Disorders of Sexual Development 2024 PDF

Disorders of sexual development Dr.Khalida Hassan Muho Specialist OB\GYN Objectives 1.Will be able to understand how the sex of each individual is determined. 2. To know which abnormalities in sex determining factors that will result in intersex. 3. Will be able to understand how these abnormaliti...

Disorders of sexual development Dr.Khalida Hassan Muho Specialist OB\GYN Objectives 1.Will be able to understand how the sex of each individual is determined. 2. To know which abnormalities in sex determining factors that will result in intersex. 3. Will be able to understand how these abnormalities are presented clinically at birth, during childhood and adolescence 4. Will be able to reach to the diagnosis of different cases of intersex and how to manage them  DSD are conditions where the sequence of events of puberty does not happen. The clinical consequences of this depend upon where within the sequence the variation occurs. DSD may be diagnosed  at birth with ambiguous or abnormal genitalia, but may also be seen  at puberty in girls who present with primary amenorrhoea or increasing virilization.  Non-structural causes of DSD  Turner syndrome The total complement of chromosomes is 45 in Turner syndrome, which results from a complete or partial absence of one X chromosome (45XO). Turner syndrome is the most common chromosomal anomaly in females, occurring in 1 in 2,500 live female births. A mosaic karyotype is not uncommon, leading to avariable presentation. , the most typical clinical features include: Short stature, webbing of the neck and a wide carrying angle. Associated medical conditions include coarctation of the aorta, inflammatory bowel disease, sensorineural and conduction deafness, renal anomalies and endocrine dysfunction, such as autoimmune thyroid disease. the ovary does not complete its normal development and only the stroma is present at birth. The gonads are called ‘streak gonads’ and do not function to produce oestrogen or oocytes. Diagnosis is usually made at birth or in early childhood from the clinical appearance of the baby or due to short stature during childhood. However, in about 10% of women, the diagnosis is not made until adolescence with delayed puberty. The ovaries do not produce oestrogen, so the normal physical changes of puberty cannot happen. In childhood, treatment is focused on growth, but in adolescence it focuses on induction of puberty. Pregnancy is only possible with ovum donation. Psychological input and support is important. In girls with mosaicism the clinical picture can vary and normal puberty and menstruation can occur, with early cessation of periods.  46XY gonadal dysgenesis In this situation, the gonads do not develop into a testis, despite the presence of an XY karyotype. In about 15% of cases, this is due to a mutation in the SRY gene on the Y chromosome, but in most cases the cause is unknown. In complete gonadal dysgenesis (Swyer syndrome), the gonad remains as a streak gonad and does not produce any hormones. In the absence of anti- Müllerian hormone (AMH), the Müllerian structures do not regress and the uterus, vagina and Fallopian tubes develop normally. The absence of testosterone means the fetus does not virilize. The baby is phenotypically female, although has an XY chromosome. The gonads do not function and presentation is usually at adolescence with delayed puberty. The dysgenetic gonad has a high malignancy risk and should be removed when the diagnosis is made laparoscopically. Puberty must be induced with oestrogen and pregnancies have been reported with a donor oocyte. psychological input is crucial.  Mixed gonadal dysgenesis is a more complex condition. The karyotype may be 46XX, but XX/XY mosaicism is present in up to 20%. In this situation, both functioning ovarian and testicular tissue can be present and if so, this condition is known as ovotesticular DSD. The anatomical findings vary depending on the function of the gonads. For example, if the testis is functional, then the baby will virilize and have ambiguous or normal male genitalia. The Müllerian structures are usually absent on the side of the functioning testis, but a unicornuate uterus may be present if there is an ovary or streak gonad  46XY DSD The most common cause of 46XY DSD, complete androgen insensitivity syndrome (CAIS),  occurs in individuals where virilization of the external genitalia does not occur, due to a partial or complete inability of the androgen receptor to respond to androgen stimulation.  In the fetus with CAIS, testes form normally due to the action of the SRY gene.  At the appropriate time, these testes secrete AMH, leading to the regression of the Müllerian ducts. Hence, CAIS women do not have a uterus. Testosterone is also produced at the appropriate time; however, due to the inability of the androgen receptor to respond, the external genitalia do not virilize and instead undergo female development.  The baby is born with  Normal female external genitalia,  an absent uterus  and testes that are found somewhere in their line of descent through the abdomen from the pelvis to the inguinal canal.  Presentation is usually at puberty with primary  amenorrhoea,  Once the diagnosis is made, initial management is psychological with full disclosure of the XY karyotype and the information that the patient will be infertile.  Gonadectomy is recommended because of the small long-term risk of testicular malignancy, Once the gonads are removed, long- term HRT will be required. The vagina is usually shortened and treatment will be required to create a vagina suitable for penetrative intercourse. Vaginal dilation is the most effective method of improving vaginal length. Surgical vaginal reconstruction operations are reserved for those women that have not responded to adilation treatment programme.  In cases of partial androgen insensitivity, the androgen receptor can respond to some extent with limited virilization. The child is usually diagnosed at birth with ambiguous genitalia.  5-Alpha-reductase deficiency In this condition, the fetus has an XY karytype and normal functioning testes that produce both testosterone and AMH. However, the fetus is unable to convert testosterone to dihydrotestosterone in the peripheral tissues and so cannot virilize normally. Presentation is usually with ambiguous genitalia at birth, but can also be with increasing virilization at puberty of a female child, due to the large increase in circulating testosterone with the onset of puberty. In the Western world, the child is usually assigned to a female sex of rearing,.  46XX DSD The most common cause of 46XX DSD, congenital adrenal hyperplasia (CAH), leads to virilization of a female fetus. It is due to an enzyme deficiency in the corticosteroid production pathway in the adrenal gland, with over 90% being a deficiency in 21-hydroxylase, which converts progesterone to deoxycorticosterone and 17-  The reduced levels of cortisol being produced drive the negative-feedback loop, resulting in hyperplasia of the adrenal glands. This leads to an excess of androgen precursors and then to elevated testosterone production. Raised androgen levels in a female fetus will lead to virilization of the external genitalia. The clitoris is enlarged and the labia are fused and scrotal in appearance. The upper vagina joins the urethra and opens as one common channel onto the perineum.  two-thirds of children with 21-hydroxylase CAH will have a ‘salt-losing’ variety, which also affects the ability to produce aldosterone. This represents a life threatening situation, and those children who are salt-losing often become dangerously unwell within a few days of birth. Affected individuals require life-long steroid replacement, such as hydrocortisone, along with fludrocortisone for salt losers. Once the infant is well and stabilized on their steroid regime,surgical treatment of the genitalia is considered.  all female infants with CAH underwent feminizing genital surgery within the first year of life. Thank you