Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis

Summary Primary amenorrhea could be caused by disorders of four parts: disorders of the outflow tract, disorders of the ovary, disorders of the anterior pituitary, and disorders of hypothalamus. Delay in diagnosis and hormone substitution therapy causes secondary osteoporosis. Herein, we report a case of a 23-year-old phenotypical female who presented with primary amenorrhea from 46, XX gonadal dysgenesis but had been misdiagnosed as Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome or Mullerian agenesis. The coexistence of gonadal dysgenesis and MRKH was suspected after laboratory and imaging investigations. However, the vanishing uterus reappeared after 18 months of hormone replacement therapy. Therefore, hormone profiles and karyotype should be thoroughly investigated to distinguish MRKH syndrome from other disorders of sex development (DSD). Double diagnosis of DSD is extremely rare and periodic evaluation should be reassessed. This case highlights the presence of estrogen deficiency state, the uterus may remain invisible until adequate exposure to exogenous estrogen. Learning points: An early diagnosis of disorders of sex development (DSD) is extremely important in order to promptly begin treatment, provide emotional support to the patient and reduce the risks of associated complications. Hormone profiles and karyotype should be investigated in all cases of the presumptive diagnosis of Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome or Mullerian agenesis. The association between 46, XX gonadal dysgenesis and Mullerian agenesis has been occasionally reported as a co-incidental event; however, reassessment of the presence of uterus should be done again after administration of exogenous estrogen replacement for at least 6–12 months. A multidisciplinary approach is necessary for patients presenting with DSD to ensure appropriate treatments and follow-up across the lifespan of individuals with DSD.

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WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

Sexual Development ◽

10.1159/000517373 ◽

2021 ◽

pp. 1-9

Author(s):

Maria T.M. Ferrari ◽

Andreia Watanabe ◽

Thatiane E. da Silva ◽

Nathalia L. Gomes ◽

Rafael L. Batista ◽

...

Keyword(s):

Kidney Development ◽

Wilms Tumor ◽

Genetic Diagnosis ◽

Germ Cell Tumors ◽

Disorders Of Sex Development ◽

Medical Attention ◽

Primary Amenorrhea ◽

Normal Female ◽

Sex Development ◽

Pathogenic Variants

Wilms’ tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

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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

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105893 ◽

2019 ◽

Vol 56 (7) ◽

pp. 434-443 ◽

Cited By ~ 3

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.

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Analysis of the Wilms' Tumor Suppressor Gene (WT1) in Patients 46,XY Disorders of Sex Development

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2804 ◽

2011 ◽

Vol 96 (7) ◽

pp. E1131-E1136 ◽

Cited By ~ 32

Author(s):

B. Köhler ◽

H. Biebermann ◽

V. Friedsam ◽

J. Gellermann ◽

R. F. Maier ◽

...

Keyword(s):

Kidney Disease ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Gonadal Dysgenesis ◽

Kidney Development ◽

Wilms Tumor ◽

Disorders Of Sex Development ◽

Suppressor Gene ◽

Sex Development ◽

Cryptorchid Testis

Abstract Context: The Wilms' tumor suppressor gene (WT1) is one of the major regulators of early gonadal and kidney development. WT1 mutations have been identified in 46,XY disorders of sex development (DSD) with associated kidney disease and in few isolated forms of 46,XY DSD. Objective: The objective of the study was the evaluation of WT1 mutations in different phenotypes of isolated 46,XY DSD and clinical consequences. Design: The design of the study was: 1) sequencing of the WT1 gene in 210 patients with 46,XY DSD from the German DSD network, consisting of 150 males with severe hypospadias (70 without cryptorchidism, 80 with at least one cryptorchid testis), 10 males with vanishing testes syndrome, and 50 raised females with partial to complete 46,XY gonadal dysgenesis; and 2) genotype-phenotype correlation of our and all published patients with 46,XY DSD and WT1 mutations. Results: We have detected WT1 mutations in six of 80 patients with severe hypospadias (7.5%) and at least one cryptorchid testis and in one of 10 patients with vanishing testes syndrome (10%). All patients except one developed Wilms' tumor and/or nephropathy in childhood or adolescence. Conclusion: WT1 analysis should be performed in newborns with complex hypospadias with at least one cryptorchid testis and in isolated 46,XY partial to complete gonadal dysgenesis. Kidney disease might not develop until later life in these cases. WT1 analysis is mandatory in all 46,XY DSD with associated kidney disease. WT1 analysis is not indicated in newborns with isolated hypospadias without cryptorchidism. Patients with WT1 mutations should be followed up closely because the risk of developing a Wilms' tumor, nephropathy, and/or gonadal tumor is very high.

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PURE GONADAL DYSGENESIS: CLINICAL CASE AND REVIEW OF THE LITERATURE

International Journal of Advanced Research ◽

10.21474/ijar01/12743 ◽

2021 ◽

Vol 9 (4) ◽

pp. 641-644

Author(s):

Rana Watfeh ◽

◽

Adam Benani ◽

Maria Hijji ◽

M. Youssfi ◽

...

Keyword(s):

Hormone Replacement Therapy ◽

Clinical Picture ◽

Gonadal Dysgenesis ◽

Clinical Case ◽

Germ Line ◽

Hormone Replacement ◽

Egg Donation ◽

Primary Amenorrhea ◽

Review Of The Literature ◽

Endocrine Secretion

XX or XY pure gonadal dysgenesis (PGD) is defined by premature destruction of the fetal gonads which reduce to an undifferentiated stroma with absence of germ line and endocrine secretion. The phenotype is unambiguously female with a clinical picture associating primary amenorrhea and impuberty. We present in this article a clinical case illustrating this pathology in a young patient who presents a primary amenorrhea. The diagnosis of pure XX gonadal dysgenesis was retained based on the clinical and para-clinical examinations. The patient was treated with hormone replacement therapy. The chances of fertility are almost absent in our context, and the only way out is egg donation.

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46 XY DISORDER

The Professional Medical Journal ◽

10.29309/tpmj/2016.23.10.1723 ◽

2016 ◽

Vol 23 (10) ◽

pp. 1202-1208

Author(s):

Muhammad Naveed Najeeb ◽

Sadiq Hussain Malik ◽

Sheikh Khurram Salam Sehgal ◽

Ameer Ahmad Malik ◽

Saqib Mehmood

Keyword(s):

Physical Examination ◽

Study Design ◽

Gonadal Dysgenesis ◽

Disorders Of Sex Development ◽

Serum Testosterone ◽

Androgen Insensitivity Syndrome ◽

Base Line ◽

Reductase Deficiency ◽

Androgen Synthesis ◽

Sex Development

Objectives: The Disorders of Sex Development are classified as 46, XY DSD,46, XX DSD and Chromosomal DSD according to the chromosomal constitution of the affectedpersons. 46, XY DSD is further classified into Androgen Synthetic Defect, Androgen InsensitivitySyndrome Gonadal Dysgenesis, 5-Alpha Reductase Deficiency, Persistent Mullerian DuctSyndrome and Isolated Hypospadias according to the pathophysiology of the disease. Theaim of present study was to classify 46, XY patients into their subclasses on the basis of theirhormonal profile and physical examination. Study Design: Observational descriptive study.Setting: Biochemistry Department University of Health Sciences for Karyotyping and Geneticassessment, and its allied institution Biochemistry Department Quaid-e-Azam Medical CollegeBahawalpur for hormonal analysis, along with Pediatric Medicine Departments of Quaid-e-AzamMedical College / Bahawal Victoria Hospital Bahawalpur for collection of Sample and clinicalassessments. Period: June 2015 to December 2015. Study Design: Observational descriptivestudy. Material and Methods: 53 patients with 46, XY DSD were recruited. Complete clinicalhistory and data of each patient was recorded in the research proforma. Genitals examinedfor the phallus length and size, position of urinary meatus, palpation of gonads and shape ofthe labioscrotal folds. Ultrasonography examination of each patient was performed to look forundescended testes and for the presence of either male or female internal reproductive organs.Results: Base line levels of serum Testosterone Dihydrotestosterone Luteinizing hormone,Follicle stimulating hormone, 17-OH-Progesteron and Anti-mullerian hormones were measuredby ELISA technique. Testosterone and DHT were measured again after hCG stimulation. Onthe basis of physical examination, ultrasonographic findings and hormonal profile diagnosisof the types of 46, XY DSD was possible in 27 (51%) of patients. Androgen synthesis defect asa cause of 46, XY DSD was diagnosed in 7(13%) patients, Androgen insensitivity syndrome in6(11%) patients, 5-Alpha reductase deficiency in 3(6%) patients, Gonadal Dysgenesis in 3 (6%),Persistent Mullerian Duct Syndrome in 3(6%) and Isolated Hypospadias in 2 (4%) patients.There were 26 (49%) patients which remain undiagnosed with the algorithm of diagnosis usedin the present study.

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Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management

Journal of Pediatric Urology ◽

10.1016/j.jpurol.2016.08.015 ◽

2016 ◽

Vol 12 (6) ◽

pp. 411-416 ◽

Cited By ~ 20

Author(s):

K.P. Wolffenbuttel ◽

R. Hersmus ◽

H. Stoop ◽

K. Biermann ◽

P. Hoebeke ◽

...

Keyword(s):

Surgical Management ◽

Gonadal Dysgenesis ◽

Disorders Of Sex Development ◽

Sex Development

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Copy Number Variation in Patients with Disorders of Sex Development Due to 46,XY Gonadal Dysgenesis

PLoS ONE ◽

10.1371/journal.pone.0017793 ◽

2011 ◽

Vol 6 (3) ◽

pp. e17793 ◽

Cited By ~ 76

Author(s):

Stefan White ◽

Thomas Ohnesorg ◽

Amanda Notini ◽

Kelly Roeszler ◽

Jacqueline Hewitt ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Gonadal Dysgenesis ◽

Disorders Of Sex Development ◽

Sex Development ◽

Xy Gonadal Dysgenesis ◽

Number Variation

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OR27-02 An Exploration of Novel Clinical Benchmarks for Assessing the Practice of Gonadectomy in Conditions Affecting Sex Development - on Behalf of the I-DSD Consortium

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1222 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Angela K Lucas-Herald ◽

Jillian Bryce ◽

Martine Cools ◽

S Faisal Ahmed

Keyword(s):

Gonadal Dysgenesis ◽

Disorders Of Sex Development ◽

Clinical Information ◽

Androgen Insensitivity Syndrome ◽

Complete Androgen Insensitivity Syndrome ◽

Sex Development ◽

Primary Indication ◽

Sex Assignment ◽

Specialist Centre ◽

Development Methods

Abstract Introduction: Although the practice of gonadectomy in the field of differences/disorders of sex development (DSD) has undergone intense scrutiny, objective knowledge regarding current practice of gonadectomy is lacking in conditions affecting sex development. Methods: The International DSD Registry (www.I-DSD.org) was examined for clinical information reported by the DSD specialist centre on age at presentation, year of birth, diagnosis, karyotype, sex of rearing and age at gonadectomy in all cases over the age of 16 years at the time of search and who had a disorder of androgen action or synthesis, gonadal dysgenesis or a non-specific DSD.Results: Of the 3,618 cases available in the registry, 757 (21%) met the inclusion criteria and data regarding gonadectomy status were available in 668 (88%) from 44 participating centres. Of these, 248 (37%) with a median age of 24 years (range 17, 75) were registered as male and 420 (63%) with a median age of 26 years (16, 86) were registered as female. Gonadectomy was reported from 36 centres in 351 of these 668 cases (53%) of whom 302 (86%) had a 46 XY karyotype. Females were more likely to undergo gonadectomy (n=311, p<0.0001) and the most common diagnoses were complete androgen insensitivity syndrome (n=161, 24%) and partial gonadal dysgenesis (n=94, 14%). Of the 351 cases, the primary indication for gonadectomy was reported in 268 (76%) cases and included mitigation of tumourigenesis risk in 172 (64%), conformity to sex assignment in 74 (28%) and another indication in 22 (8%). Gonadectomy was bilateral in 295 (84%), unilateral in 16 (5%) and unknown in 40 (11%). The median ratio for age at first presentation to age at gonadectomy in those who presented before the age of 5 years and those who presented after the age of 10 years was 0.1 (range) and 0.9 (range), respectively (p<0.0001). Of the 351 cases, 17 (5%) had undergone a gonadectomy before their first presentation to the specialist centre and these cases were distributed across 9 of the 36 centres. Conclusions: Not only does the rate of gonadectomy vary according to underlying diagnosis and sex of rearing, it also seems that there is a variable discrepancy between the age at presentation and age at gonadectomy. The use of this objective marker to identify trends in practice may improve our understanding of the causes of variation.

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ANDROGEN INSENSITIVITY SYNDROME – A CASE REPORT

International Journal of Medical and Biomedical Studies ◽

10.32553/ijmbs.v5i8.2162 ◽

2021 ◽

Vol 5 (8) ◽

Author(s):

Rohit Kiran Phadnis ◽

Niharika Arram ◽

Neha Gala ◽

Faiz Hussain ◽

Nikhita Yadav

Keyword(s):

Case Report ◽

Gender Identity ◽

Proper Time ◽

Hormone Replacement ◽

Testicular Tissue ◽

Androgen Insensitivity Syndrome ◽

Primary Amenorrhea ◽

Psychological Issues ◽

Androgen Insensitivity ◽

Müllerian Agenesis

Background: AIS is one of the most commonly diagnosed XY DSD, with an estimated prevalence of 2:100.000 to 5:100.0001 and an incidence of 1:20.0002 to 1:99.0003. The name testicular feminization syndrome was coined by John McLean Morris of Yale University in 1953. The first description of this syndrome dates back to 1817, as quoted by Morris 4. It is the third most common cause of primary amenorrhea after gonadal dysgenesis and Mullerian agenesis 5. Case Report and Discussion: A 15-year-old phenotypic girl was evaluated for primary amenorrhea to find Complete Androgen Insensitivity Syndrome (CAIS) and underwent bilateral orchidectomy with plan for vaginoplasty at AIMSR, Hyderabad. Review of Literature: The treatment of AIS is based on the reinforcement sexual identity, gender identity plan and hormone replacement therapy. The prognosis is good, if the testicular tissue is resected at proper time. Conclusion: CAIS should be considered as important differential diagnosis in delayed menarche while evaluation for primary amenorrhea and early gonadectomy can avoid gender identity disorder (GID) / psychological issues Keywords: CAIS, GID

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Detection of 46, XY Disorder of Sex Development (DSD) Based on Plasma Cell-Free DNA and Targeted Next-Generation Sequencing

Genes ◽

10.3390/genes12121890 ◽

2021 ◽

Vol 12 (12) ◽

pp. 1890

Author(s):

Luigia De Falco ◽

Carmelo Piscopo ◽

Rossana D’Angelo ◽

Eloisa Evangelista ◽

Teresa Suero ◽

...

Keyword(s):

Amniotic Fluid ◽

Exome Sequencing ◽

Single Gene ◽

Disorders Of Sex Development ◽

Prenatal Testing ◽

Primary Amenorrhea ◽

Disease Genes ◽

Non Invasive ◽

Sex Development ◽

Cell Free Fetal Dna

Mutations in the HSD17B3 gene cause HSD17B3 deficiency and result in 46, XY Disorders of Sex Development (46, XY DSD). The diagnosis of 46, XY DSD is very challenging and not rarely is confirmed only at older ages, when an affected XY female presents with primary amenorrhea or develops progressive virilization. The patient described in this paper represents a case of discrepancies between non-invasive prenatal testing (NIPT) and ultrasound based fetal sex determination detected during prenatal screening. Exome sequencing was performed on the cell free fetal DNA (cffDNA), amniotic fluid, and the parents. Libraries were generated according to the manufacturer’s protocols using TruSight One Kits (Illumina Inc., San Diego, CA, USA). Sequencing was carried out on NEXT Seq 500 (Illumina) to mean sequencing depth of at least 100×. A panel of sexual disease genes was used in order to search for a causative variant. The finding of a mutation (c.645 A>T, p.Glu215Asp) in HSD17B3 gene in amniotic fluid as well as in cffDNA and both parents supported the hypothesis of the HSD17B3 deficiency. In conclusion, we used clinical exome sequencing and non-invasive prenatal detection, providing a solution for NIPT of a single-gene disorder. Early genetic diagnoses are useful for patients and clinicians, contribute to clinical knowledge of DSD, and are invaluable for genetic counseling of couples contemplating future pregnancies.

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