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

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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

Download Full-text

46, XY DSD (Disorder of Sex Development) : Diagnosis dan Tatalaksananya.

Majalah Kedokteran UKI ◽

10.33541/mk.v37i1.2424 ◽

2021 ◽

Vol 37 (1) ◽

pp. 26-35

Author(s):

Mildi Felicia ◽

Beto Suhartono

Keyword(s):

Surgical Management ◽

Neonatal Period ◽

System Development ◽

Disorders Of Sex Development ◽

Genital Organ ◽

Optimal Care ◽

Disorder Of Sex Development ◽

Sex Development ◽

Pregnancy History ◽

Complete Physical Examination

Disorder of Sex Development (DSD) is a congenital disorder that occurs in the development of chromosomes, gonads, and internal or external genital organ. DSD of 46 XY is a condition where the children with XY genotype is not able to have complete virilization of external genital. Determination phase is an initial phase of reproductive system development. Disruption of this phase may potentially lead to DSD. Optimal care for children with Disorder of Sex Development requires a multidisciplinary team starting since neonatal period. Family and pregnancy history, complete physical examination and assessment of genital organ are the first step of ensuring the diagnose. Management of children with DSD are focusing on gender determination, hormone support therapy and surgical management. On the other hand, Children with XY genotype should be raised as a boy however if there is no responsive evidence in administration of androgen the children should be raised as a girl. Subsequent to prescribe the gender of the children, surgical management is a required treatment for removing unnecessary genital afterward. Keywords: Disorders of Sex Development, DSD, 46 XY DSD

Download Full-text

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.

Download Full-text

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

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-19-0122 ◽

2019 ◽

Vol 2019 ◽

Cited By ~ 1

Author(s):

Yotsapon Thewjitcharoen ◽

Veekij Veerasomboonsin ◽

Soontaree Nakasatien ◽

Sirinate Krittiyawong ◽

Thep Himathongkam

Keyword(s):

Gonadal Dysgenesis ◽

Hormone Replacement ◽

Disorders Of Sex Development ◽

Primary Amenorrhea ◽

List Type ◽

Hormone Substitution ◽

Mrkh Syndrome ◽

Sex Development ◽

Exogenous Estrogen ◽

Müllerian Agenesis

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.

Download Full-text

Differences of sex development (DSD)

Paediatric Endocrinology and Diabetes ◽

10.1093/med/9780198786337.003.0011 ◽

2020 ◽

pp. 335-350

Author(s):

Gary Butler ◽

Jeremy Kirk

Keyword(s):

Gonadal Dysgenesis ◽

Gonad Development ◽

Disorders Of Sex Development ◽

Androgen Insensitivity Syndrome ◽

Trisomy 13 ◽

Delayed Puberty ◽

Genetic Syndromes ◽

Sex Development ◽

Differences Of Sex Development ◽

21 Hydroxylase Deficiency

• Embryology: the gonad is initially bipotential. • The testes develop under active control of SRY and other genes. Disorders of sex development (DSDs) are classified according to the karyotype: • 46,XY DSD (incomplete masculinization of a male fetus): ◦ The commonest cause is androgen insensitivity syndrome (AIS): ■ mutations in androgen receptor (AR) gene on X chromosome in complete forms ■ alterations in androgen binding in partial forms. ◦ Abnormalities of testosterone synthesis and conversion, may be: ■ isolated, e.g. 17β‎HSD, 5α‎RD ■ occur in association with defects in steroid biosynthesis, e.g. StAR, 3β‎HSD. • Pure 46,XY gonadal dysgenesis (Swyer syndrome): ◦ phenotype unambiguously female; may present with delayed puberty ◦ Müllerian structures are present but only streak gonads are seen. • Mixed gonadal dysgenesis: ◦ usually asymmetrical, e.g. ovary/streak gonad or ovotestis ◦ karyotype is 45,X/46,XY or 46,XX/46,XY. • Pure 46,XX gonadal dysgenesis: ◦ absent puberty in a phenotypically normal female ◦ intact Müllerian structures but streak ovaries; normal genitalia. • 46,XX DSD (masculinization of a female fetus): ◦ the commonest cause is congenital adrenal hyperplasia, with the vast majority (>90%) due to 21-hydroxylase deficiency (21OHD). • Ovotesticular DSD is rare: ◦ aetiology is unknown, and karyotype usually 46,XX ◦ asymmetrical gonad development; ovary and testis or ovotestis. • DSD may also be part of other genetic syndromes, e.g. Antley–Bixler, Smith–Lemli–Opitz, trisomy 13. • Management requires careful evaluation and counselling, working as part of a multidisciplinary team.

Download Full-text