawidłowy rozwój piersi występuje u tych pacjentek niezwykle rzadko. Piętnastoletnia dziewczyna została przyjęta w celu diagnostyki pierwotnego braku miesiączki. W badaniu fizykalnym rozwój piersi wg skali Tannera oceniono na M5. W badaniach hormonalnych stwierdzono cechy hipogonadyzmu hipergonadotropowego z małym stężeniem estradiolu. W badaniu ultrasonograficznym i rezonansu magnetycznego miednicy małej zobrazowano małą macicę, brak prawidłowych jajników. W podbrzuszu prawym widoczna była struktura niewiadomego pochodzenia. W badaniu cytogenetycznym stwierdzono kariotyp męski – 46,XY. Pacjentka została zakwalifikowana do zabiegu usunięcia gonad. W pooperacyjnym badaniu histopatologicznym stwierdzono gonadoblastoma. Prezentowany opis przypadku podkreśla konieczność wzięcia pod uwagę zespołu Swyera w diagnostyce pierwotnego braku miesiączki, nawet w przypadku obecności drugorzędowych cech płciowych. Należy pamiętać, że nowotwory germinalne mogą szybko rosnąć i dawać przerzuty. Opóźnienie właściwego rozpoznania może zwiększać ryzyko zezłośliwienia nowotworu i niekorzystnie wpłynąć na rokowanie.

Disorders of sexual differentiation (DSD) with karyotype 46,XY include gonadal developmental differences such as complete gonadal dysgenesis, partial gonadal dysgenesis, testicular regression and ovotesticular sexual differentiation disorder, differences in androgen synthesis or action, such as androgen synthesis deficiency, androgen action deficits, LH receptor deficiency, AMH synthesis or action deficits, and other conditions such as severe hypospadias, cloaca estrophy, etc. Methods: A 17 years-old girl came to our attention for hirsutism, clitoral hypertrophy, primary amenorrhea, and bilateral mammary hypoplasia. According to clinical features and anamnesis, the diagnosis of 46, XY DSD was made. For diagnostic purposes, she underwent an extensive genetic analysis, hormone dosage and instrumental examinations. After a clitoridoplasty and hormone replacement treatment, the patient performs appropriate multidisciplinary follow-up and regular psychotherapy.The clinical case reported falls, according to the recent classification developed by the Chicago Consensus, within the scope of DSD with karyotype 46, XY. About 160 cases of patients with 17β-HSD3 deficiency, diagnosed at a mean age of 12 years, are described in the literature, most of them coming from Western Asia and Europe and only three cases from Eastern Asia. Clinically, about 30% of patients showed virilization, 20% clitoromegaly, ambiguous genitalia, inguinal/labial mass, 16% primary amenorrhea, and 5% absence of mammary development, features that are partly traced in the case described here.This case underscores the complexity of managing individuals with DSD. Having acquired the concept that irreversible surgery should be avoided, except in cases where failure to do so would determine health risks, the primary objective of the medical decision lies in meeting conditions aimed at harmonious sexual identification, especially regarding sexual activity and fertility, involving a team of experienced professionals (psychologists, pediatricians, surgeons, endocrinologists, radiologists), capable of promptly identifying suggestive clinical signs.

Cryptorchidism, i.e., undescended testis, is one of the most common genital malformations in newborn male babies. The birth rate of cryptorchidism varies from 1.6 to 9.0 %. Etiology of disrupted testicular descent is complex and predisposing causes include genetic, hormonal, environmental, lifestyle and maternal factors. Testicular descent occurs in two major steps and testicular hormones and normal function of hypothalamic-pituitary-testicular axis are important for normal descent. Several gene mutations are associated with syndromic cryptorchidism but they are rarely found in boys with isolated undescended testis. Testicular regression can also cause an empty scrotum. Normal male genital phenotype indicates that the boy has had functioning testis during development. Torsion of the testis can cause testicular regression but in many cases the reason for vanishing testis remains elusive. In this narrative review we discuss genetics of cryptorchidism and testicular regression.

Background Permanent progression of paternal age and development of reproductive medicine lead to increase in number of children conceived with assisted reproductive techniques (ART). Although it is uncertain if ARTs have direct influence on offspring health, advanced paternal age, associated comorbidities and reduced fertility possess significant risks of genetic disorders to the offspring. With a broad implementation of a non-invasive prenatal testing (NIPT), more cases of genetic disorders, including sex discordance are revealed. Among biological causes of sex discordance are disorders of sexual development, majority of which are associated with the SRY gene. Case presentation We report a case of a non-invasive prenatal testing and ultrasound sex discordance in a 46,XY karyotype female fetus with an SRY pathogenic variant, who was conceived through an intracytoplasmic sperm injection (ICSI) due to severe oligozoospermia of the father. Advanced mean age of ICSI patients is associated with risk of de novo mutations and monogenic disorders in the offspring. Additionally, ICSI patients have higher risk to harbour infertility-predisposing mutations, including mutations in the SRY gene. These familial and de novo genetic factors predispose ICSI-conceived children to congenital malformations and might negatively affect reproductive health of ICSI-patients’ offspring. Conclusions Oligozoospermic patients planning assisted reproduction are warranted to undergo genetic counselling and testing for possible inherited and mosaic mutations, and risk factors for de novo mutations.

International audience; In 46,XY men, testis is determined by a genetic network(s) that both promotes testis formation and represses ovarian development. Disruption of this process results in a lack of testis-determination and affected individuals present with 46,XY gonadal dysgenesis (GD), a part of the spectrum of Disorders/Differences of Sex Development/Determination (DSD). A minority of all cases of GD are associated with pathogenic variants in key players of testis-determination, SRY, SOX9, MAP3K1 and NR5A1. However, most of the cases remain unexplained. Recently, unbiased exome sequencing approaches have revealed new genes and loci that may cause 46,XY GD. We critically evaluate the evidence to support causality of these factors and describe how functional studies are continuing to improve our understanding of genotype-phenotype relationships in genes that are established causes of GD. As genomic data continues to be generated from DSD cohorts, we propose several recommendations to help interpret the data and establish causality.

Context Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (Myo-Ectodermo-Gonadal Dysgenesis (MEGD) syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD). Method We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory, and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing. Results A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low anti-Müllerian hormone, and high follicle-stimulating hormone and luteinizing hormone concentrations. All patients manifested characteristic features of MEGD syndrome. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5, and 8.5 days post coitum(dpc) revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier. Conclusion Our data indicate the essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.

Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 310 Russian patients with 46,XY disorders of sex development (DSD). Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described. We have not found any phenotype-genotype correlations and any clinical and laboratory markers that would allow to suspect this type of before conducting molecular genetic analysis.

BackgroundSRY (sex determining region of Y) is one of the important genes involved in the process of human sex determination. The disturbed sex determination caused by an SRY mutation accounts for 10% to 15% of cases with 46, XY sex reversal. Recently, 3 distal enhancers were identified upstream of the SOX9 gene.ObjectivesThe purpose of this study was to investigate the molecular etiology of 46, XY sex reversal in 3 familial patients and a sporadic patient.DesignNext-generation sequencing was used to reveal the genotype and inherited pattern. Copy number variations and single nucleotide polymorphism haplotyping were analyzed to observe the alteration of enhancers of SOX9. Transcriptional activity of SRY mutation were assessed by a dual luciferase reporting system, and nuclear translocation was observed by confocal microscopy.ResultsTwo novel SRY gene mutations, p.Arg76Leu and p.Glu89flx15, were identified. In the pedigree with multiple patients, p.Arg76Leu mutation in SRY and p.Gly212Ser mutation in NR5A1 were identified in the proband. The heterozygous deletion far upstream of the SOX9 gene in chromosome 17 was identified in the 3 patients in this family, containing the distal enhancer eSR-A of SOX9 but not eSR-B and eALDI. The frameshift mutation p.Glu89flx15 was revealed to inhibit the transcriptional activity of the target gene, whereas the missense mutation p.Arg76Leu barely showed an effect.ConclusionIn contrast to sporadic cases, inherited single nucleotide variations of SRY are not the main cause of the severe phenotype of 46, XY sex reversal, and the enhancers of SOX9 should be investigated carefully in such patients.

Objective To describe the gonadal features of patients with 45,X/46,XY mosaicism, and to evaluate the prevalence of gonadal tumor in different phenotypes. Materials and Methods The medical records of consecutive patients with 45,X/46,XY karyotype or its variants who had undergone gonadal biopsy or gonadectomy at a single institute between 1996 and 2017 were retrospectively reviewed. Results Of 34 patients with 45,X/46,XY mosaicism, a unilateral dysgenetic testis and a contralateral streak gonad was detected in 20 patients (59%), bilateral streak gonads in 9 (26%), and bilateral dysgenetic testes in 5 (15%). A gonad composed of both streak and dysgenetic testicular portions was observed in 7 gonads of 6 patients. All streak gonads were removed, and bilateral gonadectomy was performed in 15 patients raised as girls. Pathologic examination revealed gonadal tumors in 6 of the 34 (18%) patients, including a gonadoblastoma in 7 gonads among 5 patients and an association of dysgerminoma with gonadoblastoma in 1 gonad. All 6 patients who developed gonadal tumor had female genitalia. Postoperative course was uneventful except 1 boy. A seminoma was developed in his soritaly scrotal testis at the age of 16 years. Conclusion The prevalence of gonadal tumor in patients with 45,X/46,XY mosaicism may vary according to the phenotype, and high in patients with female phenotype. Considering the increased risk of gonadal tumors in such patients, early investigation and individual management, including prophylactic gonadectomy, are recommended. In male patients, a close follow-up of the preserved testes is mandatory until adulthood.

This is a histopathologic and endocrinologic study of 6 calves diagnosed with cryptorchidism. Cases 1–3 were diagnosed as resembling testicular regression syndrome. In cases 1 and 2, the extracted tissue was a small, firm, gray-white mass, and there was lack of obvious testicular tissue in case 3. Histopathologically, the excised tissue in cases 1–3 was a fibrotic testicular remnant with inflammation, mineralization, hemosiderin-laden macrophages or lipofuscin-laden macrophages, and lack of germ cells and interstitial endocrine cells. These findings were compared with cases 4–6, which were diagnosed as testicular hypoplasia due to cryptorchidism. These cases had small but otherwise grossly unremarkable intra-abdominal testicular tissue and histologically had a few germ cells and sustentacular cells with arrested spermatogenesis and an increase in interstitial endocrine cells. Cases 1–3 had more severe degenerative changes compared with cases 4–6. In case 2, the average diameter of the seminiferous tubules was much smaller than in cases 4–6, and there were few tubule cross sections. Anti-Müllerian hormone (214 pg/ml) was detected in the plasma of case 2. Based on the macroscopic and histopathologic findings as well as endocrinologic profiles, the testicular degeneration in cases 1–3 was considered similar to that of testicular regression syndrome. In this condition, it is thought that a normally developing intra-abdominal testis undergoes degeneration due to heat or a vascular disorder such as torsion.

Introduction According to the current classification of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) of Disorders of Sex Development (DSD), etiologies vary around the world. Ethnic or genetic diversity probably explains this variability. We therefore conducted the present study on etiologies of DSDs in a country from central Africa. Methods We carried out an observational retrospective study at the Pediatric Endocrinology Unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde, Cameroon from May 2013 to December 2019. All patients diagnosed with a DSD were included, and incomplete files excluded. Results We included 80 patients diagnosed with DSD during the study period. The 46,XX DSD were the most frequent in our study population (n = 41, 51.25%), with congenital adrenal hyperplasia (CAH) as the main diagnosis. The 46,XY DSD accounted for 33.75% and sex chromosome DSD group represented 15% of the study population. Conclusions DSDs are not an exceptional diagnosis in a Sub-Saharan context. 46,XX DSD are the most prevalent diagnosis in our setting. The diagnosis of all these affections is late compared to other centers, justifying advocacy for neonatal screening of DSDs in our context.

The testicular prosthesis can be an afterthought for providers when performing an orchiectomy for testicular cancer, torsion, atrophic testis, or trauma. However, data suggest that patients find the offer of a testicular prosthesis and counseling regarding placement to be extremely important from both a pragmatic and a psychosocial perspective. Only two-thirds of men undergoing orchiectomy are offered an implant at the time of orchiectomy and of those offered about one-third move forward with prosthesis placement. The relatively low acceptance rate is in stark contrast with high patient satisfaction and low complication rates for those who undergo the procedure. The most common postoperative patient concerns are minor and involve implant positioning, size, and weight. Herein, we provide an up-to-date review of modern preoperative evaluation, patient selection, expectation management, surgical technique, and expected outcomes for testicular prostheses.

Differences in Sex Development (DSD) encompasses many diagnoses, where the development of chromosomal make-up, gonadal development or anatomical development is atypical. XY, DSD is a classification under the recent international consensus statement, and XY females commonly encapsulate disorders of androgen synthesis and androgen action. Complete Androgen Insensitivity Syndrome (CAIS) is the most common XY, DSD diagnosis, which results in an individual having XY chromosomes, but the person is phenotypically female. This article explores the care and management of children and young people with a DSD and focuses on the diagnosis of CAIS in adolescence. Medical and surgical management is discussed, alongside sexual function, gender identity and the psychological impact of the diagnosis. The involvement of the multidisciplinary team is stressed, together with an emphasis on the investment that is needed in psychological and nursing support for girls with CAIS, and their families.

Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and non-visualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signalling cascades controlling sex determination in humans.

Pure gonadal dysgenesis is a situation when the karyotype is 46, XY, but for various reasons there is a disorder of differentiation of Wolffian and Mullerian structures and in consequence the phenotype is female. It is known that abdominal gonads and the presence of Y chromosome allow to qualify this condition as a high risk of tumor. In most cases breast development is limited because of lack or low level of estrogen. A 27-year-old patient with differences of sexual development (DSD), was admitted to the Department of Endocrinological Gynecology for a control examination. In the history: dysgerminoma, primary amenorrhea and ambiguous karyotype. The patient has not taken hormonal replacement therapy. The breast development is Tanner stage V.

Infertility is common among individuals with differences in sex development (DSD), and affected individuals and families desire fertility counseling. This survey sought to assess fertility knowledge and experiences with fertility counseling among DSD specialists for DSD conditions excluding congenital adrenal hyperplasia.A survey was iteratively developed by members of the DSD-Translational Research Network (DSD-TRN) Fertility Preservation Workgroup and disseminated to 5 clinician groups: the DSD-TRN, the Society for Pediatric Psychology DSD Special Interest Group (SIG), the Pediatric Endocrine Society DSD-SIG, the Societies for Pediatric Urology, and the North American Society for Pediatric and Adolescent Gynecology.Completed surveys (n = 110) were mostly from pediatric urology (40.3%), gynecology (25.4%), and endocrinology (20.9%) specialists. Most (73/108, 67.6%) respondents reported discussing fertility potential. Sixty-seven responded to questions regarding fertility potential. Many participants answered questions about the presence of a uterus in individuals with 46,XY complete gonadal dysgenesis and about the potential for viable oocytes in individuals with 46,XY partial gonadal dysgenesis incorrectly. Comments acknowledged the need for further education on fertility in individuals with DSD.Many DSD providers have some knowledge of fertility potential, but knowledge gaps remain. Experts expressed a desire for education and accessible resources to counsel effectively about fertility potential for individuals with DSD.

ObjectiveInsulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X/46,XY mosaicism.MethodsRetrospectively collected data from medical records, gonadal tissue samples, and prospectively analyzed serum samples from eighteen male patients with 45,X/46,XY mosaicism (one prepubertal, four testosterone-treated, 13 untreated) were included. Biochemical, clinical, and histological outcomes were evaluated according to serum INSL3 concentrations, quantified by LC-MS/MS methodology, and gonadal INSL3 immunohistochemical expression.ResultsSerum INSL3 concentrations spanned from below to above the reference range. In untreated patients, the median serum INSL3 SD score was -0.80 (IQR: -1.65 to 0.55) and no significant difference was observed between INSL3 and testosterone. There was no clear association between serum INSL3 and External Genitalia Score at diagnosis, spontaneous puberty, or sperm concentration. INSL3 and CYP11A1 expression overlapped, except for less pronounced INSL3 expression in areas with severe Leydig cell hyperplasia. No other apparent links between INSL3 expression and histological outcomes were observed.ConclusionsIn this pilot study, serum INSL3 concentrations ranged and seemed independent of other reproductive hormones and clinical features in males with 45,X/46,XY mosaicism. Discordant expression of INSL3 and CYP11A1 may explain low INSL3 and normal testosterone concentrations in some patients. Further studies are needed to elucidate the divergence between serum INSL3 and testosterone and the potential clinical use of INSL3.

Mutations in the gene DHH are an extremely rare cause of disorders of sex development 46,XY (DSD,46XY). The article describes the clinical cases of two unrelated patients with gonadal dysgenesis 46,XY with female phenotype. By using a next generation sequencing method, in both cases the same biallelic variant substitution c. 419Tgt;G in the DHH gene was revealed. Taking into account the data on the role of DHH in the formation of the nervous system, the diagnosis of minifascicular polyneuropathy at the preclinical stage was confirmed in both cases. These cases demonstrate the value of using NGS, which allows simultaneous analysis of a wide range of candidate genes in DSD and the diagnosis of comorbidities before the development of the clinical picture. These are the first descriptions of patients with mutations in the DHH gene in the Russian population.

OBJECTIVE: The study aimed to identify the genetic basis of partial gonadal dysgenesis (PGD) in a non-consanguineous family from Estonia. PATIENTS: Cousins P (proband) 1 (12 years; 46,XY) and P2 (18 years; 46,XY) presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and azoospermia in P2. Their distant relative, P3 (30 years; 46,XY), presented bilateral cryptorchidism and cryptozoospermia. DESIGN: Exome sequencing was targeted to P1-P3 and five unaffected family members. RESULTS: P1-P2 were identified as heterozygous carriers of NR5A1 c.991-1G > C. NR5A1 encodes the steroidogenic factor-1 essential in gonadal development and specifically expressed in adrenal, spleen, pituitary and testes. Together with a previous PGD case from Belgium (Robevska et al 2018), c.991-1G > C represents the first recurrent NR5A1 splice-site mutation identified in patients. The majority of previous reports on NR5A1 mutation carriers have not included phenotype-genotype data of the family members. Segregation analysis across three generations showed incomplete penetrance ( C. The variant pathogenicity was possibly modulated by rare heterozygous variants inherited from the other parent, OTX2 p.P134R (P1) or PROP1 c.301_302delAG (P2). For P3, the pedigree structure supported a distinct genetic cause. He carries a previously undescribed likely pathogenic variant SOS1 p.Y136H. SOS1, critical in Ras/MAPK signalling and foetal development, is a strong novel candidate gene for cryptorchidism. CONCLUSIONS: Detailed genetic profiling facilitates counselling and clinical management of the probands, and supports unaffected mutation carriers in the family for their reproductive decision making.

Disorders of sex development (DSD) have been linked to gene defects that lead to gonadal dysgenesis. Herein, we aimed to identify the genetic cause of gonadal dysgenesis in a patient with primary amenorrhoea tracing it to a phenotypic female carrying a 46,XY karyotype of a consanguineous family. Whole exome sequencing (WES) was performed and revealed in homozygosity the rare and only once reported p.Arg164Pro missense mutation in exon 2 of the desert hedgehog (DHH) gene. Sanger sequencing was used to validate this candidate variant both in the patient, the parents, and two siblings. Both brother and sister of the index patient were found negative for the p.Arg164Pro mutation, while the consanguineous parents were found to carry the mutation in the heterozygous state. Neither the parents nor the unaffected siblings showed any reproductive malformations. Defects in the DHH gene have been reported as a very rare cause of DSD, and this report increases the number of 46,XY gonadal dysgenesis cases. Additionally, the present study highlights the importance of genetic validation of patients with DSD, since this is likely to alleviate the considerable psychological distress experienced by both the patient and the parents.

Swyer syndrome also known as pure or complete gonadal dysgenesis is a very rare disorder of sex development wherein the individuals are phenotypically females with 46, XY genotype and preserved mullerian structures. These individuals characteristically have dysgenetic streak gonads which carry an increased risk of malignant transformation. Prophylactic gonadectomy is highly recommended as soon as a clinical diagnosis is established to diminish the chances of tumor development. We present a case of complete gonadal dysgenesis with bilateral small gonads with a dysgerminoma arising in a background of gonadoblastoma in one gonad and immature teratoma in the other. The present case, besides adding a rare case to the literature, highlights the importance of detailed pre-operative assessment of gonadal size and prompt prophylactic gonadectomy in cases with gonadal dysgenesis.

Historically, the terms partial (PGD) and mixed gonadal dysgenesis (MGD) have been used to describe incomplete testicular differentiation in individuals with 46,XY or 45,X/46,XY karyotypes, respectively. However, it is currently unclear to what extent clinical features actually differ between these individuals. The aim of this study was to compare clinical, laboratory, and histological findings in these 2 groups. Patients with testicular dysgenesis seen in our service between 1989 and 2013 were selected. Sixty-one patients met the inclusion criteria. Individuals with 46,XY and 45,X/46,XY karyotypes were compared regarding genital features, gonadal histology and function, growth, and associated conditions. Twenty-five had mosaicism with a 45,X cell line (MGD), while a 46,XY karyotype (PGD) was found in 36 cases belonging to 32 families. Mutations in NR5A1, WT1, and SRY genes associated with testicular dysgenesis were found in 12 families. There were no significant differences regarding parental consanguinity, degree of external androgenization, gonadal location, histology, and function, and associated conditions. However, in the MGD group, the presence of a uterus, lower birth weight and length, and short stature were more often observed. Therefore, the use of histological features to classify PDG and MGD should be abandoned and replaced by classification based on karyotype.

Ambiguous genitalia affect 1 in 5,000 live births. Diagnostic procedures can be time-consuming, and often the etiology cannot be established in this group of individuals with differences/disorders of sex development (DSD). We aimed to evaluate the clinical presentation, sex assignment, and diagnostic workup in these patients. In this retrospective observational study, we included infants who presented with ambiguous genitalia from 2006 to 2016 at the Radboudumc (Radboud University Medical Center) DSD expert center. Relevant data were collected from patient records. Sixty-two 46,XY and fourteen 46,XX individuals were included. Sex was assigned in the first days of life and based on the combination of presence or absence of a uterus on ultrasound, AMH level, palpable gonads, and the karyotype (corresponded in 96% of the patients). In 86% of the 46,XX DSD subjects, a diagnosis was made, whereas in only 15/62 (24%) of the 46,XY DSD individuals, etiology was determined. In 52 individuals, genetic testing was performed resulting in a diagnosis in 24 patients (46%). AMH, hCG-stimulated testosterone, and dihydrotestosterone levels contributed to determining etiology, whilst basal testosterone and basal dihydrotestosterone did not. Establishing a diagnosis in infants with ambiguous genitalia is complex and challenging; this study aids to enhance this process and improve current practice.

Deletion of distal 9p is associated with a rare clinical condition characterized by dysmorphic features, developmental delay, and ambiguous genitalia. The phenotype shows variable expressivity and is related to the size of the deletion. 8q24 duplication has been reported in only few cases to date, all showing dysmorphic features and mild psychomotor developmental delay. A case of chromosomal aberration involving a 9p terminal deletion with an 8q duplication has never been reported. Here, we describe a child with a female phenotype, male karyotype, dysmorphic features, ambiguous genitalia, and developmental delay. In order to assess the cause of the patient's phenotype, conventional karyotyping, FISH, and a chromosomal microarray analysis were performed on the patient and her parents. The cytogenetic and molecular analysis revealed an unbalanced chromosomal aberration with a duplication in the long arm of chromosome 8 at 8q24.11q24.3 associated with a distal deletion in the short arm of chromosome 9 at 9p24.3p24.1, derived from a maternal balanced translocation. We compared the clinical picture of our patient with other similar cases reported in the literature and found that some clinical findings, such as strabismus, symphalangism of the first finger, and cubitus valgus, have never been previously associated with 9p deletion or 8q duplication expanding the phenotypic range of this condition. This study is aimed to better define the clinical history and prognosis of patients with this rare chromosomal aberration.

In humans, mutations of Desert Hedgehog gene (DHH) have been described in patients with 46,XY gonadal dysgenesis (GD), associated or not with polyneuropathy. In this study, we describe two patients diagnosed with GD, both harboring novel DHH compound heterozygous mutations p.[Tyr176*];[Asn337Lysfs*24] and p.[Tyr176*];[Glu212Lys]. To investigate the functional consequences of p.(Asn337Lysfs*24) and p.(Glu212Lys) mutations, located within the C-terminal part of DHh on auto-processing, we performed in vitro cleavage assays of these proteins in comparison with Drosophila melanogaster Hedgehog (Hh). We found that p.(Glu212Lys) mutation retained 50% of its activity and led to a partially abolished DHh auto-processing. In contrast, p.(Asn337Lysfs*24) mutation resulted in a complete absence of auto-proteolysis. Furthermore, we found a different auto-processing profile between Drosophila Hh and human DHh, which suggests differences in the processing mechanism between the two species. Review of the literature shows that proven polyneuropathy and GD is associated with complete disruption of DHh-N, whereas disruption of the DHh auto-processing is only described with GD. We propose a model that may explain the differences between Schwann and Leydig cell development by autocrine versus paracrine DHh signaling. To our knowledge, this is the first study investigating the effect of DHH mutations on DHh in vitro auto-processing.

While the Hedgehog signalling pathway is implicated in numerous developmental processes and maladies, variants in the Desert Hedgehog (DHH) ligand underlie a condition characterised by 46,XY gonadal dysgenesis with or without peripheral neuropathy. We discuss here the role and regulation of DHH and its signalling pathway in the developing gonads and examine the current understanding of how disruption to this pathway causes this difference of sex development (DSD) in humans.

Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination.

Description of diagnosis of 45,X/46,XY ovotesticular DSD.Case report.Department of Medical Genetics, KZ a.s., Masaryk Hospital, Ústí nad Labem.45,X/46,XY ovotesticular DSD is a diagnosis, which in this case was detected by chromosomal examination was performed, in which the child showed karyotype 45,X[2]/46,XY[8] - a pathological male karyotype correlated with the syndrome 45,X/46,XY ovotesticular DSD (disorder of sexual development). At the same time, a variant of chromosome 10:45,X,inv(10) (p11q21.2)/46,XY,inv(10)(p11q21.2) was detected.The phenotype of patients with mosaic karyotype 45,X/46,XY ranges in a wide range from the female phenotype with classical Turner syndrome, through individuals with ambiguous genitals to normal but infertile men. Thus, both Turners syndrome and virilization can be expected. Gonads are usually dysgenetic with insufficiently differentiated testicular tissue, which can occur in both gonads (mixed gonadal dysgenesis) or only in one (asymmetric gonadal dysgenesis). With this type of gonadal dysgenesis, there is a risk of gonadoblastoma or other tumors.