LEYDIG CELL HYPOPLASIA: A UNIQUE PARADOX IN THE DIAGNOSIS OF 46,XY DISORDERS OF SEX DEVELOPMENT

Objective: Disorders of sex development (DSD) are defined as conditions in which chromosomal sex is inconsistent with phenotypic sex, or in which the phenotype is not classifiable as either male or female. Mutations in genes present in X, Y or autosomal chromosomes can cause abnormalities of testis determination or 46,XY DSD. Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive endocrine syndrome of 46,XY DSD. Our objective here is to present the case of a 27-year-old, phenotypic female who presented with primary amenorrhea and later found to have LCH. Methods: We used formatted history and clinical examination followed by necessary hormonal investigations. The diagnosis was confirmed by histopathology of resected testes and genetic mutation analysis. Results: The patient's physical examination was unremarkable except 2 ovoid lumps present in the inguinovulvar region. There were no müllerian structures on sonography. Estrogen and both basal and stimulated testosterone levels were low whereas luteinizing hormone and follicle-stimulating hormone were high. Her chromosomal sex was found to be 46,XY. The histopathology of the resected inguinal lumps showed atrophic testicular change lacking Leydig cells with relative preservation of Sertoli cells. Genetic mutation analysis failed to reveal any significant aberration in the LHCGR gene. At present she is on estrogen replacement therapy having undergone bilateral orchidectomy and vaginoplasty. Conclusion: LCH represents a unique example of diagnostic dilemma in gender identification. It requires a multidisciplinary approach for optimum outcome.

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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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Mutations in MAP3K1 Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2010.11.003 ◽

2010 ◽

Vol 87 (6) ◽

pp. 898-904 ◽

Cited By ~ 108

Author(s):

Alexander Pearlman ◽

Johnny Loke ◽

Cedric Le Caignec ◽

Stefan White ◽

Lisa Chin ◽

...

Keyword(s):

Signal Transduction ◽

Disorders Of Sex Development ◽

Signal Transduction Pathway ◽

Human Testis ◽

Transduction Pathway ◽

Sex Development ◽

Testis Determination ◽

Common Signal

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SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype

BMC Medical Genetics ◽

10.1186/1471-2350-13-108 ◽

2012 ◽

Vol 13 (1) ◽

Cited By ~ 10

Author(s):

Remko Hersmus ◽

Hans Stoop ◽

Erin Turbitt ◽

J Wolter Oosterhuis ◽

Stenvert LS Drop ◽

...

Keyword(s):

Mutation Analysis ◽

Deep Sequencing ◽

Disorders Of Sex Development ◽

Next Generation ◽

Chromosomal Disorders ◽

Sex Development ◽

Mosaic Karyotype

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Mutation Analysis of FOXF2 in Patients with Disorders of Sex Development (DSD) in Combination with Cleft Palate

Sexual Development ◽

10.1159/000195679 ◽

2008 ◽

Vol 2 (6) ◽

pp. 302-308 ◽

Cited By ~ 8

Author(s):

U. Jochumsen ◽

R. Werner ◽

N. Miura ◽

A. Richter-Unruh ◽

O. Hiort ◽

...

Keyword(s):

Cleft Palate ◽

Mutation Analysis ◽

Disorders Of Sex Development ◽

Sex Development

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Gonadal tumour risk in 292 phenotypic female patients with disorders of sex development containing Y chromosome or Y-derived sequence

Clinical Endocrinology ◽

10.1111/cen.13255 ◽

2016 ◽

Vol 86 (4) ◽

pp. 621-627 ◽

Cited By ~ 19

Author(s):

He Huang ◽

Chunqing Wang ◽

Qinjie Tian

Keyword(s):

Y Chromosome ◽

Disorders Of Sex Development ◽

Female Patients ◽

Sex Development ◽

Phenotypic Female

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MAMLD1 and Differences/Disorders of Sex Development: An Update

Sexual Development ◽

10.1159/000519298 ◽

2021 ◽

pp. 1-12

Author(s):

Mami Miyado ◽

Maki Fukami ◽

Tsutomu Ogata

Keyword(s):

Leydig Cell ◽

Disorders Of Sex Development ◽

External Genitalia ◽

Gene Interactions ◽

Testicular Function ◽

Ovarian Dysfunction ◽

Causative Gene ◽

Fetal Testis ◽

Sex Development ◽

Age Dependent

MAMLD1 (alias CXorf6) was first documented in 2006 as a causative gene of 46,XY differences/disorders of sex development (DSD). MAMLD1/Mamld1 is expressed in the fetal testis and is predicted to enhance the expression of several Leydig cell-specific genes. To date, hemizygous MAMLD1 variants have been identified in multiple 46,XY individuals with hypomasculinized external genitalia. Pathogenic MAMLD1 variants are likely to cause genital abnormalities at birth and are possibly associated with age-dependent deterioration of testicular function. In addition, some MAMLD1 variants have been identified in 46,XX individuals with ovarian dysfunction. However, recent studies have raised the possibility that MAMLD1 variants cause 46,XY DSD and ovarian dysfunction as oligogenic disorders. Unsolved issues regarding MAMLD1 include the association between MAMLD1 variants and 46,XX testicular DSD, gene-gene interactions in the development of MAMLD1-mediated DSD, and intracellular functions of MAMLD1.

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ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801223115 ◽

2018 ◽

Vol 115 (21) ◽

pp. 5474-5479 ◽

Cited By ~ 28

Author(s):

Abigail Harris ◽

Pam Siggers ◽

Silvia Corrochano ◽

Nick Warr ◽

Danielle Sagar ◽

...

Keyword(s):

Sex Determination ◽

Wnt Signaling ◽

Disorders Of Sex Development ◽

Ovary Development ◽

Sex Development ◽

Mutual Antagonism ◽

Testis Determination ◽

Direct Target ◽

Canonical Wnt ◽

Xy Female

Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal, or related defects. These abnormalities are associated with ectopic WNT/β-catenin activity and reduced Sox9 expression during fetal sex determination. Using exome sequencing of individuals with 46,XY disorders of sex development, we identified three human ZNRF3 variants in very rare cases of XY female presentation. We tested two missense variants and show that these disrupt ZNRF3 activity in both human cell lines and zebrafish embryo assays. Our data identify a testis-determining function for ZNRF3 and indicate a mechanism of direct molecular interaction between two mutually antagonistic organogenetic pathways.

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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.

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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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