Disorders of Sex development( DSD, defination, classification, CAH, AIS,Turners syndrome, klinefelter syndrome, investigations, management) .pptx

Presentation on DSD( Disorders of Sex Development in Human) .

1. DISORDERS OF SEX DEVELOPMENT (DSD) Moderator:- Dr. Kankan Talukdar , Asst Professor,Dept . of Obstetrics and Gynecology, FAAMCH. Presenter:- Dr. Bhimi daimari PGT

2. DEFINITION Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal , or anatomic sexual development is atypical. Previously also termed as Intersex ( stigmatising and controversial). Atypical /ambiguous genitalia- any case in which the external genitalia do not appear to be completely male or female.

3. NORMAL SEXUAL DIFFERENTIATION It consist of 3 sequential processes— Chromosomal sex- at time of fertilization (XX OR XY) Gonadal sex- testis or Ovary. Phenotypic sex- internal and external genitalia( male or female).

4. Normal sex development Every human foetus is destined to be a female foetus . Early embryo is potentially bisexual upto 6 th week of intrauterine life.

5. Flow chart 1: sex determination of embryo ( REF: Jeffcoate’s principles of Gynaecology 8 th ed.

6. Ref:- williams Gynecology 2 nd ed.

7. Classification DSD is broadly classified into 3 categories according to gonadal histology:- CAT 1- 46, XX DSD (female pseudohermaphroditism / Overvirilized XX female / Masculinized XX female). CAT 2 – 46,XY DSD (male pseudohermaphroditism / undermasculinized XY male / undervirilized XY male).

8. CAT3 – disorders of genetic or gonadal development . Sex chromosome DSD ( Turner syndrome , Klinefelter syndrome ,mixed gonadal dysgenesis ). Ovotesticular DSD (True hermaphroditism ). Embryonic testicular regression.

9. 46,XX DISORDERS OF SEX DEVELOPMENT It includes the following conditions: Ovarian development disorders Gonadal dysgenesis Ovotesticular DSD Testicular DSD Excess of androgens Fetal congenital adrenal hyperplasia. Fetoplacental enzymes deficiency ( aromatase oxidoreductase ) Maternal ingestion of androgenic drugs ( e.g danazol , progestogens , testosterone) or maternal androgen secreting tumor( e.g luteoma ). Misc: vaginal agenesis, cloacal exstrophy .

10. 46, XX DSD It occurs due to excessive fetal androgen exposure in a fetus with karyotype 46 XX at the time when genitals are forming . The ovaries, uterus , cervix and upper vagina are present. Affected Individuals are potentially fertile. External genitalia is virilized to varying degree( clitoromegaly  posterior labial fusion  phallus with penile urethra).

11. Normal relations between the hypothalamic pituitary system and adrenal cortex. (ref: Jeffcoate’s principles of Gynaecology 8 th ed.)

12. Fetal congenital adrenal hyperplasia (CAH) due to deficiency of 21- hydroxylase enzyme is most common cause of 46 XX DSD (incidence=1 in 14000 LB). CAH -It is an autosomal reccessive disorder resulting from an enzymatic defect in the cortisol synthesis pathway in the adrenal cortex.

13. Relations between the hypothalamic pituitary system and adrenal cortex in congenital adrenal hyperplasia. (ref: Jeffcoate’s principles of Gynaecology 8 th ed.)

14. In Classical form of CAH ( 21- hydroxylase enzyme deficiency) – A mbiguous genitalia, non palpable gonads In 1 st week of life – vomiting, dehydration. In milder forms- obesity, hersutism ,amenorrhea may manifest at puberty .

15. Pic showing baby (case of congenital adrenal hyperplasia) with ambiguous genitalia.

16. Diagnosis of CAH – Prenatal period- positive family history of CAH –chorionic villus sampling shows increased levels of 17-hydroxyprogesterone, androestenedione , 11 deoxycorticosterone . In Neonatal period- Hyponatremia , hypoglycemia, hyperkalemia . Raised serum 17 hydroxyprogesterone .

17. Increased urinary excretion of pregnanetriol and 17- ketosteroids USG OR MRI abdomen and pelvis- shows presence of ovaries, uterus ,fallopian tubes, vagina. Late onset of CAH- presents at puberty with obesity, hirsutism , signs of virilization . > 800ng/dl of 17 hydroxyprogesterone in serum are diagnostic.

18. The 3 embroyonic structures that are commonly affected by elevated androgen levels are the clitoris, labioscrotal folds, and urogenital sinus. Objectives of reconstructive surgery ( feminizing genitoplasty )- To decrease enlarged clitoral size while maintaining vascularity and sensory innervations( clitoroplasty )- 5-10 years of age. To reduce and feminize the labioscrotal folds. ( labial separation procedure is done at puberty) To create a separate vaginal introitus in perineum.

19. 46,XY DISORDERS OF SEX DEVELOPMENT It includes the following conditions: Testicular development disorders Swyer’s syndrome( complete gonadal dysgenesis ) Partial or incomplete gonadal dysgenesis . Gonadal regression. Ovotesticular DSD. Defective androgen synthesis or action Defective biosynthesis of androgen Defective androgen action( complete or partial androgen insensitivity) LH receptor defects. Misc:cloacal exstrophy , severe hypospadius .

20. 46,XY DSD Insufficient androgen exposure of a fetus destined to be a male ( karyotype 46,XY) leads to this condition of DSD. Etiology- Enzyme defect in biosynthesis of testosterone. Peripheral enzyme defect (5alpha reductase )- impaired conversion of testosterone to DHT. Abnormalities in the androgen receptors.

21. STEROIDOGENESIS PATHWAY ( ref: williams gynecology 2 nd ed.)

22. ANDROGEN INSENSITIVITY SYNDROME(AIS) Previously termed as male pseudohermaphroditism or testicular feminizing syndrome. It is usually X linked recessive disorder. Incidence – 1 in 13000 to 1 in 41000 LB. 2 TYPES- complete and partial AIS.

23. Partial AIS ( Reifenstein’s sydrome )- A mbiguous genitalia, poor virilization , severe male factor infertility are present. Complete AIS- A ppears phenotypically as female at birth. Presents at puberty with primary amenorrhea, scanty/absent pubic and axillary hair, short/blind vagina, absent uterus , ovaries and fallopian tubes .

24. May have breasts development during puberty due to abundant peripheral androgen to estrogen conversion . Testes may be palpable in the labia / inguinal canal/ intra abdominally. S.testosterone level are normal or slightly raised, LH is elevated.

25. Treatment of CAIS- Surgical excision of gonad/testes after puberty- to reduce risk of germ cell tumors( 20-30% high risk). Individuals are given female gender identity. Estrogen replacement therapy is given for maintaining breast development and bone mass and to provide relief from vasomotor symptoms. Vaginoplasty may be done before marriage after proper counselling in affected individuals.

26. SWYER’S SYNDROME It is also previously known as acquired male pseudohermaphroditism with pure XY gonadal dysgenesis . Mutation in SRY gene  testes not formed No testosteronemale internal and external genitalia fails to develop. Absent MIF and AMH female phenotype with absent secondary sex characters and primary amenorrhea . Individuals are reared as females.

27. Treatment- Gonadectomy done due to 30% malignancy risk. Cyclical estrogen and progesterone therapy for inducing menses . In vitro fertilization with donor egg for conception.

28. SEX CHROMOSOME DISORDERS OF SEX DEVELOPMENT It includes the following conditions: Turner syndrome ( 45,XO) Klinefelter syndrome (47,XXY) Mixed gonadal dysgenesis (45,XO/ 46,XY)

29. TURNER’S SYNDROME Karyotype 45XO (50-60% cases). Results from nondisjunction of parental chromosomes. Patients are diagnosed at adolescence, presenting with short stature, prepubertal female genitalia, primary amenorrhea. It is characterized by presence of streak gonads/ovaries , normal uterus ,fallopian tubes and vagina.

30. Pic ref: william’s Gynecology 2 nd ed.

31. S. FSH and S. LH are elevated. S. Estradiol is low(<25pg/ml). Sex chromatin study is negative in absence of Barr body( Barr body 1 st appears in trophoblast cells at about the 12 th day and in the tissue of foetus itself by the 18 th day).

32. TREATMENT- Hormone replacement therapy- it is started near age of 12 years or at time of diagnosis. Started with low dose oral estradiol 0.25 mg daily for 6 months. It is then sequentially increased every 6 months through daily doses of .5mg , .75mg . 1mg, and then 2mg. Progesterone is begun after approximately 1 year of unopposed estrogen treatment. Each month , micronized progesterone 200mg orally at bedtime is given for 12 nights and then stopped to permit withdrawal bleeding.

33. This method mimics the normal pubertal hormonal stimulation of breast tissue . The patient is then maintained on 2mg of oral estradiol and monthly withdrawal to progesterone. Alternatively a low dose OCPs can also be used instead as maintainance drug.

34. KLINEFELTER’S SYNDROME Karyotype is 47XXY. Incidence is 1:500 in males. Phenotype is male but individuals affected have tall stature, eunuchoid appearance, high pitched voice, gynaecomastia , small or normal penis , small normally place testes, sterile/infertile , mental retardation. Testicular biopsy shows- hyaline degeneration of seminiferous tubules. Treatment include testosterone replacement therapy, breast surgery for gynecomastia .

35. PIC Ref: Jeffcoate’s principles of Gynecology 8 th ed

36. OVOTESTICULAR DSD Earlier termed as true hermaphrodite. Karyotype is 46XX (most common) followed by 46XX /46XY . Affected individuals have both ovarian and testicular gonadal tissue.( includes unilateral ovovtestis with contralateral ovary or testis ,or bilateral ovatestes ). Their fertility remains poor.

37. Location of gonads-abdominal/ inguinal/scrotal. External genitalia-usually ambiguous but individuals may have female or male phenotype. Internal ductal system- depends on ipsilateral gonad and its degree of differentiation.

38. The amount of AMH and testosterone present determines the degree to which the internal ductal system is masculinized or feminized. Diagnosis- laparoscopic examination and gonadal biopsy . Dysgenetic or streak gonads are removed due to risk of malignancy.

39. CLINICAL EVALUATION OF DSD CASE ( NEWBORN WITH AMBIGUOUS GENITALIA) History – family history of dsd,consanguity , antenatal history of intake of androgenic drugs or hormones , hormone secreting tumor. Clinical examination – Dysmorphic features- webbing of neck, hyperpigmentation,edema . Overt amiguous genitalia. Female genitalia with clitoromegaly , labial fusion with or without inguinal or labial mass. Male genitalia with bilateral undescended testes, small penis and hypospadias .

40. Flow chart showing Evaluation of a neonate with ambiguous genitalia.

41. GENDER ASSIGNMENT IN NEONATE: At birth , gender assignment to the normal newborn usually involves a simple assessment of the external genitalia . In cases of baby with ambiguous genitalia , proper counselling and reassurance to parents is done and family should be involved in decision making. Counselling should include need for hormonal stimulation at puberty and potential later surgical reconstruction.

42. Appropriate assesment must be performed by a multidisciplinary team . Most Patients with 46 XX CAH and all patients with 46XY complete androgen insensitivity syndrome should be assigned female gender.

43. Patients with 5alpha reductase deficiency and partial androgen insensitivity syndrome are usually assigned female gender in infancy but may like to live as males if virilization is severe at puberty. In ovotesticular DSD , gender assignment depends upon potential for fertility as per gonadal differentiation, genital development and surgical procedure performed.

44. SURGICAL TREATMENT More emphasis is given to functional outcome instead of cosmetic outcome. Gonadectomy is performed in AIS and gonadal dysgenesis due to risk of gonadoblastoma .