DISORDERS OF SEXUAL DEVELOPMENT BASICS.PPT

DSD BASICS

1. DISORDERS OF SEXUAL DEVELOPMENT Dr V V A CH SEKHAR REDDY 1 st YEAR DrNB APOLLO,JUBILEE HILLS

2. OBJECTIVES INTRODUCTION EMBRYOLOGY, NORMAL DEVELOPMENT, PHYSIOLOGY OF SEXUAL DEVELOPMENT. CLASSIFICATION OF DSD CONGENITAL ADRENAL HYPERPLASIA EVALUATION OF NEWBORN WITH AMBIGUOUS GENITALIA MEDICAL MANAGEMENT SURGICAL MANAGEMENT

3. 1 INTRODUCTION

4. 1 IN 5000 BIRTHS CAH AND MIXED GONADAL DYSGENESIS ARE MOST COMMON FORMS OF DSD (50% OF CASES) OLD TERMINOLOGY LIKE INTERSEX, HERMAPHRODITES HAVE BEEN REPLACED CAN BE AN ENDOCRINE EMERGENCY IN NEWBORNS AND PSYCHOSOCIAL STIGMA FOR BOTH PARENTS AND GROWING CHILD

5. DSD DSD DEFINED AS ANY ATYPICAL DEVELOPMENT OF CHROMOSOMAL/GONADAL/PHENOTYPIC SEX SUSPECT IF ANY ATYPICAL EXTERNAL GENITALIA, DELAYED PUBERTY, AMENORRHOEA, INFERTILITY ETC. 2006 CHICAGO CONSENSUS STILL FORMS BASIS FOR MANAGEMENT OF DSD

6. AMBIGUOUS GENITALIA AN INFANT WITH 2 OR MORE OF CRYPTORCHIDISM HYPOSPADIAS MICROPHALLUS <2.5CM OR CLITOROMEGALY >1CM

7. 2 EMBRYOLOGY NORMAL DEVELOPMENT PHYSIOLOGY OF SEXUAL DEVELOPMENT STERIOD HORMONE SYNTHESIS PHYSIOLOGY

8. MALE FEMALE CHROMOSOMAL SEX 46XY 46XX GONADAL SEX (6 WEEKS OF GESTATION BIPOTENTIAL GONAD WILL BECOME TESTIS IN THE PRESENCE OF SRY GENE BIPOTENTIAL GONAD WILL BECOME OVERY IN THE ABSENCE OF SRY GENE HORMONAL SEX SERTOLI CELLS -> AMH -> WOLFIAN DUCT DEVELOPS INTO MALE INTERNAL GENITALIA LEYDIG CELLS -> TESTOSTERONE -> MALE EXTERNAL GENITALIA NO AMH & TESTOSTERONE -> WOLFFIAN DUCT REGRESS, MULLERIAN DUCT DEVELOPS INTO FEMNALE INTERNAL AND EXTERNAL GENITALIA PHENOTYPIC SEX MALE FETUS FEMALE FETUS

9. 3 CLASSIFICATION OF DSD

10. NOMENCLATURE

11. 1.DISORDERS OF GONDAL DIFFERENTIATION KLINFELTER SYNDROME – 46XXY MALE TURNER SYNDROME – 46X0 FEMALE 46XX MALE PURE GONDAL DYSGENESIS MIXED GONADAL DYSGENESIS PARTIAL GONADAL DYSGENESIS BILATERAL VANISHING TESTIS AND EMBRYONIC TESTICULAR REGRESSION SYNDROME

12. 46XX MALE MALE PHENOTYPE WITH NORMAL SKELETAL ARCHITECTURE COMPARED TO KLINFELTER ALL ARE INFEERTILE DUE TO TRANSLOCATION OF SRY GENE OF Y TO X CHROMOSOME. NEEDS ANDROGENS FOR ATTAINING PUBERTY AND SECONDARY SEXUAL CHARACTERISTICS

13. PURE GONADAL DYSGENESIS – 46 XX 46XX WITH NORMAL FEMALE DEVELOPMENT WITH STREAK OVARIES WITH LACK OF SECONDARY SEXUAL CHARACTERSTICS COMPARED WITH TURNER SYNDOME, NO SOMATIC FEATURES EXIST TREATMENT IS REPLACEMENT OF SEX STEROIDS

14. PURE GONADAL DYSGENESIS – 46 XY(SWYER SYNDROME) NORMAL FEMALE WITH MULLERIAN STRUCTURES WITH STREAK GONADS PRESENT IN THEIR TEENS WITH DELAYED PUBERTY WITH AMENORRHOEA ELEVATED GONADOTROPIN LEVELS GIVES THE CLUE SIGNIFICANT RISK OF DEVELOPING GERM CELL TUMORS (GONADOBLASTOMA) B/L GONADECTOMY WITH ESTROGEN AND PROGESTRONE THERAPY IS THE TREATMENT

15. MIXED GONADAL DYSGENESIS UNILATERAL UNDESCENDED TESTIS WITH OPPOSITE STREAK OVARY WITH PERSISTENT MULLERIAN STRUCTURES AND FEATURES OF MASCULIZATION 45X0/46XY 2 ND MOST COMMON CAUSE OF AMBIGUOUS GENITALIA AFTER CAH INCREASED RISK FOR GERM CELL TUMORS AND WILMS TUMOR(DENYS DRASH SYNDROME) TREATMENT CONSISTS OF GENDER ASSIGNMENT, GONADECTOMY, SCREENING FOR WILMS.

16. PARTIAL GONADAL DYSGENESIS SIMILAR TO MIXED GONADAL DYSGENESIS BUT WITH TWO DYSGENTIC TESTIS VARYING DEGREES OF AMH AND TESTOSTERONE PRODUCTION LEAD TO VARIED DEVELOPMENT OF MULLERIAN STRUCTURES INCREASED RISK FOR GERM CELL TUMORS TREATMENT IS SIMILAR TO MIXED GONADAL DYSGENESIS

17. B/L VANISHING TESTIS SYNDROME AND EMBRYONIC TESTICULAR REGRESSION 46 XY WITH ABSENT TESTIS WITH EVIDENCE OF TESTICULAR FUNCTION AT SOME POINT OF DEVELOPMENT DUE TO GENETIC MUTATION/TERATOGEN/BILATERAL TORSION EMBRYONIC TESTICULAR REGRESSION A/W AMBIGUOUS GENITALIA WHEREAS B/L VANISHING TESTIS A/W NORMAL MALE WITH EMPTY SCROTUM, MICROPHALLUS. LOW TESTOSTERONE WITH ELEVATED GONADOTROPINS WITH BLIND ENDING VAS DURING LAPAROSCOPY.

18. 2.OVOTESTICULAR DSD(TRUE HERMAPHRODITISM) HAVING BOTH TESTIS AND OVARY WITH 46XX/46XY PRESENTED WITH AMBIGUOUS EXTERNAL GENITALIA WITH VARIED DEVELOPMENT OF INTERNAL STRUCTURES MOST OF THE TIMES PRESENT AS MALE WITH HYPOSPADIAS AND CHORDEE OVARY IF PRESENT ON LEFT SIDE AND TESTIS WILL BE USUALLY ON RIGHT SIDE ANYWHERE ALONG ITS PATH OF DESCENT AND MOSTLY DYSGENETIC GONADS DISCOVERED IN LABIOSCRIOTAL FOLD/INGUINAL CANAL MOSTLY WILL BE OVOTESTIS AND DIFFERNCE IN FIRMNESS IN THE POLAR REGION. RAISED AS FEMALE BECAUSE OVARY IS FUNCTIONAL MOST OF THE TIMES

19. 3.46XX DSD ( MASCULINISED FEMALE) MOST CAMMON CAUSE OF AMBIGUOUS GENITALIA AND IS DUE TO CAH RARELY CAUSED BY MATERNAL ANDROGEN SUPPLEMENT/VIRILIZING TUMORS IN MOTHER 95% OF CASES OF CAH ARE DUE TO 21 HYDROXYLASE DEFECIENCY AND 5% DUE TO 11 β HYDROXYLASE DEFECIENCY

20. 5 CONGENITAL ADRENAL HYPERPLASIA

21. HAVING MINERALO CORTICOID PROPERTY

22. 21 HYDROXYLASE DEFECIENCY DIVIDED INTO 3 CATEGORIES SALT WASTERS SIMPLE VIRILIZERS NONCLASSIC 75% ARE SALT WASTERS AND 25% ARE VIRILIZERS NEONATAL SCREENING WITH 17 HYDROXY PROGESTERONE IS VALUABLE TOOL IN BETWEEN 1 ST AND 2 ND WEEKS PRESENTS WITH SYMPTOMS LIKE FAILURE TO THRIVE, FAILURE TO GAIN WEIGHT,VOMITINGS, DEHYDRATION MAY MIMIC PYLORIC STENOSIS/SEPSIS. MALES LOOKS LIKE LITTLE HERCULES WITH PRECOCIOUS PUBERTY WITH SHORT STATURE AND INFERTILITY( DUE TO TESTICULAR ADRENAL REST TISSUE)

23. 4.46XY DSD ( UNDERMASCULINISED MALE) LEYDIG CELL APLASIA(LH RECEPTOR ABNORMALITY) DISORDERS OF TESTOSTERONE BIOSYNTHESIS ANDROGEN RECEPTOR AND POSTRECEPTOR DEFECTS 5 α REDUCTASE DEFECIENCY PERSISTENT MULLERIAN DUCT SYNDROME

24. LEYDIG CELL APLASIA(LH RECEPTOR ABNORMALITY) 46XY WITH FEMALE PHENOTYPE WITH TESTIS PALPABLE IN INGUINAL CANAL OR LABIA WITHOUT ANY MULLERIAN STRUCTURES DELAYED PUBERTY WITH NO SECONDARY SEXUAL CHARECTERISTICS WITH ABSENCE OF RAISE IN SERUM TESTOSTERONE AFTER HCG STIMULATION IS THE HALLMARK

25. DISORDERS OF TESTOSTERONE BIOSYNTHESIS

26. STAR(STEROIDOGENIC ACUTE REGULATORY PROTEIN) DEFECIENCY – CONGENITAL LIPOID ADRENAL HYPERPLASIA DUE TO DEFECT IN CHOLESTEROL TRANSPORT INTO ADRENAL CELL NEONATE, NON VIRILIZED FEMALE WITH ACUTE ADRENAL INSUFFICIENCY WITH CT S/O LARGE LIPID LADEN ADRENAL GLANDS ARE THE HALLMARK FEATURES.

27. 3 β HSD DEFECIENCY SIMILAR TO STAR DEFECIENCY WITH VARYING DEGREES OF MASCULIZATIONDUE TO PARTIAL ACTIVITY OF ENZYME. TREATMENT IS LIKE 21 HYDROXYLASE DEFECIENCY

28. 17 α HYDROXYLASE DEFECIENCY UNDERVIRILISED MALE WITH HYPERALDOSTERONISM i.e. HTN, SALT AND WATER RETENTION WITH HYPOKALEMIA TREATMENT WITH ADMINISTRATION OF GLUCOCORTICOIDS WITH TESTOSTERONE

29. 17,20 LYASE DEFECIENCY UNDERVIRILIZED OR FEMALE LOOKING MALE WITH AMBIGUOUS GENITALIA WITH ABSENT MULLERIAN STRUCTURES WITH NORMAL MINERALOCORTICOIDS AND GLUCOCORTCOIDS

30. 17 β HSD DEFECIENCY AT BIRTH FEMALE PHENOTYPE WITHOUT VIRILIZATION AND AT PUBERTY WILL DEVELOP MALE SECONDARY SEXUAL CHARECTERISTICS WITH PHALLIC GROWTH PROBABLY DUE TO ACTION OF ANDROSTENEDIONE(GENDER REVERSAL ALSO SEEN IN 5 ALFA REDUCTASE DEFECIENCY) GENDER ASSIGNMENT IS CRUCIAL AT PUBERTY AND MAINLY DEPENDS ON PATIENT AND PARENTS PREFERENCE.

31. ANDROGEN RECEPTOR AND POSTRECEPTOR DEFECTS UNDERVIRILIZED 46 XY MALES WITH COMPLETE EXTERNAL FEMINIZATION(CAIS) TO AMBIGUOUS GENITALIA(PAIS) WITH INFERTILITY WITH NO MULLERIAN DERIVATIVES

32. COMPLETE ANDROGEN INSENSITIVITY SYNDROME 46 XY WITH BOTH TESTIS, FEMALE EXTERNAL GENITALIA WITH NO MULLERIAN DERIVATIVES AND FEMALE SECONDARY SEXUAL CHARACTERISTICS DUE TO AROMATIZATION OF TESTOSTERONE WITH SPARSE PUBIC AND AXILLARY HAIR PATIETNS PRESENT WITH AMENORRHOEA WITH NO PUBIC HAIR WITH BOTH TESTIS IN INGUINAL AREA GONADECTOMY DELAYED UNTIL PUBERTY BECAUSE TESTIS IS SOURCE OF ESTROGEN AND MALIGNANCY RISK IS LOW.

33. PARTIAL ANDROGEN INSENSITIVITY SYNDROME X LINKED DISORDER WITH VARYING DEGREES OF PRESENTATION WITH AMBIGUOUS GENITALIA MANAGEMENT IS INDIVIDUALIZED

34. 5 α REDUCTASE DEFECIENCY 46XY WITH AMBIGUOUS GENITALIA OR FEMALE PRESENTATION WITH NORMAL WOLFFIAN STRUCTURES AND ABSENT MULLERIAN DERIVATIVES AND AT PUBERTY MALE SECONDARY SEXUAL CHARECTERISTICS WILL DEVELOP(GENDER REVERSAL ALSO SEEN IN 17 β HSD DEFECIENCY) ELEVATED T WITH LOW DHT IS THE HALLMARK. GENDER ASSIGNMENT IS AGAIN TO BE DISCUSSED WITH PATIENT AND FAMILY

35. PERSISTENT MULLERIAN DUCT SYNDROME(HERNIA UTERI INGUINALE) 46XY WITH NORMAL MALE EXTERNAL GENITALIA WITH INTERNAL MULLERIAN DERIVATIVES WITH VAGINA DRAINING INTO PROSTATIC UTRICLE. DUE TO MUTATIONS IN AMH GENE ORCHIDOPEXY IS THE TREATMENT SHOUD NOT DISTRUB MULLERIAN STRUCTURES BECAUSE OF CLOSE VICINITY TO VAS DEFERENS

36. 5.UNCLASSIFIED – MAYER ROKITANSKY KUSTER HAUSER SYNDROME 46 XX WITH NORMAL FEMALE WITH SECONDARY SEXUAL CHARACTERISTICS AND NORMAL EXTERNAL GENITALIA WITH ABSENT UTERUS AND UPPER PART OF VAGINA PRESENTED WITH PRIMARY AMENORRHOEA ASSOCIATED URINARY TRACT ANAMOLIES LIKE RENAL AGENESIS, HORSE SHOE KIDNEY AND PELVIC KIDNEY CAN OCCUR.

37. 4 EVALUATION OF NEWBORN WITH AMBIGUOUS GENITALIA

38. 6 MEDICAL MANAGEMENT

39. HISTORY FULL NEWBORN HISTORY (PRENATAL, PREGNANCY AND BIRTH HISTORIES) ANY MATERNAL VIRILIZATION DURING THE PREGNANCY: ACNE, HIRSUTISM, FRONTAL BALDING, VOICE DEEPENING OR CLITOROMEGALY MATERNAL HORMONAL DISORDERS PRENATAL DRUG USE CONSANGUINITY DETAILED FAMILY HISTORY LIKE ANY UNEXPLAINED NEONATAL DEATH, AMBIGUOUS GENITALIA, ABNORMAL PUBERTY, INFERTILITY OR AMENORRHEA

40. PHYSICAL EXAMINATION VITALS (INCLUDING BLOOD PRESSURE), WEIGHT, LENGTH, HEAD CIRCUMFERENCE INSPECT FOR DEVELOPMENTAL ABNORMALITIES CONSISTENT WITH A POSSIBLE SYNDROME INSPECT FOR SKIN TURGOR AND HYPERPIGMENTATION DOCUMENT THE NUMBER AND LOCATION OF UROGENITAL OPENINGS PALPATE LABIOSCROTAL FOLDS AND INGUINAL REGION FOR GONADS INSPECT LABIOSCROTAL FOLDS FOR ASYMMETRY, MASCULINIZATION, SWELLING, PIGMENTATION, FUSION AND CREASES INSPECT PENIS FOR HYPOSPADIAS, URETHRAL DEFECTS, OR CHORDEE MEASURE PHALLIC LENGTH; MEASURE CLITORAL LENGTH

41. NVESTIGATIONS KARYOTYPING AND RAPID ANEUPLOIDY TEST USG ABDOMEN AND PELVIS WITH INGUINAL REGION SERUM 17-HYDROXYPROGESTERONE LEVEL SERUM SODIUM, POTASSIUM, RENIN LEVELS SERUM AMH, TESTOSTERONE, LH, FSH, CORTISOL LEVELS

42. TREATMENT INVOLVES MULTIDISCIPLINARY TEAM OF ENDOCRINOLOGIST, PEDIATRICIAN, UROLOGIST, GYNECOLOGIST, PSYCHOLOGIST DEPENDS MAINLY ON THE DIAGNOSIS 3 MOST COMMONLY FOUND DIAGNOSES ARE CAH,MIXED GONADAL DYSGENESIS, ANDROGEN INSENSITIVITY SYNDROME.

43. TRRATMENT OF CAH IN SALT WASTING 21-HYDROXYLASE DEFECIENCY CAH START WITH HYDROCORTISONE, FLUDROCORTISONE PRENATAL DEXAMETHASONE TO MOTHER F/B CHORIONIC VILLLOUS SAMPLING TO DETERMINE SEX AT 12-14 WEEEKS ADVISED IN CARRIERS OR H/O CAH IN MOTHER.

44. CERNOS DEPOT

45. 7 SURGICAL MANAGEMENT

46. FEMINISING GENITOPLASTY MASCULINISING GENITOPLASTY LAPAROSCOPY

47. FEMINISING GENITOPLASTY CREATION OF FEMALE LOOKING LABIA MAJORA, MINORA WITH INTROITUS INVERTED V-Y VAGINOPLASTY F/B VAGINAL DILATATIONS TO PROVIDE ADEQUATE FUNCTIONAL VAGINA OPENING INTO INTROITUS REDUCTION CLITOROPLASTY WITH REDUCTION OF ERECTILE TISSUE i.e. REDUCTION OF PHALLUS WITH PRESERVATION OF GLANS AND ITS NEUROVASCULAR SUPPLY WITH CLITORAL HOOD

48. MASCULINISING GENITOPLASTY REPAIR HYPOSPADIAS WITH CORRECTION OF CHORDEE ORCHIDOPEXY SCROTAL TRANSPOSITION i.e. CORRECT BIFID SCROTUM AND PREPENILE POSITION OF SCROTUM SEPARATE MULLERIAN STRUCTURES FROM URETHRA EXCISE IF ANY GONADAL TISSUE WHICH IS AT RISK OF MALIGNANCY

49. LAPAROSCOPY INDICATIONS TO DIAGNOSE INTRAABDOMINAL ANATOMY WHEN IN DOUBT BIOPSY/EXCISION OF DYSPLASTIC GONADS CONTAINING Y CHROMOSOME EXCISION OF INTERNAL GENITALIA IF NOT REQUIRED FOR ASSIGNED GENDER DIGNOSIS OF COMPLEX CLOACAL ANAMOLIES