scholarly journals Complete Androgen Insensitivity Syndrome: From the Relevance of an Accurate Genetic Diagnosis to the Challenge of Clinical Management. A Case Report

Medicina ◽  
2021 ◽  
Vol 57 (11) ◽  
pp. 1142
Author(s):  
Federica Barbagallo ◽  
Rossella Cannarella ◽  
Matteo Bertelli ◽  
Andrea Crafa ◽  
Sandro La Vignera ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Genetic Diagnosis ◽  
Androgen Insensitivity Syndrome ◽  
Inguinal Region ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Androgen Insensitivity ◽  
Sex Development ◽  
Observation Methods ◽  
Chd7 Gene

Introduction: Androgen insensitivity syndrome (AIS), an X-linked recessive disorder of sex development (DSD), is caused by variants of the androgen receptor (AR) gene, mapping in the long arm of the X chromosome, which cause a complete loss of function of the receptor. Case presentation: We report a patient diagnosed with complete AIS (CAIS) at birth due to swelling in the bilateral inguinal region. Transabdominal ultrasound revealed the absence of the uterus and ovaries and the presence of bilateral testes in the inguinal region. The karyotype was 46,XY. She underwent bilateral orchiectomy at 9 months and was given estrogen substitutive therapy at the age of 11 years. Genetic analysis of the AR gene variants was requested when, at the age of 20, the patient came to our observation. Methods: The genetic testing was performed by next-generation sequence (NGS) analysis. Results: The genetic analysis showed the presence of the c.2242T>A, p.(Phe748Ile) variant in the AR gene. To the best of our knowledge, this variant has not been published so far. Furthermore, the patient has a heterozygous c.317A>G, p.(Gln106Arg) variation of the gonadotropin-releasing hormone receptor (GNRHR) gene, a heterozygous c.2273G>A, p.Arg758His variation of the chromodomain helicase DNA binding protein 7 (CHD7) gene, and compound heterozygous c.875A>G, p.Tyr292Cys, and c.8023A>G, p.Ile2675Val variations of the Dynein Axonemal Heavy Chain 11 (DNAH11) gene. Conclusions: The case herein reported underlines the importance of an accurate genetic analysis that has to include karyotype and AR gene variant analysis. This is useful to confirm a clinical diagnosis and establish the proper management of patients with CAIS. Numerous variants of the AR gene have not yet been identified. Moreover, several pitfalls are still present in the management of these patients. More studies are needed to answer unresolved questions, and common protocols are required for the clinical follow-up of patients with CAIS.

scholarly journals Androgen insensitivity syndrome in a cohort of Sri Lankan children with 46, XY disorders of sex development

2016 ◽  
Vol 60 (4) ◽  
pp. 139 ◽  
Author(s):  
K.S.H. De Silva ◽  
N.D. Sirisena ◽  
H.K. Wijenayaka ◽  
J.G. Cooray ◽  
R.W. Jayasekara ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
Sri Lankan ◽  
Androgen Insensitivity ◽  
Sri Lankan Children ◽  
Sex Development

scholarly journals A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics

2021 ◽  
Vol 67 (5) ◽  
pp. 48-52
Author(s):  
N. Y. Kalinchenko ◽  
V. M. Petrov ◽  
A. V. Panova ◽  
A. N. Tiulpakov
Keyword(s):  
Genetic Diagnosis ◽  
Androgen Insensitivity Syndrome ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Coding Region ◽  
Sex Development ◽  
Intronic Mutation ◽  
Androgen Resistance ◽  
Differences Of Sex Development ◽  
Intron Mutation

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450–42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.

scholarly journals Disorders of sex development: a study of 194 cases

2018 ◽  
Vol 7 (2) ◽  
pp. 364-371 ◽  
Author(s):  
R Walia ◽  
M Singla ◽  
K Vaiphei ◽  
S Kumar ◽  
A Bhansali
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Sex Chromosome ◽  
Tertiary Care ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
North India ◽  
Care Hospital ◽  
Adrenal Hyperplasia ◽  
Androgen Insensitivity ◽  
Sex Development

Objective To study the clinical profile and the management of patients with disorders of sex development (DSD). Design and setting Retrospective study from a tertiary care hospital of North India. Methods and patients One hundred ninety-four patients of DSD registered in the Endocrine clinic of Postgraduate Institute of Medical Education and Research, Chandigarh between 1995 and 2014 were included. Results One hundred and two patients (52.5%) had 46,XY DSD and seventy-four patients (38.1%) had 46,XX DSD. Sex chromosome DSD was identified in seven (3.6%) patients. Of 102 patients with 46,XY DSD, 32 (31.4%) had androgen insensitivity syndrome and 26 (25.5%) had androgen biosynthetic defect. Of the 74 patients with 46,XX DSD, 52 (70.27%) had congenital adrenal hyperplasia (CAH) and eight (10.8%) had ovotesticular DSD. Five patients with sex chromosome DSD had mixed gonadal dysgenesis. Excluding CAH, majority of the patients (90%) presented in the post-pubertal period. One-fourth of the patients with simple virilising CAH were reared as males because of strong male gender identity and behaviour and firm insistence by the parents. Corrective surgeries were performed in twenty patients (20%) of 46,XY DSD without hormonal evaluation prior to the presentation. Conclusion Congenital adrenal hyperplasia is the most common DSD in the present series. Most common XY DSD is androgen insensitivity syndrome, while CAH is the most common XX DSD. Delayed diagnosis is a common feature, and corrective surgeries are performed without seeking a definite diagnosis.

Spectrum of Pathogenic Variants in SRD5A2 in Indian Children with 46,XY Disorders of Sex Development and Clinically Suspected Steroid 5α-Reductase 2 Deficiency

2019 ◽  
Vol 13 (5-6) ◽  
pp. 228-239
Author(s):  
Anil Kumar ◽  
Rajni Sharma ◽  
Mohammed Faruq ◽  
Varun Suroliya ◽  
Manoj Kumar ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Wide Spectrum ◽  
Disorders Of Sex Development ◽  
Pathogenic Variant ◽  
Compound Heterozygous ◽  
Phenotype Correlation ◽  
Indian Children ◽  
Sex Development ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation

The aim of this study was to assess the prevalence of pathogenic variants in the <i>SRD5A2</i> gene in children with 46,XY disorders of sex development (DSD) with normal to high serum testosterone levels and absence of Müllerian structures on imaging and to evaluate the genotype-phenotype correlation. Seventy-five patients with 46,XY DSD and probable clinical diagnosis of 5α-reductase 2 deficiency or androgen insensitivity syndrome were enrolled. Genetic analysis was done for pathogenic variants in <i>SRD5A2</i>, and the genotype-phenotype correlation was studied. As a result, 10 pathogenic or likely pathogenic biallelic variants in <i>SRD5A2, </i>either homozygous or compound heterozygous, were identified in 25 of 75 (33.3%) patients. The hCG stimulated testosterone: dihydrotestosterone (T:DHT) ratio was elevated in all patients with pathogenic variants in <i>SRD5A2</i> and in nearly 90% of those without pathogenic variants in <i>SRD5A2</i> in whom this was assessed. The missense pathogenic variant p.R246Q was a hotspot. One novel pathogenic variant p.Y178*, and a variant p.F194I, not previously reported in patients with 5α-reductase 2 deficiency, were identified. The missense variant p.F194I was predicted as deleterious and damaging by in silico analysis and as likely to reduce the enzyme activity by protein modeling. In conclusion, pathogenic variants in <i>SRD5A2 </i>can be detected in a wide spectrum of Indian patients with 46,XY DSD. Molecular genetic analysis should be considered as a first-line test as the T:DHT ratio lacks specificity and a hotspot variant is present in a vast majority.

scholarly journals The LH/FSH ratio is not a sex-dimorphic marker after infancy: data from 6417 healthy individuals and 125 patients with Differences of Sex Development

2020 ◽  
Vol 35 (10) ◽  
pp. 2323-2335
Author(s):  
Marie L Ljubicic ◽  
Kirstine Jespersen ◽  
Lise Aksglaede ◽  
Casper P Hagen ◽  
Jørgen H Petersen ◽  
...  
Keyword(s):  
Androgen Insensitivity Syndrome ◽  
Environmental Research ◽  
Reference Ranges ◽  
Healthy Individuals ◽  
Androgen Insensitivity ◽  
Sex Development ◽  
Differences Of Sex Development ◽  
Males And Females ◽  
Healthy Participants ◽  
Healthy Males

Abstract STUDY QUESTION What is the course of the LH/FSH ratio from infancy into adulthood in healthy individuals and in patients with Differences of Sex Development (DSD)? SUMMARY ANSWER The LH/FSH ratio had a marked overlap between the sexes after infancy and onwards throughout adulthood in healthy individuals and it was not a marker of hypogonadism in DSD patients. WHAT IS KNOWN ALREADY The LH/FSH ratio is a distinct marker of sex during minipuberty. No study has evaluated the LH/FSH ratio from infancy into adulthood. STUDY DESIGN, SIZE, DURATION This was a combined study of prospective longitudinal and cross-sectional cohorts of healthy individuals totaling 6417 males and females aged 0–80 years. Retrospective data from a single, tertiary center on 125 patients with DSD was also included. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the healthy males (n = 3144) and females (n = 3273) aged 0–80 years, reference ranges for LH, FSH and the LH/FSH ratio were established from infancy (after minipuberty) and onwards. LH, FSH, and the LH/FSH ratio in 125 patients with DSD not undergoing treatment were compared to the reference ranges. Included DSD diagnoses were: Klinefelter syndrome including mosaic variants (males: n = 14), Turner syndrome including mosaic variants without Y-chromosome material (females: n = 48), 45,X/46,XY mosaicism (males: n = 24 and females: n = 6), partial androgen insensitivity syndrome (males: n = 11), complete androgen insensitivity syndrome (females: n = 13) and anorchia (males: n = 9). MAIN RESULTS AND THE ROLE OF CHANCE An overlap was observed in the LH/FSH ratio reference curves between males and females. However, when comparing the sexes at specific time points, the LH/FSH ratio was significantly higher in healthy males during childhood and adulthood and significantly higher in healthy females during puberty. When compared with healthy participants, male patients with anorchia and 45,X/46,XY mosaicism had significantly lower ratios, while patients with androgen insensitivity, regardless of sex, had significantly higher ratios. LIMITATIONS, REASONS FOR CAUTION The limitations of this study include that; (i) all healthy individuals were Caucasian, so conclusions may not apply to non-Caucasians; (ii) the calculated LH/FSH ratios were restricted to the specific analytical method used and may not be applicable to other laboratories; (iii) the samples from healthy individuals were stored for varying amounts of time up to 20 years which may affect the durability; and (iv) DSD diagnoses are heterogeneous thus making sturdy conclusions across diagnoses impossible. WIDER IMPLICATIONS OF THE FINDINGS In this study of combined cohorts of healthy participants, the largest normative ranges of LH, FSH, and the LH/FSH ratio to date were created. These reference ranges provide the opportunity for clinical as well as research use for all three markers. However, the previously rather undescribed LH/FSH ratio was not a distinct marker of sex after infancy nor a new marker of hypogonadism. Although there were significant differences between subgroups of DSD patients compared to healthy controls, the clinical significance of the LH/FSH ratio after infancy lacked. However, it can be speculated whether there are other areas of clinical application not investigated in this article, for example as a marker of fertility in select patient groups. As gonadotropin assays are readily available and gonadotropin measurements are part of regular workups, the LH/FSH ratio can easily be explored in further research without additional costs. STUDY FUNDING/COMPETING INTEREST(S) M.L.L. was funded by the Absalon Foundation. Cohort 1 was funded by the European Commission, through the Biomed 2 Program (BMH4-CT96-0314), Environmental Reproductive Health (QLK4-CT1999-01422) and EXPORED (QLK4-2001-00269), by the Danish Council for Independent Research (9700833 and 9700909), and by the Svend Andersens Foundation. Cohort 2 was funded by the Danish Environmental Research Program (96.01.015.16.05). Cohort 3 was funded by Kirsten and Freddy Johansens Foundation. TRIAL REGISTRATION NUMBER NA DATE OF FIRST PATIENT’S ENROLMENT June 1990 (the launch of the department from which this project stems).

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