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

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Presentation on theme: "Disorders of gonadal and sexual development BESHG Postgraduate course in human genetics 2013 - 2014."— Presentation transcript:

1 Disorders of gonadal and sexual development BESHG Postgraduate course in human genetics

2 1.Normal Sexual differentiation A. History B. General picture C. Genes implicated 2. Anomalies of sexual differentiation A. Abnormal number of sex Chromosomes: B. Abnormal sex differentiation with normal Karyotype C. True Hermaphrodism D. Induced pseudohermaphrodism

3 1.Normal Sexual differentiation A. History

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

5 B. General picture DETERMINATION 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 bipotential In 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


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

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

10 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

11 C. Genes implicated


13 2.Abnormal Sexual differentiation Between 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.

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

15 Turner Syndrome (45 X, monosomy X) Cystic hygroma and Hydrops fetalis.Congenital Heart disease, including coarction of the aortaShort statureCommon cause of female hypogonadismFailure to develop secondary sex characteristicsAtrophic streaked ovariesPrimary amenorrhea > InfertilityNo Barr body present

16 Turner Syndrome 1/5000 birth

17 Turner Syndrome short stature; short webbed neck; cubitus valgus; Lymphedema.

18 Turner Syndrome

19 - 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 Gynecomastia 1/2000 birth

20 - 47, XYY syndrome not associated to a particular phenotype normal intelligence, not dysmorphic normally fertile > hyperactivity and impulsivity is frequent, True psychopathology (« crime chromosome ») is not common. 1/2000 birth

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

22 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

23 Campomelic dysplasia mutation of SOX9 - Dysmorphic - bowing of long bones - abnormal extremities - Sex Reversal - Gonadal Dysgenesis

24 Congenital Adrenal Hyperplasia (CAH) Deficiency of 21-Hydroxylase (90 % of the cases) mineralocorticoid deficiency > Female pseudohermaphrodism 60 % of the intersex cases at birth 1/15000 live birth

25 Congenital Adrenal Hyperplasia (CAH) Ambiguous genitalia in CAH

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

27 5 alpha-reductase deficiency Testosterone is not converted in DHT Male pseudohermaphrodism Mostly female phenotype or ambiguous genitalia Virilisation at puberty The gene is located in 2p23 Autosomal recessive

28 5 alpha-reductase deficiency


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

31 Androgen Insensitivity Syndrome (AIS) Mild form Complete

32 Persistent Müllerian Duct Syndrome (PMDS) Mutation of AMH gene Autosomal recessive normally virilised XY patients Develop both wolffian and müllerian structures Often a late discovery during surgery or during investigation for undescended testis

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

34 Sporadic and/or environmental syndromes (2) * Caudal regression syndrome Variable defects of lumbar spine and inferior limbs Uro-genital anomaly extreme form > Sirenomelia Associated to gestational diabetes

35 35 Caudal regression

36 36 Caudal regression (2)

37 37 Caudal regression (3) / sirenomelia

38 C. True Hermaphrodism Presence of both ovarian and testicular tissue Genetic Sex: 46XX/46XY, 45X/ 46XY mosaics Gonadal 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 mixed Phenotypic sex : Ambigous genitalia Exceptionally rare.

39 C. True Hermaphrodism

40 C. True Hermaphrodism ovotestes

41 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.

42 Questions ?

43 43 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: Info or questions:

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