Disorder of sexual development DISORDER OF SEXUAL DEVELOPMENT PROF. SANA ABID BARKI HUSSAIN BY GROUP NO.04 GROUP MEMBERS G1F18BSZL0045 DUR E NAJAF G1F18BSZL0049 RABIA SATTAR G1F18BSZL0058 MAHRUKH G1F18BSZL0064 ZARA G1F18BSZL0065 SUMBAL G1F18BSZL0164 SHEHROZ CONTENT INTRODUCTION EMBRYOLOGY SEX DETERMINED BY GENETICS DIFFERENTIATION OF SERTOLI CELLS OVARY DIFFERENTIATION DIFFERENTIATION OF GERM CELLS CLASSIFICATION OF SDS 5 BIOLOGICAL SEXES XX DSD XY DSD SEX CHROMOSOMES DSD OVOTESTICULAR DISORDER GENETIC TESTING IN DSD REFERENCES INTRODUCTION A group of congenital conditions associated with atypical development of internal and external genital structures. These conditions can be associated with variations in genes, developmental programming, and hormones. Affected individuals may be recognized at birth due to ambiguity of the external genitalia. Others may present later with postnatal virilization, delayed/absent puberty, or infertility. Sex does not indicate gender Sex refers to the biology of the internal and external genital structures That is traditionally considered to be a binary categorization. Gender identity is the self-defined experience of one’s gender. EMBRYOLOGY Sexually dimorphic development of the reproductive tracts is influenced by multiple factors. Normal sex development is dependent on the synergistic orchestration of activating and repressing factors. Sex determination is governed by the sex chromosomes. The Sex Determining Region on the Y chromosome (SRY) gene located on the short arm of the Y chromosome is the binary switch that initiates the male developmental program. SEX DETERMINED BY GENETICS The SRY gene (blue band) on the male Y chromosome regulates sex determination in mammals. In placental mammals, the presence of a Y chromosome determines sex. Normally cells from females contain two X chromosomes and cells from males contain an X and a Y chromosome. DIFFERENTIATION OF SERTOLI CELLS The urogenital ridges develop by 4-6 weeks of gestation. Subsequently, the urogenital ridges develop into the kidneys, adrenal cortices, gonads, and reproductive tracts. SRY functions as a transcription factor to trigger the developmental trajectory that directs differentiation of the bipotential gonad into a testis during the 6th week of human gestation. SRY induces SOX9 expression CONTINUE SOX9 activates and maintains the male gonadal differentiation pathway. With differentiation of the Sertoli cells, the developing testis becomes organized into two compartments. One compartment consists of the testis cords that are aggregates of the germ cells surrounded by Sertoli cells and encased by the peritubular myoid cells. The other compartment is the testis interstitium, which contains the Leydig cells and testis vasculature. OVARY DIFFERENTIATION Ovarian differentiation occurs slightly later than testicular differentiation. In the absence of SRY in the female fetus, the ovary specific transcription factors initiate and maintain ovarian differentiation. In the absence of testosterone and dihydrotestosterone (DHT), the external genital structures develop into the clitoris, vagina, and labia. Both the urethra and the vagina open onto the perineum. DIFFERENTIATION OF GERM CELLS Differentiation of germ cells to a spermatogenic or an oogenic fate does not depend on their XY or XX karyotype. Rather, the neighboring somatic cells in the gonads influence germ cell differentiation. In the female embryo, germ cells are exposed to high levels of retinoic acid which induce the expression of STRA8 leading to germ cell meiosis and development of oocytes. In the developing testis, the absence of retinoic acid causes the germ cells to develop into gonocytes that differentiate into spermatogonia. CLASSIFICATION OF SDS DSDs are classified into several categories. The category of 46,XX DSD includes 1. virilized females such as girls with a virilizing congenital adrenal hyperplasia 2. Girls with aberrant ovarian development. The category of 46, XY DSD patients includes 1. patients with abnormal testicular differentiation 2. defects in testosterone biosynthesis 3. impaired testosterone action. Sex chromosome DSDs include Turner Syndrome, Klinefelter Syndrome, and 45,X/46,XY gonadal dysgenesis. In general, patients with Turner Syndrome and Klinefelter Syndrome do not present with genital ambiguity. Other DSDs include XX sex reversal, XY sex reversal, and ovotesticular disorder. 5 BIOLOGICAL SEXES The Six Most Common Karyotypes X – Roughly 1 in 2,000 to 1 in 5,000 people (Turner's ) XX – Most common form of female. XXY – Roughly 1 in 500 to 1 in 1,000 people (Klinefelter) XY – Most common form of male. XYY – Roughly 1 out of 1,000 people. XXXY – Roughly 1 in 18,000 to 1 in 50,000 births. XX DSD The 46,XX disorders of sex development (DSDs) cause virilisation or masculinisation of the female foetus. The final common pathway of all 46,XX DSDs is excess dihydrotestosterone (DHT) or potent foreign androgen in the genital tissue during the critical period of sexual differentiation. Whereas the foetal testis is source of androgen in the male it is the foetal adrenal that produces the DHT precursors in the female. XY DSD A 46, XY disorder of sex development (DSD) is a condition in which an individual with one X chromosome and one Y chromosome in each cell The pattern normally found in males have genitalia that is not clearly male or female. Infants with this condition tend to have penoscrotal hypospadias, abnormal development of the testes, and reduced to no sperm production. Some individuals with 46, XY DSD have fully to underdeveloped female reproductive organs (e.g., uterus and fallopian tubes) while others do not. People with 46, XY DSD may be raised as males or females. Treatment involves surgery and hormone replacement therapy. People with 46, XY DSD are at an increased risk for gonadal tumors and benefit from regular surveillance or surgery to remove abnormally developed gonads. SEX CHROMOSOMES DSD Ordinary looking genitals but different sex development Some people have a chromosome pattern other than the usual XY or XX. They may have one X chromosome (XO), or they may have an extra chromosome (XXY). Their internal and external sex organs can be either male or female, but they may not go through a full physical development at puberty. For example, a child with female sex organs may not start having periods. EXAMPLES One type is Klinefelter syndrome, which is where a boy is born with an extra X chromosome (XXY). This can mean they do not produce the usual level of testosterone, the sex hormone responsible for the development of male characteristics, such as the testes and body hair. Testosterone is also important for bone strength and fertility in men. Another example of this type of DSD is Turner syndrome, which is where a girl is born with a missing X chromosome. Girls and women with Turner syndrome are often infertile and their height may be shorter than average. Ovo testicular disorder Ovotesticular disorder is defined by the presence of both ovarian follicles and seminiferous tubules in the same patient. The specific phenotype depends on relative gene expression patterns and the function of the gonads particularly related to hormone secretion. Gonadal histology can include ovarian, testicular, ovotesticular, and dysgenetic patterns. GENETIC TESTING IN DSD Genetic testing plays an important role in the evaluation of a patient with a possible DSD because knowing the genetic etiology improves the ability to predict the patient’s phenotype Clarifies recurrence risk And can be utilized in medical decision-making. Peripheral blood karyotype analyses can be useful to detect the X and Y chromosomes Balanced chromosomal rearrangements And large structural rearrangements. REFERENCES 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866176/ 2. https://www.nhs.uk/conditions/differences-in-sexdevelopment/#:~:text=Ordinary%20looking%20genitals%20but%20different%20sex%20devel opment&text=Their%20internal%20and%20external%20sex,call%20this%20sex%20chromoso me%20DSD 3. https://rarediseases.org/gard-rare-disease/46-xy-disorders-of-sexualdevelopment/#:~:text=A%2046%2C%20XY%20disorder%20of,not%20clearly%20male%20or %20female 4. https://www.sciencedirect.com/science/article/abs/pii/S1521690X09001420
