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Testosterone levels measured by electrochemiluminescence at different ages in patients with partial gonadal dysgenesis. FSH values are presented on the y-axis on a linear scale. Dotted lines on the y-axis represent the upper and lower normal limits for testosterone levels in pubertal boys (2.86–8.10 ng/mL).
Source publication
Aims
. Studies on 46,XY partial gonadal dysgenesis (PGD) have focused on molecular, gonadal, genital, and hormone features; little is known about follow-up. Our aim was to analyze long-term outcomes of PGD.
Methods
. Retrospective longitudinal study conducted at a reference service in Brazil. Ten patients were first evaluated in the 1990s and follo...
Citations
... This finding is in line with other studies on pubertal development of patients with a DSD and NR5A1/SF-1 variants, which describe a wide spectrum of pubertal courses with considerable virilization at puberty in 46, XY individuals, irrespective of the degree of virilization of the external genitalia at birth. [91][92][93] Thus, the severity of the DSD phenotype based on the assessment of the external genitalia at birth may not be a reliable predictor of later pubertal development in individuals with NR5A1/SF-1 variants. Similarly, the severity of external genital undervirilization at birth does not necessarily reflect the potential of virilization in patients with a loss of 5α-reductase activity or partial androgen resistance syndromes. ...
Background
Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained.
Methods
We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network.
Findings
Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably.
Interpretation
The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors.
Funding
10.13039/100000001Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.
... In a few cases, virilization might not occur, and spontaneous breast development might even be present (2). Patients with ambiguous genitalia at birth and male sex assignment who showed spontaneous puberty and normal testosterone values have been reported, supporting the idea of preserved Leydig cell function later in life (4,8,9). ...
... Most 46, xY subjects with NR5A1 mutations reared as girls will undergo progressive masculinization if the gonads are not removed, and boys with NR5A1 mutations can undergo spontaneous puberty as well as preserved fertility, suggesting that a 46, xY individual with an NR5A1 mutation reared as a boy has certain advantages (4,8,9,13). In a literature review, 46% of patients with NR5A1 mutations were assigned female, and 54% were assigned male (5). ...
... In a few cases, virilization might not occur, and spontaneous breast development might even be present (2). Patients with ambiguous genitalia at birth and male sex assignment who showed spontaneous puberty and normal testosterone values have been reported, supporting the idea of preserved Leydig cell function later in life (4,8,9). ...
... Most 46, xY subjects with NR5A1 mutations reared as girls will undergo progressive masculinization if the gonads are not removed, and boys with NR5A1 mutations can undergo spontaneous puberty as well as preserved fertility, suggesting that a 46, xY individual with an NR5A1 mutation reared as a boy has certain advantages (4,8,9,13). In a literature review, 46% of patients with NR5A1 mutations were assigned female, and 54% were assigned male (5). ...
... In this study, we evaluate the pubertal development in a cohort of 10 patients with 46,XY DSD due to NR5A1 mutations with detailed longitudinal clinical and hormonal data. All patients of our cohort who first presented during infancy showed signs of spontaneous pubertal development and virilization with growth of genitalia and development of genital hair at pubertal age consistent with previously published single case reports [34][35][36]. Spontaneous signs of virilization at the age of puberty also occurred in all but one patient with until then apparently female external genitalia. ...
... Despite serum concentrations of testosterone within the male reference range and spontaneous progression of Tanner stages, all patients living as males at the time of puberty showed impaired testicular growth throughout puberty. This observation is in alignment with previous case reports about 46,XY DSD patients with NR5A1 mutations, in whom low testicular volume, but normal testosterone concentrations have been reported [35][36][37]. Therefore, in this patient group a decreased testicular volume does not exclude spontaneous pubertal development and testicular volume does not correlate well with a possibly preserved Leydig cell function in puberty. ...
... Only in one patient, testosterone concentrations declined during puberty below the male reference range. Several patients with ambiguous genitalia at birth and male sex assignment who showed spontaneous puberty and normal testosterone values have been reported recently [34][35][36]41] supporting the idea of a well preserved Leydig cell function later in life. Interestingly, despite normal testosterone levels, LH levels were elevated in the vast majority of patients and further increased during the course of puberty. ...
Purpose
Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age.
Methods
We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition.
Results
Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty.
Conclusion
Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.
... The clinical presentation of 46XY CGD includes unambiguous female genitalia, bilateral streak gonads, and amenorrhea [7]. PGD patients may have a wide spectrum of phenotypes associated with varying degrees of hypospadias, ambiguous genitalia, cryptorchidism, and variable testis sizes [8]. DSD patients with the 17β-HSD3 gene mutation could display complete or predominantly female genitalia, cryptorchidism, hypospadias, gynecomastia, and sparse body hair [9]. ...
... The imaging findings in PGD are similar to those of CGD but could range from normal male internal genitalia to a rudimentary uterus with a blind-ended vagina. The gonads could be dysgenesis testes located along the path from pelvic descending to scrotum [8]. Most of the 17β-HSD3 mutation patients have bilateral cryptorchidism and Wolffian derivatives, as with SRD5A2 gene mutation, CAIS, and PAIS patients. ...
... For CGD patients, gonadotropin hormones (LH and FSH) are elevated in the absence of gonadal steroid production [6]. In comparison, although PGD patients have elevated gonadotropin, the gonadal steroid level depends on the degree of testicular tissue present [8]. Short-term hCG administration to PGD patients shows a poor T response. ...
Background
46XY partial gonadal dysgenesis (PGD) is a rare subtype of disorder of sex development (DSD). 46YY PGD is a congenital disease with atypical chromosomal, gonadal, or anatomical sex development. The patient in this case report had male and female genitalia simultaneously. We created a flowchart of the differential diagnosis for clinicians.
Case presentation
A 41-year-old male was admitted to the hospital complaining of lower quadrant abdominal pain for 1 day. Physical examination revealed that his penis size was normal, but a urethral orifice was located in the perineum area between the scrotum and anus. One small testicle was in the left scrotum, but no testicle was present on the right. The patient’s abdomen was bulging, and he had lower abdominal pain. According to the emergency CT scan, a lesion (74*65 mm) was found in the right pelvis between the bladder and rectum. The lesion showed an unclear boundary and hematocele appearance. The lesion was removed by emergency surgery, and the pathology report indicated a mixed germ cell tumor with a seminoma and yolk sac tumors.
Conclusion
This article is a case report of germ cell tumors in 46XY PGD patients. The literature review summarizes the clinical diagnosis, and a flowchart is provided for physicians in future practice. The importance of this report is that it will help acquaint physicians with this rare disease and make the right initial clinical decision quickly through the use of this flowchart. However, the variants of special subtypes of 46XY DSD are myriad, and all the diagnoses could not be covered in one flowchart.
... Partial 46, XY GD is an uncommon disorder characterized by uncertain genitalia and a variable degree of testicular dysgenesis with or without Müllerian structures (Crone et al. 2002). The degree of genital ambiguity differs along a spectrum, ranging from an overt male phenotype with isolated hypospadias at one extreme to an overt female phenotype with clitoromegaly (or macroclitoris) at the other (Ap et al. 2013;Gabriel Ribeiro de Andrade et al. 2014). Similar phenotypes can also occur from a mixed GD (Gabriel Ribeiro de Andrade et al. 2014). ...
Disorders of sex development (DSD) are a wide-ranging group of complex conditions that influence chromosomal, gonadal, and phenotypic sex. The prevalence of DSD is very low, but affected patients deserve individualized management to improve psychological, sexual, and reproductive outcomes. This review aims to clarify the fertility potential of DSD patients who can be reared as females and their chance of becoming pregnant, especially using assisted reproductive techniques (ART). Due to the effects of DSD on internal and external genital organs, these conditions result in varying degrees of fertility potential. Fertility rate depends on the phenotype and is inversely related to the severity of the disorder. Reproductive endocrinologists and infertility specialists must be considered active partners of the interdisciplinary treatment team. With current advances in ART, pregnancy is more achievable in patients who were considered infertile at first glance. Due to the complexity of the medical management in DSD patients, more studies should be conducted to conclusively suggest the best choice for improving their fertility potential.Abbreviations: AIS: Androgen Insensitivity Syndrome; AMH: Anti-Müllerian Hormone; ART: Assisted Reproductive Technology; ASRM: American Society for Reproductive Medicine; CAH: Congenital Adrenal Hyperplasia; CAIS: Complete Androgen Insensitivity Syndrome; DHT: Dihydrotestosterone; DSD: Disorders of Sexual Development; FSH: Follicle Stimulating Hormone; GD: Gonadal Dysgenesis; ICSI: Intracytoplasmic Sperm Injection; IUGR: Intrauterine Growth Restriction; IVF: In Vitro Fertilization; IVF-ET: IVF and Embryo Transfer; LH: Luteinizing Hormone; MGD: Mixed Gonadal Dysgenesis; MRI: Magnetic Resonance Imaging; MRKH: Mayer-Rokitansky-Kuster-Hauser; US: Ultrasonography; HSG: Hysterosalpingography; PAIS: Partial Androgen Insensitivity Syndrome; PGD: Preimplantation Genetic Diagnosis; POR: P450 Oxidoreductase; PROM: Premature Rupture of Membranes; TS: Turner Syndrome; 17β-HSD III: 17β-Hydroxysteroid Dehydrogenase III; 21-OHD: 21-hydroxylase deficiency; 5α-RD-2: 5α-reductase-2.
... PGD patients and MGD patients possess similar gonadal and external genitalia characteristics; however, MGD patients also have a 45X cell line and one or more chimeras with a normal or abnormal Y lineage structure. Therefore, MGD patients may present with clinical manifestations of Turner syndrome, including short stature, deformity, and cardiovascular and renal malformations (14). ...
The sex-determining region Y (SRY) gene is a key gene involved in male sex differentiation and development. Patients with 46,XY disorders of sex development related to mutations in the high mobility group (HMG) box typically present with complete gonadal dysgenesis. In this study, we report a case of novel missense mutation c.T281G within the HMG domain of SRY in a 15-year-old patient of the female gender with 46,XY partial gonadal dysgenesis (PGD). The novel missense mutation caused the substitution of codon 94 for leucine in the HMG box of the SRY protein with an arginine codon. Leucine and arginine are aliphatic amino acids, and three-dimensional protein structure prediction revealed only slight structural changes in the SRY protein. Thus, the SRY protein had maintained some of its functions, and the patient presented with PGD. In conclusion, we identified a novel SRY mutation in a patient with 46,XY PGD. Based on the protein model, we believe that the mutation in the HMG domain helped to maintain the partial function of the SRY protein. The condition of our patient differed from the well-known 46,XY complete gonadal dysgenesis caused by mutations in the HMG region. In fact, this is the first case of 46,XY PGD caused by mutations in the HMG region to be reported, and therefore, our experience has expanded the mutation spectrum of the SRY gene. Furthermore, the present case demonstrates that mutations located in the HMG domain of SRY gene cannot be ruled out in patients with a clinical diagnosis of 46,XY PGD.
... Individuals with 46,XY partial gonadal dysgenesis (PGD) present with variable genital ambiguity and varying degrees of testicular dysgenesis or streak gonads [156]. Whilst severe oligozoospermia has been reported in a long-term follow-up study of males with PGD [156], for phenotypic males with mild abnormalities of gonadal development or external genitalia (e.g., hypospadias), fertility may be possible. ...
... Individuals with 46,XY partial gonadal dysgenesis (PGD) present with variable genital ambiguity and varying degrees of testicular dysgenesis or streak gonads [156]. Whilst severe oligozoospermia has been reported in a long-term follow-up study of males with PGD [156], for phenotypic males with mild abnormalities of gonadal development or external genitalia (e.g., hypospadias), fertility may be possible. ...
Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary ‘male’ pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.
... The diagnosis of complet Y-chromosome GD was considered by bilateral streak gonads and female internal and external genitalia. The diagnosis of Partial Y-chromosome GD was made by the findings of 46,XY or 45,X/46,XY karyotype, ambiguous genitalia, low testeosteron response to hCG stimulation test at prepubertal ages, low basal testosteron levels at pubertal ages, low AMH levels, bilaterally dysgenetic and/or unilateral dysgenetic and contrlateral streak gonad (13). External genitalia was rated using the Sinnecker Classification (14). ...
Objective:
Y-chromosome gonadal dysgenesis (GD) is a rare subgroup of disorders of sexual development (DSD) which results from underdeveloped testis, which may consist heterogenous symptoms. They are phenotypically classified into 2 groups as complete and partial; while karyotypic description was as 46,XY GD and 45,X/46,XY GD.
Methods:
Thirty eight cases were followed-up between 1998 and 2016. The age of admission were within 0 to 17,16 decimal years. Clinical and laboratory findings as well as follow-up characteristics of cases were evaluated retrospectively from the patient reports.
Results:
There were 26 cases (4 complete, 22 partial) in the 46,XY GD group, and 12 cases (4 complete, 8 partial) in 45,X/46,XY GD group. The mean age at admission were; 6.2±4.6 years for all cases. Patients with complete GD in the 45,X/46,XY GD group were diagnosed earlier that the patients with complete GD in the 46,XY group (11 years of age vs 14,31 years of age). There was no additional findings in 55% of all patients. Additional clinical findings, mainly short stature, were detected in 75% of the patients in the 45,X/46,XY GD and 30% of the patients in the 46,XY GD groups. All patients with complete 46,XY and 45,X/46,XY GD were raised as females. There was no gender dysphoria in patients that were raised as females, except one. Gonadectomy was applied to the 14 patients with a mean age of 8.75±2.3 years and gonadal pathology results were normal in all cases with no malignency.
Conclusion:
Y-chromosome GD is a very heterogenous clinical and genetic disorder with different aspects in diagnosis, treatment, and also for approach to additional problems. Whether having syndromic features or not, associated clinical features may lead to earlier diagnosis, especially in complete form of GD than others. Challenges in the long-term follow-up of patients make impossible to evaluation of appropriateness of sex of rearing decision. Decision of gonadectomy during first decade of these patients seems to be a preventive factor for tumoral development which are usually seen during second decade.
... Mutations in NR5A1 are emerging as a frequent genetic cause of human 46,XY disorders of sex development (DSD), having been identified throughout the globe. In South America, familial and sporadic DSD patients bearing NR5A1 defects have been described in Brazil and Argentina (Lourenc¸o et al., 2009;Ciaccio et al., 2012;Gabriel Ribeiro de Andrade et al., 2014;Fabbri et al., 2016). Here, we review the phenotype associated with ten novel and one previously described NR5A1 allelic variants identified in a Brazilian cohort of 46,XY and 46,XX DSD patients followed at a single tertiary center. ...
... Progressive androgen production and virilization in adolescence has been observed in several XY patients with NR5A1 mutations, in contrast to the severe undervirilized external genitalia found in most patients (Cools et al., 2012;Gabriel Ribeiro de Andrade et al., 2014;Tantawy et al., 2014;Fabbri et al., 2016). The almost normal testosterone levels after hCG stimulation or at pubertal age suggest that NR5A1 action may be less implicated in pubertal steroidogenesis than during fetal life. ...
Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction.
