scholarly journals Clinical and molecular characteristics of patients with 46,XY DSD due to NR5A1 gene mutations

2020 ◽  
Vol 66 (3) ◽  
pp. 62-69
Author(s):  
Natalia Yu. Kalinchenko ◽  
Anna A. Kolodkina ◽  
Nadezda Y. Raygorodskaya ◽  
Anatoly N. Tiulpakov
Keyword(s):  
Gonadal Dysgenesis ◽  
Case Reports ◽  
Molecular Genetic ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Gonadal Development ◽  
Molecular Genetic Analysis ◽  
Molecular Characteristics ◽  
Sex Development ◽  
Reproductive Axis

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.

scholarly journals Etiology and Clinical Presentation of Disorders of Sex Development in Kenyan Children and Adolescents

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Prisca Amolo ◽  
Paul Laigong ◽  
Anjumanara Omar ◽  
Stenvert Drop
Keyword(s):  
Children And Adolescents ◽  
Sex Chromosome ◽  
Clinical Laboratory ◽  
Molecular Genetic ◽  
Management Strategies ◽  
Disorders Of Sex Development ◽  
Ambiguous Genitalia ◽  
Molecular Genetic Analysis ◽  
High Rate ◽  
Sex Development

Objective. The purpose of this study was to describe baseline data on etiological, clinical, laboratory, and management strategies in Kenyan children and adolescents with Disorders of Sex Development (DSD). Methods. This retrospective study included patients diagnosed with DSD who presented at ages 0–19 years from January 2008 to December 2015 at the Kenyatta National (KNH) and Gertrude’s Children’s (GCH) Hospitals. After conducting a search in the data registry, a structured data collection sheet was used for collection of demographic and clinical data. Data analysis involved description of the frequency of occurrence of various variables, such as etiologic diagnoses and patient characteristics. Results. Data from the records of 71 children and adolescents were reviewed at KNH (n = 57, 80.3%) and GCH (n = 14, 19.7%). The mean age at the time of diagnosis was 2.7 years with a median of 3 months. Thirty-nine (54.9%) children had karyotype testing done. The median age (IQR) of children with reported karyotypes and those without was 3.3 years (1.3–8.9) and 8.3 years (3.6–12.1), respectively (p=0.021). Based on karyotype analysis, 19 (48.7%) of karyotyped children had 46,XY DSD and 18 (46.2%) had 46,XX DSD. There were two (5.1%) children with sex chromosome DSD. Among the 71 patients, the most common presumed causes of DSD were ovotesticular DSD (14.1%) and CAH (11.3%). Majority (95.7%) of the patients presented with symptoms of DSD at birth. The most common presenting symptom was ambiguous genitalia, which was present in 66 (93.0%) patients either in isolation or in association with other symptoms. An ambiguous genitalia was initially observed by the patient’s mother in 51.6% of 62 cases despite the high rate (84.7%) of delivery in hospital. Seventeen (23.9%) of the cases had a gender reassignment at final diagnosis. A psychologist/psychiatrist or counselor was involved in the management of 23.9% of the patients. Conclusion. The commonest presumed cause of DSD was ovotesticular DSD in contrast to western studies, which found CAH to be more common. Investigation of DSD cases is expensive and needs to be supported. We would have liked to do molecular genetic analysis outside the country but financial challenges made it impossible. A network for detailed diagnostics in resource-limited countries would be highly desirable. There is a need to train health care workers and medical students for early diagnosis. Psychological evaluation should be carried out for all patients at diagnosis and support given for families.

Reasonable diagnostic pathways in disorders of sex development

2012 ◽  
Vol 36 (2) ◽  
pp. 1-6
Author(s):  
Olaf Hiort
Keyword(s):  
Molecular Genetic ◽  
Disorders Of Sex Development ◽  
Reference Intervals ◽  
Molecular Genetic Analysis ◽  
Diagnostic Process ◽  
Sex Development ◽  
Specialized Center ◽  
Sexual Determination ◽  
Therapeutic Decision Making ◽  
Diagnostic Pathways

AbstractDisorders of sex development or “DSD” describe a heterogeneous group of abnormalities of sexual determination and differentiation. This may be caused by chromosomal as well as monogenic aberrations, which may lead either primarily or through endocrine mechanisms to abnormal sexual development. Laboratory investigations play an important role in the diagnostic process. However, special analytical methods have to be taken into account and the usual reference intervals do not apply. Therefore, laboratory results should be interpreted in a specialized center in context with clinical and imaging findings. Furthermore, molecular genetic analysis can be performed for several entities. In a majority of cases, however, a definitive diagnosis is not possible even today. Therefore, management by a highly specialized multidisciplinary team is necessary for stringent diagnosis, prognosis and overall therapeutic decision-making. The team must include physicians from different subspecialties as well as psychosocial experts to counsel patients and their families appropriately.

scholarly journals PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

2019 ◽  
Vol 180 (5) ◽  
pp. 291-309 ◽  
Author(s):  
Tulay Guran ◽  
Gozde Yesil ◽  
Serap Turan ◽  
Zeynep Atay ◽  
Emine Bozkurtlar ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Clinical Laboratory ◽  
Disorders Of Sex Development ◽  
Cell Types ◽  
Regulatory Subunit ◽  
Cone Dystrophy ◽  
Molecular Characteristics ◽  
Multiple Organs ◽  
Sex Development ◽  
Complete Gonadal Dysgenesis

Context Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.

scholarly journals The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD)

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Maria Luisa Granada ◽  
Laura Audí
Keyword(s):  
Multidisciplinary Team ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Abnormal Development ◽  
Sex Characteristics ◽  
Fetal Life ◽  
Sex Development ◽  
Male Sex

Abstract Objectives The development of female or male sex characteristics occurs during fetal life, when the genetic, gonadal, and internal and external genital sex is determined (female or male). Any discordance among sex determination and differentiation stages results in differences/disorders of sex development (DSD), which are classified based on the sex chromosomes found on the karyotype. Content This chapter addresses the physiological mechanisms that determine the development of female or male sex characteristics during fetal life, provides a general classification of DSD, and offers guidance for clinical, biochemical, and genetic diagnosis, which must be established by a multidisciplinary team. Biochemical studies should include general biochemistry, steroid and peptide hormone testing either at baseline or by stimulation testing. The genetic study should start with the determination of the karyotype, followed by a molecular study of the 46,XX or 46,XY karyotypes for the identification of candidate genes. Summary 46,XX DSD include an abnormal gonadal development (dysgenesis, ovotestes, or testes), an androgen excess (the most frequent) of fetal, fetoplacental, or maternal origin and an abnormal development of the internal genitalia. Biochemical and genetic markers are specific for each group. Outlook Diagnosis of DSD requires the involvement of a multidisciplinary team coordinated by a clinician, including a service of biochemistry, clinical, and molecular genetic testing, radiology and imaging, and a service of pathological anatomy.

scholarly journals Clinical heterogeneity and molecular genetic causes in a cohort of patients with disorders/differences of sex development

2021 ◽  
pp. 194-202
Author(s):  
Irina L. Nikitina ◽  
Leyla R. Sarakaeva ◽  
Anna A. Kostareva ◽  
Elena K. Kudryashova
Keyword(s):  
Genetic Counseling ◽  
Clinical Examination ◽  
Gonadal Dysgenesis ◽  
Molecular Genetic ◽  
Management Strategies ◽  
Clinical Manifestations ◽  
Disorders Of Sex Development ◽  
Targeted Sequencing ◽  
Genetic Causes ◽  
Sex Development

Background. Disorders of sex development (DSD) are a group of rare congenital conditions. Clinical management of patients with DSD is often difficult and requires multidisciplinary approach. Aim. Analysis of the frequency of establishing genetic causes in various forms of DSD by using an original targeted sequencing panel with subsequent establishment of associations of the identified genetic variants with the nature of clinical manifestations. Materials and methods. Conducted a clinical examination, karyotype analysis followed by the next generation sequencing (NGS) using MiSeq (Illumina) with the twenty-eight patients with different forms of 46, XY DSD were included. We designed HaloPlex (Agilent) gene panel that included coding regions of 80 candidate genes associated with DSD. All variants identified by NGS were confirmed by Sanger sequencing. We performed bioinformatics analysis using OMIM, 1000 genomes, ESP6500, Genome Aggregation Database projects. To assess the clinical significance of the identified variants we used ClinVar database and American College of Medical Genetics and Genomics criteria. Results. Out of 28 patients pathogenic, likely pathogenic, variants with unknown significance were identified in 11 patients (39%). In combination with clinical phenotype these variants were determined as causative for DSD. Nine patients (82%) had likely causative variants in one gene (of monogenic origin), while 18% had variants in two genes simultaneously (of oligogenic origin). 43% of the identified gene variants have not been previously reported. The variants in NR5A1 were associated with gonadal dysgenesis in two patients; the variants in MAP3K1 were also found in another two patients with gonadal dysgenesis, variants in AR in three patients with CAIS, variant in MAMLD1 was associated with proximal form of hypospadias, variant in CYP17A1 was associated with testosterone biosynthetic defect. Among the two patients with variants of oligogenic origin, one had variants in MAP3K1 and MAMLD1 genes and was clinically characterized by hypospadias; the second had variants in AR and SEMA3A and was diagnosed with PAIS. There were also two patients with variants in NR5A1 of familial inheritance. Conclusion. NGS-based targeted sequencing is a promising technique to improve the differential diagnosis, genetic counseling and management strategies for patients with DSD. Complex clinical examination followed by molecular genetic analysis improves the diagnosis, genetic counseling, and management strategies for patients with DSD including the assignment of sex of rearing.

scholarly journals The first clinical presentation of disorders of sex development 46 XY due to mutation in Steroidogenic factor 1 (SF1) in Russian Literature

2016 ◽  
Vol 62 (1) ◽  
pp. 55-59
Author(s):  
Natalia Yur'evna Kalinchenko ◽  
Tatiana Aleksandrovna Anosova ◽  
Vitaliy Alekseevich Ioutsi ◽  
Anatoly Nikolaevich Tiulpakov
Keyword(s):  
Molecular Genetic ◽  
Critical Role ◽  
Disorders Of Sex Development ◽  
Russian Literature ◽  
Molecular Genetic Analysis ◽  
Heterozygous Mutation ◽  
Steroidogenic Factor 1 ◽  
Sex Development ◽  
And Function ◽  
First Time

Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a critical role in different processes of sex development. Homozygous mutations in SF1 result in adrenal failure and complete testicular disgenesis in 46,XY individuals. According to recent studies heterozygous mutations in SF1 are associated with milder phenotype: they are found in children with 46,XY disorders of sex development (DSD) but with apparently normal adrenal structure and function. Here we present for the first time in Russian literature a case of SF1 deficiency. Molecular genetic analysis of NR5A1 gene revealed a novel heterozygous mutation c.951delC p.H317QfsX17. This clinical case demonstrates the importance of molecular genetic studies in DSD 46,XY, especially severe forms.

NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes

2019 ◽  
Vol 13 (5-6) ◽  
pp. 258-263
Author(s):  
Maria F. Faienza ◽  
Mariangela Chiarito ◽  
Fulvia Baldinotti ◽  
Domenico Canale ◽  
Carmela Savino ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Cell Function ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Reproductive Function ◽  
In Silico Analysis ◽  
Gonadal Development ◽  
Gene Variants ◽  
Psychological Outcome ◽  
Sex Development

<i>NR5A1</i> (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous <i>NR5A1 </i>mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with <i>NR5A1</i> genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous <i>NR5A1</i> genetic variants. In the boys, pathogenetic<i> NR5A1</i> gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that <i>NR5A1 </i>gene mutations may present with variable genital phenotypes. Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with <i>NR5A1</i> mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward.

scholarly journals Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development

2019 ◽  
Vol 56 (7) ◽  
pp. 434-443 ◽  
Author(s):  
Katie Ayers ◽  
Jocelyn van den Bergen ◽  
Gorjana Robevska ◽  
Nurin Listyasari ◽  
Jamal Raza ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Disorders Of Sex Development ◽  
Culture Method ◽  
Significant Loss ◽  
Subcellular Localisation ◽  
Gene Variants ◽  
Gene Variant ◽  
Clinical Interpretation ◽  
Sex Development ◽  
Desert Hedgehog

BackgroundDesert hedgehog (DHH) gene variants are known to cause 46,XY differences/disorders of sex development (DSD). We have identified six patients with 46,XY DSD with seven novel DHH gene variants. Many of these variants were classified as variants of uncertain significance due to their heterozygosity or associated milder phenotype. To assess variant pathogenicity and to refine the spectrum of DSDs associated with this gene, we have carried out the first reported functional testing of DHH gene variant activity.MethodsA cell co-culture method was used to assess DHH variant induction of Hedgehog signalling in cultured Leydig cells. Protein expression and subcellular localisation were also assessed for DHH variants using western blot and immunofluorescence.ResultsOur co-culture method provided a robust read-out of DHH gene variant activity, which correlated closely with patient phenotype severity. While biallelic DHH variants from patients with gonadal dysgenesis showed significant loss of activity, variants found as heterozygous in patients with milder phenotypes had no loss of activity when tested with a wild type allele. Taking these functional results into account improved clinical interpretation.ConclusionOur findings suggest heterozygous DHH gene variants are unlikely to cause DSD, reaffirming that DHH is an autosomal recessive cause of 46,XY gonadal dysgenesis. Functional characterisation of novel DHH variants improves variant interpretation, leading to greater confidence in patient reporting and clinical management.

scholarly journals Non-Syndromic 46,XY Disorders of Sex Development

2018 ◽  
Vol 18 (1) ◽  
pp. 35-41
Author(s):  
J Gecz ◽  
J Breza ◽  
P Banovcin
Keyword(s):  
Genetic Testing ◽  
Slovak Republic ◽  
Molecular Genetic ◽  
Disorders Of Sex Development ◽  
Gene Variants ◽  
Molecular Genetic Testing ◽  
The Past ◽  
Sex Development

Abstract Non-syndromic 46,XY DSD (disorders of sex development) represent a phenotypically diversiform group of disorders. We focus on the association between gene variants and the most frequent types of non-syndromic 46,XY DSD, options of molecular genetic testing which has surely taken its place in diagnostics of DSD in the past couple of years. We emphasize the need of molecular genetic testing in individuals with non-syndromic 46,XY DSD in Slovak Republic.

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