Isolated 17,20-Lyase Deficiency in a CYB5A Mutated Female With Normal Sexual Development and Fertility

Abstract Isolated 17,20-lyase deficiency may be caused by mutations in the CYP17A1 (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase) and CYB5A (coding for microsomal cytochrome b5) genes. Of these, mutations in the CYB5A gene have thus far only been described in genetic males who presented with methemoglobinemia and 46,XY disorders of sex development (DSD) due to 17,20-lyase deficiency. A 24-year-old Chinese woman presented to the hematology outpatient clinic with purplish discoloration of fingers, toes, and lips since childhood. Investigations confirmed methemoglobinemia. A homozygous c.105C>G (p.Tyr35Ter) nonsense mutation was detected in the CYB5A gene. Hormonal studies showed isolated 17,20-lyase deficiency. Interestingly, she had a completely normal female phenotype with no DSD, normal pubertal development, and spontaneous pregnancy giving birth uneventfully to a healthy female infant. The sex hormone-related features of genetic females with 17,20-lyase deficiency due to cytochrome b5 gene mutation appear to differ from that of females with 17,20-lyase deficiency caused by other genetic defects who presented with hypergonadotropic hypogonadism and infertility and differ from genetic males with the same mutation.

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Female Hyperandrogenism in Elite Sports and the Athletic Triad

Seminars in Reproductive Medicine ◽

10.1055/s-0041-1736337 ◽

2021 ◽

Author(s):

Angelica Lindén Hirschberg

Keyword(s):

Female Athletes ◽

Polycystic Ovary ◽

Disorders Of Sex Development ◽

Normal Female ◽

Menstrual Disorders ◽

Mineral Density ◽

Energy Deficiency ◽

Sex Development ◽

Endocrine Disturbances ◽

Increased Risk

AbstractEssential hyperandrogenism seems to be overrepresented in female elite athletes. This applies to mild forms such as polycystic ovary syndrome, as well as rare differences/disorders of sex development (DSD). The reason is likely a selection bias since there is increasing evidence that androgens are beneficial for athletic performance by potent anabolic effects on muscle mass and bone mass, and stimulation of erythropoiesis. XY DSD may cause a greatly increased production of testosterone in the male range, that is, 10 to 20 times higher than the normal female range. The established regulations concerning the eligibility of female athletes with severe hyperandrogenism to compete in the female classification remain controversial. The most common cause of menstrual disorders in female athletes, however, is probably an acquired functional hypothalamic disturbance due to energy deficiency in relation to energy expenditure, which could lead to low bone mineral density and increased risk of injury. This condition is particularly common in endurance and esthetic sports, where a lean body composition is considered an advantage for physical performance. It is important to carefully evaluate endocrine disturbances and menstrual disorders in athletes since the management should be specific according to the underlying cause.

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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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Comprehensive Transcriptome Analysis of Hypothalamus Reveals Genes Associated With Disorders of Sex Development in Pigs

10.21203/rs.3.rs-45383/v1 ◽

2020 ◽

Author(s):

Shuwen Tan ◽

Yi Zhou ◽

Haiquan Zhao ◽

Jinhua Wu ◽

Hui Yu ◽

...

Keyword(s):

Expression Profiles ◽

Disorders Of Sex Development ◽

External Genitalia ◽

Rna Isolation ◽

Functional Enrichment ◽

Regulation Mechanism ◽

Normal Female ◽

Sex Development ◽

Mirna Expression Profiles ◽

Hormone Biosynthesis

Abstract Background Disorders of sex development (DSD) is a chronic autoimmune disease characterized by systemic inflammation, pathological osteogenesis, and endocrine abnormality. However, its genetic etiology remains mostly unknown. In addition, little research focuses on the regulation mechanism from the view of transcriptomics in the hypothalamic-pituitary-gonadal axis (HPGA). The hypothalamus is the integrated center of the HPGA mediating neural, hormonal, and environmental stimulus to sex development. Methods Three XX-DSD (SRY-negative) pig (DSD) and three NF pigs (five months old, 40 kg ± 5 kg) were selected by external genitalia observation and sex determining region Y gene (SRY) detection. The hypothalamus were sampled for RNA isolation, and the mRNA, lncRNA and miRNA expression profiles were analyzed by sequencing. Results A total of 1,258 lncRNAs, 1,086 mRNAs, and 61 microRNAs were found to differentially express in XX-DSD pigs compared with normal female pigs. Many genes in hormone biosynthesis and secretion pathway are significantly up-regulated, and the up-regulation of GNRH1, KISS1 and AVP may be the candidate genes leading the abnormal secretion of GnRH. Next, we predicted the lncRNA-miRNA-mRNA co-expression triplets and constructed three competing endogenous RNA (ceRNA) potentially associated with DSD. Functional enrichment suggested TCONS_00340886, TCONS_00000204 and miR-181a were related to GnRH secretion. Conclusions Our research revealed the first transcriptomic profile in the hypothalamus of XX-DSD pigs and provided new insight in coding and non-coding RNAs that may be associated with DSD in pigs.

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Breast Augmentation in Swyer Syndrome Patient

Jurnal Plastik Rekonstruksi ◽

10.14228/jpr.v1i5.111 ◽

1970 ◽

Vol 1 (5) ◽

Author(s):

Vika Tania ◽

Aditya Wardhana

Keyword(s):

Breast Augmentation ◽

Disorders Of Sex Development ◽

Later Life ◽

Normal Female ◽

Complete Evaluation ◽

Sex Development ◽

Sexual Characteristics ◽

Classi Cation ◽

History Of ◽

Serious Disease

Background: The number of breast augmentation in Indonesia has been raised, especially in young women. Women with disorders of sex development (DSD) can be one of our patients that come for breast augmentation. These patients may also have other problems that can lead to serious disease in her later life, such as malignancies which has 30% probability.Patients and Methods: We report one case of female with 46 XY karyotype and normal female phenotype. She appeared to be normal female but did not develop secondary sexual characteristics at puberty with Tanner classi!cation M1P1, did not menstruate, and had streak gonads in ovarian localization. This gonadal dysgenesis syndrome is also called Swyer syndrome.Result: A clinical team consists of plastic surgeons, gynecologist, psychiatrist, geneticist was build to manage our patient comprehensively. We performed breast augmentation, laparoscopic gonadectomy, and psychological support.Summary: Patient with disorder of sex development (DSD) can be one of our patients who come for breast augmentation. One must pay attention to subtle sign leading to DSD patients such as, history of amenorrhea, wide chest and lack of women body curve. Complete evaluation of sexual development is needed before performing breast augmentation.

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Prenatal diagnosis of 17-hydroxylase/17,20-lyase deficiency (17OHD) in a case of 46,XY sex discordance and low maternal serum estriol

Case Reports in Perinatal Medicine ◽

10.1515/crpm-2018-0009 ◽

2018 ◽

Vol 8 (1) ◽

Author(s):

Lauren Mohnach ◽

Sarah Mazzola ◽

Daniel Shumer ◽

Deborah R. Berman

Keyword(s):

Prenatal Diagnosis ◽

Parental Stress ◽

Disorders Of Sex Development ◽

Rare Condition ◽

Maternal Serum ◽

Diagnostic Challenge ◽

Lyase Deficiency ◽

Sex Development ◽

Seamless Transition ◽

Endocrine Profile

Abstract Background A discrepancy between the fetal karyotype and the appearance of genitalia on ultrasound can be a diagnostic challenge. In these cases, it is difficult to shorten the extensive list of differential diagnoses without information on internal anatomy and endocrine profile. Case presentation Here, we describe a diagnosis of 17-hydroxylase/17,20-lyase deficiency (17OHD), which was suspected based on low maternal serum estriol in the setting of 46,XY genitalia discordance. Through collaboration between maternal-fetal medicine and disorders of sex development (DSD) teams, the patient was counseled about the diagnosis and postnatal management plans were made. Conclusions This case illustrates how prenatal diagnosis of this rare condition led to reduced parental stress and seamless transition to postnatal care.

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A Missense Mutation in the Human Cytochrome b5 Gene causes 46,XY Disorder of Sex Development due to True Isolated 17,20 Lyase Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-2413 ◽

2012 ◽

Vol 97 (3) ◽

pp. E465-E475 ◽

Cited By ~ 59

Author(s):

Jan Idkowiak ◽

Tabitha Randell ◽

Vivek Dhir ◽

Pushpa Patel ◽

Cedric H. L. Shackleton ◽

...

Keyword(s):

Missense Mutation ◽

Cytochrome B5 ◽

Disorder Of Sex Development ◽

Lyase Deficiency ◽

Sex Development ◽

Human Cytochrome

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46,XX DSD and Antley-Bixler syndrome due to novel mutations in the cytochrome P450 oxidoreductase gene

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302012000800020 ◽

2012 ◽

Vol 56 (8) ◽

pp. 578-585 ◽

Cited By ~ 8

Author(s):

Guilherme Guaragna-Filho ◽

Carla Cristina Telles de Sousa Castro ◽

Rodrigo Ribeiro De Carvalho ◽

Fernanda Borchers Coeli ◽

Lúcio Fábio Caldas Ferraz ◽

...

Keyword(s):

Disorders Of Sex Development ◽

First Year ◽

The Novel ◽

Hypergonadotropic Hypogonadism ◽

Steroidogenic Enzyme ◽

P450 Oxidoreductase ◽

Sex Development ◽

Skeletal Malformations ◽

Cytochrome P450 Oxidoreductase ◽

First Year Of Life

Deficiency of the enzyme P450 oxidoreductase is a rare form of congenital adrenal hyperplasia with characteristics of combined and partial impairments in steroidogenic enzyme activities, as P450 oxidoreductase transfers electrons to CYP21A2, CYP17A1, and CYP19A1. It results in disorders of sex development and skeletal malformations similar to Antley-Bixley syndrome. We report the case of a 9-year-old girl who was born with virilized genitalia (Prader stage V), absence of palpable gonads, 46,XX karyotype, and hypergonadotropic hypogonadism. During the first year of life, ovarian cyst, partial adrenal insufficiency, and osteoarticular changes, such as mild craniosynostosis, carpal and tarsal synostosis, and limited forearm pronosupination were observed. Her mother presented severe virilization during pregnancy. The molecular analysis of P450 oxidoreductase gene revealed compound heterozygosis for the nonsense p.Arg223*, and the novel missense p.Met408Lys, inherited from the father and the mother, respectively. Arq Bras Endocrinol Metab. 2012;56(8):578-85

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Recent advancement in the treatment of boys and adolescents with hypogonadism

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/20420188211065660 ◽

2022 ◽

Vol 13 ◽

pp. 204201882110656

Author(s):

Rodolfo A. Rey

Keyword(s):

Pubertal Development ◽

Clinical Manifestations ◽

Disorders Of Sex Development ◽

Long Term Results ◽

Need For Treatment ◽

Sex Development ◽

Infancy And Childhood ◽

Constitutional Delay ◽

Recent Advancement

Clinical manifestations and the need for treatment varies according to age in males with hypogonadism. Early foetal-onset hypogonadism results in disorders of sex development (DSD) presenting with undervirilised genitalia whereas hypogonadism established later in foetal life presents with micropenis, cryptorchidism and/or micro-orchidism. After the period of neonatal activation of the gonadal axis has waned, the diagnosis of hypogonadism is challenging because androgen deficiency is not apparent until the age of puberty. Then, the differential diagnosis between constitutional delay of puberty and central hypogonadism may be difficult. During infancy and childhood, treatment is usually sought because of micropenis and/or cryptorchidism, whereas lack of pubertal development and relative short stature are the main complaints in teenagers. Testosterone therapy has been the standard, although off-label, in the vast majority of cases. However, more recently alternative therapies have been tested: aromatase inhibitors to induce the hypothalamic-pituitary-testicular axis in boys with constitutional delay of puberty and replacement with GnRH or gonadotrophins in those with central hypogonadism. Furthermore, follicle-stimulating hormone (FSH) priming prior to hCG or luteinizing hormone (LH) treatment seems effective to induce an enhanced testicular enlargement. Although the rationale for gonadotrophin or GnRH treatment is based on mimicking normal physiology, long-term results are still needed to assess their impact on adult fertility.

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