DSD (Disorders of sexual development), Intersex.pptx
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Disorders of sexual differentiation can cause ambiguity between male and female characteristics. These include differences in chromosomes, gonads, genitals or hormone levels. Evaluation of an infant with ambiguous genitalia involves a thorough history, physical exam, lab tests like karyotyping and hormone levels, and imaging to determine the underlying condition. Management is usually by a multidisciplinary team and may involve counselling, hormone treatment or surgery depending on the specific diagnosis and assigned sex of rearing. The goal is to properly diagnose and treat the condition while avoiding harming the individual's psychosocial well-being.
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DSD (Disorders of sexual development), Intersex.pptx
- 1. Disorders of sexual differentiation By Dr. Ahmed Mohamed Amin Nasef Assistant lecturer in obstetrics& gynecology department Benha University
- 2. DSD Group of disorders in which differentiation between male and female couldn’t be done clearly Intersexuality (intersex) There is discordance between any two of the organic sex criteria (chromosomal, gonadal, internal genitalia, external genitalia or phenotypic sex) Transsexuality discordance between organic sex & psychological sex components
- 3. Chromosomal sex XX or XY gonadal sex ovary or testis internal genitalia tubes, uterus, vagina or epididymis, vas external genitalia vulva, penis& scrotum phenotype sex feminization or masculinization
- 4. Sex determination time 1st at fertilization Indifferent stage till 6 weeks During rest of pregnancy become differentiated At delivery
- 5. Indifferent stage of sexual development 2 longitudinal tube are present on each side of the midline The mesonephric duct (Wolffian duct) The paramesonephric duct (Mullerian duct)
- 6. What is Mullerian duct? Mullerian ducts are the primordial form of the female reproductive tract They are two longitudinal tubes one on each side of the midline They differentiate to form the fallopian tubes, uterus, the uterine cervix, and the superior part of the vagina
- 7. So, what is the mesonephric duct? It’s the primitive duct which will develop into the male genital system (the epididymis, vas deferens, ejaculatory duct, and seminal vesicle)
- 9. Requirements for male XY Intact SRY region on Y chromosome Testis secreting AMH& testosterone 5 alpha reductase enzyme Intact receptor sensitivity for testosterone
- 10. SRY region on Y chromosome The only gene on Y chromosome responsible for sex determination If absent the differentiation to male will never occur
- 11. AMH Secreted by Sertoli cells Responsible for regression of Mullerian duct If absent fetus will develop into female internal genitalia
- 12. Testosterone Secreted by ley dig cells Stimulate development of wolffian duct (vas, epididymis& seminal vesicles) If absent so wolffian ducts will not develop Its effect is paracrine effect
- 13. DHT 5 alpha reductase enzyme transform circulating testosterone into DHT which act locally on external genitalia to develop into male So, in presence of DHT locally external genitalia will develop into male In absence of DHT locally (whether due to absent 5 alpha reductase enzyme or receptor insensitivity to DHT) external genitalia will develop by default into female So, circulating testosterone level can affect external genitalia development
- 14. Requirements for female XX Ovaries Internal genitalia develop in absence of AMH External genitalia develop by default in absence of androgen Normal adrenal gland function (21 hydroxylase enzyme, 11 beta hydroxylase enzyme& 3 beta hydroxysteroid dehydrogenase enzyme)
- 15. DSD classification A- Female pseudo hermaphroditism Excess fetal androgen CAH Excess maternal androgen Maternal androgen secreting tumors (ovary, adrenal) Maternal ingestion of androgenic drugs (testosterone, synthetic progestins, minoxidil, streptomycin& penicillamine) B- Male pseudo hermaphroditism Failure to produce testosterone Sweyer syndrome Testicular regression syndrome Leydig cell agenesis Enzymatic testicular failure Failure to utilize testosterone 5 alpha reductase deficiency Testicular feminization syndrome (TFS) androgen insensitivity
- 16. DSD classification C- Sex chromosome DSD Turner syndrome Klinefelter syndrome Mixed gonadal dysgenesis True hermaphroditism
- 17. Historical origin of the word hermaphrodite Hermaphroditus, the son of the Greek god Hermes (the symbol of power) and the goddess Aphrodite (the symbol of beauty), origin of the word "hermaphrodite“ Salmacis loved Hermaphroditus till madness, but he didn’t love her She asked gods of Olympias to make their bodies unit And they agreed her, and their bodies melted and united together, so Hermaphroditus had both male and female external& internal genitals, also he has both male and female phenotypic criteria So, in medical field the word hermaphrodite was given to those persons who has inability to be distinguished whether male or female
- 19. CAH
- 21. Congenital adrenal hyperplasia (CAH) Autosomal recessive trait, Familial disease The commonest cause of genital ambiguity at birth Congenital as the pathology occur during intrauterine life Adrenal hyperplasia as there is overproduction of adrenal hormones including androgens
- 22. CAH pathogenesis • Deficiency of 21 hydroxylase enzyme • Leading to reduced cortisol levels • Increased ACTH • Bilateral adrenal hyperplasia • Increased secretion of all adrenal gland hormones including androgens • Increased 17 hydroxyprogesterone in blood & its metabolite 17 ketosteroid in urine • Excess androgens in female fetus affect external genitalia making it develop into male external genitalia despite being chromosomally female XX
- 23. Other enzymatic deficiency causes CAH 11 beta hydroxylase Hypertensive form of CAH Hypertension at delivery Salt retaining form Due to increased deoxy cortisol and deoxy corticosterone 3 beta hydroxysteroid dehydrogenase Hypotensive form of CAH May present with shock at delivery Lethal Salt losing form of CAH
- 24. Chromosomes 46 XX Gonads ovary Internal genitalia Mullerian (tubes, uterus & vagina) External genitalia disturbed genital folds fuse instead of labia minora phallus enlarges so appear to be male at birth with hypospadias misdiagnosed as male with non descended testes
- 25. Clinical picture At birth ambiguous genitalia Precocious puberty (heterosexual) virilization symptoms in female earlier with pubic and axillary hair appearance with deepening of voice at 2-4 years Ovaries are normally developed but excess androgen leads to anovulation If male child was affected by CAH, this will present by precocious masculinity (infant Hercules)
- 26. Investigations 17 hydroxyprogesterone levels increased in blood 17 ketosteroids levels increased in urine
- 27. Treatment Small dose of corticosteroid preparations to inhibit ACTH release and to allow adrenal gland to function normally Treatment must be continued throughout life Plastic surgery to the external genitalia Early management is very important
- 29. Sweyer syndrome 46XY No SRY No androgens Female External genitalia No AMH Female Internal genitalia Streak gonads
- 30. Testicular regression syndrome 46 XY Testes Testes self destruction Testosterone decreased or deficient Female external genitalia or ambiguous genitalia AMH Male internal genitalia
- 31. Ley dig cell agenesis 46 XY Testes Absent ley dig cells Absent testosterone Female external genitalia or ambiguous genitalia AMH Male internal genitalia
- 32. Testicular enzymatic failure 46 XY Testes Defect in testosterone synthesis Increased testosterone precursors Decreased DHT Ambiguous external genitalia AMH Male internal genitalia
- 33. 5 alpha reductase deficiency 46 XY Testes Testosterone Decreased 5 alpha reductase Decreased DHT Female or ambiguous external genitalia AMH Male internal genitalia
- 34. Testicular feminization syndrome (TFS) 46 XY Testes Testosterone 5 alpha reductase DHT Absent androgen receptors Female external genitalia Male internal genitalia AMH Male internal genitalia
- 37. Turner syndrome
- 38. Henry Hubert Turner • American endocrinologist and he is the first one to describe Turner syndrome in 1938
- 39. Turner syndrome is a genetic disorder affecting girls and women. The cause of Turner syndrome is a completely or partially missing X chromosome
- 40. It is the most common sex chromosomal abnormality found in females about 1 in every 2,500 female babies is born with Turner syndrome
- 41. Genotype 45 chromosomes (45 XO) Or may be mosaic containing this cell line
- 42. For normal female development 2 X chromosomes should be present Presence of the second X chromosome is essential for ovarian development and maintenance
- 43. Why there is deficient other X chromosome? Deletion of the other sex chromosome during division Mosaicism Inherited turner but very rare
- 44. Turner syndrome is usually not inherited but is a random event during reproduction
- 45. Mosaicism during division of chromosomes they may divide across their centrosomes instead of longitudinal division---- isochromosome formation This happens in only one or 2 cells during early stage of segmentation of the fertilized ovum---- these cells reproduce in their offspring cells ---- so 2 cell lines develop in the fetus (e.g 46XX- 45XO, 46XY-45XO)
- 46. Effects on genital apparatus& phenotype depend on which cell line is dominant and their tissue distribution if predominant 45XO gonad isn't likely to develop, other tissues in the body are 46XX if predominant 46XX ovary develop and function despite elsewhere dominant cell line is 45XO if predominant 46XY testes will develop despite elsewhere cell line is 45XO
- 47. Genes which protect against physical malformations of Turner syndrome are carried on short arm of two matching XX Genes which protect against streak gonads are on long arms short arm deletion---- short fertile long arm deletion---- long infertile
- 48. Genitalia External infantile Internal streak ovaries (fibrous bands with no follicles)
- 49. Phenotype
- 52. Does people with Turner syndrome have developmental delays? People with Turner syndrome typically have normal intelligence
- 53. Suspicion in neonate Lymphedema of dorsum of hand& feet Short 4th metacarpal
- 54. Investigations This is a case of hypergonadotrophic hypogonadism so decreased estrogen & increased FSH Karyotyping
- 56. Management 1- cyclic E&P to stimulate breast, menstruation, prevent osteoporosis& CVD GH may be added 2- in mosaic types with Y cell line oophorectomy was done as there is risk for malignancy 3- oocyte donation which is forbidden in some societies for cultural& religious beleifs
- 57. Note Turner female may get pregnant but will enter in menopause early due to poor ovarian reserve from premature ovarian failure Turner female may be tall and get menses
- 58. Klinefelter syndrome 47 XXY Male phenotype Caused by nondisjunction Tall Testicular& genital hypoplasia Female distribution of fat & gynecomastia Mental defects Hypoplastic external genitalia Small phallus with undescended testes
- 59. True hermaphroditism Very rare Gonads ovary on one side & testes on other side or bilateral ovotestis Karyotype 46 XX, XY Internal Mullerian & wolffian Gonadal biopsy is needed for definitive diagnosis
- 60. Mixed gonadal dysgenesis Combined features of Turner syndrome & male pseudo hermaphroditism Short stature Streak gonads on one side with testes on other side Karyotype 46 XY / 46 X0
- 61. Very difficult to reach a definitive diagnosis but its not impossible so proper management must be done
- 63. Clinical presentation of intersex At birth ambiguous genitalia During childhood heterosexual features During adolescence delayed puberty or heterosexual precocious puberty
- 65. Ambiguous genitalia Term given when the external genital organs look unusual, making it impossible to identify the sex or the newborn from its outward appearance
- 66. Ambiguous genitalia causes A- Female pseudo hermaphroditism Excess fetal androgen CAH Excess maternal androgen Maternal androgen secreting tumors (ovary, adrenal) Maternal ingestion of androgenic drugs (testosterone, synthetic progestins, minoxidil, streptomycin& penicillamine) B- Male pseudo hermaphroditism Failure to produce testosterone Testicular regression syndrome Leydig cell agenesis Enzymatic testicular failure Failure to utilize testosterone 5 alpha reductase deficiency Testicular feminization syndrome (TFS) androgen insensitivity
- 67. Ambiguous genitalia causes C- True hermaphroditism D- Mixed gonadal dysgenesis
- 68. Risk factors Family history Maternal drug exposure during pregnancy Maternal ovarian or adrenal androgen secreting tumors Unexplained death in early infancy
- 69. Clinical picture of ambiguous genitalia Any of the following Small, hypospadic phallus with unilateral undescended gonads Enlarged phallus with bilateral impalpable gonads Enlarged phallus & vagina
- 70. Management of ambiguous genitalia Should include the following items General guidelines History taking Examination Investigations Surgical considerations
- 71. General guidelines Ambiguous genitalia is a medical& social emergency Avoid immediate declaration of sex Proper counselling & psychiatric support of parents Sex may not be clearly defined till age of 1.5 years MDT management (obstetrician, hematologist, pediatrician, endocrinologist, genetist& pediatric surgeon)
- 72. History taking Thorough history taking as regard Family history Consanguinity Pregnancy Drugs given during pregnancy
- 73. Examination General hypertension in the hypertensive form of CAH hypotension& shock at delivery in the lethal form of CAH Abdominal abdominal masses (ovarian or adrenal) Fredman rule a palpable gonads below inguinal ligament is testes till prove otherwise Local hypospadias fused labia clitoromegaly undescended testes
- 74. Investigations 1st priority is to rule out CAH by sending 2 samples to the laboratory One blood sample ------ to detect 17 hydroxyprogesterone The other is urine sample ------ to detect 17 ketosteroids Karyotyping buccal smear Testosterone, DHT, testosterone precursors Pelvic US, MRI Skin biopsy to detect activity of 5 alpha reductase enzyme Laparoscopy & gonadal biopsy to confirm diagnosis
- 75. Diagnosis of XY pseudo hermaphroditism Testosterone concentration low Testosterone precursors concentration Increased Testicular enzymatic failure Decreased Absent testes or ley dig cell agenesis Normal male level DHT low 5 alpha reductase deficiency Normal TFS
- 76. Surgical considerations Remove any intra abdominal gonads Clitoral reduction if the assigned sex is female Vaginal reconstruction and repair around puberty
- 77. Take home message • Never declare sex at birth until being sure cause you will harm this individual all his life • If confused call for help • Please be a doctor and don’t be Om Elsaad