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Disorders of gonadal and sexual development

Disorders of gonadal and sexual development. BESHG Postgraduate course in human genetics 2013 - 2014.

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Disorders of gonadal and sexual development

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  1. Disorders of gonadal and sexual development BESHG Postgraduate course in human genetics 2013 - 2014

  2. 1.Normal Sexual differentiationA. HistoryB. General pictureC. Genes implicated 2. Anomalies of sexual differentiationA. Abnormal number of sex Chromosomes:B. Abnormal sex differentiation with normal KaryotypeC. True HermaphrodismD. Induced pseudohermaphrodismwww.ipg.be

  3. 1.Normal Sexual differentiationA. History

  4. -1940 role of the gonads (Jost)-1960 discovery of the role of Y chromosome. (Welshons and Russel)-1989 discovery of SRY(Lovell-Badge)

  5. B. General pictureDETERMINATION OF SEX.-Karyotypic ( genetic) sex:presence of a Y chromosome results in testicular development.-Gonadal sex:Presence of ovarian or testicular tissue-Ductal Sex: Presence of Mullerian (female) or Wolffian (male) ducts-Phenotypic ( genital ) sex:external appearance of the genitalia.

  6. Until 7 week of gestation , gonads are bipotentialIn male fetus the Y chromosome acts as a dominant male determinant this result of the action of a single gene, SRY. SRY initiate testis rather than ovary development

  7. C. Genes implicated Active in Male and Female fetuses- WT1 (11p13): formation of the primitive gonads - SF1 (9q33): regulation of steroidogenesis

  8. Active in Male fetuses- SRY (Yp11.3): Induce testis differentiation- SOX9 (17q24): Activate expression of AMH- AMH (19p13.3): Induce regression of Müllerian ducts

  9. Active in Female fetuses- DAX1 (X p21.3): Inhibit SRY and SOX9- WNT4 (1p35): regulation of female development, antagonism of testosterone- RSPO1(1p34): Inhibit SOX9

  10. C. Genes implicated

  11. 2.Abnormal Sexual differentiationBetween 0.1% and 0.2% of live births are ambiguous enough to become the subject of specialist medical attention. But for a lot of the following syndromes, problems may only appear at puberty or later (infertility).The specialists use the term « DSD »:Disorders of Sex Development.

  12. A. Abnormal number of sex Chromosomes:46 YY and 45 Y are fatal. We need at least one X chromosome to surviveTrisomy X (47 XXX)Female, generally asymptomaticextra Xs are inactivatedmild mental retardation (more severe in 48 XXXX and 49 XXXXX patients)1/2000 birth

  13. Turner Syndrome (45 X, monosomy X)•Cystic hygroma and Hydrops fetalis.•Congenital Heart disease, including coarction of the aorta•Short stature•Common cause of female hypogonadism•Failure to develop secondary sex characteristics•Atrophic streaked ovaries•Primary amenorrhea> Infertility•No Barr body present

  14. Turner Syndrome1/5000 birth

  15. Turner Syndromeshort stature;short webbed neck; cubitus valgus; Lymphedema.

  16. Turner Syndrome

  17. - Klinefelter syndrome (47,XXY) & Klinefelter variants (48,XXXY 49,XXXXY,etc)•Caused by meiotic nondisjunction•Common cause of male hypogonadism•Testicular atrophy•Infertility due to azoospermia•Female distribution of hair•Long limbs, narrow shoulders•Gynecomastia1/2000 birth

  18. -   47, XYY syndromenot associated to a particular phenotypenormal intelligence, not dysmorphicnormally fertile> hyperactivity and impulsivity is frequent,True psychopathology (« crime chromosome ») is not common.1/2000 birth

  19. B. Abnormal sex differentiation with normal KaryotypeAlteration (duplication, deletion or mutation) of any of the implicated genes could result in sex reversal and/or gonadal dysgenesis

  20. 46XY female - SRY deletion / mutation (Swyer Syndrome) - WNT4 duplication - DAX1duplication - SOX9 deletion (campomelic dysplasia) - WT1 mutation (Frasier & Denys-Drash Syndrome) 46 XX male - SRY translocation - SOX9 duplication - RSPO1 mutation

  21. Campomelic dysplasiamutation of SOX9- Dysmorphic- bowing of long bones- abnormal extremities- Sex Reversal- Gonadal Dysgenesis

  22. Congenital Adrenal Hyperplasia (CAH)Deficiency of21-Hydroxylase(90 % of the cases)mineralocorticoid deficiency > Female pseudohermaphrodism60 % of the intersex cases at birth1/15000 live birth

  23. Congenital Adrenal Hyperplasia (CAH)Ambiguous genitalia in CAH

  24. Virtually all enzymes of the chain may be deficient and cause more or less severe disorder including DSD

  25. 5 alpha-reductase deficiency Testosterone is not converted in DHTMale pseudohermaphrodismMostly female phenotypeor ambiguous genitaliaVirilisation at pubertyThe gene is located in 2p23 Autosomal recessive

  26. 5 alpha-reductase deficiency

  27. 5 alpha-reductase deficiency

  28. Androgen Insensitivity Syndrome (AIS)mutations in AR, gene for the human Androgen Receptor, located at Xq11-12three subtypes : complete * (female phenotype) partial (male, female or ambiguous) mild (male genitalia)* =(Testicular feminization Syndrome)1/20.000 birth

  29. Androgen Insensitivity Syndrome (AIS)Mild form Complete

  30. Persistent Müllerian Duct Syndrome (PMDS)Mutation of AMH geneAutosomal recessivenormally virilised XY patientsDevelop both wolffian and müllerian structures Often a late discovery during surgeryor during investigation for undescended testis

  31. Sporadic and/or environmental syndromes (1)* Mayer Rokitansky Kuster Hauser Syndrome (MRKH)Vaginal agenesis or incomplete vaginaBetween 1940 and 1980, cases were associated to maternal intake of Diethylstilbestrol (DES)* MURCS associationMullerian ducts hypoplasia (aplasia)Renal agenesis Cervical Somite dysplasia

  32. Sporadic and/or environmental syndromes (2)* Caudal regression syndromeVariable defects of lumbar spine and inferior limbsUro-genital anomalyextreme form > Sirenomelia Associated to gestational diabetes

  33. Caudal regression

  34. Caudal regression (2)

  35. Caudal regression (3) / sirenomelia

  36. C. True Hermaphrodism Presence of both ovarian and testicular tissue Genetic Sex: 46XX/46XY, 45X/ 46XY mosaicsGonadal Sex:Ovotestes: A gonad with both testicular and ovarian tissue.or more rarely ovary on one side and testes on the other.Ductal Sex: Often mixedPhenotypic sex : Ambigous genitaliaExceptionally rare.

  37. C. True Hermaphrodism

  38. C. True Hermaphrodism ovotestes

  39. D. Induced pseudohermaphrodism - iatrogenic: female pseudohermaphrodism due to an intake of progestational agents or androgens during the first trimester. - maternal endocrine disorders:most endocrine maternal abnormalities usually prevent pregnancy if initially present.Some ovarian tumours have been reported as a cause of virilisation of female fetus.

  40. Questions ?

  41. This part of the course covers the chapters “The sex chromosomes and their abnormalities” and “disorder of gonadal and sexual development” of the Thompson & Thompson genetics in medicine” p98 to 113. • A summary of the course is available on our website: http://www.ipg.be/fr/activites-28.htm • Info or questions: christian.dugauquier@ipg.be

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