|
1
|
Mangone A, Profka E, Rodari G, Giavoli C, Mantovani G. Sexual health in adult women with complete androgen insensitivity syndrome: a single centre cross-sectional study. J Endocrinol Invest 2025:10.1007/s40618-025-02592-7. [PMID: 40304984 DOI: 10.1007/s40618-025-02592-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/19/2025] [Indexed: 05/02/2025]
Abstract
OBJECTIVE We aimed to assess sexual health and body uneasiness in patients with complete androgen insensitivity syndrome (CAIS) using validated questionnaires, since literature is limited and heterogeneous. METHODS Single-center, cross-sectional study on 34 adults with 46, XY karyotype and confirmed androgen receptor mutation (age = 34 ± 8.6 years), 29 gonadectomized and 5 with gonads in situ. All gonadectomized patients but 3 were receiving hormonal replacement therapy (HRT): 14 with transdermal oestradiol, 10 with oral oestradiol, 2 with testosterone. We measured hormonal levels and adherence to HRT, and we administered Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R) and Body Uneasiness Test (BUT) questionnaires. RESULTS We registered sexual dysfunction with FSFI score < 26.55 and FSDS-R score > 11 respectively in 77% and 52.9% of the cohort; body uneasiness (BUT-Global Severity Index > 1.2) was also present in 50%. In patients with gonads in situ, body uneasiness and sexual distress were common, with 4/5 pathological scores at FSFI and BUT, and 2/5 at FSDS-R. In gonadectomized patients, no significant differences among type of HRT and questionnaires' results were registered. Despite receiving HRT and referring optimal compliance, most (69%) patients still had oestradiol concentration < 50 pg/ml, with no significant correlation with sexual function. 10/34 patients (29%) had vaginal hypoplasia and 9 underwent vaginal dilation treatment, with no correlation with sexual scores. CONCLUSIONS Sexual dysfunction and body uneasiness are worryingly common in CAIS. Preservation of gonads and HRT do not guarantee adequate sexual function nor optimal hormone levels. Psychological and sexual aspects must be considered in the management and therapeutic choices for these patients, as they highly impact quality of life.
Collapse
Affiliation(s)
- Alessandra Mangone
- Department of Clinical Sciences and Community Health, Department of Excellence 2023-2027, University of Milan, Milan, Italy
- Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Eriselda Profka
- Department of Clinical Sciences and Community Health, Department of Excellence 2023-2027, University of Milan, Milan, Italy.
- Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
- Endocrine Unit, Department of Clinical Sciences and Community Health, Department of Excellence 2023-2027, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122, Milan, Italy.
| | - Giulia Rodari
- Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Claudia Giavoli
- Department of Clinical Sciences and Community Health, Department of Excellence 2023-2027, University of Milan, Milan, Italy
- Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanna Mantovani
- Department of Clinical Sciences and Community Health, Department of Excellence 2023-2027, University of Milan, Milan, Italy
- Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| |
Collapse
|
|
2
|
Giuliatti S, Benedetti AFF, Ramos RM, Petroli RJ, Domenice S, Mendonca BB, Batista RL. Hydropathic AF-2 variants in the androgen receptor gene among androgen insensitivity patients. Andrology 2025; 13:447-458. [PMID: 38923406 DOI: 10.1111/andr.13680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 05/20/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Androgen insensitivity syndrome (AIS) is a common condition among individuals with differences of sexual development (DSD) and results from germline allelic variants in the androgen receptor (AR) gene. Understanding the phenotypic consequences of AR allelic variants that disrupt the activation function 2 (AF2) region is essential to grasping its clinical significance. OBJECTIVES This study aims to provide insights into the phenotypic characteristics and clinical impact of AR mutations affecting the AF2 region in AIS patients. We achieve this by reviewing reported AR variants in the AF2 region among individuals with AIS, including identifying a new phenotype associated with the c.2138T>C variant (p.Leu713Pro) in the AR gene. MATERIALS AND METHODS We comprehensively reviewed AR variants within the AF2 region reported in AIS and applied molecular dynamics simulations to assess the impact of the p.Leu713Pro variant on protein dynamics. RESULTS Our review of reported AR variants in the AF2 region revealed a spectrum of phenotypic outcomes in AIS patients. Molecular dynamics simulations indicated that the p.Leu713Pro variant significantly alters the local dynamics of the AR protein and disrupts the correlation and covariance between variables. DISCUSSION The diverse phenotypic presentations observed among individuals with AR variants in the AF2 region highlight the complexity of AIS. The altered protein dynamics resulting from the p.Leu713Pro variant further emphasize the importance of the AF2 region in AR function. CONCLUSION Our study provides valuable insights into AR mutations' phenotypic characteristics and clinical impact on the AF2 region in AIS. Moreover, the disruption of protein dynamics underscores the significance of the AF2 region in AR function and its role in the pathogenesis of AIS.
Collapse
Affiliation(s)
- Silvana Giuliatti
- Department of Genetics, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Anna Flavia Figueredo Benedetti
- Developmental Endocrinology Unit, Hormone and Molecular Genetics Laboratory (LIM/42), Endocrinology Division, Internal Medicine Department, University of São Paulo (USP), São Paulo, Brazil
| | - Raquel Martinez Ramos
- Developmental Endocrinology Unit, Hormone and Molecular Genetics Laboratory (LIM/42), Endocrinology Division, Internal Medicine Department, University of São Paulo (USP), São Paulo, Brazil
| | - Reginaldo José Petroli
- Faculdade de Medicina da Universidade Federal de Alagoas (UFAL), Programa de Pós-Graduação em Ciências Médicas - UFAL, Alagoas, Brazil
| | - Sorahia Domenice
- Developmental Endocrinology Unit, Hormone and Molecular Genetics Laboratory (LIM/42), Endocrinology Division, Internal Medicine Department, University of São Paulo (USP), São Paulo, Brazil
| | - Berenice Bilharinho Mendonca
- Developmental Endocrinology Unit, Hormone and Molecular Genetics Laboratory (LIM/42), Endocrinology Division, Internal Medicine Department, University of São Paulo (USP), São Paulo, Brazil
| | - Rafael Loch Batista
- Developmental Endocrinology Unit, Hormone and Molecular Genetics Laboratory (LIM/42), Endocrinology Division, Internal Medicine Department, University of São Paulo (USP), São Paulo, Brazil
- Instituto do Câncer do Estado de São Paulo da Faculdade de Medicina da Universidade de São Paulo (ICESP), São Paulo, Brazil
| |
Collapse
|
|
3
|
Handelsman DJ. Toward a Robust Definition of Sport Sex. Endocr Rev 2024; 45:709-736. [PMID: 38578952 DOI: 10.1210/endrev/bnae013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 01/17/2024] [Accepted: 03/26/2024] [Indexed: 04/07/2024]
Abstract
Elite individual sports in which success depends on power, speed, or endurance are conventionally divided into male and female events using traditional binary definitions of sex. Male puberty creates durable physical advantages due to the 20- to 30-fold increase in circulating testosterone producing a sustained uplift in men's muscle, bone, hemoglobin, and cardiorespiratory function resulting from male puberty and sustained during men's lives. These male physical advantages provide strong justification for a separate protected category of female events allowing women to achieve the fame and fortune from success they would be denied if competing against men. Recent wider social acceptance of transgender individuals, together with the less recognized involvement of intersex individuals, challenge and threaten to defeat the sex classifications for elite individual female events. This can create unfair advantages if seeking inclusion into elite female events of unmodified male-bodied athletes with female gender identity who have gained the physical advantages of male puberty. Based on reproductive physiology, this paper proposes a working definition of sport sex based primarily on an individual's experience of male puberty and can be applied to transgender and various XY intersex conditions. Consistent with the multidimensionality of biological sex (chromosomal, genetic, hormonal, anatomical sex), this definition may be viewed as a multistrand cable whose overall strength survives when any single strand weakens or fails, rather than as a unidimensional chain whose strength is only as good as its weakest link.
Collapse
Affiliation(s)
- David J Handelsman
- Andrology Department, ANZAC Research Institute, University of Sydney, Concord Hospital, Syndey, NSW 2139, Australia
| |
Collapse
|
|
4
|
Ramgir SS, Annamalai S, Abilash VG. In Silico Analysis of Functional SNPs in Genes of Complete Androgen Insensitivity Syndrome (CAIS): A Retrospective, Case-Control Study. J Obstet Gynaecol India 2024; 74:136-143. [PMID: 38707871 PMCID: PMC11065807 DOI: 10.1007/s13224-023-01876-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 10/04/2023] [Indexed: 05/07/2024] Open
Abstract
Background Complete androgen insensitivity syndrome (CAIS) is one of the categories of androgen insensitivity syndrome (AIS) described as complete failure of the cell to react to androgens with external genitalia of a normal female. People with AIS condition are genetically male, with XY karyotype in each cell, but their bodies are unable to respond to male sex hormones (called androgens). It is associated with infertility as well as developing cancerous conditions. The genetic association of CAIS involves polymorphism of genes such as NR5A1, SOX9, SRD5A2, CBX2, GATA4, and SRY. Their mutation and participation in genetics of CAIS can be studied by Single Nucleotide polymorphism (SNP) analysis which is a way to detect genetic variations. SNP in coding region leads to synonymous and non-synonymous mutations. Hence, this study highlights analysis of SNPs associated with CAIS. Our aim is to study SNP analysis of NR5A1, SOX9, SRD5A2, CBX2, GATA4, SRY genes in Complete Androgen Insensitivity Syndrome. Methods SIFT and Polyphen analysis was performed for all the genes and samples were subjected for PCR-SSCP technique. Results SNPs were analyzed for the genes associated with CAIS. Benign and damaging SNPs were identified. DNA Samples were amplified using PCR technique and they will be analyzed using Single-strand conformation polymorphism (SSCP). Conclusions As SNPs have decreased stability, damaging and benign character, they can be used as candidate hallmarks in study of Complete Androgen Insensitivity Syndrome.
Collapse
Affiliation(s)
- Shalaka S. Ramgir
- Assistant professor at Symbiosis Institute of Health Sciences (SIHS), Symbiosis International (Deemed University), Mulshi, Lavale, Maharashtra 412115 India
| | - Sivakumar Annamalai
- Quality Assurance-Executive, GLR Laboratories Pvt. Ltd., Chennai, Tamilnadu 600068 India
| | - V. G. Abilash
- Associate Professor, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamilnadu 632014 India
| |
Collapse
|
|
5
|
Hunter SK, S Angadi S, Bhargava A, Harper J, Hirschberg AL, D Levine B, L Moreau K, J Nokoff N, Stachenfeld NS, Bermon S. The Biological Basis of Sex Differences in Athletic Performance: Consensus Statement for the American College of Sports Medicine. Med Sci Sports Exerc 2023; 55:2328-2360. [PMID: 37772882 DOI: 10.1249/mss.0000000000003300] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023]
Abstract
ABSTRACT Biological sex is a primary determinant of athletic performance because of fundamental sex differences in anatomy and physiology dictated by sex chromosomes and sex hormones. Adult men are typically stronger, more powerful, and faster than women of similar age and training status. Thus, for athletic events and sports relying on endurance, muscle strength, speed, and power, males typically outperform females by 10%-30% depending on the requirements of the event. These sex differences in performance emerge with the onset of puberty and coincide with the increase in endogenous sex steroid hormones, in particular testosterone in males, which increases 30-fold by adulthood, but remains low in females. The primary goal of this consensus statement is to provide the latest scientific knowledge and mechanisms for the sex differences in athletic performance. This review highlights the differences in anatomy and physiology between males and females that are primary determinants of the sex differences in athletic performance and in response to exercise training, and the role of sex steroid hormones (particularly testosterone and estradiol). We also identify historical and nonphysiological factors that influence the sex differences in performance. Finally, we identify gaps in the knowledge of sex differences in athletic performance and the underlying mechanisms, providing substantial opportunities for high-impact studies. A major step toward closing the knowledge gap is to include more and equitable numbers of women to that of men in mechanistic studies that determine any of the sex differences in response to an acute bout of exercise, exercise training, and athletic performance.
Collapse
Affiliation(s)
- Sandra K Hunter
- Exercise Science Program, Department of Physical Therapy, and Athletic and Human Performance Center, Marquette University, Milwaukee, WI
| | | | - Aditi Bhargava
- Department of Obstetrics and Gynecology, Center for Reproductive Sciences, University of California, San Francisco, CA
| | - Joanna Harper
- Loughborough University, Loughborough, UNITED KINGDOM
| | - Angelica Lindén Hirschberg
- Department of Women's and Children's Health, Karolinska Institutet, and Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, SWEDEN
| | - Benjamin D Levine
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, and the Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX
| | - Kerrie L Moreau
- Department of Medicine, Division of Geriatric Medicine, University of Colorado Anschutz Medical Campus, and Eastern Colorado Health Care System, Geriatric Research Education and Clinical Center, Aurora, CO
| | - Natalie J Nokoff
- Department of Pediatrics, Section of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Nina S Stachenfeld
- The John B. Pierce Laboratory and Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT
| | - Stéphane Bermon
- Health and Science Department, World Athletics, Monaco and the LAMHESS, University Côte d'Azur, Nice, FRANCE
| |
Collapse
|
|
6
|
Delli Paoli E, Di Chiano S, Paoli D, Lenzi A, Lombardo F, Pallotti F. Androgen insensitivity syndrome: a review. J Endocrinol Invest 2023; 46:2237-2245. [PMID: 37300628 DOI: 10.1007/s40618-023-02127-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023]
Abstract
PURPOSE Androgen insensitivity syndrome (AIS) is a disorder characterized by peripheral androgen resistance due to androgen receptor mutations in subjects with 46 XY karyotype. The severity of hormone resistance (complete, partial or mild) determines the wide spectrum of phenotypes. METHODS We performed a literature review on Pubmed focusing on etiopathogenesis, molecular alterations, and diagnostic-therapeutic management. RESULTS AIS is determined by a large variety of X-linked mutations that account for the wide phenotypic spectrum of subjects; it represents one of the most frequent disorders of sexual development (DSD). Clinical suspicion can arise at birth in partial AIS, due to the presence of variable degrees of ambiguity of the external genitalia, and at pubertal age in complete AIS, due to the development of female secondary sex characteristics, primary amenorrhea, and absence of female primary sex characteristics (uterus and ovaries). Laboratory tests showing elevated LH and testosterone levels despite mild or absent virilization may be helpful, but diagnosis can be achieved only after genetic testing (karyotype examination and androgen receptor sequencing). The clinical phenotype and especially the decision on sex assignment of the patient, if the diagnosis is made at birth or in the neonatal period, will guide the following medical, surgical and psychological management. CONCLUSIONS For the management of AIS, a multidisciplinary team consisting of physicians, surgeons, and psychologists is highly recommended to support the patient and his/her family on gender identity choices and subsequent appropriate therapeutic decisions.
Collapse
Affiliation(s)
- E Delli Paoli
- Laboratory of Seminology‑Sperm Bank "Loredana Gandini", Department of Experimental Medicine, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - S Di Chiano
- Laboratory of Seminology‑Sperm Bank "Loredana Gandini", Department of Experimental Medicine, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - D Paoli
- Laboratory of Seminology‑Sperm Bank "Loredana Gandini", Department of Experimental Medicine, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - A Lenzi
- Laboratory of Seminology‑Sperm Bank "Loredana Gandini", Department of Experimental Medicine, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - F Lombardo
- Laboratory of Seminology‑Sperm Bank "Loredana Gandini", Department of Experimental Medicine, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - F Pallotti
- Laboratory of Seminology‑Sperm Bank "Loredana Gandini", Department of Experimental Medicine, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
- Faculty of Medicine and Surgery, University of Enna "Kore", Contrada Santa Panasia, 94100, Enna, Italy.
| |
Collapse
|
|
7
|
VanderLaan DP, Skorska MN, Peragine DE, Coome LA. Carving the Biodevelopment of Same-Sex Sexual Orientation at Its Joints. ARCHIVES OF SEXUAL BEHAVIOR 2023; 52:2939-2962. [PMID: 35960401 DOI: 10.1007/s10508-022-02360-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/30/2022] [Accepted: 06/04/2022] [Indexed: 06/15/2023]
Abstract
Sexual orientation is a core aspect of human experience and understanding its development is fundamental to psychology as a scientific discipline. Biological perspectives have played an important role in uncovering the processes that contribute to sexual orientation development. Research in this field has relied on a variety of populations, including community, clinical, and cross-cultural samples, and has commonly focused on female gynephilia (i.e., female sexual attraction to adult females) and male androphilia (i.e., male sexual attraction to adult males). Genetic, hormonal, and immunological processes all appear to influence sexual orientation. Consistent with biological perspectives, there are sexual orientation differences in brain development and evidence indicates that similar biological influences apply across cultures. An outstanding question in the field is whether the hypothesized biological influences are all part of the same process or represent different developmental pathways leading to same-sex sexual orientation. Some studies indicate that same-sex sexually oriented people can be divided into subgroups who likely experienced different biological influences. Consideration of gender expression in addition to sexual orientation might help delineate such subgroups. Thus, future research on the possible existence of such subgroups could prove to be valuable for uncovering the biological development of sexual orientation. Recommendations for such future research are discussed.
Collapse
Affiliation(s)
- Doug P VanderLaan
- Department of Psychology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON, L5L 1C6, Canada.
- Child and Youth Psychiatry, Centre for Addiction and Mental Health, Toronto, ON, Canada.
| | - Malvina N Skorska
- Child and Youth Psychiatry, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Diana E Peragine
- Department of Psychology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON, L5L 1C6, Canada
| | - Lindsay A Coome
- Department of Psychology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON, L5L 1C6, Canada
| |
Collapse
|
|
8
|
Chen Z, Li P, Lyu Y, Wang Y, Gao K, Wang J, Lan F, Chen F. Molecular genetics and general management of androgen insensitivity syndrome. Intractable Rare Dis Res 2023; 12:71-77. [PMID: 37287652 PMCID: PMC10242393 DOI: 10.5582/irdr.2023.01024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/25/2023] [Accepted: 05/15/2023] [Indexed: 06/09/2023] Open
Abstract
Androgen insensitivity syndrome (AIS) is a rare genetic disorder that affects the development of the male reproductive system in individuals with a 46,XY karyotype. In addition to physical impacts, patients with AIS may face psychological distress and social challenges related to gender identity and acceptance. The major molecular etiology of AIS results from hormone resistance caused by mutations in the X-linked androgen receptor (AR) gene. Depending on the severity of androgen resistance, the wide spectrum of AIS can be divided into complete AIS (CAIS), partial AIS (PAIS), or mild AIS (MAIS). Open issues in the treatment and management of AIS include decisions about reconstructive surgery, genetic counseling, gender assignment, timing of gonadectomy, fertility and physiological outcomes. Although new genomic approaches have improved understanding of the molecular causes of AIS, identification of individuals with AIS can be challenging, and molecular genetic diagnosis is often not achievable. The relationship between AIS genotype and phenotype is not well established. Therefore, the optimal management remains uncertain. The objective of this review is to outline the recent progress and promote understanding of AIS related to the clinical manifestation, molecular genetics and expert multidisciplinary approach, with an emphasis on genetic etiology.
Collapse
Affiliation(s)
- Zhongzhong Chen
- Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Clinical Research Center for Hypospadias Pediatric College, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Urogenital Development Research Center, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Pin Li
- Department of Endocrinology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yiqing Lyu
- Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yaping Wang
- Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kexin Gao
- Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Wang
- Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fuying Lan
- Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fang Chen
- Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Clinical Research Center for Hypospadias Pediatric College, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
9
|
Goodman M, Yacoub R, Getahun D, McCracken CE, Vupputuri S, Lash TL, Roblin D, Contreras R, Cromwell L, Gardner MD, Hoffman T, Hu H, Im TM, Prakash Asrani R, Robinson B, Xie F, Nash R, Zhang Q, Bhai SA, Venkatakrishnan K, Stoller B, Liu Y, Gullickson C, Ahmed M, Rink D, Voss A, Jung HL, Kim J, Lee PA, Sandberg DE. Cohort profile: pathways to care among people with disorders of sex development (DSD). BMJ Open 2022; 12:e063409. [PMID: 36130763 PMCID: PMC9494584 DOI: 10.1136/bmjopen-2022-063409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
PURPOSE The 'DSD Pathways' study was initiated to assess health status and patterns of care among people enrolled in large integrated healthcare systems and diagnosed with conditions comprising the broad category of disorders (differences) of sex development (DSD). The objectives of this communication are to describe methods of cohort ascertainment for two specific DSD conditions-classic congenital adrenal hyperplasia with 46,XX karyotype (46,XX CAH) and complete androgen insensitivity syndrome (CAIS). PARTICIPANTS Using electronic health records we developed an algorithm that combined diagnostic codes, clinical notes, laboratory data and pharmacy records to assign each cohort candidate a 'strength-of-evidence' score supporting the diagnosis of interest. A sample of cohort candidates underwent a review of the full medical record to determine the score cutoffs for final cohort validation. FINDINGS TO DATE Among 5404 classic 46,XX CAH cohort candidates the strength-of-evidence scores ranged between 0 and 10. Based on sample validation, the eligibility cut-off for full review was set at the strength-of-evidence score of ≥7 among children under the age of 8 years and ≥8 among older cohort candidates. The final validation of all cohort candidates who met the cut-off criteria identified 115 persons with classic 46,XX CAH. The strength-of-evidence scores among 648 CAIS cohort candidates ranged from 2 to 10. There were no confirmed CAIS cases among cohort candidates with scores <6. The in-depth medical record review for candidates with scores ≥6 identified 61 confirmed cases of CAIS. FUTURE PLANS As the first cohort of this type, the DSD Pathways study is well-positioned to fill existing knowledge gaps related to management and outcomes in this heterogeneous population. Analyses will examine diagnostic and referral patterns, adherence to care recommendations and physical and mental health morbidities examined through comparisons of DSD and reference populations and analyses of health status across DSD categories.
Collapse
Affiliation(s)
- Michael Goodman
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Rami Yacoub
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Darios Getahun
- Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
- Health Systems Science, Kaiser Permanente Bernard J Tyson School of Medicine, Pasadena, California, USA
| | - Courtney E McCracken
- Center for Research and Evaluation, Kaiser Permanente Georgia, Atlanta, Georgia, USA
| | - Suma Vupputuri
- Mid-Atlantic Permanente Research Institute, Kaiser Permanente, Rockville, Maryland, USA
| | - Timothy L Lash
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
- Aarhus Universitet, Aarhus, Midtjylland, Denmark
| | - Douglas Roblin
- Mid-Atlantic Permanente Research Institute, Kaiser Permanente, Rockville, Maryland, USA
| | - Richard Contreras
- Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | - Lee Cromwell
- Center for Research and Evaluation, Kaiser Permanente Georgia, Atlanta, Georgia, USA
| | - Melissa D Gardner
- Susan B Meister Child Health and Evaluation Research Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Trenton Hoffman
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Haihong Hu
- Mid-Atlantic Permanente Research Institute, Kaiser Permanente, Rockville, Maryland, USA
| | - Theresa M Im
- Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | | | - Brandi Robinson
- Center for Research and Evaluation, Kaiser Permanente Georgia, Atlanta, Georgia, USA
| | - Fagen Xie
- Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | - Rebecca Nash
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Qi Zhang
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Sadaf A Bhai
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | | | - Bethany Stoller
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Yijun Liu
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | | | - Maaz Ahmed
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - David Rink
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Ava Voss
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Hye-Lee Jung
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Jin Kim
- Epidemiology, Rollins School of Public Health, Atlanta, Georgia, USA
| | - Peter A Lee
- Division of Endocrinology, Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - David E Sandberg
- Susan B Meister Child Health and Evaluation Research Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
| |
Collapse
|
|
10
|
Mild androgen insensitivity syndrome: the current landscape. Endocr Pract 2022; 28:911-917. [PMID: 35660466 DOI: 10.1016/j.eprac.2022.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 11/24/2022]
Abstract
OBJECTIVE Mild Androgen Insensitivity (MAIS) belongs to the Androgen Insensitivity Syndrome (AIS) spectrum, an X-linked genetic disease that is the most common cause of differences in sex development (DSD). Unfortunately, AIS studies mainly focus on the partial and the complete phenotype, and the mild phenotype (MAIS) has been barely reported. Our purpose is to explore the MAIS facets, clinical features, and molecular aspects. METHODS We collected all reported MAIS cases in the medical literature and presented them based on the phenotype and the molecular diagnosis. RESULTS We identified 49 different AR mutations in 69 individuals in the literature. We compared the AR mutations presented in MAIS individuals with AR mutations previously reported in other AIS phenotypes (CAIS and PAIS) regarding the type, location, genotype-phenotype correlation, and functional studies. CONCLUSION This review provides a landscape of the mild phenotype of AIS. Most MAIS patients present with male infertility. Therefore, AR gene sequencing should be considered during male infertility investigation, even in males with typically male external genitalia. In addition, MAIS can be part of other medical conditions, such as X-linked spinal and bulbar muscular atrophy (Kennedy's disease).
Collapse
|
|
11
|
Wang KN, Chen QQ, Zhu YL, Wang CL. Complete androgen insensitivity syndrome caused by the c.2678C>T mutation in the androgen receptor gene: A case report. World J Clin Cases 2021; 9:11036-11042. [PMID: 35047615 PMCID: PMC8678886 DOI: 10.12998/wjcc.v9.i35.11036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/09/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene (AR). However, the underlying molecular mechanisms for the majority of AR variants remain unclear. In this study, we identified a point variant in three patients with complete androgen insensitivity syndrome (CAIS), summarized the correlation analysis, and performed a literature review.
CASE SUMMARY The proband was raised as a girl. In infancy, she was first referred to hospital with a right inguinal hernia. Ultrasonography revealed the absence of a uterus and ovaries, and a testis-like structure located at the inguinal canal. Further diagnostic workup detected a 46, XY karyotype, and fluorescence in situ hybridization analysis showed the presence of the SRY gene. Histological analysis revealed the excised tissue to be testicular. Twelve years later, she was admitted to our hospital with a lack of breast development. Her pubic hair and breasts were Tanner stage I. She had normal female external genitalia. Blood hormone tests showed normal testosterone levels, low estradiol levels, and high gonadotropin levels. Her two siblings underwent similar examinations, and all three had a rare hemizygous missense mutation in AR: c.2678C>T. In vitro functional analyses revealed decreased nuclear translocation in AR-c.2678C>T mutation cells.
CONCLUSION This case of CAIS was caused by an AR variant (c.2678C>T). Functional studies showed impaired nuclear translocation ability of the mutant protein.
Collapse
Affiliation(s)
- Ka-Na Wang
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Qing-Qing Chen
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Yi-Lin Zhu
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Chun-Lin Wang
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| |
Collapse
|
|
12
|
Thurston LT, Coome LA, Skorska MN, Peragine DE, Saokhieo P, Kaewthip O, Chariyalertsak S, VanderLaan DP. Mental rotation task performance in relation to sexual and gender diversity in Thailand. Psychoneuroendocrinology 2021; 133:105428. [PMID: 34600175 DOI: 10.1016/j.psyneuen.2021.105428] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 09/10/2021] [Accepted: 09/20/2021] [Indexed: 11/27/2022]
Abstract
Neurohormonal theory argues that organizational effects of hormone exposure influence sexual orientation and gender identity, as well as sex differences in visuospatial cognition. This study examined mental rotation task (MRT) performance in a diverse Thai sample (N = 980). Thai culture has several third genders: individuals assigned male at birth (AMAB) who are feminine and attracted to cis men (i.e., sao praphet song); individuals assigned female at birth (AFAB) who are masculine and attracted to feminine individuals (i.e., toms); AFAB individuals who are feminine and attracted to toms (i.e., dees); and sexual orientation categories similar to Western culture (e.g., gay, lesbian, bi). On the MRT, straight cis men outperformed straight cis women. Results were consistent with organizational effects among AMAB individuals, with straight cis men outperforming gay cis men and sao praphet song. Among AFAB individuals, however, only bi and lesbian cis women outperformed dees. Overall, support for neurohormonal theory was limited among AFAB individuals, but MRT performance among AMAB individuals was consistent with organizational effects. This study informs our understanding of visuospatial sex/gender differences and the applicability of neurohormonal theory across cultures.
Collapse
Affiliation(s)
- Lindsey T Thurston
- Department of Psychology, University of Toronto Mississauga, Mississauga, L5L 1C6 ON, Canada
| | - Lindsay A Coome
- Department of Psychology, University of Toronto Mississauga, Mississauga, L5L 1C6 ON, Canada
| | - Malvina N Skorska
- Department of Psychology, University of Toronto Mississauga, Mississauga, L5L 1C6 ON, Canada; Child and Youth Psychiatry, Centre for Addiction and Mental Health, Toronto, M6J 1H4 ON, Canada
| | - Diana E Peragine
- Department of Psychology, University of Toronto Mississauga, Mississauga, L5L 1C6 ON, Canada
| | - Pongpun Saokhieo
- Research Institute of Health Sciences, Chiang Mai University, Sriphum, Muang Chiang Mai 50200, Thailand
| | - Oranitcha Kaewthip
- Research Institute of Health Sciences, Chiang Mai University, Sriphum, Muang Chiang Mai 50200, Thailand
| | - Suwat Chariyalertsak
- Faculty of Public Health and Research Institute of Health Sciences, Chiang Mai University, Sriphum, Muang Chiang Mai 50200, Thailand
| | - Doug P VanderLaan
- Department of Psychology, University of Toronto Mississauga, Mississauga, L5L 1C6 ON, Canada; Child and Youth Psychiatry, Centre for Addiction and Mental Health, Toronto, M6J 1H4 ON, Canada.
| |
Collapse
|
|
13
|
Analyses of Molecular Characteristics and Enzymatic Activities of Ovine HSD17B3. Animals (Basel) 2021; 11:ani11102876. [PMID: 34679897 PMCID: PMC8532638 DOI: 10.3390/ani11102876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 11/16/2022] Open
Abstract
17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) converts androstenedione (A4) into testosterone (T), which regulates sex steroid production. Because various mutations of the HSD17B3 gene cause disorder of sex differentiation (DSD) in multiple mammalian species, it is very important to reveal the molecular characteristics of this gene in various species. Here, we revealed the open reading frame of the ovine HSD17B3 gene. Enzymatic activities of ovine HSD17B3 and HSD17B1 for converting A4 to T were detected using ovine androgen receptor-mediated transactivation in reporter assays. Although HSD17B3 also converted estrone to estradiol, this activity was much weaker than those of HSD17B1. Although ovine HSD17B3 has an amino acid sequence that is conserved compared with other mammalian species, it possesses two amino acid substitutions that are consistent with the reported variants of human HSD17B3. Substitutions of these amino acids in ovine HSD17B3 for those in human did not affect the enzymatic activities. However, enzymatic activities declined upon missense mutations of the HSD17B3 gene associated with 46,XY DSD, affecting amino acids that are conserved between these two species. The present study provides basic information and tools to investigate the molecular mechanisms behind DSD not only in ovine, but also in various mammalian species.
Collapse
|
|
14
|
Concepción-Zavaleta MJ, García-Villasante EJ, Zavaleta-Gutiérrez FE, Barrantes Ticlla JL, Massucco Revoredo FG. Late Diagnosis of Partial Androgen Insensitivity Syndrome in a Peruvian Child. Cureus 2021; 13:e16565. [PMID: 34430167 PMCID: PMC8380050 DOI: 10.7759/cureus.16565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2021] [Indexed: 11/15/2022] Open
Abstract
Disorders of sexual differentiation are congenital pathologies characterized by atypical development of genetic, gonadal, or phenotypic sex. These are caused by the alteration of any primordial phases of sexual development and may be evident at birth or in the later stage of life. Here, we present the case of a nine-year-old Peruvian school patient who has female gender assigned at birth, has no contributory antecedents and was found to have clitoromegaly and hypospadia on physical examination. In the blood tests, anti-Müllerian hormone and testosterone were found, and 46 XY karyotype and sex-determining region Y (SRY) genes were present. On abdominal ultrasound, testicles were found in the inguinal canals. The human chorionic gonadotropin (HCG) stimulation test was conducted, which allowed us to rule out defects in testosterone biosynthesis and enzyme defects in dihydrotestosterone production; the main suspected diagnosis was partial androgen insensitivity syndrome (PAIS). A multidisciplinary medical meeting was held, accepting the patient’s desire to opt for the male gender, after acceptance by the parents. Thus, the patient underwent bilateral orchidopexy and genitoplasty. He is currently receiving therapy with testosterone, with an adequate response to the treatment and the molecular study confirmed the androgen-receptor gene mutation. In conclusion, we highlight the importance of a timely multidisciplinary diagnosis and management of disorders of sexual differentiation to avoid premature gender assignment and major social and family repercussions that it implies.
Collapse
|
|
15
|
Bangalore Krishna K, Kogan BA, Mazur T, Hoebeke P, Bogaert G, Lee PA. Individualized care for patients with intersex (differences of sex development): part 4/5.Considering the Ifs, Whens, and Whats regarding sexual-reproductive system surgery. J Pediatr Urol 2021; 17:338-345. [PMID: 33691983 DOI: 10.1016/j.jpurol.2021.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/01/2021] [Accepted: 02/09/2021] [Indexed: 10/22/2022]
Abstract
Issues and concerns regarding surgery of the sexual-reproductive anatomy during infancy and early childhood are discussed using four actual examples. A case of a 46, XX infant with 21 hydroxylase deficiency congenital adrenal hyperplasia (CAH) with atypical (ambiguous) genitalia is discussed regarding timing and potential harms and benefits of surgery. We present the perspective of balancing the child's rights to bodily autonomy and right to an open future versus parents' decision making authority regarding what they perceive as their child's future best interests. The second case is a newborn with complete androgen insensitivity syndrome and we discuss the harms, benefits and timing of gonadectomy. The third case examines the physical and psychological impact of penile shaft hypospadias, raising the question of whether surgery is justified to prevent what may or may not be considered a permanent disability. The fourth case involves an adult woman with classic CAH, born with a urogenital sinus and clitoromegaly, who never had genital surgery and is now requesting vaginoplasty, but not clitoral reduction. The primary message of this article, as the previous articles in this series, is to encourage patient-family centered care that individualizes treatment guided by shared decision making.
Collapse
Affiliation(s)
| | | | | | | | - Guy Bogaert
- University Hospital, UZLeuven, Leuven, Belgium
| | - Peter A Lee
- Penn State College of Medicine, Hershey, PA, 17033, USA
| |
Collapse
|
|
16
|
|
|
17
|
Tyutyusheva N, Mancini I, Baroncelli GI, D’Elios S, Peroni D, Meriggiola MC, Bertelloni S. Complete Androgen Insensitivity Syndrome: From Bench to Bed. Int J Mol Sci 2021; 22:ijms22031264. [PMID: 33514065 PMCID: PMC7865707 DOI: 10.3390/ijms22031264] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 12/13/2022] Open
Abstract
Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.
Collapse
Affiliation(s)
- Nina Tyutyusheva
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
| | - Ilaria Mancini
- Gynecology and Human Reproduction Physiopathology Unit, IRCCS Policlinico di Sant’Orsola, DIMEC, University of Bologna, 40138 Bologna, Italy; (I.M.); (M.C.M.)
| | - Giampiero Igli Baroncelli
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
| | - Sofia D’Elios
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
| | - Diego Peroni
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
| | - Maria Cristina Meriggiola
- Gynecology and Human Reproduction Physiopathology Unit, IRCCS Policlinico di Sant’Orsola, DIMEC, University of Bologna, 40138 Bologna, Italy; (I.M.); (M.C.M.)
| | - Silvano Bertelloni
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
- Correspondence: ; Tel.: +39-050-992743; Fax: +39-050-992641
| |
Collapse
|
|
18
|
Peng Y, Zhu H, Han B, Xu Y, Liu X, Song H, Qiao J. Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis. Front Endocrinol (Lausanne) 2021; 12:731107. [PMID: 34867780 PMCID: PMC8637961 DOI: 10.3389/fendo.2021.731107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 10/25/2021] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Androgen insensitivity syndrome (AIS) is a rare X-linked genetic disease and one of the causes of 46,XY disorder of sexual development. The unstraightforward diagnosis of AIS and the gender assignment dilemma still make a plague for this disorder due to the overlapping clinical phenotypes. METHODS Peripheral blood mononuclear cells (PBMCs) of partial AIS (PAIS) patients and healthy controls were separated, and RNA-seq was performed to investigate transcriptome variance. Then, tissue-specific gene expression, functional enrichment, and protein-protein interaction (PPI) network analyses were performed; and the key modules were identified. Finally, the RNA expression of differentially expressed genes (DEGs) of interest was validated by quantitative real-time PCR (qRT-PCR). RESULTS In our dataset, a total of 725 DEGs were captured, with functionally enriched reproduction and immune-related pathways and Gene Ontology (GO) functions. The most highly specific systems centered on hematologic/immune and reproductive/endocrine systems. We finally filtered out CCR1, PPBP, PF4, CLU, KMT2D, GP6, and SPARC by the key gene clusters of the PPI network and manual screening of tissue-specific gene expression. These genes provide novel insight into the pathogenesis of AIS in the immune system or metabolism and bring forward possible molecular markers for clinical screening. The qRT-PCR results showed a consistent trend in the expression levels of related genes between PAIS patients and healthy controls. CONCLUSION The present study sheds light on the molecular mechanisms underlying the pathogenesis and progression of AIS, providing potential targets for diagnosis and future investigation.
Collapse
Affiliation(s)
- Yajie Peng
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Zhu
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Han
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Xu
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuemeng Liu
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huaidong Song
- Research Centre for Clinical Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Qiao, ; Huaidong Song,
| | - Jie Qiao
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Qiao, ; Huaidong Song,
| |
Collapse
|
|
19
|
Palmieri A, Meconi F, Vallesi A, Capizzi M, Pick E, Marcato S, Kleinbub JR, Sorarù G, Sessa P. Enhanced Neural Empathic Responses in Patients with Spino-Bulbar Muscular Atrophy: An Electrophysiological Study. Brain Sci 2020; 11:E16. [PMID: 33374355 PMCID: PMC7824338 DOI: 10.3390/brainsci11010016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/16/2020] [Accepted: 12/21/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Spino-bulbar muscular atrophy is a rare genetic X-linked disease caused by testosterone insensitivity. An inverse correlation has been described between testosterone levels and empathic responses. The present study explored the profile of neural empathic responding in spino-bulbar muscular atrophy patients. METHODS Eighteen patients with spino-bulbar muscular atrophy and eighteen healthy male controls were enrolled in the study. Their event-related potentials were recorded during an "Empathy Task" designed to distinguish neural responses linked with experience-sharing (early response) and mentalizing (late response) components of empathy. The task involved the presentation of contextual information (painful vs. neutral sentences) and facial expressions (painful vs. neutral). An explicit dispositional empathy-related questionnaire was also administered to all participants, who were screened via neuropsychological battery tests that did not reveal potential cognitive deficits. Due to electrophysiological artefacts, data from 12 patients and 17 controls were finally included in the analyses. RESULTS Although patients and controls did not differ in terms of dispositional, explicit empathic self-ratings, notably conservative event-related potentials analyses (i.e., spatio-temporal permutation cluster analyses) showed a significantly greater experience-sharing neural response in patients compared to healthy controls in the Empathy-task when both contextual information and facial expressions were painful. CONCLUSION The present study contributes to the characterization of the psychological profile of patients with spino-bulbar muscular atrophy, highlighting the peculiarities in enhanced neural responses underlying empathic reactions.
Collapse
Affiliation(s)
- Arianna Palmieri
- Department of Philosophy, Sociology, Education and Applied Psychology (FISPPA), University of Padova, Piazza Capitaniato, 35139 Padova, Italy; (A.P.); (E.P.); (S.M.); (J.R.K.)
- Padova Neuroscience Centre (PNC), University of Padova, Via Giuseppe Orus, 35131 Padova, Italy
| | - Federica Meconi
- School of Psychology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK;
| | - Antonino Vallesi
- Department of Neurosciences (DNS) & Padova Neuroscience Centre, University of Padova, Via Giustiniani, 35128 Padova, Italy; (A.V.); (G.S.)
- Brain Imaging & Neural Dynamics Research Group, IRCCS San Camillo Hospital, 30126 Venice, Italy
| | | | - Emanuele Pick
- Department of Philosophy, Sociology, Education and Applied Psychology (FISPPA), University of Padova, Piazza Capitaniato, 35139 Padova, Italy; (A.P.); (E.P.); (S.M.); (J.R.K.)
| | - Sonia Marcato
- Department of Philosophy, Sociology, Education and Applied Psychology (FISPPA), University of Padova, Piazza Capitaniato, 35139 Padova, Italy; (A.P.); (E.P.); (S.M.); (J.R.K.)
| | - Johann R. Kleinbub
- Department of Philosophy, Sociology, Education and Applied Psychology (FISPPA), University of Padova, Piazza Capitaniato, 35139 Padova, Italy; (A.P.); (E.P.); (S.M.); (J.R.K.)
| | - Gianni Sorarù
- Department of Neurosciences (DNS) & Padova Neuroscience Centre, University of Padova, Via Giustiniani, 35128 Padova, Italy; (A.V.); (G.S.)
| | - Paola Sessa
- Padova Neuroscience Centre (PNC), University of Padova, Via Giuseppe Orus, 35131 Padova, Italy
- Department of Developmental and Socialization Psychology (DPSS), University of Padova, Via Venezia, 35131 Padova, Italy
| |
Collapse
|
|
20
|
Malliou-Becher MN, Vogt PH, Capp E, Frank-Herrmann P. Varianten der Geschlechtsentwicklung in der Frauenheilkunde. GYNAKOLOGISCHE ENDOKRINOLOGIE 2020. [DOI: 10.1007/s10304-020-00358-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
|
|
21
|
Nagahama Y, Chakraborty T, Paul-Prasanth B, Ohta K, Nakamura M. Sex determination, gonadal sex differentiation, and plasticity in vertebrate species. Physiol Rev 2020; 101:1237-1308. [PMID: 33180655 DOI: 10.1152/physrev.00044.2019] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
A diverse array of sex determination (SD) mechanisms, encompassing environmental to genetic, have been found to exist among vertebrates, covering a spectrum from fixed SD mechanisms (mammals) to functional sex change in fishes (sequential hermaphroditic fishes). A major landmark in vertebrate SD was the discovery of the SRY gene in 1990. Since that time, many attempts to clone an SRY ortholog from nonmammalian vertebrates remained unsuccessful, until 2002, when DMY/dmrt1by was discovered as the SD gene of a small fish, medaka. Surprisingly, however, DMY/dmrt1by was found in only 2 species among more than 20 species of medaka, suggesting a large diversity of SD genes among vertebrates. Considerable progress has been made over the last 3 decades, such that it is now possible to formulate reasonable paradigms of how SD and gonadal sex differentiation may work in some model vertebrate species. This review outlines our current understanding of vertebrate SD and gonadal sex differentiation, with a focus on the molecular and cellular mechanisms involved. An impressive number of genes and factors have been discovered that play important roles in testicular and ovarian differentiation. An antagonism between the male and female pathway genes exists in gonads during both sex differentiation and, surprisingly, even as adults, suggesting that, in addition to sex-changing fishes, gonochoristic vertebrates including mice maintain some degree of gonadal sexual plasticity into adulthood. Importantly, a review of various SD mechanisms among vertebrates suggests that this is the ideal biological event that can make us understand the evolutionary conundrums underlying speciation and species diversity.
Collapse
Affiliation(s)
- Yoshitaka Nagahama
- Laboratory of Reproductive Biology, National Institute for Basic Biology, Okazaki, Japan.,South Ehime Fisheries Research Center, Ehime University, Ainan, Japan.,Faculty of Biological Science and Technology, Kanazawa University, Ishikawa, Japan
| | - Tapas Chakraborty
- Laboratory of Reproductive Biology, National Institute for Basic Biology, Okazaki, Japan.,South Ehime Fisheries Research Center, Ehime University, Ainan, Japan.,Laboratory of Marine Biology, Faculty of Agriculture, Kyushu University, Fukouka, Japan.,Karatsu Satellite of Aqua-Bioresource Innovation Center, Kyushu University, Karatsu, Japan
| | - Bindhu Paul-Prasanth
- Laboratory of Reproductive Biology, National Institute for Basic Biology, Okazaki, Japan.,Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidapeetham, Kochi, Kerala, India
| | - Kohei Ohta
- Laboratory of Marine Biology, Faculty of Agriculture, Kyushu University, Fukouka, Japan
| | - Masaru Nakamura
- Sesoko Station, Tropical Biosphere Research Center, University of the Ryukyus, Okinawa, Japan.,Research Center, Okinawa Churashima Foundation, Okinawa, Japan
| |
Collapse
|
|
22
|
Simchovitz-Gesher A, Soreq H. Pharmaceutical Implications of Sex-Related RNA Divergence in Psychiatric Disorders. Trends Pharmacol Sci 2020; 41:840-850. [DOI: 10.1016/j.tips.2020.09.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 08/29/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023]
|
|
23
|
Liu C, Lyu Y, Li P. A hemizygous mutation in the androgen receptor gene causes different phenotypes of androgen insensitivity syndrome in two siblings by disrupting the nuclear translocation. Mol Genet Genomics 2020; 295:1103-1111. [PMID: 32435981 DOI: 10.1007/s00438-020-01686-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 05/06/2020] [Indexed: 12/19/2022]
Abstract
The androgen insensitivity syndrome (AIS) is a congenital disease characterized by androgen resistance due to androgen receptor (AR) gene mutations, resulting in disorders of sex differentiation in 46,XY individuals. However, the underlying mechanisms in the majority of AR variants and the phenotype-genotype correlations are unclear. Here, we identified a p.Y764H variant of the AR gene that results in different phenotypes in a family. Structural analyses revealed that amino acid substitution affected protein properties and spatial conformation, and in vitro, functional studies showed impaired nuclear translocation ability of the mutated protein. Moreover, the extent to which this variant reduced nuclear translocation depends on the dihydrotestosterone (DHT) concentrations. Our results, for the first time, demonstrated a pathogenesis of the p.Y764H mutations in AR resulting in AIS phenotype, and indicated that AIS patients with p.Y764H mutation and preserved gonad might have residual AR activity at high androgen levels, putting patients at risk for pubertal virilization in the future. We provide an in-depth insight into the pathogenesis in AIS based on the amino acid substitution, which may help aid its precise diagnosis, personalized treatment, and organized follow-up to avoid gender dysphoria.
Collapse
Affiliation(s)
- Chunjie Liu
- Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People's Republic of China
| | - Yongfen Lyu
- Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People's Republic of China
| | - Pin Li
- Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People's Republic of China.
| |
Collapse
|
|
24
|
Kalinchenko NY, Kolodkina AA, Petrov VM, Vasiliev EV, Tiulpakov AN. [Somatic mutations in the androgen receptor gene as the cause of androgen insensitivity syndrome]. ACTA ACUST UNITED AC 2019; 65:268-272. [PMID: 32202729 DOI: 10.14341/probl10166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 08/02/2019] [Accepted: 08/02/2019] [Indexed: 11/06/2022]
Abstract
Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.
Collapse
|
|
25
|
Wisniewski AB, Batista RL, Costa EMF, Finlayson C, Sircili MHP, Dénes FT, Domenice S, Mendonca BB. Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life. Endocr Rev 2019; 40:1547-1572. [PMID: 31365064 DOI: 10.1210/er.2019-00049] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 07/23/2019] [Indexed: 12/11/2022]
Abstract
Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions that result in discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. Advances in the clinical care of patients and families affected by 46,XY DSD have been achieved since publication of the original Consensus meeting in 2006. The aims of this paper are to review what is known about morbidity and mortality, diagnostic tools and timing, sex of rearing, endocrine and surgical treatment, fertility and sexual function, and quality of life in people with 46,XY DSD. The role for interdisciplinary health care teams, importance of establishing a molecular diagnosis, and need for research collaborations using patient registries to better understand long-term outcomes of specific medical and surgical interventions are acknowledged and accepted. Topics that require further study include prevalence and incidence, understanding morbidity and mortality as these relate to specific etiologies underlying 46,XY DSD, appropriate and optimal options for genitoplasty, long-term quality of life, sexual function, involvement with intimate partners, and optimizing fertility potential.
Collapse
Affiliation(s)
- Amy B Wisniewski
- Psychology Department, Oklahoma State University, Stillwater, Oklahoma
| | - Rafael L Batista
- Division of Endocrinology, Department of Internal Medicine, University of São Paulo Medical School, University of São Paulo, São Paulo, Brazil
| | - Elaine M F Costa
- Division of Endocrinology, Department of Internal Medicine, University of São Paulo Medical School, University of São Paulo, São Paulo, Brazil
| | - Courtney Finlayson
- Division of Endocrinology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Maria Helena Palma Sircili
- Division of Endocrinology, Department of Internal Medicine, University of São Paulo Medical School, University of São Paulo, São Paulo, Brazil
| | - Francisco Tibor Dénes
- Division of Urology, Department of Surgery, University of São Paulo Medical School, University of São Paulo, São Paulo, Brazil
| | - Sorahia Domenice
- Division of Endocrinology, Department of Internal Medicine, University of São Paulo Medical School, University of São Paulo, São Paulo, Brazil
| | - Berenice B Mendonca
- Division of Endocrinology, Department of Internal Medicine, University of São Paulo Medical School, University of São Paulo, São Paulo, Brazil
| |
Collapse
|
|
26
|
Batista RL, Yamaguchi K, Rodrigues ADS, Nishi MY, Goodier JL, Carvalho LR, Domenice S, Costa EMF, Kazazian HH, Mendonca BB. Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome. J Clin Endocrinol Metab 2019; 104:6385-6390. [PMID: 31393562 PMCID: PMC6834070 DOI: 10.1210/jc.2019-00144] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 08/02/2019] [Indexed: 11/19/2022]
Abstract
CONTEXT Androgen insensitivity syndrome (AIS) is the most common cause of disorders of sex development in 46,XY individuals. It is an X-linked condition usually caused by pathogenic allelic variants in the androgen receptor (AR) gene. The phenotype depends on the AR variant, ranging from severe undervirilization (complete AIS) to several degrees of external genitalia undervirilization. Although 90% of those with complete AIS will have AR mutations, this will only be true for 40% of those with partial AIS (PAIS). OBJECTIVE To identify the genetic etiology of AIS in a large multigenerational family with the PAIS phenotype. PARTICIPANTS Nine affected individuals with clinical and laboratory findings consistent with PAIS and a normal exonic AR sequencing. SETTINGS Endocrine clinic and genetic institute from two academic referral centers. DESIGN Analysis of whole exons of the AR gene, including splicing regions, was performed, followed by sequencing of the 5'untranslated region (UTR) of the AR gene. Detailed phenotyping was performed at the initial diagnosis and long-term follow-up, and circulating levels of steroid gonadal hormones were measured in all affected individuals. AR expression was measured using RT-PCR and cultured fibroblasts. RESULTS All 46,XY family members with PAIS had inherited, in hemizygosity, a complex defect (∼1100 bp) in the 5'UTR region of the AR surrounded by a duplicated 18-bp sequence (target site duplication). This sequence is 99.7% similar to an active, long, interspersed element present on the X chromosome (AC002980; Xq22.2), which was inserted in the 5'UTR of the AR gene, severely reducing AR expression and leading to PAIS. CONCLUSION The molecular diagnosis of PAIS remains challenging. The genomic effect of retrotransposon mobilization should be considered a possible molecular cause of AIS and other AR diseases.
Collapse
Affiliation(s)
- Rafael Loch Batista
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Hospital, Baltimore, Maryland
- Correspondence and Reprint Requests: Rafael Loch Batista, MD, PhD, Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM/42), da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, Eneas Carvalho de Aguiar, 255, 05403900 São Paulo, São Paulo, Brazil. E-mail:
| | - Katsumi Yamaguchi
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Hospital, Baltimore, Maryland
| | - Andresa di Santi Rodrigues
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Mirian Yumie Nishi
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - John L Goodier
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Hospital, Baltimore, Maryland
| | - Luciani Renata Carvalho
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Sorahia Domenice
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Elaine M F Costa
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Haig H Kazazian
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Hospital, Baltimore, Maryland
| | - Berenice Bilharinho Mendonca
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| |
Collapse
|
|
27
|
Skarin Nordenvall A, Chen Q, Norrby C, Lundholm C, Frisén L, Nordenström A, Almqvist C, Nordenskjöld A. Fertility in adult men born with hypospadias: A nationwide register‐based cohort study on birthrates, the use of assisted reproductive technologies and infertility. Andrology 2019; 8:372-380. [DOI: 10.1111/andr.12723] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/18/2019] [Accepted: 10/28/2019] [Indexed: 11/29/2022]
Affiliation(s)
- Anna Skarin Nordenvall
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
| | - Qi Chen
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
| | - Christina Norrby
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
| | - Cecilia Lundholm
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
| | - Louise Frisén
- Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden
- Child and Adolescent Psychiatry Research CenterStockholm Sweden
| | - Anna Nordenström
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Department of Pediatric Endocrinology Astrid Lindgren Children’s HospitalKarolinska University Hospital Stockholm Sweden
| | - Catarina Almqvist
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
- Pediatric Allergy and Respiratory Medicine Astrid Lindgren Children's HospitalKarolinska University Hospital Stockholm Sweden
| | - Agneta Nordenskjöld
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Center for Molecular Medicine Karolinska Institutet Stockholm Sweden
- Department of Pediatric Surgery Astrid Lindgren Children´s HospitalKarolinska University Hospital Stockholm Sweden
| |
Collapse
|
|
28
|
Malcher A, Jedrzejczak P, Stokowy T, Monem S, Nowicka-Bauer K, Zimna A, Czyzyk A, Maciejewska-Jeske M, Meczekalski B, Bednarek-Rajewska K, Wozniak A, Rozwadowska N, Kurpisz M. Novel Mutations Segregating with Complete Androgen Insensitivity Syndrome and their Molecular Characteristics. Int J Mol Sci 2019; 20:ijms20215418. [PMID: 31671693 PMCID: PMC6861889 DOI: 10.3390/ijms20215418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 01/12/2023] Open
Abstract
We analyzed three cases of Complete Androgen Insensitivity Syndrome (CAIS) and report three hitherto undisclosed causes of the disease. RNA-Seq, Real-timePCR, Western immunoblotting, and immunohistochemistry were performed with the aim of characterizing the disease-causing variants. In case No.1, we have identified a novel androgen receptor (AR) mutation (c.840delT) within the first exon in the N-terminal transactivation domain. This thymine deletion resulted in a frameshift and thus introduced a premature stop codon at amino acid 282. In case No.2, we observed a nonsynonymous mutation in the ligand-binding domain (c.2491C>T). Case No.3 did not reveal AR mutation; however, we have found a heterozygous mutation in CYP11A1 gene, which has a role in steroid hormone biosynthesis. Comparative RNA-Seq analysis of CAIS and control revealed 4293 significantly deregulated genes. In patients with CAIS, we observed a significant increase in the expression levels of PLCXD3, TM4SF18, CFI, GPX8, and SFRP4, and a significant decrease in the expression of SPATA16, TSACC, TCP10L, and DPY19L2 genes (more than 10-fold, p < 0.05). Our findings will be helpful in molecular diagnostics of patients with CAIS, as well as the identified genes could be also potential biomarkers for the germ cells differentiation process.
Collapse
Affiliation(s)
- Agnieszka Malcher
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland.
| | - Piotr Jedrzejczak
- Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 60-535 Poznan, Poland.
| | - Tomasz Stokowy
- Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.
| | - Soroosh Monem
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland.
| | | | - Agnieszka Zimna
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland.
| | - Adam Czyzyk
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland.
| | - Marzena Maciejewska-Jeske
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland.
| | - Blazej Meczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland.
| | | | - Aldona Wozniak
- Department of Clinical Pathology, Poznan University of Medical Sciences, 60-355 Poznan, Poland.
| | - Natalia Rozwadowska
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland.
| | - Maciej Kurpisz
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland.
| |
Collapse
|
|
29
|
Abstract
Male infertility is a multifactorial pathological condition affecting approximately 7% of the male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2,000 genes are involved in spermatogenesis. The highest frequency of known genetic factors contributing to male infertility (25%) is in azoospermia, but the number of identified genetic anomalies in other semen and aetiological categories is constantly growing. Genetic screening is relevant for its diagnostic value, clinical decision making, and appropriate genetic counselling. Anomalies in sex chromosomes have major roles in severe spermatogenic impairment. Autosome-linked gene mutations are mainly involved in central hypogonadism, monomorphic teratozoospermia or asthenozoospermia, congenital obstructive azoospermia, and familial cases of quantitative spermatogenic disturbances. Results from whole-genome association studies suggest a marginal role for common variants as causative factors; however, some of these variants can be important for pharmacogenetic purposes. Results of studies on copy number variations (CNVs) demonstrate a considerably higher CNV load in infertile patients than in normozoospermic men, whereas whole-exome analysis has proved to be a highly successful diagnostic tool in familial cases of male infertility. Despite such efforts, the aetiology of infertility remains unknown in about 40% of patients, and the discovery of novel genetic factors in idiopathic infertility is a major challenge for the field of androgenetics. Large, international, and consortium-based whole-exome and whole-genome studies are the most promising approach for the discovery of the missing genetic aetiology of idiopathic male infertility.
Collapse
|
|
30
|
Yuan SM, Zhang YN, Du J, Li W, Tu CF, Meng LL, Lin G, Lu GX, Tan YQ. Phenotypic and molecular characteristics of androgen insensitivity syndrome patients. Asian J Androl 2019; 20:473-478. [PMID: 29785970 PMCID: PMC6116692 DOI: 10.4103/aja.aja_17_18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Androgen insensitivity syndrome (AIS), an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor (AR) gene, and is characterized by partial or complete inability of specific tissues to respond to androgens in individuals with the 46, XY karyotype. This study aimed to investigate AR gene mutations and to characterize genotype–phenotype correlations. Ten patients from unrelated families, aged 2–31 years, were recruited in the study. Based on karyotype, altered hormone profile, and clinical manifestations, nine patients were preliminarily diagnosed with complete AIS and one with partial AIS. Genetic analysis of AR gene revealed the existence of 10 different mutations, of which five were novel (c.2112 C>G[p.S704R], c.2290T>A[p.Y764N], c.2626C>T[p.Q876X], c.933dupC[p.K313Qfs*28], and c.1067delC[p.A356Efs*123]); the other five were previously reported (c.1789G>A[p.A597T], c.2566C>T[p.R856C], c.2668G>A[p.V890M], c.2679C>T[p.P893L], and c.1605C>G[p.Y535X]). Regarding the distribution of these mutations, 60.0% were clustered in the ligand-binding domain of AR gene. Exons 1 and 8 of AR gene each accounted for 30.0% (3/10) of all mutations. Most of the truncation mutations were in exon 1 and missense mutations were mainly located in exons 4–8. Our study expands the spectrum of AR gene mutations and confirms the usefulness of AR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening.
Collapse
Affiliation(s)
- Shi-Min Yuan
- Reproductive and Genetic Hospital of Citic-Xiangya, Changsha 410078, China
| | - Ya-Nan Zhang
- Maternal and Child Health Hospital of Hunan Province, Changsha 410078, China
| | - Juan Du
- Reproductive and Genetic Hospital of Citic-Xiangya, Changsha 410078, China.,Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha 410078, China
| | - Wen Li
- Reproductive and Genetic Hospital of Citic-Xiangya, Changsha 410078, China.,Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha 410078, China
| | - Chao-Feng Tu
- Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha 410078, China
| | - Lan-Lan Meng
- Reproductive and Genetic Hospital of Citic-Xiangya, Changsha 410078, China
| | - Ge Lin
- Reproductive and Genetic Hospital of Citic-Xiangya, Changsha 410078, China.,Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha 410078, China
| | - Guang-Xiu Lu
- Reproductive and Genetic Hospital of Citic-Xiangya, Changsha 410078, China.,Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha 410078, China
| | - Yue-Qiu Tan
- Reproductive and Genetic Hospital of Citic-Xiangya, Changsha 410078, China.,Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha 410078, China
| |
Collapse
|
|
31
|
Kosti K, Athanasiadis L, Goulis DG. Long-term consequences of androgen insensitivity syndrome. Maturitas 2019; 127:51-54. [PMID: 31351520 DOI: 10.1016/j.maturitas.2019.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 06/02/2019] [Accepted: 06/04/2019] [Indexed: 11/18/2022]
Abstract
Androgen insensitivity syndrome (AIS) is one of the most common sexual developmental disorders. According to the grade of the remaining androgen receptor (AR) function, AIS is classified as complete (CAIS), partial (PAIS) or mild (MAIS). In CAIS, the prevalence of germ cell tumours is increased compared with the general population. Although patients with CAIS used to undergo gonadectomy before puberty, nowadays a gonadectomy is recommended after spontaneous puberty, and up to 15% of patients retain their gonads. Nevertheless, the risk of germ cell tumour increases gradually after puberty. Annual follow-up with ultrasound or magnetic resonance imaging (MRI) is recommended. Unfortunately, these imaging methods are not sensitive enough for the diagnosis of an in situ germ cell tumour. In PAIS, the risk of germ cell tumour is higher than in CAIS; therefore, an early gonadectomy or an orchidopexy is indicated. Optimal hormone replacement therapy (HRT) is necessary for long-term health. The risks of osteopenia and of regimen osteoporosis are higher, ESPECIALLY in patients with early gonadectomy. Infertility is the rule in CAIS and PAIS. A few mutations do not affect fertility detrimentally, and these are responsible for MAIS. In PAIS leading to a predominantly male phenotype or ambiguous genitalia, multiple surgical procedures for gynaecomastia and/or hypospadias are required. Some small studies have found a higher risk of obesity, hyperlipidaemia and impaired insulin sensitivity. Psychological support is essential, as the prevalence of psychiatric disorders is increased. In conclusion, the diagnosis of AIS has long-term consequences for which shared decision-making (physicians, patients, parents) is appropriate.
Collapse
Affiliation(s)
- Konstantia Kosti
- Unit of Reproductive Endocrinology, 1(st) Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Greece.
| | - Loukas Athanasiadis
- Third Department of Psychiatry, Medical School, Aristotle University of Thessaloniki, Greece
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, 1(st) Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Greece
| |
Collapse
|
|
32
|
Lanciotti L, Cofini M, Leonardi A, Bertozzi M, Penta L, Esposito S. Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS). INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16071268. [PMID: 30970592 PMCID: PMC6480640 DOI: 10.3390/ijerph16071268] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/01/2019] [Accepted: 04/04/2019] [Indexed: 01/08/2023]
Abstract
Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive genetic disorder resulting from maternally inherited or de novo mutations involving the androgen receptor gene, situated in the Xq11-q12 region. The diagnosis is based on the presence of female external genitalia in a 46, XY human individual, with normally developed but undescended testes and complete unresponsiveness of target tissues to androgens. Subsequently, pelvic ultrasound or magnetic resonance imaging (MRI) could be helpful in confirming the absence of Mullerian structures, revealing the presence of a blind-ending vagina and identifying testes. CAIS management still represents a unique challenge throughout childhood and adolescence, particularly regarding timing of gonadectomy, type of hormonal therapy, and psychological concerns. Indeed this condition is associated with an increased risk of testicular germ cell tumour (TGCT), although TGCT results less frequently than in other disorders of sex development (DSD). Furthermore, the majority of detected tumoral lesions are non-invasive and with a low probability of progression into aggressive forms. Therefore, histological, epidemiological, and prognostic features of testicular cancer in CAIS allow postponing of the gonadectomy until after pubertal age in order to guarantee the initial spontaneous pubertal development and avoid the necessity of hormonal replacement therapy (HRT) induction. However, HRT is necessary after gonadectomy in order to prevent symptoms of hypoestrogenism and to maintain secondary sexual features. This article presents differential clinical presentations and management in patients with CAIS to emphasize the continued importance of standardizing the clinical and surgical approach to this disorder.
Collapse
Affiliation(s)
- Lucia Lanciotti
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy.
| | - Marta Cofini
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy.
| | - Alberto Leonardi
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy.
| | - Mirko Bertozzi
- Pediatric Surgery, Azienda Ospedaliera Santa Maria della Misericordia, 20122 Perugia, Italy.
| | - Laura Penta
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy.
| | - Susanna Esposito
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, 06132 Perugia, Italy.
| |
Collapse
|
|
33
|
Loch Batista R, Inácio M, Prado Arnhold IJ, Gomes NL, Diniz Faria JA, Rodrigues de Moraes D, Frade Costa EM, Domenice S, Bilharinho Mendonça B. Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development. J Clin Endocrinol Metab 2019; 104:1160-1170. [PMID: 30388241 DOI: 10.1210/jc.2018-01866] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/29/2018] [Indexed: 12/20/2022]
Abstract
CONTEXT In 46,XY disorders of sexual development (DSD) patients, several factors may affect psychosexual development, leading to gender identity discrepancy and gender change later in life. Prenatal sexual steroid exposure and external genital virilization are considered to influence human psychosexual development, but their roles not completely understood yet. DESIGN A total of 144 individuals (18 to 60 years of age) with a clinical/molecular diagnosis of 46,XY DSD from a single tertiary center were enrolled. Psychosexual outcomes (gender role, gender identity, and sexual orientation) were assessed using questionnaires and psychological test. The Sinnecker score was used for genital virilization measurement. Prenatal androgen exposure was estimated according to 46,XY DSD etiology. RESULTS We found a positive association between prenatal androgen exposure and male psychosexual outcomes. Alternatively, prenatal estrogen exposure, age of gonadectomy, and the degree of external genital virilization did not influence any psychosexual outcome. There were 19% (n = 27) with gender change, which was associated with prenatal androgen exposure (P < 0.001) but not with the external genital virilization. The median age of gender change was 15 years, but most of the patients reported the desire for gender change earlier. CONCLUSIONS Prenatal androgen exposure influenced psychosexual development in 46,XY DSD favoring male psychosexuality in all psychosexual outcomes, whereas the degree of external genital virilization did not influence these outcomes. The organizational effect of sexual steroids on psychosexuality at puberty appears to be weak in comparison with the prenatal effects. Prenatal androgen exposure also influenced female-to-male gender change frequency. All 46,XY DSD conditions with prenatal androgen exposure must be followed for gender issues in their management.
Collapse
Affiliation(s)
- Rafael Loch Batista
- Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Marlene Inácio
- Psychology Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Ivo Jorge Prado Arnhold
- Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Nathália Lisboa Gomes
- Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - José Antônio Diniz Faria
- Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Daniela Rodrigues de Moraes
- Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Elaine Maria Frade Costa
- Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Sorahia Domenice
- Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Berenice Bilharinho Mendonça
- Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| |
Collapse
|
|
34
|
Touzon MS, Garrido NP, Marino R, Ramirez P, Costanzo M, Guercio G, Berensztein E, Rivarola MA, Belgorosky A. Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort. J Clin Res Pediatr Endocrinol 2019; 11:24-33. [PMID: 30251955 PMCID: PMC6398199 DOI: 10.4274/jcrpe.galenos.2018.2018.0185] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
OBJECTIVE The aim of this study was the molecular characterization of the AR gene as the cause of 46,XY disorder in our population. METHODS We studied 41, non related, 46,XY disorder of sexual differentiation index cases, having characteristics consistent with androgen insensivity syndrome (AIS). Genomic DNA was isolated from peripheral blood leukocytes of all patients and 25 family members from 17 non-related families. RESULTS The AR gene analysis revealed an abnormal sequence in 58.5% of the index patients. All of the complete AIS (CAIS) cases were genetically confirmed, while in the partial form (PAIS) a mutation in AR was detected in only 13 (43.3%). Molecular studies revealed other affected or carrier relatives in 87% of the index cases. The AR mutations were found spread along the whole coding sequence, with a higher prevalence in the ligand binding domain. Nine out of 23 (39%) AR mutations were novel. In 17% of patients with detected AR mutations, somatic mosaicism was detected in leucocyte DNA. In our cohort, long-term follow up gender dysphoria, raised as male or female, was not found. Finally, in suspected PAIS, the identification of AR mutation occurred significantly less than in CAIS patients. CONCLUSION Improved knowledge of the components of the AR complex and signaling network might contribute to long term outcome and genetic counseling in AIS patients.
Collapse
Affiliation(s)
- Maria Sol Touzon
- Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina,National Scientific and Technical Research Council (CONICET), Endocrinology Service, Buenos Aires, Argentina
| | | | - Roxana Marino
- Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina
| | - Pablo Ramirez
- Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina
| | - Mariana Costanzo
- Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina
| | - Gabriela Guercio
- Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina,National Scientific and Technical Research Council (CONICET), Endocrinology Service, Buenos Aires, Argentina
| | | | - Marco A. Rivarola
- Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina,National Scientific and Technical Research Council (CONICET), Endocrinology Service, Buenos Aires, Argentina
| | - Alicia Belgorosky
- Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina,National Scientific and Technical Research Council (CONICET), Endocrinology Service, Buenos Aires, Argentina,* Address for Correspondence: Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina Phone: +541143080034 E-mail:
| |
Collapse
|
|
35
|
Vaidyanathan P, Kaplowitz P. Partial androgen insensitivity syndrome presenting as pubertal gynecomastia: clinical and hormonal findings and a novel mutation in the androgen receptor gene. Endocrinol Diabetes Metab Case Rep 2019; 2018:EDM180128. [PMID: 30601762 PMCID: PMC6311465 DOI: 10.1530/edm-18-0128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 12/05/2018] [Indexed: 11/08/2022] Open
Abstract
Pubertal gynecomastia is common, can be seen in 65% of the adolescent boys and is considered physiological. It is thought to be due to transient imbalance between the ratio of testosterone and estradiol in the early stages of puberty. It resolves in 1-2 years and requires no treatment. However, more persistent and severe pubertal gynecomastia is less common and can be associated with pathological disorders. These can be due to diminished androgen production, increased estrogen production or androgen resistance. We report a case of persistent pubertal gynecomastia due to partial androgen insensitivity syndrome (PAIS), classical hormone findings and a novel mutation in the androgen receptor (AR) gene. Learning points: Laboratory testing of follicle-stimulating hormone (FSH), leutinizing hormone (LH) and testosterone for pubertal gynecomastia is most helpful in the setting of undervirization. The hormonal finding of very high testosterone, elevated LH and estradiol and relatively normal FSH are classical findings of PAIS. Gynecomastia due to PAIS will not resolve and surgery for breast reduction should be recommended.
Collapse
Affiliation(s)
- Priya Vaidyanathan
- Division of Endocrinology, Children's National Health System, Washington, District of Columbia, USA
| | - Paul Kaplowitz
- Division of Endocrinology, Children's National Health System, Washington, District of Columbia, USA
| |
Collapse
|
|
36
|
Khanna K, Sharma S, Gupta DK. A Clinical Approach to Diagnosis of Ambiguous Genitalia. J Indian Assoc Pediatr Surg 2019; 24:162-169. [PMID: 31258263 PMCID: PMC6568146 DOI: 10.4103/jiaps.jiaps_70_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Disorders of sex development (DSD) are a sensitive and stressful condition for the family as well as the treating physician to deal with. The main issue in managing such cases is sex assignment. The decision is influenced by the cultural background, the sex of rearing, clinical features, the biochemical parameters including hormonal studies, the imaging reports, parental preference, fertility potential, and the assessment of mental make-up of the child when possible. In third world countries, there is diagnostic dilemma as most children with DSD present late and a detailed-lengthy work-up often delay their definitive treatment. In this article, the authors try to identify the important clinical features in children presenting with various types of DSD, which may aid in making a quick provisional clinical diagnosis and expediting the diagnostic work-up. The data have been gathered from 38 years of experience of the senior author while managing about 1200 cases of DSD in the pediatric intersex clinic at the tertiary care level institute.
Collapse
Affiliation(s)
- Kashish Khanna
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Shilpa Sharma
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Devendra K Gupta
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
37
|
Wang S, Xia P, Cacalano NA, Xu H, Li D. Complete androgen insensitivity syndrome caused by c.1769-1G > C mutation and activation of a cryptic splice acceptor site in the androgen receptor gene. Steroids 2018; 137:64-69. [PMID: 29859233 DOI: 10.1016/j.steroids.2018.05.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 05/28/2018] [Indexed: 12/21/2022]
Abstract
Androgen insensitivity syndrome (AIS) is the most common cause of 46,XY disorders of sex development (46,XY DSD). This syndrome is an X-linked recessive genetic disease characterized by resistance to the actions of androgens in an individual with a male karyotype and it is caused by mutations in the androgen receptor (AR) gene. We evaluated two siblings with primary amenorrhea, normal secondary sex characteristics, absence of uterus and ovaries, intra-abdominal testis, and elevated testosterone levels. Sequence analysis of the AR gene revealed a splice acceptor site mutation in intron 2 (c.1769-1G > C). The analysis of mRNA showed that this mutation resulted in the activation of a cryptic splice acceptor site located in intron 2 and in the synthesis of an aberrant mRNA transcript with 69 nucleotides insertion between exon 2 and exon 3, leading to an insertion of 23 amino acids in the AR protein instead of generating a premature termination codon. The additional 23 amino acids insertion affects AR intracellular trafficking by impairing its translocation from the cytoplasm to the nucleus after hormone stimulation. The c.1769-1G > C mutation provides new insights into the molecular mechanism involved in splicing defects and expands the spectrum of mutations associated with the androgen insensitivity syndrome.
Collapse
Affiliation(s)
- Song Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China
| | - Peng Xia
- Department of Spinal Surgery, Orthopedics Hospital, The Second Hospital of Jilin University, Changchun, Jilin 130041, PR China
| | - Nicholas A Cacalano
- Department of Radiation Oncology, University of California Los Angeles School of Medicine, Los Angeles, CA 90095, USA
| | - Haikun Xu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China.
| | - Dejun Li
- Center for Prenatal Diagnosis, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China.
| |
Collapse
|
|
38
|
Rousseaux MWC, Tschumperlin T, Lu HC, Lackey EP, Bondar VV, Wan YW, Tan Q, Adamski CJ, Friedrich J, Twaroski K, Chen W, Tolar J, Henzler C, Sharma A, Bajić A, Lin T, Duvick L, Liu Z, Sillitoe RV, Zoghbi HY, Orr HT. ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism. Neuron 2018; 97:1235-1243.e5. [PMID: 29526553 PMCID: PMC6422678 DOI: 10.1016/j.neuron.2018.02.013] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 12/18/2017] [Accepted: 02/15/2018] [Indexed: 12/30/2022]
Abstract
Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity.
Collapse
Affiliation(s)
- Maxime W C Rousseaux
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Tyler Tschumperlin
- Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Hsiang-Chih Lu
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Elizabeth P Lackey
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Vitaliy V Bondar
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ying-Wooi Wan
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Qiumin Tan
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Carolyn J Adamski
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jillian Friedrich
- Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Kirk Twaroski
- Department of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Weili Chen
- Department of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jakub Tolar
- Department of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Christine Henzler
- RISS Bioinformatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ajay Sharma
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Aleksandar Bajić
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Tao Lin
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lisa Duvick
- Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Zhandong Liu
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Roy V Sillitoe
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Huda Y Zoghbi
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA.
| | - Harry T Orr
- Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
| |
Collapse
|
|
39
|
Batista RL, Costa EMF, Rodrigues ADS, Gomes NL, Faria JA, Nishi MY, Arnhold IJP, Domenice S, Mendonca BBD. Androgen insensitivity syndrome: a review. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2018; 62:227-235. [PMID: 29768628 PMCID: PMC10118986 DOI: 10.20945/2359-3997000000031] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 01/18/2018] [Indexed: 11/23/2022]
Abstract
Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype - phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.
Collapse
Affiliation(s)
- Rafael Loch Batista
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Elaine M Frade Costa
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Andresa de Santi Rodrigues
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil.,Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Nathalia Lisboa Gomes
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - José Antonio Faria
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Mirian Y Nishi
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil.,Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Ivo Jorge Prado Arnhold
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Sorahia Domenice
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Berenice Bilharinho de Mendonca
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil.,Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| |
Collapse
|
|
40
|
Batista RL, Rodrigues ADS, Machado AZ, Nishi MY, Cunha FS, Silva RB, Costa EMF, Mendonca BB, Domenice S. Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor. J Pediatr Endocrinol Metab 2018; 31:223-228. [PMID: 29267169 DOI: 10.1515/jpem-2017-0095] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 11/01/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Androgen insensitivity syndrome (AIS) is the most frequent etiology of 46,XY disorders of sex development (DSDs), and it is an X-linked disorder caused by mutations in the androgen receptor (AR) gene. AIS patients present a broad phenotypic spectrum and individuals with a partial phenotype present with different degrees of undervirilized external genitalia. There are more than 500 different AR gene allelic variants reported to be linked to AIS, but the presence of somatic mosaicisms has been rarely identified. In the presence of a wild-type AR gene, a significant degree of spontaneous virilization at puberty can be observed, and it could influence the gender assignment, genetic counseling and the clinical and psychological management of these patients and the psychosexual outcomes of these patients are not known. CASE PRESENTATION In this study, we report two patients with AR allelic variants in heterozygous (c.382G>T and c.1769-1G>C) causing a partial AIS (PAIS) phenotype. The first patient was raised as female and she had undergone a gonadectomy at puberty. In both patients there was congruency between gender of rearing and gender identity and gender role. CONCLUSIONS Somatic mosaicism is rare in AIS and nonsense AR variant allelic can cause partial AIS phenotype in this situation. Despite the risk of virilization and prenatal androgen exposure, the gender identity and gender role was concordant with sex of rearing in both cases. A better testosterone response can be expected in male individuals and this should be considered in the clinical management.
Collapse
Affiliation(s)
- Rafael Loch Batista
- Laboratório de Hormônios e Genética Molecular (LIM/42), Unidade de Endocrinologia do Desenvolvimento, Disciplina de Endocrinologia e Metabologia do Hospital das Clınicas, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 155, 7 andar, São Paulo, SP CEP 05403-900, Brasil
| | - Andresa De Santi Rodrigues
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| | - Aline Zamboni Machado
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| | - Mirian Yumie Nishi
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| | - Flávia Siqueira Cunha
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| | - Rosana Barbosa Silva
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| | - Elaine M F Costa
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| | - Berenice B Mendonca
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| | - Sorahia Domenice
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| |
Collapse
|
|
41
|
Miranda BH, Charlesworth MR, Tobin DJ, Sharpe DT, Randall VA. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life. FASEB J 2018; 32:795-806. [PMID: 29046359 PMCID: PMC5928870 DOI: 10.1096/fj.201700260rr] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Male sex hormones-androgens-regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny vellus hairs with larger, darker terminal hairs ( e.g., beard). Follicle response is epigenetically varied: some remain unaffected ( e.g., eyelashes) or are inhibited, causing balding. How sex steroid hormones alter such developmental processes is unclear, despite high incidences of hormone-driven cancer, hirsutism, and alopecia. Unfortunately, existing development models are not androgen sensitive. Here, we use hair follicles to establish an androgen-responsive human organ culture model. We show that women's intermediate facial follicles respond to men's higher androgen levels by synthesizing more hair over several days, unlike donor-matched, androgen-insensitive, terminal follicles. We demonstrate that androgen receptors-androgen-activated gene transcription regulators-are required and are present in vivo within these follicles. This is the first human organ that involves multiple cell types that responds appropriately to hormones in prolonged culture, in a way which mirrors its natural behavior. Thus, intermediate hair follicles offer a hormone-switchable human model with exceptional, unique availability of genetically identical, but epigenetically hormone-insensitive, terminal follicles. This should enable advances in understanding sex steroid hormone signaling, gene regulation, and developmental and regenerative systems and facilitate better therapies for hormone-dependent disorders.-Miranda, B. H., Charlesworth, M. R., Tobin, D. J., Sharpe, D. T., Randall, V. A. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.
Collapse
Affiliation(s)
- Benjamin H Miranda
- Centre for Skin Sciences, University of Bradford, Bradford, United Kingdom.,Plastic Surgery and Burns Research Unit, University of Bradford, Bradford, United Kingdom
| | | | - Desmond J Tobin
- Centre for Skin Sciences, University of Bradford, Bradford, United Kingdom
| | - David T Sharpe
- Centre for Skin Sciences, University of Bradford, Bradford, United Kingdom.,Plastic Surgery and Burns Research Unit, University of Bradford, Bradford, United Kingdom
| | - Valerie A Randall
- Centre for Skin Sciences, University of Bradford, Bradford, United Kingdom
| |
Collapse
|
|
42
|
Abstract
Irregular menstrual cycles are a common complaint among adolescents. There are multiple etiologies for menstrual irregularities. It is important to have a stepwise approach, including obtaining a thorough medical history and performing a physical examination, when patients present. Understanding the characteristics of the menstrual cycle helps determine the etiology. This article discusses the differential diagnosis of irregular menstrual cycles, as well as the approach to evaluation and management. The common conditions and defining characteristics are also discussed. [Pediatr Ann. 2018;47(1):e23-e28.].
Collapse
|
|
43
|
Fertility outcome and information on fertility issues in individuals with different forms of disorders of sex development: findings from the dsd-LIFE study. Fertil Steril 2017; 108:822-831. [PMID: 28923284 DOI: 10.1016/j.fertnstert.2017.08.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 08/04/2017] [Accepted: 08/07/2017] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To investigate fertility outcome in individuals with different forms of disorders of sex development (DSD), if assisted reproductive technology (ART) was used, and the patients' satisfaction with the information they had received. DESIGN A cross-sectional multicenter study, dsd-LIFE. SETTING Not applicable. PATIENT(S) A total of 1,040 patients aged ≥16 years with different DSD diagnoses participated. INTERVENTION(S) A web-based questionnaire was filled out by all participants. The participants could chose to take part in somatic investigations including ultrasonography. MAIN OUTCOME MEASURE(S) Information on partner, number of children, ART, adoption and step-children, general health, presence of gonads and uterus, current education and economic situation, received information on fertility issues, and satisfaction with the information, was collected. RESULT(S) In the total cohort, mean age 32 years, 33% lived with a partner, but only 14% reported having at least one child including 7% with ART, 4% adopted. Only 3.5% of the total cohort had been able to reproduce without ART, most frequently women with congenital adrenal hyperplasia, and only 0.7% of participants with other diagnoses. Of the participants, 72% had received information on fertility, but 17% were not satisfied with the information. CONCLUSION(S) Fertility outcome is significantly reduced in all types of DSD; however, fertility potential should be assessed individually. The satisfaction with how fertility problems have been discussed can be improved. The care of patients with DSD is complex, should be individualized, and new treatment possibilities incorporated. A close collaboration in multidisciplinary teams is therefore essential to improve the situation for individuals with DSD.
Collapse
|
|
44
|
Kim JH, Lee H, Shin EA, Kim DH, Choi JB, Kim SH. Implications of Bcl-2 and its interplay with other molecules and signaling pathways in prostate cancer progression. Expert Opin Ther Targets 2017; 21:911-920. [PMID: 28816549 DOI: 10.1080/14728222.2017.1369044] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Among several genetic alterations involved in the progression of prostate cancer, B cell lymphoma gene number 2 (BCL-2) is an important target molecule in the progression of androgen-independent prostate cancer (AIPC) after androgen ablation or castration. Nevertheless, the molecular mechanism of BCL-2 in prostate cancer progression remains elusive and controversial. In the current review, we discuss the critical role of BCL-2 in the carcinogenesis of prostate cancer with experimental evidences on the BCL-2 molecular networks in AIPC and androgen-dependent prostate cancer (ADPC) and subsequently suggest perspective research targeting BCL-2. Areas covered: This review focused on the molecular implications of BCL-2 in association with other molecules and signaling pathways involved in the progression and carcinogenesis of prostate cancer. Expert opinion: BCL-2 plays a pivotal role in the progression of AIPC than in ADPC since androgen represses BCL-2. BCL-2 acts as a pro-survival molecule in association with androgen-related signaling in the progression of ADPC, while BCL-2 upregulation, PTEN loss, PI3K/AKT phosphorylation and receptor tyrosine kinase (RTK) activation are primarily involved in AIPC. To identify more effective prostate cancer therapy, further mechanistic studies are required with BCL-2 inhibitors in AIPC and ADPC, considering a multi-target therapy against BCL-2 and its related signaling.
Collapse
Affiliation(s)
- Ju-Ha Kim
- a Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine , Kyung Hee University , Seoul , South Korea
| | - Hyemin Lee
- a Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine , Kyung Hee University , Seoul , South Korea
| | - Eun Ah Shin
- a Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine , Kyung Hee University , Seoul , South Korea
| | - Dong Hee Kim
- b Department of East West Medical Science, Graduate School of East West Medical Science , Kyung Hee University , Yongin , South Korea
| | - Jhin Baek Choi
- b Department of East West Medical Science, Graduate School of East West Medical Science , Kyung Hee University , Yongin , South Korea
| | - Sung-Hoon Kim
- a Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine , Kyung Hee University , Seoul , South Korea
| |
Collapse
|
|
45
|
Pyle LC, Nathanson KL. A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2017; 175:304-314. [PMID: 28544305 DOI: 10.1002/ajmg.c.31562] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Revised: 04/12/2017] [Accepted: 04/13/2017] [Indexed: 01/16/2023]
Abstract
Differences of Sex Development (DSD) includes a wide spectrum of etiologies and phenotypes. A subset of individuals with DSDs are predisposed to gonadal germ cell tumor (GCT). In this setting, GCT risk varies widely, depending on the DSD molecular etiology and penetrance. Prognostication based on molecular diagnosis remains challenging, as natural history data specific to recently identified molecular causes of DSD is lacking. In this review, we provide a framework for the clinical geneticist to consider GCT tumor risk in the patient with DSD. We discuss germ cell development and etiology of GCT growth, along with parameters to consider when recommending prophylactic gonadectomy including fertility, hormonal output, and malignant GTC treatment outcomes. Shortly after the 2006 reorganization of DSD nomenclature, literature reviews of natural history publications stratified GCT risk by a chromosomal, pathological, and hormonal taxonomy. Our 2017 literature review reveals a larger body of publications. However, the broad DSD GCT risk stratification within the 2006 taxonomy remains stable. We discuss precise GCT risk assessment for specific diagnoses, including androgen insensitivity, Smith-Lemli-Opitz, and 46,XY with MAP3K1 mutations and gonadal dysgenesis, as examples. We also examine the GCT risk in non-DSD syndromes, in addition to the cancer risks in DSD patients with dimorphic gonads and genitalia. This review is intended to provide a nuanced assessment of relative germ cell tumor risk in the DSD patient, including modern precise molecular diagnosis, for use by the clinical geneticist.
Collapse
Affiliation(s)
- Louise C Pyle
- Translational Medicine/Human Genetics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Katherine L Nathanson
- Translational Medicine/Human Genetics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| |
Collapse
|
|
46
|
Savic I, Frisen L, Manzouri A, Nordenstrom A, Lindén Hirschberg A. Role of testosterone and Y chromosome genes for the masculinization of the human brain. Hum Brain Mapp 2017; 38:1801-1814. [PMID: 28070912 DOI: 10.1002/hbm.23483] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 10/18/2016] [Accepted: 11/21/2016] [Indexed: 01/18/2023] Open
Abstract
Women with complete androgen insensitivity syndrome (CAIS) have a male (46,XY) karyotype but no functional androgen receptors. Their condition, therefore, offers a unique model for studying testosterone effects on cerebral sex dimorphism. We present MRI data from 16 women with CAIS and 32 male (46,XY) and 32 female (46,XX) controls. METHODS FreeSurfer software was employed to measure cortical thickness and subcortical structural volumes. Axonal connections, indexed by fractional anisotropy, (FA) were measured with diffusion tensor imaging, and functional connectivity with resting state fMRI. RESULTS Compared to men, CAIS women displayed a "female" pattern by having thicker parietal and occipital cortices, lower FA values in the right corticospinal, superior and inferior longitudinal tracts, and corpus callosum. Their functional connectivity from the amygdala to the medial prefrontal cortex, was stronger and amygdala-connections to the motor cortex weaker than in control men. CAIS and control women also showed stronger posterior cingulate and precuneus connections in the default mode network. Thickness of the motor cortex, the caudate volume, and the FA in the callosal body followed, however, a "male" pattern. CONCLUSION Altogether, these data suggest that testosterone modulates the microstructure of somatosensory and visual cortices and their axonal connections to the frontal cortex. Testosterone also influenced functional connections from the amygdala, whereas the motor cortex could, in agreement with our previous reports, be moderated by processes linked to X-chromosome gene dosage. These data raise the question about other genetic factors masculinizing the human brain than the SRY gene and testosterone. Hum Brain Mapp 38:1801-1814, 2017. © 2017 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Ivanka Savic
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SE-113 30, Sweden.,Department of Neurology, Stockholm, SE-113 30, Sweden
| | - Louise Frisen
- Dept of Clinical Neuroscience, Stockholm, SE-113 30, Sweden.,Child and Adolescent Psychiatry Research Center, Stockholm, SE-113 30, Sweden
| | - Amirhossein Manzouri
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SE-113 30, Sweden
| | - Anna Nordenstrom
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SE-113 30, Sweden
| | - Angelica Lindén Hirschberg
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SE-113 30, Sweden.,Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
47
|
Ittiwut C, Pratuangdejkul J, Supornsilchai V, Muensri S, Hiranras Y, Sahakitrungruang T, Watcharasindhu S, Suphapeetiporn K, Shotelersuk V. Novel mutations of the SRD5A2 and AR genes in Thai patients with 46, XY disorders of sex development. J Pediatr Endocrinol Metab 2017; 30:19-26. [PMID: 27849622 DOI: 10.1515/jpem-2016-0048] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 09/05/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND Abnormalities of dihydrotestosterone conversion [5α-reductase deficiency: online Mendelian inheritance in man (OMIM) 607306] or actions of androgens [partial androgen insensitivity syndrome (PAIS): OMIM 312300] during the 8th-12th weeks of gestation cause varying degrees of undervirilized external genitalia in 46, XY disorders of sex development (DSD) with increased testosterone production. The objective of the study was to determine clinical and genetic characteristics of Thai patients with 46, XY DSD. METHODS A cross-sectional study was conducted in 46, XY DSD with increased testosterone production (n=43) evaluated by a human chorionic gonadotropin (hCG) stimulation test or clinical features consistent with 5α-reductase deficiency or PAIS. PCR sequencing of the entire coding regions of the SRD5A2 and AR genes was performed. Molecular modeling analysis of the androgen receptor-ligand-binding domain (AR-LBD) of a novel mutation was constructed. RESULTS Mutations were found in seven patients (16.3%): five (11.6%) and two (4.7%) patients had mutations in SRD5A2 and AR, respectively. Two novel mutations, SRD5A2 c.383A>G (p.Y128C) and AR c.2176C>T (p.R726C), were identified. Dimensional structural analysis of the novel mutated AR (p.R726C) revealed that it affected the co-activator binding [binding function-3 (BF-3)], not the testosterone binding site. Short phallus length was associated with 5α-reductase deficiency. CONCLUSIONS Around 16.3% of our patients with 46, XY DSD had 5α-reductase deficiency or PAIS. Two novel mutations of SRD5A2 and AR were identified. The novel mutated AR (p.R726C) might affect the co-activator binding (BF-3), not the testosterone binding site.
Collapse
MESH Headings
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics
- Amino Acid Sequence
- Androgens/metabolism
- Biomarkers/metabolism
- Child
- Child, Preschool
- Cross-Sectional Studies
- Dihydrotestosterone/metabolism
- Disorder of Sex Development, 46,XY/genetics
- Disorder of Sex Development, 46,XY/metabolism
- Disorder of Sex Development, 46,XY/pathology
- Female
- Follow-Up Studies
- Humans
- Infant
- Male
- Membrane Proteins/genetics
- Mutation/genetics
- Prognosis
- Protein Conformation
- Receptors, Androgen/chemistry
- Receptors, Androgen/genetics
- Sequence Homology, Amino Acid
- Testosterone/metabolism
- Thailand
Collapse
|
|
48
|
Mouriquand PDE, Gorduza DB, Gay CL, Meyer-Bahlburg HFL, Baker L, Baskin LS, Bouvattier C, Braga LH, Caldamone AC, Duranteau L, El Ghoneimi A, Hensle TW, Hoebeke P, Kaefer M, Kalfa N, Kolon TF, Manzoni G, Mure PY, Nordenskjöld A, Pippi Salle JL, Poppas DP, Ransley PG, Rink RC, Rodrigo R, Sann L, Schober J, Sibai H, Wisniewski A, Wolffenbuttel KP, Lee P. Surgery in disorders of sex development (DSD) with a gender issue: If (why), when, and how? J Pediatr Urol 2016; 12:139-49. [PMID: 27132944 DOI: 10.1016/j.jpurol.2016.04.001] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 03/25/2016] [Accepted: 04/04/2016] [Indexed: 01/25/2023]
Abstract
Ten years after the consensus meeting on disorders of sex development (DSD), genital surgery continues to raise questions and criticisms concerning its indications, its technical aspects, timing and evaluation. This standpoint details each distinct situation and its possible management in 5 main groups of DSD patients with atypical genitalia: the 46,XX DSD group (congenital adrenal hyperplasia); the heterogeneous 46,XY DSD group (gonadal dysgenesis, disorders of steroidogenesis, target tissues impairments …); gonosomic mosaicisms (45,X/46,XY patients); ovo-testicular DSD; and "non-hormonal/non chromosomal" DSD. Questions are summarized for each DSD group with the support of literature and the feed-back of several world experts. Given the complexity and heterogeneity of presentation there is no consensus regarding the indications, the timing, the procedure nor the evaluation of outcome of DSD surgery. There are, however, some issues on which most experts would agree: 1) The need for identifying centres of expertise with a multidisciplinary approach; 2) A conservative management of the gonads in complete androgen insensitivity syndrome at least until puberty although some studies expressed concerns about the heightened tumour risk in this group; 3) To avoid vaginal dilatation in children after surgical reconstruction; 4) To keep asymptomatic mullerian remnants during childhood; 5) To remove confirmed streak gonads when Y material is present; 6) It is likely that 46,XY cloacal exstrophy, aphallia and severe micropenis would do best raised as male although this is based on limited outcome data. There is general acknowledgement among experts that timing, the choice of the individual and irreversibility of surgical procedures are sources of concerns. There is, however, little evidence provided regarding the impact of non-treated DSD during childhood for the individual development, the parents, society and the risk of stigmatization. The low level of evidence should lead to design collaborative prospective studies involving all parties and using consensual protocols of evaluation.
Collapse
Affiliation(s)
- Pierre D E Mouriquand
- Department of Paediatric Urology/Paediatric Surgery, Université Claude-Bernard, Hospices Civils de Lyon, Lyon, France; Centre National de Référence Maladies Rares sur les Anomalies Congénitales du Développement Génito-Sexuel, Lyon, France.
| | - Daniela Brindusa Gorduza
- Department of Paediatric Urology/Paediatric Surgery, Université Claude-Bernard, Hospices Civils de Lyon, Lyon, France; Centre National de Référence Maladies Rares sur les Anomalies Congénitales du Développement Génito-Sexuel, Lyon, France
| | - Claire-Lise Gay
- Department of Paediatric Urology/Paediatric Surgery, Université Claude-Bernard, Hospices Civils de Lyon, Lyon, France; Centre National de Référence Maladies Rares sur les Anomalies Congénitales du Développement Génito-Sexuel, Lyon, France
| | - Heino F L Meyer-Bahlburg
- NYS Psychiatric Institute, New York, NY, USA; College of Physicians & Surgeons of Columbia University, New York City, NY, USA
| | - Linda Baker
- Children's Medical Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Laurence S Baskin
- Pediatric Urology, UCSF Benioff Children's Hospital, San Francisco, CA, USA
| | - Claire Bouvattier
- Service d'Endocrinologie de l'enfant, GHU Paris-Sud, Hôpital de Bicêtre, Paris, France; Centre National de Référence Maladies Rares sur les Anomalies Congénitales du Développement Génito-Sexuel, Paris, France
| | - Luis H Braga
- Division of Urology, Department of Surgery, McMaster University, Toronto, Canada
| | - Anthony C Caldamone
- Pediatric Urology, Hasbro Children's Hospital, Providence, RI, USA; Surgery (Urology) and Pediatrics, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - Lise Duranteau
- Centre National de Référence Maladies Rares sur les Anomalies Congénitales du Développement Génito-Sexuel, Paris, France; Adolescent Gynaecology, Hôpitaux Universitaires Paris Sud (Bicêtre), Paris, France
| | - Alaa El Ghoneimi
- Pediatric Surgery and Urology, University Hospital Robert Debré, APHP, University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Terry W Hensle
- College of Physicians & Surgeons of Columbia University, New York City, NY, USA
| | - Piet Hoebeke
- Urology, Ghent University Hospital, Gent, Belgium
| | - Martin Kaefer
- Riley Children's Hospital, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nicolas Kalfa
- Service de Chirurgie Viscérale et Urologique Pédiatrique, Hôpital Lapeyronie, CHU de Montpellier, Université de Montpellier, France
| | - Thomas F Kolon
- Pediatric Urology, Children's Hospital of Philadelphia, PA, USA; Perelman School of Medicine at University of Pennsylvania, PA, USA
| | - Gianantonio Manzoni
- Pediatric Urology, Fondazione IRCCS CaGranda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Pierre-Yves Mure
- Department of Paediatric Urology/Paediatric Surgery, Université Claude-Bernard, Hospices Civils de Lyon, Lyon, France; Centre National de Référence Maladies Rares sur les Anomalies Congénitales du Développement Génito-Sexuel, Lyon, France
| | - Agneta Nordenskjöld
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - J L Pippi Salle
- Department of Surgery, Sidra Medical and Research Center, Doha, Qatar
| | - Dix Phillip Poppas
- Komansky Center for Children's Health, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
| | - Philip G Ransley
- Great Ormond Street Hospital, Institute of Child Health, London, UK
| | - Richard C Rink
- Service de Chirurgie Viscérale et Urologique Pédiatrique, Hôpital Lapeyronie, CHU de Montpellier, Université de Montpellier, France
| | - Romao Rodrigo
- Department of Surgery, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Urology, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada
| | - Léon Sann
- Conseil d'éthique pédiatrique, Centre Hospitalo-Universitaire de Lyon, France
| | | | - Hisham Sibai
- Paediatric Surgery, University of Casablanca, Morocco
| | | | - Katja P Wolffenbuttel
- Department of Urology and Pediatric Urology, Erasmus MC Sophia Children's Hospital, Rotterdam
| | - Peter Lee
- Penn State Hershey Pediatric Endocrinology, PA, USA
| |
Collapse
|
|
49
|
Mota BC, Oliveira LMB, Lago R, Brito P, Canguçú-Campinho AK, Barroso U, Toralles MBP. Clinical profile of 93 cases of 46, XY disorders of sexual development in a referral center. Int Braz J Urol 2016; 41:975-81. [PMID: 26689524 PMCID: PMC4756975 DOI: 10.1590/s1677-5538.ibju.2014.0544] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 12/15/2014] [Indexed: 12/04/2022] Open
Abstract
The term DSD refers to disorders that affect the normal process of sexual development causing disagreement between chromosomal, gonadal and phenotypic sex, and this study aimed to describe the clinical profile of a group with DSD 46, XY joined on DSD Clinic of Hospital of Salvador, Bahia Clinics. It was a retrospective study of medical records of survey data of 93 patients with DSD 46, XY. Among the patients studied 50.5% had no defined etiology and 20.4% had androgen insensitivity syndrome (AIS), 63.4% had been initially recorded in males, 31 (33.3%) in females, being that in two it was necessary to reassignment. All patients with complete AIS pure gonadal dysgenesis and had female genitalia. Others have been diagnosed with genital ambiguity or severe hypospadias and cryptorchidism. The gonads were palpable at the first consultation in 75.3% of patients. It is important to establish an active surveillance program for these patients. The first assessment took place before the age of ten in more than 50% of cases, which shows that much needs to be done for medical education and community about the DSD. Because the phenotypic variability of sexual development disorders was noted that the clinical profile of patients studied ranged between different etiologies, including hindering the diagnostic conclusion of these individuals.
Collapse
Affiliation(s)
- Bianca Costa Mota
- Universidade Federal da Bahia - Hospital Universitário Professor Edgard Santos, Laboratório de Pesquisa em Infectologia (LAPI), Salvador, BA, Brasil
| | | | - Renata Lago
- Departamento de Pediatria, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - Paula Brito
- Universidade Federal da Bahia, Salvador, BA, Brasil
| | - Ana Karina Canguçú-Campinho
- Universidade Federal da Bahia - Hospital Universitário Professor Edgard Santos, Laboratório de Pesquisa em Infectologia (LAPI), Salvador, BA, Brasil
| | - Ubirajara Barroso
- Departamento de Urologia, Universidade Federal da Bahia, Salvador, BA, Brasil
| | | |
Collapse
|
|
50
|
Abstract
Our understanding of disorders of sexual differentiation (DSD) has evolved from aberrations of human genital development to a broad group of complex disorders of etiological and functional significance. The unique challenge of DSD conditions is that they create a cause for significant angst and concern for both parents and physician, as they frequently lead to questions with regards to gender assignment, surgically corrective options, long-term outlook regarding gender identity, and reproductive potential. To further add to the burden, many patients who present with genital abnormalities do not have a clear explanation as to the underlying basis of their disorder. This review looks at DSD from a pediatric urology point of view with emphasis on evaluation, diagnosis, and algorithm for work-up. We also discuss novel genetic analysis techniques and their value in diagnosis. Overall, this is an all-encompassing review on a diagnostic approach to DSD, with inclusion of recent developments and controversies, which will benefit urologists and other physicians alike.
Collapse
|