This document provides an overview of current concepts in disorders of sexual development (DSD). It discusses the physiology of sex development and factors involved in testicular and ovarian differentiation. It describes the proposed classification system for DSDs put forth by consensus groups, which categorizes DSDs into three main groups: sex chromosome DSDs, 46,XY DSDs, and 46,XX DSDs. The document also discusses changes in nomenclature for DSDs from previous terms like "intersex" to the current umbrella term of DSD.
Reproductive Genetics: Introduction to Genetic Testing Optionskanew396
GenomeSmart can help you navigate the different reproductive genetic testing options to allow you to make informed decisions for the health of yourself and your family.
This document provides an overview of genetic disorders and infectious diseases. It discusses several types of genetic disorders including autosomal dominant disorders like Huntington's disease, autosomal recessive disorders like Niemann-Pick disease, X-linked dominant disorders like Incontinentia pigmenti, X-linked recessive disorders like color blindness, and Y-linkage disorders like male infertility. For infectious diseases, it describes miliary tuberculosis caused by Mycobacterium tuberculosis and feline leukemia virus (FeLV) in cats. Diagnosis of these conditions involves tests such as genetic testing, imaging, semen analysis, and blood tests to detect viral proteins for conditions like FeLV. Treatment depends on the specific condition but may include medications, gene
1) Medical genetics is the study of the inheritance of disease. Genetic disorders are caused by abnormal genes or chromosomes which are passed down from generation to generation.
2) Chromosomal disorders occur when there is a gain or loss of whole chromosomes or segments of chromosomes. While individually rare, genetic disorders collectively make a significant contribution to childhood morbidity and mortality.
3) Chromosomal abnormalities are a major cause of miscarriages and stillbirths, with the risk being highest earlier in gestation. Survivors of chromosomal disorders often have malformations, intellectual disabilities, or other health issues.
This document discusses different types of genetic tests. It provides examples of molecular tests like testing the DMD gene for muscular dystrophy and KRAS gene testing for colon cancer. Cytogenetic tests like karyotyping and arrayCGH are explained. Biochemical tests like newborn screening for phenylketonuria are also summarized. The uses and implications of genetic testing for various clinical purposes are covered.
Preimplantation genetic diagnosis (PGD) is a technique that tests embryos created through in vitro fertilization for genetic abnormalities before implantation. This allows only unaffected embryos to be implanted, preventing the transmission of serious genetic disorders. PGD was originally developed as an alternative to prenatal testing and termination for couples at high risk of passing on genetic conditions. It has provided insights into early human development but also raises ethical issues regarding assisted reproduction.
This document summarizes preimplantation genetic diagnosis (PGD), which screens embryos for genetic disorders prior to embryo transfer during in vitro fertilization (IVF). PGD can detect single-gene disorders, chromosomal abnormalities, and HLA types. It allows transferring only unaffected embryos, avoiding termination of affected pregnancies. PGD is requested for couples at high risk of passing genetic disorders to offspring or to select euploid embryos to improve IVF success rates. The document outlines the PGD process and discusses its use for various genetic conditions like recessive, dominant, sex-linked, and chromosomal disorders. While PGD aims to prevent disease transmission, some argue its use for selecting traits could enable eugenics.
Identification of a Novel Mutation (p.G328W) in the NR5A1 Gene in a Boy with ...CrimsonPublishersGJEM
This document summarizes a case report of a 46,XY newborn with ambiguous genitalia presenting with a novel mutation in the NR5A1 gene. The key points are:
- The newborn presented with micropenis, hypospadias, and bilateral inguinal gonads. Hormone testing showed a normal testosterone response to hCG.
- Genetic testing identified a novel heterozygous p.G328W mutation in the NR5A1 gene, which had not been previously reported. This mutation occurred de novo.
- The mutation affects a highly conserved residue in the ligand binding domain of SF1. While adrenal function was normal, the mutation is believed
Reproductive Genetics: Introduction to Genetic Testing Optionskanew396
GenomeSmart can help you navigate the different reproductive genetic testing options to allow you to make informed decisions for the health of yourself and your family.
This document provides an overview of genetic disorders and infectious diseases. It discusses several types of genetic disorders including autosomal dominant disorders like Huntington's disease, autosomal recessive disorders like Niemann-Pick disease, X-linked dominant disorders like Incontinentia pigmenti, X-linked recessive disorders like color blindness, and Y-linkage disorders like male infertility. For infectious diseases, it describes miliary tuberculosis caused by Mycobacterium tuberculosis and feline leukemia virus (FeLV) in cats. Diagnosis of these conditions involves tests such as genetic testing, imaging, semen analysis, and blood tests to detect viral proteins for conditions like FeLV. Treatment depends on the specific condition but may include medications, gene
1) Medical genetics is the study of the inheritance of disease. Genetic disorders are caused by abnormal genes or chromosomes which are passed down from generation to generation.
2) Chromosomal disorders occur when there is a gain or loss of whole chromosomes or segments of chromosomes. While individually rare, genetic disorders collectively make a significant contribution to childhood morbidity and mortality.
3) Chromosomal abnormalities are a major cause of miscarriages and stillbirths, with the risk being highest earlier in gestation. Survivors of chromosomal disorders often have malformations, intellectual disabilities, or other health issues.
This document discusses different types of genetic tests. It provides examples of molecular tests like testing the DMD gene for muscular dystrophy and KRAS gene testing for colon cancer. Cytogenetic tests like karyotyping and arrayCGH are explained. Biochemical tests like newborn screening for phenylketonuria are also summarized. The uses and implications of genetic testing for various clinical purposes are covered.
Preimplantation genetic diagnosis (PGD) is a technique that tests embryos created through in vitro fertilization for genetic abnormalities before implantation. This allows only unaffected embryos to be implanted, preventing the transmission of serious genetic disorders. PGD was originally developed as an alternative to prenatal testing and termination for couples at high risk of passing on genetic conditions. It has provided insights into early human development but also raises ethical issues regarding assisted reproduction.
This document summarizes preimplantation genetic diagnosis (PGD), which screens embryos for genetic disorders prior to embryo transfer during in vitro fertilization (IVF). PGD can detect single-gene disorders, chromosomal abnormalities, and HLA types. It allows transferring only unaffected embryos, avoiding termination of affected pregnancies. PGD is requested for couples at high risk of passing genetic disorders to offspring or to select euploid embryos to improve IVF success rates. The document outlines the PGD process and discusses its use for various genetic conditions like recessive, dominant, sex-linked, and chromosomal disorders. While PGD aims to prevent disease transmission, some argue its use for selecting traits could enable eugenics.
Identification of a Novel Mutation (p.G328W) in the NR5A1 Gene in a Boy with ...CrimsonPublishersGJEM
This document summarizes a case report of a 46,XY newborn with ambiguous genitalia presenting with a novel mutation in the NR5A1 gene. The key points are:
- The newborn presented with micropenis, hypospadias, and bilateral inguinal gonads. Hormone testing showed a normal testosterone response to hCG.
- Genetic testing identified a novel heterozygous p.G328W mutation in the NR5A1 gene, which had not been previously reported. This mutation occurred de novo.
- The mutation affects a highly conserved residue in the ligand binding domain of SF1. While adrenal function was normal, the mutation is believed
Clinical genetics is one of the most rapidly advancing fields in medicine. Spectacular progress has been achieved in this century with unravelling of the entire draft sequence of the human genome. A major contribution of these advances has been in diagnosis, management and prenatal diagnosis of genetic disorders as treatment in most cases is difficult or impossible and where available beyond the means of most families. Genetic technology is advancing rapidly, bringing new, safer and more sensitive ways to diagnose genetic conditions pre- and postnatally. These advances will bring about profound changes in the way we deliver obstetric services to women and their families. Diagnosing a genetic disorder not only allows for disease-specific management options but also has implications for the affected individual's entire family. Hence, a working understanding of the underlying concepts of genetic disease is important for all practicing clinicians. Although it is impossible to know all aspects of clinical and molecular genetics, basic knowledge of certain topics is a must for all practicing obstetrician/gynecologists.
Genetic screening and gene therapy can detect and treat genetic disorders. Genetic screening techniques like carrier screening, newborn screening, and prenatal diagnosis identify genetic risks. Gene therapy aims to treat diseases by replacing faulty genes, such as inserting functional genes into somatic cells. While promising, gene therapy faces challenges like safety concerns over viral vectors and ensuring proper expression of inserted genes. Genetic counseling educates patients on genetic risks and testing options.
Bases of human genetic. Method of studying of human heredityEneutron
The document discusses various methods used to study human genetics including genealogical, twins, dermatoglyphic, cytogenetic, biochemical, and molecular biology methods. It provides details on genealogical pedigrees, characteristics of autosomal dominant and recessive and X-linked inheritance patterns, twin studies to distinguish genetic from environmental influences, dermatoglyphic analysis of skin ridge patterns, cytogenetic analysis of chromosomes, and examples of sex-linked traits.
This document discusses the radiologist's role in evaluating ambiguous genitalia. It begins with an overview of reproductive system development and sexual differentiation. It then classifies disorders of sex development (DSDs) and discusses various types of male pseudohermaphroditism. It outlines the multidisciplinary workup and emphasizes the role of ultrasound, MRI, and fluoroscopy in evaluation. It notes imaging findings for different internal reproductive structures and DSDs. It concludes by discussing risks of neoplasms associated with different DSDs.
Genetics- Principles & Disoreders in Paediatric DentistryDrSusmita Shah
The document discusses genetics principles and disorders relevant to pediatric dentistry. It begins with an overview of the history of genetics including discoveries by Mendel, Watson, Crick and others. It then covers basic genetics terminology, DNA structure, karyotyping, chromosomal abnormalities, inheritance patterns, genetic disorders and genetic counseling. Specific topics discussed in more depth include trisomies, Klinefelter syndrome, chromosomal deletions, duplications and other structural abnormalities. The document provides foundational information on genetics and inheritance patterns important for pediatric dentistry.
Intersex and Microscopic Identification of SexSoreingam Ragui
This document discusses intersex conditions and methods for microscopic identification of sex. It defines intersex as the intermingling of sexual characteristics of both sexes in an individual. The main types of intersex conditions are described, including gonadal agenesis, gonadal dysgenesis, true hermaphroditism, and pseudohermaphroditism. Methods for microscopic sex identification discussed include examination of Barr bodies, Davidson bodies, karyotyping, and demonstration of the Y-chromosome with staining techniques. Determining sex is important for individual identification, and microscopic examination provides accurate sex identification where external genitalia may be ambiguous in intersex cases.
Androgen Insensitivity Syndrome (AIS) is a genetic condition where people have male chromosomes and male gonads but experience partial or complete feminization of the external genitals. It is caused by mutations in the androgen receptor gene that results in cells not responding properly to androgens like testosterone. People with AIS show a spectrum of physical traits from fully female to ambiguous external genitalia depending on the severity of the mutation. Testing and treatment involves genetic testing, surgery, and hormone replacement therapy, while psychological support is also important.
Dr. Laxmi Shrikhande is a leading fertility expert in India. She has held numerous leadership positions in national obstetrics and gynecology societies. Some of her accomplishments include receiving awards for women's health, publishing over 30 papers nationally and internationally, and conducting health programs that have reached over 25,000 women and girls. She is the Medical Director of Shrikhande Fertility Clinic in Nagpur, India.
This document provides an overview of genetics and health. It discusses the history of genetics from Darwin and Mendel's early work establishing genetics as a field to modern advances like the structure of DNA being discovered and the human genome project. It also summarizes different types of genetic disorders like monogenic, chromosomal, and polygenic disorders and their inheritance patterns. The document discusses the large disease burden from genetic disorders globally and in India. It introduces concepts like gene-environment interaction and the difference between genetics and genomics. Finally, it summarizes results from the human genome project like the number of genes identified.
General overview of patterns of transmission of single gene traitsPaul Adepoju
I delivered this presentation to fellow postgraduate students. It's on the various traits, normal and pathological, that are transmitted by single genes.
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is an open access international journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Chromosomal Abnormalities in a Male Partner Who was a Candidate for Assisted ...Apollo Hospitals
A 30-year-old man presented with 5 years of infertility. Cytogenetic analysis revealed a chromosomal translocation between chromosomes 1 and 21 in the male [46, XY t (1; 21) (q32; q22)], which was likely the cause of his infertility. The female partner showed a normal karyotype. Chromosomal abnormalities are a known cause of male infertility and genetic testing is recommended for infertile men prior to assisted reproduction techniques to identify abnormalities. The couple was counseled on their options which included assisted reproduction followed by preimplantation genetic diagnosis.
This document provides an overview of genetics and its application to nursing. It begins with basic concepts such as DNA, genes, chromosomes, and inheritance patterns. It then discusses genetic disorders including chromosomal and mendelian diseases. The document outlines advances in molecular genetics including DNA technology, gene therapy, and genome projects. It notes the importance of prevention, early diagnosis, treatment and rehabilitation for genetic disorders. Finally, it mentions the practical application of genetics knowledge in nursing.
1. Intersexuality, or intersex, refers to individuals born with reproductive or sexual anatomy that does not fit typical definitions of male or female.
2. It can involve discordance between chromosomal, gonadal, internal genital, and phenotypic sex.
3. Causes include congenital adrenal hyperplasia, androgen exposure during fetal development, and disorders of sexual development.
The document summarizes a genetics course taught by Dr. Ahmed Elshebiny. The course covers basic principles of medical genetics including the structure of DNA and chromosomes. It examines the genetic basis of various diseases and inheritance patterns. The course also explores applications of genetics in clinical practice such as genetic testing and gene therapy.
Genetic screening uses techniques like karyotyping, amniocentesis, and preimplantation genetic diagnosis to detect abnormalities or predict diseases. Karyotyping examines chromosomes for changes in number or structure. Amniocentesis analyzes amniotic fluid to detect fetal abnormalities, while chorionic villus sampling analyzes placental tissue. Preimplantation genetic diagnosis screens embryos before implantation. Genetic screening can prevent birth of babies with diseases but also raises issues like determining which genes to screen and the economic and social impact of results.
Detection of genetic diseases can be done through various techniques such as karyotyping, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR). Karyotyping involves analyzing chromosomes to detect abnormalities. RFLP detects variations in DNA fragments after digestion with restriction enzymes. PCR can amplify small amounts of DNA and is used for genetic testing and disease detection. Newer techniques like single strand conformation polymorphism (SSCA) and enzyme-linked immunosorbent assay (ELISA) are also used for genetic testing and disease detection.
This document discusses genetics and genetic disorders. It begins by defining genetics as the study of genes, genetic variation, and heredity. It then provides information on several genetic disorders including Huntington's disease, Down syndrome, cystic fibrosis, and Barth syndrome. For Huntington's disease specifically, it details the signs and symptoms, diagnosis through genetic testing, management through various treatments, and differential diagnosis compared to other conditions. It also provides details on the causes and diagnosis of Down syndrome.
E-Mail [email protected]Clinical Genetic Aspects of Consangu.docxsagarlesley
E-Mail [email protected]
Clinical Genetic Aspects of Consanguinity
Hum Hered 2014;77:108–117
DOI: 10.1159/000360763
Consanguinity and Disorders of
Sex Development
Anu Bashamboo Ken McElreavey
Human Developmental Genetics, Institut Pasteur, Paris , France
Introduction
Disorders of sex development (DSD) are defined as
‘congenital conditions in which the development of chro-
mosomal, gonadal, or anatomical sex is atypical’ [1] . DSD
has recently been coined to encompass terms such as in-
tersex, pseudohermaphroditism, hermaphroditism and
sex-reversal, which can be confusing to clinicians, pa-
tients and parents. The definition provides a rational ba-
sis for designating each phenotype. 46,XY DSD includes
errors of testis determination or undermasculinization of
an XY male due to errors in either androgen synthesis or
androgen action. 46,XY gonadal dysgenesis is an error of
testis determination that is either complete (complete go-
nadal dysgenesis; CGD) or partial (partial gonadal dys-
genesis; PGD). 46,XY CGD is characterized by complete-
ly female external genitalia, well-developed Müllerian
structures and a gonad composed of a streak of fibrous
tissue. On the other hand, 46,XY PGD is characterized by
partial testis formation, usually a mixture of Wolffian and
Müllerian ducts and varying degrees of masculinization
of the external genitalia. 46,XX DSD includes overviril-
ization or masculinization of an XX individual due to an-
drogen excess, and the vast majority of cases of 46,XX
DSD are associated with congenital adrenal hyperplasia
(CAH) [2] . The much rarer 46,XX testicular DSD refers
to a male with testes and a normal male habitus, whereas
46,XX ovotesticular DSD refers to individuals that have
Key Words
Consanguinity · Disorders of sex development
Abstract
Disorders of sex development (DSD) are defined as ‘congen-
ital conditions in which the development of chromosomal,
gonadal, or anatomical sex is atypical’ [Lee et al., Pediatrics
2006; 118:e488–e500]. Studies conducted in Western coun-
tries, with low rates of consanguinity, show that truly am-
biguous genitalia have an estimated incidence of 1: 5,000
births. There are indications that the prevalence of DSD is
higher in endogamous communities. The incidence of am-
biguous genitalia in Saudi Arabia has been estimated at
1: 2,500 live births; whilst in Egypt, it has been estimated at
1: 3,000 live births. This may be due in part to an increase in
disorders of androgen synthesis associated with 46,XX DSD.
There is clearly a need for further studies to address the fre-
quency of DSD in communities with high levels of consan-
guinity. This will be challenging, as an accurate diagnosis is
difficult and expensive even in specialized centres. In devel-
oping countries with high levels of consanguinity, these lim-
itations can be compounded by cultural, social and religious
factors. Overall there is an indication that consan ...
The document discusses the stages of human development from fertilization through birth. It describes how a zygote is formed through the joining of an egg and sperm, and the early embryonic development of major organs over the first 8 weeks. The fetal stage from 8 weeks until birth is a period of rapid growth and differentiation, with the fetus increasing 20 times in length and developing functioning organs. The document also notes some potential problems in pregnancy like infertility, miscarriage, abortion, and threats to development from environmental factors and a mother's health behaviors during pregnancy.
Clinical genetics is one of the most rapidly advancing fields in medicine. Spectacular progress has been achieved in this century with unravelling of the entire draft sequence of the human genome. A major contribution of these advances has been in diagnosis, management and prenatal diagnosis of genetic disorders as treatment in most cases is difficult or impossible and where available beyond the means of most families. Genetic technology is advancing rapidly, bringing new, safer and more sensitive ways to diagnose genetic conditions pre- and postnatally. These advances will bring about profound changes in the way we deliver obstetric services to women and their families. Diagnosing a genetic disorder not only allows for disease-specific management options but also has implications for the affected individual's entire family. Hence, a working understanding of the underlying concepts of genetic disease is important for all practicing clinicians. Although it is impossible to know all aspects of clinical and molecular genetics, basic knowledge of certain topics is a must for all practicing obstetrician/gynecologists.
Genetic screening and gene therapy can detect and treat genetic disorders. Genetic screening techniques like carrier screening, newborn screening, and prenatal diagnosis identify genetic risks. Gene therapy aims to treat diseases by replacing faulty genes, such as inserting functional genes into somatic cells. While promising, gene therapy faces challenges like safety concerns over viral vectors and ensuring proper expression of inserted genes. Genetic counseling educates patients on genetic risks and testing options.
Bases of human genetic. Method of studying of human heredityEneutron
The document discusses various methods used to study human genetics including genealogical, twins, dermatoglyphic, cytogenetic, biochemical, and molecular biology methods. It provides details on genealogical pedigrees, characteristics of autosomal dominant and recessive and X-linked inheritance patterns, twin studies to distinguish genetic from environmental influences, dermatoglyphic analysis of skin ridge patterns, cytogenetic analysis of chromosomes, and examples of sex-linked traits.
This document discusses the radiologist's role in evaluating ambiguous genitalia. It begins with an overview of reproductive system development and sexual differentiation. It then classifies disorders of sex development (DSDs) and discusses various types of male pseudohermaphroditism. It outlines the multidisciplinary workup and emphasizes the role of ultrasound, MRI, and fluoroscopy in evaluation. It notes imaging findings for different internal reproductive structures and DSDs. It concludes by discussing risks of neoplasms associated with different DSDs.
Genetics- Principles & Disoreders in Paediatric DentistryDrSusmita Shah
The document discusses genetics principles and disorders relevant to pediatric dentistry. It begins with an overview of the history of genetics including discoveries by Mendel, Watson, Crick and others. It then covers basic genetics terminology, DNA structure, karyotyping, chromosomal abnormalities, inheritance patterns, genetic disorders and genetic counseling. Specific topics discussed in more depth include trisomies, Klinefelter syndrome, chromosomal deletions, duplications and other structural abnormalities. The document provides foundational information on genetics and inheritance patterns important for pediatric dentistry.
Intersex and Microscopic Identification of SexSoreingam Ragui
This document discusses intersex conditions and methods for microscopic identification of sex. It defines intersex as the intermingling of sexual characteristics of both sexes in an individual. The main types of intersex conditions are described, including gonadal agenesis, gonadal dysgenesis, true hermaphroditism, and pseudohermaphroditism. Methods for microscopic sex identification discussed include examination of Barr bodies, Davidson bodies, karyotyping, and demonstration of the Y-chromosome with staining techniques. Determining sex is important for individual identification, and microscopic examination provides accurate sex identification where external genitalia may be ambiguous in intersex cases.
Androgen Insensitivity Syndrome (AIS) is a genetic condition where people have male chromosomes and male gonads but experience partial or complete feminization of the external genitals. It is caused by mutations in the androgen receptor gene that results in cells not responding properly to androgens like testosterone. People with AIS show a spectrum of physical traits from fully female to ambiguous external genitalia depending on the severity of the mutation. Testing and treatment involves genetic testing, surgery, and hormone replacement therapy, while psychological support is also important.
Dr. Laxmi Shrikhande is a leading fertility expert in India. She has held numerous leadership positions in national obstetrics and gynecology societies. Some of her accomplishments include receiving awards for women's health, publishing over 30 papers nationally and internationally, and conducting health programs that have reached over 25,000 women and girls. She is the Medical Director of Shrikhande Fertility Clinic in Nagpur, India.
This document provides an overview of genetics and health. It discusses the history of genetics from Darwin and Mendel's early work establishing genetics as a field to modern advances like the structure of DNA being discovered and the human genome project. It also summarizes different types of genetic disorders like monogenic, chromosomal, and polygenic disorders and their inheritance patterns. The document discusses the large disease burden from genetic disorders globally and in India. It introduces concepts like gene-environment interaction and the difference between genetics and genomics. Finally, it summarizes results from the human genome project like the number of genes identified.
General overview of patterns of transmission of single gene traitsPaul Adepoju
I delivered this presentation to fellow postgraduate students. It's on the various traits, normal and pathological, that are transmitted by single genes.
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is an open access international journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Chromosomal Abnormalities in a Male Partner Who was a Candidate for Assisted ...Apollo Hospitals
A 30-year-old man presented with 5 years of infertility. Cytogenetic analysis revealed a chromosomal translocation between chromosomes 1 and 21 in the male [46, XY t (1; 21) (q32; q22)], which was likely the cause of his infertility. The female partner showed a normal karyotype. Chromosomal abnormalities are a known cause of male infertility and genetic testing is recommended for infertile men prior to assisted reproduction techniques to identify abnormalities. The couple was counseled on their options which included assisted reproduction followed by preimplantation genetic diagnosis.
This document provides an overview of genetics and its application to nursing. It begins with basic concepts such as DNA, genes, chromosomes, and inheritance patterns. It then discusses genetic disorders including chromosomal and mendelian diseases. The document outlines advances in molecular genetics including DNA technology, gene therapy, and genome projects. It notes the importance of prevention, early diagnosis, treatment and rehabilitation for genetic disorders. Finally, it mentions the practical application of genetics knowledge in nursing.
1. Intersexuality, or intersex, refers to individuals born with reproductive or sexual anatomy that does not fit typical definitions of male or female.
2. It can involve discordance between chromosomal, gonadal, internal genital, and phenotypic sex.
3. Causes include congenital adrenal hyperplasia, androgen exposure during fetal development, and disorders of sexual development.
The document summarizes a genetics course taught by Dr. Ahmed Elshebiny. The course covers basic principles of medical genetics including the structure of DNA and chromosomes. It examines the genetic basis of various diseases and inheritance patterns. The course also explores applications of genetics in clinical practice such as genetic testing and gene therapy.
Genetic screening uses techniques like karyotyping, amniocentesis, and preimplantation genetic diagnosis to detect abnormalities or predict diseases. Karyotyping examines chromosomes for changes in number or structure. Amniocentesis analyzes amniotic fluid to detect fetal abnormalities, while chorionic villus sampling analyzes placental tissue. Preimplantation genetic diagnosis screens embryos before implantation. Genetic screening can prevent birth of babies with diseases but also raises issues like determining which genes to screen and the economic and social impact of results.
Detection of genetic diseases can be done through various techniques such as karyotyping, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR). Karyotyping involves analyzing chromosomes to detect abnormalities. RFLP detects variations in DNA fragments after digestion with restriction enzymes. PCR can amplify small amounts of DNA and is used for genetic testing and disease detection. Newer techniques like single strand conformation polymorphism (SSCA) and enzyme-linked immunosorbent assay (ELISA) are also used for genetic testing and disease detection.
This document discusses genetics and genetic disorders. It begins by defining genetics as the study of genes, genetic variation, and heredity. It then provides information on several genetic disorders including Huntington's disease, Down syndrome, cystic fibrosis, and Barth syndrome. For Huntington's disease specifically, it details the signs and symptoms, diagnosis through genetic testing, management through various treatments, and differential diagnosis compared to other conditions. It also provides details on the causes and diagnosis of Down syndrome.
E-Mail [email protected]Clinical Genetic Aspects of Consangu.docxsagarlesley
E-Mail [email protected]
Clinical Genetic Aspects of Consanguinity
Hum Hered 2014;77:108–117
DOI: 10.1159/000360763
Consanguinity and Disorders of
Sex Development
Anu Bashamboo Ken McElreavey
Human Developmental Genetics, Institut Pasteur, Paris , France
Introduction
Disorders of sex development (DSD) are defined as
‘congenital conditions in which the development of chro-
mosomal, gonadal, or anatomical sex is atypical’ [1] . DSD
has recently been coined to encompass terms such as in-
tersex, pseudohermaphroditism, hermaphroditism and
sex-reversal, which can be confusing to clinicians, pa-
tients and parents. The definition provides a rational ba-
sis for designating each phenotype. 46,XY DSD includes
errors of testis determination or undermasculinization of
an XY male due to errors in either androgen synthesis or
androgen action. 46,XY gonadal dysgenesis is an error of
testis determination that is either complete (complete go-
nadal dysgenesis; CGD) or partial (partial gonadal dys-
genesis; PGD). 46,XY CGD is characterized by complete-
ly female external genitalia, well-developed Müllerian
structures and a gonad composed of a streak of fibrous
tissue. On the other hand, 46,XY PGD is characterized by
partial testis formation, usually a mixture of Wolffian and
Müllerian ducts and varying degrees of masculinization
of the external genitalia. 46,XX DSD includes overviril-
ization or masculinization of an XX individual due to an-
drogen excess, and the vast majority of cases of 46,XX
DSD are associated with congenital adrenal hyperplasia
(CAH) [2] . The much rarer 46,XX testicular DSD refers
to a male with testes and a normal male habitus, whereas
46,XX ovotesticular DSD refers to individuals that have
Key Words
Consanguinity · Disorders of sex development
Abstract
Disorders of sex development (DSD) are defined as ‘congen-
ital conditions in which the development of chromosomal,
gonadal, or anatomical sex is atypical’ [Lee et al., Pediatrics
2006; 118:e488–e500]. Studies conducted in Western coun-
tries, with low rates of consanguinity, show that truly am-
biguous genitalia have an estimated incidence of 1: 5,000
births. There are indications that the prevalence of DSD is
higher in endogamous communities. The incidence of am-
biguous genitalia in Saudi Arabia has been estimated at
1: 2,500 live births; whilst in Egypt, it has been estimated at
1: 3,000 live births. This may be due in part to an increase in
disorders of androgen synthesis associated with 46,XX DSD.
There is clearly a need for further studies to address the fre-
quency of DSD in communities with high levels of consan-
guinity. This will be challenging, as an accurate diagnosis is
difficult and expensive even in specialized centres. In devel-
oping countries with high levels of consanguinity, these lim-
itations can be compounded by cultural, social and religious
factors. Overall there is an indication that consan ...
The document discusses the stages of human development from fertilization through birth. It describes how a zygote is formed through the joining of an egg and sperm, and the early embryonic development of major organs over the first 8 weeks. The fetal stage from 8 weeks until birth is a period of rapid growth and differentiation, with the fetus increasing 20 times in length and developing functioning organs. The document also notes some potential problems in pregnancy like infertility, miscarriage, abortion, and threats to development from environmental factors and a mother's health behaviors during pregnancy.
This document provides an overview of genetics and its influence on orthodontics. It discusses the molecular basis of inheritance, different modes of inheritance like autosomal dominant and recessive traits. It explores population genetics and methods to study the role of genes like twin studies. It examines genetic mutations and homeobox genes that influence craniofacial development. It analyzes disorders in tooth morphogenesis and the genetic influence on traits like malocclusion, tooth number and position. It discusses practical implications for orthodontics treatment of genetically influenced malocclusions.
Sex reversal refers to the process by which an organism undergoes a change
in its sexual phenotype. Typically involving the transformation of primary
and/orsecondary sexual characteristics from one sex to another. This can
occur through genetic, hormonal, or environmental influences, leading to
the development of reproductive organs and features that are atypical
for the organism's genetic sex
1. The study examines the gene and protein expression of HDAC3 and GDF11 in endometriosis.
2. Results show that HDAC3 is upregulated in endometriotic tissues and cell lines compared to normal endometrium. HDAC3 expression is also differentially regulated by steroid hormones in endometrial cells.
3. GDF11 is downregulated in endometriosis lesions and its protein expression is negatively correlated with HDAC3 protein expression in tissue samples. This suggests HDACs may regulate GDF11 expression in endometriosis.
This paper discusses epigenetic studies using twins to further understand genetic influences on diseases and traits. Identical twins provide a unique opportunity to study epigenetics since they share the same DNA sequence but can differ in phenotypes. The paper reviews studies on Huntington's disease, spinocerebellar ataxia, and Alzheimer's that found epigenetic differences between identical twins affected these diseases. Epigenetic modifications like DNA methylation and histone modifications can influence disease expression. Epigenetic twin studies are also being applied to sociological research areas like criminology.
This document discusses medical genetics and the study of hereditary diseases. It covers several key topics:
1) The importance of heredity in disease etiology and pathogenesis. Hereditary factors play a role in clinical symptoms and treatment outcomes.
2) Classification of genetic disorders such as single gene, multifactorial, chromosomal, and mitochondrial disorders.
3) Methods used in medical genetics including genealogical analysis, karyotyping, biochemical analysis, and DNA/RNA analysis to study inheritance patterns and identify genetic variations.
Prenatal Diagnosis of Denys-Drash Syndromenavasreni
Denys-Drash syndrome consists of the triad of progressive nephropathy characterised by diffuse
mesangial sclerosis (DMS), genital abnormalities, and Wilms tumour. Nephropathy may range
from early onset proteinuria to nephrotic syndrome to end stage renal failure. Genital malformations affects both external and internal genitalia. It may range from penoscrotal hypospadias,
bilateral cryptorchidism to an enlarged clitoris with fused labia and a urogenital sinus to atrophic
uterus to streak ovaries or dysgenetic testes. The risk of developing Wilms’ tumor may be as high
as 50%.
Denys-Drash syndrome consists of the triad of progressive nephropathy characterised by diffuse mesangial sclerosis (DMS), genital abnormalities, and Wilms tumour. Nephropathy may range from early onset proteinuria to nephrotic syndrome to end stage renal failure. Genital malformations affects both external and internal genitalia...
Prenatal Diagnosis of Denys-Drash Syndromepateldrona
This document presents a case study of prenatal diagnosis of Denys-Drash Syndrome. Antenatal ultrasound found oligohydramnios, failure of fetal growth, and suspected ambiguous genitalia. Chromosomal microarray analysis identified a 20 kilobase pair microdeletion in the WT1 gene on chromosome 11p13, which is associated with Denys-Drash Syndrome. This syndrome consists of nephropathy, genital abnormalities, and risk of Wilms' tumor. The deletion affected exonic and intronic regions of the WT1 gene. Postnatal outcomes of Denys-Drash Syndrome can include genital malformations and early-onset nephropathy evolving into end-stage renal failure.
Prenatal Diagnosis of Denys-Drash Syndromeeshaasini
Denys-Drash syndrome consists of the triad of progressive nephropathy characterised by diffuse
mesangial sclerosis (DMS), genital abnormalities, and Wilms tumour. Nephropathy may range
from early onset proteinuria to nephrotic syndrome to end stage renal failure. Genital malformations affects both external and internal genitalia. It may range from penoscrotal hypospadias,
bilateral cryptorchidism to an enlarged clitoris with fused labia and a urogenital sinus to atrophic
uterus to streak ovaries or dysgenetic testes. The risk of developing Wilms’ tumor may be as high
as 50%.
Prenatal Diagnosis of Denys-Drash Syndromegeorgemarini
Denys-Drash syndrome consists of the triad of progressive nephropathy characterised by diffuse mesangial sclerosis (DMS), genital abnormalities, and Wilms tumour. Nephropathy may range from early onset proteinuria to nephrotic syndrome to end stage renal failure. Genital malformations affects both external and internal genitalia...
Prenatal Diagnosis of Denys-Drash Syndromekomalicarol
Denys-Drash syndrome consists of the triad of progressive nephropathy characterised by diffuse
mesangial sclerosis (DMS), genital abnormalities, and Wilms tumour. Nephropathy may range
from early onset proteinuria to nephrotic syndrome to end stage renal failure. Genital malformations affects both external and internal genitalia. It may range from penoscrotal hypospadias,
bilateral cryptorchidism to an enlarged clitoris with fused labia and a urogenital sinus to atrophic
uterus to streak ovaries or dysgenetic testes. The risk of developing Wilms’ tumor may be as high
as 50%.
Prenatal Diagnosis of Denys-Drash SyndromeSarkarRenon
Denys-Drash syndrome consists of the triad of progressive nephropathy characterised by diffuse mesangial sclerosis (DMS), genital abnormalities, and Wilms tumour. Nephropathy may range from early onset proteinuria to nephrotic syndrome to end stage renal failure.
Prenatal Diagnosis of Denys-Drash SyndromeAnonIshanvi
Denys-Drash syndrome consists of the triad of progressive nephropathy characterised by diffuse mesangial sclerosis (DMS), genital abnormalities, and Wilms tumour. Nephropathy may range from early onset proteinuria to nephrotic syndrome to end stage renal failure. Genital malformations affects both external and internal genitalia...
This chapter discusses child development from a genetic and prenatal perspective. It covers topics like fertilization and the stages of prenatal development, the role of genes and chromosomes in heredity, genetic disorders, the interaction between nature and nurture, and threats to healthy prenatal development like maternal diet and environmental factors. The chapter aims to explain how genetics and the prenatal environment work together to influence human growth and characteristics.
The document summarizes key concepts from a chapter on child development, genetics, and the prenatal environment. It discusses how genetics and the environment interact to influence human traits and characteristics. It covers topics like fertilization, fetal development, inherited disorders, genetic testing, and threats to healthy prenatal development like a mother's diet and age.
This document discusses disorders of sex development (DSD), formerly known as intersex conditions. It defines DSD and outlines its various types including 46,XX virilized female, 46,XY undervirilized male, gonadal differentiation disorders, and sex chromosome DSD. It discusses the embryology, incidence, evaluation, and management of DSD. Evaluation involves history, examination, imaging, genetics, endocrinology, and sometimes surgery. Treatment aims to match gender assignment with chromosomal and gonadal sex when possible while preserving fertility and future function. A multidisciplinary team approach is important for management of DSD.
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
• Equipping health professionals to address questions, concerns and health misinformation
• Assessing risk and mitigating harm from adverse health narratives in communities, health workforce and health system
Our backs are like superheroes, holding us up and helping us move around. But sometimes, even superheroes can get hurt. That’s where slip discs come in.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Clinic ^%[+27633867063*Abortion Pills For Sale In Tembisa Central19various
Clinic ^%[+27633867063*Abortion Pills For Sale In Tembisa Central Clinic ^%[+27633867063*Abortion Pills For Sale In Tembisa CentralClinic ^%[+27633867063*Abortion Pills For Sale In Tembisa CentralClinic ^%[+27633867063*Abortion Pills For Sale In Tembisa CentralClinic ^%[+27633867063*Abortion Pills For Sale In Tembisa Central
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
2. Öçal Gönül
Disorders of Sexual Development
gonads, kidneys and adrenal cortex. SF1 located on The second step in male sex differentiation is a more
chromosome 9p33, is important for the biosynthesis of straightforward process. The production of anti-Müllerian
adrenal and gonadal steroids and for the development of hormone (AMH) by Sertoli cells and androgens by
the ventral nucleus of the hypothalamus. SF1 is expressed Leydig cells in a critical concentration-dependent and
in the bipotential gonad of both sexes. Expression of SF1 time-dependent manner induces male sexual differentiation
continues in the developing testis, but is repressed in the by means of a hormone–dependent process. AMH acts on
ovary. The WT1 gene is located on chromosome 11p13 its receptor in the Müllerian ducts to cause their regression.
and encodes a transcription factor necessary for the Testosterone (T) acts on the androgen receptor (AR) in the
development of the bipotential gonad and the kidneys. Wolffian ducts to induce the formation of epidydimis,
Wilms tumor suppressor gene activates transcription of deferent ducts and seminal vesicles. The Leydig cells also
SRY (15,16). The important event in gonadal differentiation produce insulin-like factor 3 (INSL3, relaxin-like factor),
is the commitment of the bipotential gonad to become which causes the testes to descend to the scrotum. T is
either an ovary or a testis. The essential genes affecting further reduced to dihydrotestosterone (DHT), which acts
this process are as follows: WT1, SF1,CBX2, SOX9, on the androgen receptor of the prostate and external
fibroblast growth factor 9 (FGF9), prostaglandin D2 (PGD2), genitalia to cause its masculinization. Binding of T or DHT to
DAX1, WNT4, forkhead family transcription factor 2 AR is necessary for androgen effect. Various coregulators
(FOXL2), R-Spondin 1 (RSPO1) and β-catenin. While SOX9, interact probably for transcriptional activity of AR. By
FGF9 and PGD2 have more testis-promoting activity, DAX1, contrast, coregulators such as corepressors repress
WNT4, FOXL2, RSPO1 and β-catenin are predominantly transcriptions (22,23).
ovary-promoting genes (12). SOX9/FGF9 and WNT4/RSPO1 Female Differentiation: The factors involved in ovarian
act as antagonistic signals in early gonadal differentiation. differentiation are given in Figure 2 (24,25,26,27). In the
Male Differentiation: The factors involved in testicular absence of SRY, the support cell precursors differentiate as
differentiation are given in Figure 1 (14,15,16,17,18,19,20,21). granulosa cells, thus initiating the ovarian pathway. DAX1 is
Male phenotypic development can be viewed as a two-step necessary for both testicular and ovarian development, with
process: 1) testis formation from the primitive gonad a need for precise gene expression dosage. Overexpression in
(sexual determination) and 2) internal and external genitalia
DMRT1
WT1
ATRX
DHH
SF1
differentiation by action of hormones secreted by the fetal CBX2
testis (sexual differentiation) (10). PGD2
The first step involves the interplay of several transcription
SOX9
FGF9
SRY
factors and signaling cells (14,15,16,17,18,19,20,21). The LHX9, LIM1, WT1, SF1,
PAX2, EMX2 GATA4/FOG2, WNT4
DAX1 gene region on Xp21 is necessary for gonadal
(+)
development in both sexes. A single copy of the DAX1 is MAP3K1
essential for normal testicular cord formation. However, UROGENITAL RIDGE BIPOTENTIAL Testis
DAX1 overexpression in an XY fetus impairs testis GONAD
differentiation. Testis determination occurs at about the
sixth week of gestation. SRY gene that is located on the β-CATEN‹N
Y-chromosome (Yp11.3) initiates sex determination by WNT4/RSPO1
downstream regulation of sex-determining factors.
Expression of several genes including WT1,CBX2(M33),
Figure 1. Factors involved in testes differentation
SF1, GATA4/FOG2 is critical to SRY activation. The SRY
gene encodes a unique transcription factor that activates a
F9
testis-forming pathway (12,18,19). After expression of SRY,
FG
WT1, SF1, LHX9, LIM1,PAX2, GATA4,
SOX9
SOX9 (SRY-related HMG box gene) expression is EMX2, WNT4 Double
upregulated in the developing testis (20). The SOX9 gene, DAX1
located on 7q24.3-25.1, is essential for early testis UROGENITAL BIPOTENTIAL
Ovary
development. SOX9 up-regulates PGD2 and FGF9 genes. RIDGE GONAD
(+)
FGF9 and PGD2 maintain SOX9 expression, forming a FOXL2
(+)
β--CATEN‹N
positive feed-forward loop in XY gonads (21). The balance
(+)
between FGF9 and WNT4/RSPO1/β-catenin signals is
WNT4/RSPO1
shifted in favor of FGF9, establishing the male pathway. On
the other hand, DMRT1, ATRX and DHH and several
Figure 2. Factors involved in ovarian differentation
autosomal genes are also involved in testes determination (12).
106
3. Öçal Gönül
Disorders of Sexual Development
either DAX1 or WNT4/RSPO1 antagonizes testis formation. and conditions associated with prenatal virilization of 46,XX
WNT4/RSPO1/β-catenin pathway blocks FGF9 and promotes subjects. The nomenclature used to describe atypical
the ovarian fate (24). In XX gonads, WNT4 dominates and sexual differentiation has since changed (2,3,4,5). Instead of
results in an induction of β-catenin and silencing of FGF9 and using the confusing and/or controversial terms such as
SOX9. WNT4-signaling pathway plays a major role in ovarian "intersex," "hermaphroditism" and "sex reversal", the
development and maintenance, regulation of Müllerian ducts consensus statement recommended a new taxonomy based
formation and ovarian steroidogenesis (26,27,28). WNT4 has on the umbrella term, “DSD” (3). This broad category
been shown to play a critical role in the development of the includes common entities such as Turner syndrome and
reproductive system and also in the formation of the Klinefelter syndrome as well as rare disorders such as
kidneys, adrenals, pituitary gland, and mammary tissues. cloacal exstrophy and aphallia. Many DSDs are associated
Absence of WNT4 leads to testis-like development within with ambiguous genitalia, however, a few may present with
the ovary. Conversely, overexpression of WNT4 in the male delayed puberty or primary amenorrhea. The Lawson Wilkins
leads to female sex reversal. RSPO1 is another gene Pediatric Endocrine Society (LWPES) and the European
essential in sex determination responsible for the protein Society for Paediatric Endocrinology (ESPE) consensus
RSPO1, which plays an important role in suppression of the group proposed the classification of DSDs into: 1) Sex
SOX9 gene (27,28). Loss of function mutations in the human chromosome DSDs (45,X Turner and variants, 47,XXY
RSPO1 gene in mice results in the formation of ovotestes in Klinefelter and variants, 45X/46XY mixed gonadal disgenesis
the XX fetus (28). WNT4, RSPO1 and β-catenin seem to (MGD) and chromosomal ovotesticular DSD “46XX/46XY
have both pro-ovarian and anti-testicular activities from early chimeric type or mosaic type”); 2) 46,XY DSDs (disorders of
embryonic life, while FOXL2 may also have similar actions testicular development or disorders in androgen
postnatally.* FOXL2 is expressed early within the genital ridge synthesis/action); and 3) 46,XX DSDs (disorders of ovarian
of the fetal, postnatal and adult ovary and eyelids. FOXL2 is development or fetal androgen excess) (Table 1). Additional
involved in granulosa cell differentiation, follicle development categorization based on sex chromosome complement was
and maintenance during fertile life (29). Müllerian ducts give recommended but not clearly defined (30,31). It is recognized
rise to the fallopian tubes, uterus and the upper two-third of that some conditions do not fit exactly into one specific
the vagina. In the female, the genital tubercle becomes the diagnostic category or may be placed in more than one category
clitoris, the labio-scrotal folds become the labia majora, and (5). The DSD nomenclature has recently divided "ovotesticular
the urethral folds become the labia minora. DSD" (formerly true hermaphroditism) into 46,XY ovotesticular
Nomenclature and Definitions DSD, 46,XX ovotesticular DSD, and chromosomal ovotesticular
Formerly, intersex disorders were subdivided into three DSD (46,XX/46,XY” chimerism or 45,X/46,XY” mosaic type).
main groups as: associated with gonadal dysgenesis, 1) Sex chromosome DSDs (45,X Turner and variants,
associated with undervirilization of 46,XY individuals, 47,XXY Klinefelter and variants, 45X/46XY MGD,
Table 1. Disorders of sexual development (New DSD nomenclature) (3)
Sex Chromosome DSD 46,XY DSD 46,XX DSD
• 45,X Turner and Variants Disorders of Testicular Disorders of Disorders of Ovarian Fetal Androgen Excess
• 47,XXY Klinefelter and Variants Development Androgen Development CAH Non CAH
• 45,X/46XY MGD •Complete Gonadal Synthesis/Action • Ovotesticular DSD • 21-OH Deficiency • Aromatase
• Chromosomal Ovotesticular Dysgenesis • Testicular DSD (eg. • 11-OH Deficiency Deficiency
• Androgen Synthesis
SRY+, dup SOX9) • POR Gene
DSD • Partial Gonadal Defect
• Gonadal Defect
Dysgenesis • LH-Receptor Defect
Dysgenesis • Maternal
• Androgen Insentivity
• Gonadal Regression • Luteoma
• 5α-Reductase
• Ovotesticular DSD • Iatrogenic
Deficiency
• Disorders AMH
• Timing Defect
• Endocrine Disrupters
• Cloacal Extrophy
MGD: mixed gonadal dysgenesis, DSD: disorders of sexual development, AMH: anti-Müllerian hormone, CAH: congenital adrenal hyperplasia
107
4. Öçal Gönül
Disorders of Sexual Development
choromosomal ovotesticular DSD (46XX/46XY chimeric type gonadal dysgenesis, characterized by partial testicular
or mosaic type): This type of DSDs is associated with a differentiation and ambiguous genitalia, is usually observed
numerical sex chromosome abnormality leading to in the newborn period. Mutation in WT1 gene results in
abnormal gonadal development (2,3,5,30,31,32,33,34, Denys-Drash syndrome (without uterus) or Frasier
35,36,37). Sex chromosome DSD was formerly termed as syndrome (with uterus) characterized by 46,XY partial
gonadal dysgenesis in most of the patients in this group (5). gonadal dysgenesis and severe renal dysfunction with or
If a testis is poorly formed, it is called a dysgenetic testis, and without Wilms tumor (16). Complete gonadal dysgenesis in
if an ovary is poorly formed, it is called a streak gonad. A 46,XY individuals (Swyer syndrome) is characterized by a
patient with a Y chromosome is at high risk of developing a female phenotype with full development of unambiguous
tumor in a streak or dysgenetic gonad. Klinefelter and Turner female genitalia, normally developed Müllerian structures,
syndromes (TS) are the most frequently encountered sex and streak gonads. These streak gonads are removed due
chromosomal abnormalities (34,35,36). More than half of to their association with gonadoblastoma. In general, these
girls with TS have chromosomal mosaicism. The most patients present because of delayed puberty. In agonadism
common genotype of Klinefelter syndrome is XXY, although (vanishing testes syndrome, testicular regression) boys
variants exist with different numbers of X chromosome. In present with normal male genitalia, indicating that they
patients with 45X/46XY MGD, clinical manifestations are must have had testicular function in the fetal period, and
highly variable, ranging from partial virilization and ambiguous bilateral anorchia.
genitalia at birth to a completely male or female phenotype. The defects in peptide hormones and their receptors as
The most common feature of MGD is asymmetric well as the timing of hormonal exposure are also critical to
development of the testes, often with a dysgenetic testis on appropriate male development. Leydig cell aplasia/hypoplasia,
one side and a streak gonad on the other. Asymmetrical due to abnormalities in hCG/LH receptor, and T
external and internal genitalia may also be present. The biosynthesis defects (STAR deficiency, P450scc deficiency,
presence of 45,X cell lines is frequently associated with Y 3-β hydroxysteroid dehydrogenase type II deficiency,
chromosome rearrangements (commonly dicentric and ring 17α-hydroxylase and 17,20-lyase deficiency, isolated
Y chromosomes), which may also have an impact on the 17,20-lyase deficiency, P450 oxidoreductase ”POR gene”
phenotype. Chromosomal ovotesticular DSD (chimeric type defect, 17β-hydroxysteroid dehydrogenase III deficiency)
or mosaic type) is associated with ovarian and testicular result in androgen synthesis defect. Severely affected
tissues found in either the same or opposite gonad just as in infants for POR gene of both sexes have ambiguous
46,XX and 46,XY ovotesticular DSD. The genital duct genitalia. The males are undervirilized because of defective
develops according to the ipsilateral gonad. 17,20-lyase activity of P450c17. Disorders of AMH and
2) 46,XY disorders of sex development (46,XY DSD): AMH receptors result in persistent Müllerian duct
The term “male pseudohermaphrodite” was used to syndrome (PMDS). PMDS is inherited in a sex-limited
describe the patients with incompletely masculinized autosomal recessive manner caused by a mutation in the
external genitalia possessing an XY chromosome.** 46,XY AMH or AMH-receptor genes. 5α-reductase type 2
DSD can result either from disorders of testicular deficiency (38,39,40) and complete/partial forms of
development or disorders in androgen synthesis/androgen androgen insensitivity syndromes (CAIS, PAIS) result in
action (6). These patients are characterized by ambiguous disorders of androgen action (22,23).
or female external genitalia, caused by incomplete 3) 46,XX disorders of sex development (46,XX DSD):
intrauterine masculinization. Male gonad(s) are palpable in The term female pseudohermaphrodite was used
the majority of 46,XY DSD patients. Abnormalities in to describe the patients with 46,XX karyotype and with
the expression of genes involved in the cascade of testis masculinized external genitalia. Currently, these disorders
determination can cause anomalies of gonadal are described as 46,XX DSD.** 46,XX DSD can result either
development and consequently, 46,XY DSD (complete or from disorders of ovarian development or fetal androgen
partial forms of gonadal dysgenesis with or without excess (6). SRY positivity; WNT4, RSPO1, β−catenin gene
syndromic phenotype, ovotesticular DSD, testicular defects; and duplication of SOX9 gene lead to testis-like
regression syndrome). formation within the ovary (streak gonad, dysgenetic testis
Failure of testis determination results in the development or ovotestis) in the 46,XX patients. A single copy of the
of the female phenotype, while genetic alterations resulting WNT4 gene in females causes Müllerian abnormalities,
in partial testicular development can give rise to a wide renal abnormalies (e.g. renal agenesis), and androgen
spectrum of incomplete masculinization. 46,XY partial excess. Their phenotype resembles that of patients with
108
5. Öçal Gönül
Disorders of Sexual Development
the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. aromatase deficiency, sulfatase deficiency, virilizing
With absence of both copies of this gene, females show luteoma of pregnancy, glucocorticoid receptor mutation.
male sex and SERKAL syndrome (female to male sex Aromatase deficiency is rare in humans (43). Aromatase
reversal; renal, adrenal and lung dysgenesis) (26). RSPO1 is is the enzyme that catalyzes conversion of androgens into
essential in sex determination and skin differentiation. estrogens, and if aromatase is nonfunctional because of an
RSPO1 gene mutations lead to XX sex reversal, inactivating mutation, estrogen can not be synthesized. If
palmoplantar hyperkeratosis and predisposition to the fetus lacks aromatase activity, DHEA produced by the
squamous cell carcinoma of the skin (27,28). FOXL2 fetal adrenal glands cannot be converted to estrogen by the
mutations result in a variety of phenotypes, from adult placenta, and is converted to T peripherally. This results in
ovarian failure to development of streak gonads (29). virilization of both fetus and mother.
Mutations in FOXL2 are responsible for blepharophimosis- Cystic ovaries and delayed bone maturation can occur
ptosis-epicanthus inversus syndrome (BPES) and can be during childhood and adolescence in these girls. They may
associated with premature ovarian failure. Ovarian present at pubertal ages with primary amenorrhea, failure
dysgenesis coexisting with sensorineural deafness is of breast development except in partial cases, virilization,
diagnosed as Perrault syndrome. In ovotesticular DSDs, the and hypergonadotrophic hypogonadism.
most common karyotype is 46,XX followed by 46,XX/46,XY Sulfotransferase deficiency is a monogenic cause of
chimerism or mosaicism, and 46,XY. Most 46,XX hyperandrogenism. DHEA sulfotransferase, known as
ovotesticular DSDs are SRY-negative, and the genes SULT2A1, converts the androgen precursor DHEA to its
responsible have not yet been identified. A mutated inactive sulfate ester, DHEAS, thereby preventing the
downstream gene in the sex determination cascade is conversion of DHEA to an active androgen. If this pathway
likely to allow for testicular determination. 46,XX testicular is blocked, more DHEA will be converted to androstenedione
DSD is distinct from XX ovotesticular DSD and is and hyperandrogenism may occur (44).
associated with male habitus, small testes, azoospermia Investigation of DSD Patients
and no evidence of uterus or ovaries. Optimal care of patients with DSD requires a
Virilized females with two ovaries, XX karyotype multidisciplinary team and begins in the newborn period. A
and ambiguous genitalia are usually exposed to external family history, prenatal history, a general physical
genitalia androgens of fetal origin or to androgens of examination with attention to any associated dysmorphic
maternal origin. The majority of virilized 46,XX infants will features, and an assessment of the genital anatomy are the
first steps towards a correct diagnosis. The diagnostic
have congenital adrenal hyperplasia (CAH) (most
evaluation of DSD includes hormone measurements,
commonly 21α-hydroxylase and 11β- hydroxylase or rarely
imaging, cytogenetic and molecular studies and in some
3β-hydroxysteroid dehydrogenase deficiencies). Apparent
cases endoscopic, laparoscopic and gonadal biopsy
combined P450c17 and P450c21 deficiency is a rare
(6,7,8,45,46,50,51,52,53,54,55). The genetic evaluation
variant of CAH. Mutations of POR gene cause disordered
includes karyotype, FISH and, more recently, specific
steroidogenesis with prenatal virilization without worsening
molecular studies to screen the presence of mutations or
of postnatal virilization in female fetuses (41,42).
gene dosage imbalance (AR, SRY, SF1, WT1, CYP21, SOX9,
Cytochrome POR is a protein that transfers electrons from
DAX-1, 17β hydroxysteroid dehydrogenase, 5α-reductase-2,
NADPH to all microsomal cytochrome P450 enzymes and
and others). However, current molecular diagnosis is limited
three steroidogenic enzymes, namely, P450c17
by cost, accessibility, and quality control. Ultrasonography
(17α-hydroxylase/17,20 lyase), P450c21 (21-hydroxylase),
shows the presence or absence of Müllerian/Wolfian
and P450aro (aromatase). Severely affected female
structures and can locate the gonads and their echo texture.
infants for POR gene are virilized because of defective
Ultrasonography also can identify associated malformations
aromatase activity and because of the diversion of
such as renal abnormalities.
17-hydroxyprogesterone (17OHP) to DHT via the “backdoor
Common findings suggesting DSD are male appearance
pathway” to androgens that bypass dihydroepiandrosterone with associated abnormalities of genitalia including severe
(DHEA), androstenedione (A) and T (42). Severely affected hypospadias with bifid scrotum, undescended testis/testes
infants also have the Antley-Bixler skeletal malformation with hypospadias, bilateral non-palpable testes, and
syndrome (ABS) characterized by craniosynostosis and micropenis with chordee (47,48) or female appearance
radio-humeral or radio-ulnar synostosis. Rarer causes of with associated abnormalities of genitalia including
fetal androgen excess in XX infants are maternal androgen enlarged clitoris, posterior labial fusion, and an
ingestion, maternal virilizing disease, fetoplacental inguinal/labial mass (49). An initial assessment, based on
109
6. Öçal Gönül
Disorders of Sexual Development
the location of the gonads and presence or absence of a stimulation of T production by hCG is used to pinpoint
uterus, will provide a provisional clinical diagnosis (45). This abnormalities in T biosynthesis and to detect functioning
information combined with karyotype, will provide the basis testicular tissue. Testosterone, DHT, A should be measured
for more focussed further investigation. Figures 3a and 3b at baseline and 72 hours after hCG stimulation. The T
illustrate chromosomal and gonadal characteristics of increment should be at least threefold (56). A failure to
DSDs. If no gonads are palpable, all options are possible. respond to hCG in combination with elevated LH/FSH
Of these, 46,XX DSD (with 2 ovaries) is the most levels and low/undetectable value of AMH is consistent
commonly seen, followed by MGD. The presence of a with anorchia or gonadal dysgenesis. Androgen
uterus and absence of palpable gonads in a virilized female insensitivity should be considered in individuals with a
primarily suggest a clinical diagnosis of 21-hydroxylase 46,XY karyotype and with normal T biosynthesis. The
deficiency. If one gonad is palpable, 46,XX DSD and diagnosis of androgen insensitivity is difficult in absence of
complete gonadal dysgenesis are ruled out because ovaries a defined androgen receptor mutation. Patients with
and streak gonads do not descend. MGD, ovotesticular, and 5α-reductase deficiency have normal T levels, low or
46,XY DSD remain as diagnostic possibilities. If two gonads normal DHT levels and a high T/DHT ratio after hCG
are palpable, 46,XY DSD and ovotesticular DSD are the stimulation test. The diagnosis of 17βHSD deficiency is
most likely diagnoses. Symmetrical external genitalia, with made when a 10-15-fold elevation is observed in the ratio of
or without palpable gonads, and an absent uterus suggest A/T. Minimum A/T ratio in a cohort of 24 individuals with a
an undervirilized XY male. The presence of a uterus and confirmed mutation was 0.7 (57). Inhibin B and AMH are
asymmetric external genitalia and palpable gonad(s) useful markers for the presence of Sertoli cells and their
suggest gonadal dysgenesis with Y and ovotesticular DSD. assessment could help in the diagnosis of testis
A gonadal biopsy is required to classify the type of gonadal determination disorders. In boys with bilateral
dysgenesis and ovotesticular DSD, to assess gonadal cryptorchidism, serum AMH and inhibin B correlate with
chromosomal mosaicism and to detect the presence of a the presence of testicular tissue and undetectable
gonadal tumor. values are highly suggestive of absence of testicular tissue
Hormone measurements should be interpreted in (58). In XY patients, AMH was found low when the intersex
relation to specific assay characteristics and also condition was caused by abnormal testicular determination
considering normal values for gestational and chronological (including complete and partial gonadal dysgenesis) but
age. In some cases serial measurements may be needed. was normal or elevated in patients with impaired
The results of decision making algorithms are available to T secretion, whereas serum T was low in both groups.
guide further investigation. These include hCG and ACTH AMH was also elevated during the first year of life and at
stimulation tests to assess testicular and adrenal steroid puberty in intersex states caused by androgen insensitivity.
biosynthesis. The endocrine evaluation of patients In 46,XX patients with ambiguous genitalia, a serum AMH
with 46,XY DSDs and sex chromosome DSDs include level higher than 75 pmol/L is indicative of the presence of
assessment of testicular function by basal measurement of testicular tissue and correlates with the mass of functional
LH, FSH, inhibin B, T, DHT, AMH, A, and DHEAS. In patients testicular parenchyma. In conclusion, serum AMH
with T synthesis defects, neonatal and post pubertal determination is a powerful means to assess Sertoli cell
diagnosis is made based on basal steroid levels. The function in children with intersex , and helps to distinguish
46, XX DSD 46,XX
OVARY-OVARY
46,XX Testicular DSD
(Fetal Androgen Excess)
Testis Testis
46, XY DSD 46,XX
TESTIS-TESTIS Complete Gonadal Dysgenesis
(Disorder Androgen Synthesis/Action)
Streak Streak
46,XX or 46,XY or 46,XY
OVOTESTIS
Chromosomal Complete Gonadal Dysgenesis
Ovotesticular DSD
NO GONADAL 46,XX
STREAK-TESTIS 45,X/46,XY TISSUE Agonadism (Testicular
Mixed Gonadal Regression)
Dysgenesis
Figure 3a. Gonadal and chromosomal characteristics of DSD Figure 3b. Gonadal and chromosomal characteristics of DSD
DSD: disorders of sexual development DSD: disorders of sexual development
110
7. Öçal Gönül
Disorders of Sexual Development
between defects of abnormal testicular determination and factors such as exposure to androgens, sex chromosome
of isolated impairment of T secretion or action. genes, social circumstances and family dynamics.
The diagnosis of 21-hydroxylase deficiency in 46,XX Outcomes can be influenced by timing, dose and type of
DSDs with two ovaries relies on the detection of elevated androgen exposure, receptor availability, and modification
17-OHP levels either as a basal measurement or after by the social environment. Pre- and postnatal hormonal
a short ACTH stimulation test. High concentration of conditions, sex rearing, timing of sex reassignment and
11-deoxycortisol and deoxycortisol (DOC) with low levels of corrective surgery appear to be important components for
plasma renin activity (PRA) will help differentiate 11- from the development of gender-role behavior and gender
21-hydroxylase deficiency. identity in DSD patients. Karyotype, gonadal function,
Supported by good facilities for investigation, clinicians phenotype, internal genitalia (i.e. presence of uterus),
can follow an algorithm that in many cases will lead to an potential for fertility and sexuality, risk of future malignancy,
aetiological diagnosis, but with the spectrum of findings and prenatal brain virilization are some of the many factors
and diagnosis, no single evaluation protocol can be which must be taken into account when assessing gender
recommended in all circumstances (59,60). in a child with DSD. Each patient should be evaluated
Chromosomal characteristics, gonadal histology and individually by a multidisciplinary approach. Gender
presence or absence uterus are taken into consideration in assignment should be done after completion of the
the classification of DSDs. In our department, we use the diagnostic process, including full clinical, genetic,
diagnostic algorithm prepared in accordance with the new biochemical and psychiatric investigation. The whole
classification for 46,XY DSD and for 46,XX DSD, as given in procedure should be fully explained to the parents and they
Figures 4 and 5. should partake in the discussions and decisions.
Management The traditional gender assignments for some medical
The psychological and social implications of conditions leading to DSDs are as follows: assignment of
gender assignment and those relating to treatment are very female gender for 46,XX DSD resulting from fetal androgen
important and require a multidisciplinary approach with the exposure, CAIS, and 46,XY complete gonadal dysgenesis;
inclusion of geneticists, neonatologists, endocrinologists, assignment of male gender for 46,XY cloacal exstrophy;
gynaecologists, psychiatrists, surgeon and social workers in assignment of male or female gender for PAIS, 5α-
the team. The members of such a team should have a reductase deficiency, ketoreductase deficiency, 46,XY
special interest in DSD and possess sufficient experience partial gonadal dysgenesis, MGD and ovotesticular DSD.
with this group of patients. The current intense debate on Underlying endocrine disturbances are present in most
the management of patients with intersexuality and related cases and usually require long-term medication. The current
conditions focuses on four major issues, namely, recommendation for a girl with CAH is to rear her as a
aetiological diagnosis, assignment of gender, indications for female and perform a feminizing genitoplasty depending
and timing of genital surgery, and disclosure of medical on the degree of masculinization. However, male sex
information to the patient (61,62,63,64,65,66,67,68, assignment may be mandatory in severely virilized 46,XX
69,70,71,72,73). Gender identity is a multifactorial process CAH patients in whom the diagnosis was not made in the
involving both prenatal and postnatal variables. early stage. Recommendations for sex of rearing
Psychosexual development is influenced by multiple especially in infants with genital ambiguity, testicular
Ambiguous Genitalia/Pubertal Problems Ambiguous Genitalia/Pubertal Problems
Karyotype 46,XY Karyotype 46, XX
Absent Testis-Testis
GONADS GONADS
Ovary-Ovary
Streak-Streak Uterine - Ovotestis Streak-Streak Testis-Testis
Uterine± Ovotestis Disgenetic Testis
Disgenetic Testis Uterine +
Disorder Androgen
Agonadism Synthesis or Action Uterine +
Uterine± Uterine± Uterine+ Uterine + Uterine −
Testerone Biyosynthetic Virilized
Female
Defect
Ovotesticular Ovotesticular GONADAL
Partial Gonadal Complete LH-Receptor Mutation DSD DYSGENESIS
DSD 17OH - Progesterone
Dysgenesis Gonadal Androjen Resistant Syndrome
Dysgenesis High Normal
5α-Reductase Deficieney
XX TESTICULAR
POR Gene Defect CAH DSD
NON-CAH
Timing Defect
Figure 4. Diagnostic algorithm of 46,XY DSD for new classification Figure 5. Diagnostic algorithm of 46,XX DSD for new classification
DSD: disorders of sexual development DSD: disorders of sexual development, CAH: congenital adrenal hyperplasia
111
8. Öçal Gönül
Disorders of Sexual Development
differentiation disorders and Y chromosome continue to be 5. Houk CP, Lee PA. Consensus statement on terminology
challenging. Genital masculinization is a poor predictor of and management: Disorders of sex development. Sex Dev
2008;2:172-180.
the masculinization of the brain (63). Patients with PAIS, 6. Damian D, Paulo S. Disorder of sexual development: Still a
5α-reductase and ketoreductase deficiency, partial gonadal big challenge. J Pediatr Endocrinol Metab 2007;20:749-50.
dysgenesis, and MGD may be female or predominantly 7. Carillo AA, Damian M, Bercovitz G. Disorders of
female at birth and generally are raised as females, but they sexual differentiation. From Pediatric Endocrinology Fifth
ed. Ed by Lifshitz F. London. ‹nforma Health Care
change their social sex to male at puberty. Sex assignment
2007;2:365-413.
is more problematic in this group. The decision on sex of 8. Hughes IA. Testes: Disorders of sexual differantiation and
rearing in ovotesticular DSD should be based on gonadal puberty in male. From Texbook Pediatric Endocrinology.
and internal ductal formation. Third edition. Ed by Sperling MA. Saunders comp. Pittsburg
2008. pp. 662-685.
Surgical techniques of 'feminization' and 'masculinization' 9. Arboleda VA, Flaming AA and Vilain E. Disorders of sex
and their outcomes have also evolved over time (72,73). development from texbook of Genetic Diagnosis of
Surgeons should have both pediatric training and expertise in Endocrine Disorders. Ed by Weiss RE, and Refetoff S,
Press in Elsevier. London 2010. pp. 227-243.
DSD surgery. Functional outcome should be taken into
10. MacLaughlin DT, Donahoe PK. Sex determination and
consideration rather than a strictly cosmetic appearance. In differentiation. N Engl J Med 2004;350:367-378.
children assigned a male sex, hypospadias or chordee, if present, 11. Biason-Lauber A. Control of sex development. Best Pract
requires early surgical correction. Scrotal testis/testes should be Res Endocrinol Metab 2010;24:163-186.
12. Houmart B, Small C, Yang L, Naluai–Cecchinit, Cheng E,
monitored and, if needed, biopsied, to rule out malignancy. A Hassold T, Griswold M. Global gene expression in human
streak ovary should be removed. The testis/testes may also fetal testis or ovary. Biol Reproduct 2009;81:438-443.
need to be removed if there is any risk of malignancy on clinical 13. Brennan J, Capel B. One tissue two fates: molecular
genetic events that underlie testis versus ovary
suspicion or biopsy specimens. T replacement may be required development. Nat Rev Genet 2004;5:509-521.
at puberty. The testes in patients with DSD raised as females 14. Ahmed SF, Hughes A. The genetics of male
should be removed to prevent malignancy in pre-puberty or after undermasculinization. Clin Endocrinol 2002;56:1-10.
15. Willhelm D, and Englerd C. The Wilms tumor suppressor
puberty. Feminizing surgery has three main aims: reducing the WT1 regulates early gonad development by activation of
size of the enlarged masculinized clitoris, reconstructing the SF1. Genes Dev 2002;16:1839-1851.
female labia, and increasing the opening and if possible, the 16. Cetinkaya E, Ocal G, Berberoglu M, Adiyaman P, Ekim M,
Yalcinkaya F, Orun E. Association of partial gonadal
length of the vagina. Early surgery should only be considered in dysgenesis, nephropathy and WT1 gene mutation without
cases of severe virilization (Prader III-V) and should be carried out Wilm’s tumor: Incomplete Denys-Drash syndrome.
in conjunction, when appropriate, with repair of the common J Pediatr Endocrinol Metab 2001;14:561-564.
17. Biason-Lauber A, Konrad D, Meyer M, de Baufort C,
urogenital sinus. As orgasmic function and erectile sensation Schoenle EJ. Ovaries and female phenotype in a girl with
may be disturbed by clitoral surgery, the surgical procedure should 46,XY karyotype and mutation CBX2 gene. Horm Res
be anatomically based to preserve erectile function and the LSPES/ESPE 8th Joint Meeting Abstract book. New York
2009, pp. 53-54.
innervation of the clitoris. Consensus conferences recommend
18. Palanco JC, Koopman P. SRY and hesistant begining of
not to perform genital surgery between 12 months and male development. Dev Biol 2007;302:13-24.
adolescence (except for compelling medical indications). Vaginal 19. Sekido R, Lovel-Badge R. Sex determination and SRY:
dilatation should not be recommended before adolescence. down to a wink and a nudge? Trends Genet 2009;25:19-29.
20. Morais da Silva S, Hacker A, Harley V, Goodfellow, Swain A
and Lovell-Badge R. SOX9 expression during gonadal
References development implies a conserved role for the gene in
testis differentiation in mammals and birds. Nat Genet
1. Allen L. Disorders of sexual development. Obstet Gynecol 1996;14:62-68.
21. Hiramatsu R, Harikae K, Tsunekawa N, Kurohmaru M,
Clin North Am 2009;36:25-45.
Matsuo Kanai Y. FGF signaling directs a center-to-pole
2. Dreger AD, Chase C, Sausa A, Gruppusa A, Frader J.
expansion of tubulogenesis in mouse testis differentiation.
Changing nomenclature/ Toxonomy for intersex, scientific Development 2010:137;303-312.
and clinical rationale J Pediatr Endocrinol Metab 22. Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete
2005;18:729-733. androgen insensitivity syndrome-a review. J Pediatr
3. Lee PA, Houk CP, Ahmet F, Hughes IA, and in collaboration Adolesc Gynecol 2008;21:305-310.
with participants in the international consensus conference 23. Choi JH, Kim GH, Seo EJ, Kim KS, Kim SH, Yoo HW.
on intersex organized by the Lawson Wilkinns Pediatric Molecular analysis of the AR and SRD5A2 genes in patients
Endocrine Society and the European Society for Pediatric with 46,XY disorders of sex development. J Pediatr
Endocrinology. Consensus statement on management of Endocrinol Metab 2008;21:545-553.
intersex disorders. Pediatrics 2006;118:488-500. 24. Yao, HH. The pathway to femaleness: current knowledge
4. Hughes IA. Disorders of sexual differentiation. Horm Res on embryonic development of the ovary. Mol Cell
2007;67(suppl1):91-95. Endocrinol 2005;230:87-93.
112
9. Öçal Gönül
Disorders of Sexual Development
25. Edson MA, Nagaraja AK, Matzuk MM. The mammalian 40. Ocal G, Adiyaman P, Berberoglu M, Cetinkaya E, Akar N,
ovary from genesis to revelation. Endocr Rev 2009;30: Uysal A, Duman T, Evliyaoglu O, Aycan Z, Lumbroso S,
624-712. Sultan C. Mutation of the 5α steroid reductase type 2 gene
26. Vainio S, Heikkil AM, Kispert A, Chin N, McMohon AP. in six unrelated patients from unrelated families and a large
Female development in mammals is regulated by WNT4 pedigree of an isolated Turkish village. J Pediatr Endocrinol
signalling. Nat 1999;4:405-409. Metab 2002;15:411-421.
27. Biason-Lauber A: WNT4 and R-Spontin1 signalling in 41. Miller WL. P450 oxireductase deficiency: a new disorder of
ovarian development. Highlights. 46th Meeting ESPE, steroidogenesis with multiple clinical manifestation. Trends
2010, Praque. Endocrinol Metab 2004;15:311-315.
28. Parma P, Radi O, Vidal V, Chaboissier MC, Dellambra E, 42. Arlt W, Walker EA, Draper N, Ivison HE, Ride JP, Hammer
Valentini S, Guerra L, Schedl A. R-spondin1 is essential in F, Chalder SM, Borucka-Mankiewicz M, Hauffa BP,
sex determination, skin differentiation and malignancy. Nat Malunowicz EM, Stewart PM, Shackleton CH. Congenital
Genet 2006;38:1304-1309. adrenal hyperplasia caused by mutant P450 oxireductase
29. Ottolenghi C, Omari S, Garcia-Ortis JE, Uda M, Crisponi L, and human androgen synthesis: analytical studies. Lancet
Foraboska A, Pilia G, Schlessinger D. FOXL2 is required for 2004;363:2128-2135.
commitment to ovary differentiation. Hum Mol Genet 43. Carani C, Simpson ER. Recognizing rare disorders:
2005;14:205. aromatase deficiency. Nat Clin Pract Endocrinol Metab
30. Aaronson IA. Terminology for disorders of sex 2007;3:414–421.
development: clarity or confusion. J Urol 2011;185: 44. Noordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA,
388-389. Smeitink JA, Smeets R, Sweep FC, Claahsen-van der Grinten
31. Barthold JS. Disorders of sex differentiation: a HL, Arlt W. Inactivating PAPSS2 mutations in a patient with
pediatric urologist's perspective of new terminology and premature pubarche. N Engl J Med 2009;360:2310-2318.
recommendations. J Urol 2011;185:393-400. 45. Lee PA. A perspective on the approach to the intersex child
32. Wijchers PJ, Yandim C, Panousopoulou E, Ahmad M, born with genital ambiquity. J Pediatr Endocrinol Metab
Harker N, Saveliev A, Burgoyne PS, Festenstein R . Sexual 2004;17:133-140.
dimorphism in mammalian autosomal gene regulation is 46. Brown J, and Warner G. Practical manegement of the
determined not only by SRY but by sex chromosome intersex infants. J Pediatr Endocrinol Metab 2005;18:3-23.
complement as well. Dev Cell 2010;19:477-484 47. Guerra-Junior G, Marciel-Guerra AT. The role of the
33. Nishi MY, Costa EM, Oliveira SB, Mendonca BB, Domenice pediatrician in the management of children with genital
S. The role of SRY mutations in the etiology of gonadal
ambiquities. J Pediatr (Rio J) 2007;83:184-191.
dysgenesis in patients with 45,X/46,XY disorder of
48. Ouigley CA, De-Bellis A, Marschke KB, el-Awady MK, Wilso
sex development and variants. Horm Res Paediatr
M, French FS. Androgen receptor defects. Endocr Rev
2011;75;26-31.
1995;16:271-321.
34. Oliveira RM, Verreschi IT, Lipay MV, Eça LP, Guedes AD,
49. Sinnecker GH, Hiort O, Dibbelt L, Albers N, Dörr HG, et al.
Bianco B. Y chromosome in Turner syndrome: review of
Phenotypic classification of male pseudohermaphroidism
the literature. Sao Paulo Med J 2009;127:373-378.
35. Khandelwal A, Agarwal A, Jiloha RC. A 47,XXY female due to steroid 5α reductase 2 deficiency. Am J Med Genet
with gender identity disorder. Arch Sex Behav 1996;63:223-230.
2010;39:1021-1023. 50. Prader A. Der genital befund be im pseudohermaphroditismus
36. Siklar Z, Berberoglu M, Adiyaman P, Salih M, Tukun A, femininus des kongenitalen androgenitalen syndroms.
Cetinkaya E, Aycan Z, Evliyaoglu O, Ergur AT, Ocal G. Helvetica Paediatr Acta 1954;3:231-248.
Disorders of gonadal development: a broad clinical, 51. Ocal G, Berberoglu M, Siklar Z, Bilir P, Uslu R, Yagmurlu A,
cytogenetic and histopathologic spectrum. Pediatr Tukun A, Akar N, Soygur T, Gultan S, Toykukuk G.
Endocrinol Rev 2007;4:210-217. Disorders Sexual Development: an overviev of 18 years
37. Balkan M, Akbas H, Isi H, Oral D, Turkyilmaz A, Kalkanli S, experience in Pediatric Endocrinology Department of
Simsek S, Fidanboy M, Alp MN, Gedik A, Budak T. Ankara University. J Pediatr Endocrinol Metab
Cytogenetic analysis of 4216 patients referred for 2010;23:1123-1132.
suspected chromosomal abnormalities in Southeast 52. Al-Agha AE, Thomset MJ, Batch JA. The child of uncertain
Turkey Genet Mol Res 2010;11:1094-1103. sex: 17 years of experiance. J Pediatr Child Health
38. Maimoun L, Philibert P, Cammas B, Audran F, Bouchard P, 2001;37:348-351.
Fenichel P, Cartigny M, Pienkowski C, Polak M, Skordis N, 53. Mazen I, Hiort O, Bassiouny R, El-Gammal M. Differential
Mazen I, Ocal G, Berberoglu M, Reynaud R, Baumann C, diagnosis of disorders of sex development in Egypt.
Cabrol S, Simon D, Kayemba-Kay's K, De Kerdanet M, Kurtz Horm Res 2008;70:118-123.
F, Leheup B, Heinrichs C, Tenoutasse S, Van Vliet G, 54. Al- Muttair A, Igbal MA, Ashwal A: Cytogenetic and
Grüters A, Eunice M, Ammini AC, Hafez M, Hochberg Z, etiology of ambiquous genitaliain 120 pediatric patients.
Einaudi S, Al Mawlawi H, Nuñez CJ, Servant N, Lumbroso Ann Sauidi Med 2004;37:348-351.
S, Paris F CJ, Servant N, Lumbroso S, Paris F, Sultan C. 55. Zdravkovic D, Milankovic T, Sedlecki K, Guc-Scekic M, Rajic
Phenotypical, biological, and molecular heterogeneity of V, Banicevic M. Causes of ambiquous genitalia in neonates.
5α-reductase deficiency: an extensive international experience Srp Arh Celok Lek 2001;129:57-60.
of 55 patients. J Clin Endocrinol Metab 2011;96:296-307. 56. Kolon TF, Miller OF. Comparison of single versus multible
39. Maimoun L, Philibert P, Bouchard P, Ocal G, Leheup B, dose regimens for the human chorionic gonadotropin
Fenichel P, Servant N, Paris F,Sultan C. Primary stimulation test. J Urol 2001;166:1451-1454.
amenorrhea in four adolescents revealed 5α-reductase 57. Simard J, Moisan AM, Michel LC, Morel Y. Males with 17β- β
deficiency confirmed by molecular analysis. Fertil Steril hydroxysteroiddehydrogenase deficiency. Endocrinologist
2011;95:804. 2003;13:195-200.
113
10. Öçal Gönül
Disorders of Sexual Development
58. Grinspon RP, Rey RA. Anti-Müllerian hormone and Sertoli 68. Ocal G, Berberoglu M, Siklar Z, Bilir P. Gender dysphoria
cell function in paediatric male hypogonodism. Horm Res and gender change in an adolescent with 45,X/46,XY mixed
2010;73:81-92. gonadal dysgenesis. Exp Clin Endocrinol Diabetes
59. Garel L. Abnormal sex differentiation: who, how and when
2009;117:301-304.
to image. Pediatr Radiol 2008;38(suppl3):508-511.
60. Katorza E, Pinhas-Hamail O, Mazkereth R, Gilboa Y, Achiron 69. Uslu R, Oztop D, Ozcan O, Yilmaz S, Berberoglu M,
R. Sex differentiation disorders (SDD) prenatal sonographic Adiyaman P, Cakmak M, Kerimoglu E, Ocal G. Factors
diagnosis, genetic and hormonal work-up. Pediatr contributing to sex assignment and reassignment decisions
Endocrinol Rev 2009;7:11-21. in Turkish children with 46,XY disorders of sex development. J
61. Money C. Amative orientation. The hormonal hypothesis Pediatr Endocrinol Metab 2007;20:1001-1015.
rexemined. J Pediatr Endocrinol Metab 2002;15:951-957.
62. Houk CP, Dayner J, Lee PA. Genital ambiquity with Y 70. de Vries AL, Doreleijers TA, Cohen-Kettenis PT. Disorders
choromosome: Des gender assigment matter? J Pediatr of sex development and gender identity outcome in
Endocrinol Metab 2004;17:825-839. adolescence ande adulthood: Understandig gender identity
63. Ahmet SF, Morrison S, Hughes IA. Intersex and gender development and its clinical implications. Pediatr
assignment ; the third way? Arch Dis Child 2004;89:847-850. Endocrinol Rev 2007;4:343-351.
64. Meyer-Bahlburg HFL. Gender assignment and 71. Daaboul J and Frader J. Ethics and the management of the
reassignment in 46,XY pseudohermaphroditism and related
condition. J Clin Endocrinol Metab 1999;84:3455-3458. patient with intersex: A middle way. J Pediatr Endocrinol
65. Reiner WG. Gender identity and sex-of–rearing in children Metab 2001;14:1575–1583.
with disorders sexual differentation. J Pediatr Endocrinol 72. Crouch NS and Creighton SM. Minimal surgical intervention in
Metab 2005;18:549-553. the manegement of intersex conditions. J Pediatr
66. Reiner WG. Case study: Sex re-assigment in a teenage girl. Endocrinol Metab 2004;17:1591-1596.
Am Acad Child Adolesc Psychiatry 1996;35:799-803.
73. Vidal I, Gorduza DB, Haraux E, Gay CL, Chatelain P, Nicolino
67. Birnbacher R, Marberger M, Weissenbacher G, Schober E,
Frisch H. Gender identity reversal in an adolescent with M, Mure PY, Mouriquand P. Surgical options in disorders
mixed gonadal dysgenesis. J Pediatr Endocrinol Metab of sex development (DSD) with ambiguous genitalia.
1999;12:687-690. Best Pract Res Clin Endocrinol Metab 2010;24:311-324.
114