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Special Issue "Molecular Aspects of Sex Development in Mammals: New Insight"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 January 2020.

Special Issue Editors

Dr. Silvano Bertelloni
E-Mail Website
Guest Editor
Adolescent Medicine, Pediatric Division, Department of Obstetrics, Gynecology and Pediatrics, Azienda Ospedaliero-Universitaria Pisana, I-56126 Pisa, Italy
Tel. +39-050-992.743; Fax: +39-50-992.641
Interests: pediatric and adolescent andrology; pediatric and adolescent gynecology; puberty, precocious puberty; delayed puberty; Klinefelter syndrome; Kallman syndrome; gonadal dysgenesis; disorders of sex development; androgen insensitivity syndrome; bone health; Turner syndrome; HOX deficiency; androgen hormones
Dr. Laura Audì
E-Mail
Guest Editor
Growth and Development Research Unit, Vall d’Hebron Research Institute (VHIR), Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Interests: Genetics of rare endocrine diseases
Prof. Dr. Christa Flück
E-Mail
Guest Editor
Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Interests: Steroid hormone defects, DSD

Special Issue Information

Dear Colleagues,

The mechanisms producing males and females via sexuate reproduction have fascinated humans since ancient times, but only since the last century and especially through immense efforts in genetics-related knowledge of the molecular mechanisms governing sex development and dimorphism in humans and in other mammals have they been elucidated. It is now clear that early events during embryogenesis controlled by master sex-determining genes (GSD) trigger both male and female sex-specific pathways. New genetic and analytical methods permitted the discovery of these male and female sex pathways and allowed one to understand the molecular basis of disorders (or differences) of sex development (DSD). This Special Issue aims to provide an update of current knowledge in the field of DSD by review articles and original research papers. Manuscripts on the molecular mechanisms of sex development, on their phenotypic expression and pathogenetic background, as well as on new techniques to explore DSD in clinical practice are welcome.

Dr. Silvano Bertelloni
Dr. Laura Audì
Prof. Dr. Christa Flück
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (4 papers)

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Review

Open AccessReview
Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology
Int. J. Mol. Sci. 2019, 20(20), 5017; https://doi.org/10.3390/ijms20205017 - 10 Oct 2019
Abstract
The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY [...] Read more.
The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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Open AccessReview
46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features
Int. J. Mol. Sci. 2019, 20(18), 4605; https://doi.org/10.3390/ijms20184605 - 17 Sep 2019
Abstract
The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for [...] Read more.
The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46,XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11-hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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Graphical abstract

Open AccessReview
The Insulin/IGF System in Mammalian Sexual Development and Reproduction
Int. J. Mol. Sci. 2019, 20(18), 4440; https://doi.org/10.3390/ijms20184440 - 09 Sep 2019
Abstract
Persistent research over the past few decades has clearly established that the insulin-like family of growth factors, which is composed of insulin and insulin-like growth factors 1 (IGF1) and 2 (IGF2), plays essential roles in sexual development and reproduction of both males and [...] Read more.
Persistent research over the past few decades has clearly established that the insulin-like family of growth factors, which is composed of insulin and insulin-like growth factors 1 (IGF1) and 2 (IGF2), plays essential roles in sexual development and reproduction of both males and females. Within the male and female reproductive organs, ligands of the family act in an autocrine/paracrine manner, in order to guide different aspects of gonadogenesis, sex determination, sex-specific development or reproductive performance. Although our knowledge has greatly improved over the last years, there are still several facets that remain to be deciphered. In this review, we first briefly outline the principles of sexual development and insulin/IGF signaling, and then present our current knowledge, both in rodents and humans, about the involvement of insulin/IGFs in sexual development and reproductive functions. We conclude by highlighting some interesting remarks and delineating certain unanswered questions that need to be addressed in future studies. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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Open AccessReview
The Role of International Databases in Understanding the Aetiology and Consequences of Differences/Disorders of Sex Development
Int. J. Mol. Sci. 2019, 20(18), 4405; https://doi.org/10.3390/ijms20184405 - 07 Sep 2019
Abstract
The International Disorders of Sex Development (I-DSD) and International Congenital Adrenal Hyperplasia registry (I-CAH) Registries were originally developed over 10 years ago and have since supported several strands of research and led to approximately 20 peer-reviewed publications. In addition to acting as an [...] Read more.
The International Disorders of Sex Development (I-DSD) and International Congenital Adrenal Hyperplasia registry (I-CAH) Registries were originally developed over 10 years ago and have since supported several strands of research and led to approximately 20 peer-reviewed publications. In addition to acting as an indispensable tool for monitoring clinical and patient-centered outcomes for improving clinical practice, the registries can support a wide nature of primary and secondary research and can also act as a platform for pharmacovigilance, given their ability to collect real world patient data within a secure, ethics approved virtual research environment. The challenge for the future is to ensure that the research community continues to use the registries to improve our understanding of Disorders of Sex Development (DSD). Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Predicting gonadal cancer in people with disorders of sex development; omics-based approaches
Yolande van Bever, Leendert Looijenga
The risk of development of a gonadal germ cell cancer (GGCC) is increased in selective subgroups of patients with Disorders of Sex Development (DSD). This is related to the presence of a part of the Y chromosome, i.e., the GBY region, as well as the anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present, being at risk when blocked in an embryonic stage of development. The cancer originates from either Germ Cell Neoplasia In situ (in a testicular environment) or Gonadoblastoma (in an ovarian-like environment). These precursors are characterized by the presence of the pluripotency markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY and  cKIT and its ligand KITLG. One of the aims is to stratify patients with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies (GWAS), and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with mRNA and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of the modern omics approaches in the context of predicting the risk of GGCC in individual patients. 

NR5A1/SF variants: clinical phenotypes
by S. Bertelloni et al.

Molecular pathways of mammalian ovarian differentiation
by A. Biason-Lauber

Pluripotent cell models for DSD research
by A. Biason-Lauber

Molecular characterization of XX maleness
by R. Rey

46,xx DSD in monogenic disorders of steroidogenesis: genetics, biochemistry and clinical features
by A. Balsamo

Newer forms of DSD – PORD and AKR1C2/4
by C. Flück

Genetic work-up of DSD 2019
by A. Bashamboo

Digenic/Oligogenic inheritance in DSD
by C. Flück, and L. Audí

Brain sex differentiation: genes or hormones?
by M. Maggi

The insulin-like growth factor family and its role in mediating the development and function of testes and ovaries
by S. Nef

The role of international databases in understanding the aetiology & consequences of DSD
by F. Ahmed

The clinical role of sex steroid analysis in diagnosis and monitoring
by N. Krone

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