LECTURE – 4 Learning objectives 1. Sex chromosome disorders 2. Sexual ambiguity 3. Chromosomal instability syndromes

3 SEX CHROMOSOME DISEASE Common than autosomal Common than autosomal Better tolerated, mostly recognized at puberty Better tolerated, mostly recognized at puberty Induce subtle, problems in sexual development & fertility Induce subtle, problems in sexual development & fertility Higher # of X chromosomes – greater the mental retardation Higher # of X chromosomes – greater the mental retardation

Man is wise. Woman is otherwise.

5 KLINEFELTER SYNDROME Karyotypes  80% 47, XXY  15% mosaic, 46, XY/47, XXY  Rarely, 48, XXXY/49, XXXXY Clinical features 1:850, leading cause of male infertility, eunuchoid body habitus, minimal mental retardation, failure to develop secondary sexual characters, gynecomastia, female distribution of hair, atrophic testis, ↑ FSH and estrogen, ↓ testosterone levels

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7 Supernumerary Y chromosome (Y polysomy) Supernumerary Y chromosome (Y polysomy) I in 1000 live births I in 1000 live births Phenotypically normal: excessively tall, more acne Phenotypically normal: excessively tall, more acne Normal intelligence Normal intelligence Some aggressive / antisocial Some aggressive / antisocial

10 1 in 3000 female births 1 in 3000 female births Hypogonadism in phenotypic females - complete or partial monosomy of X chromosome Hypogonadism in phenotypic females - complete or partial monosomy of X chromosome Only 1% survive till birth Only 1% survive till birth Diagnosis - 45, X at birth Diagnosis - 45, X at birth Accelerated loss of oocytes in ovary, completed by 2 years Accelerated loss of oocytes in ovary, completed by 2 years Menopause before menarche Menopause before menarche

11 TURNER SYNDROME KARYOTYPES : Classic: 45, X (57%) Classic: 45, X (57%) Defective second X chromosome (40%) Defective second X chromosome (40%) 46, X, i(Xq) 46, X, i(Xq) 46, XXq – 46, XXq – 46, XXp – 46, XXp – 46, X, r(X) 46, X, r(X) Mosaic (3%): 45, X /46, XX Mosaic (3%): 45, X /46, XX

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13 MULTI – X SYNDROME Karyotype: 47, XXX or more Karyotype: 47, XXX or more 1 in 1200 new born females 1 in 1200 new born females Mostly women are normal Mostly women are normal Some have amenorrhea, other have menstrual irregularities Some have amenorrhea, other have menstrual irregularities Mental retardation: proportion to number of X chromosomes Mental retardation: proportion to number of X chromosomes

15 GENDER / SEXUAL ORIENTATION

16 Male ; Wolfian/mesonephric duct Male ; Wolfian/mesonephric duct Female; Mullerian/paramesonephric Female; Mullerian/paramesonephric TDF on short arm of Y chromosome TDF on short arm of Y chromosome Anti-Mullerian factor by Sertoli cells Anti-Mullerian factor by Sertoli cells Testosterone by Leydig cells – cause masculinization of external genitalia Testosterone by Leydig cells – cause masculinization of external genitalia

17 Sexual orientation Genetic sex Genetic sex Gonadal sex Gonadal sex Ductal sex Ductal sex Phenotypic sex Phenotypic sex Sexual ambiguity True hermaphrodite True hermaphrodite Pseudohermaphrodite Pseudohermaphrodite  Male  Female

18 TRUE HERMAPHRODITE Presence of testicular/ ovarian tissues Presence of testicular/ ovarian tissues Ovotestis or separate ovary / testis Ovotestis or separate ovary / testis Genitalia ambiguous / poorly developed Genitalia ambiguous / poorly developed Karyotype: 46, XX (75%), translocation of Y chromosome ; mosaic: XX / XXY Karyotype: 46, XX (75%), translocation of Y chromosome ; mosaic: XX / XXY Heterogeneous group with two X and complete / partial Y chromosomes Heterogeneous group with two X and complete / partial Y chromosomes

20 MALE PSEUDOHERMAPHRODITISM Karyotype : 46, XY Karyotype : 46, XY Normal testis or streak Normal testis or streak Defective virilization of the male embryo Defective virilization of the male embryo Ext. genitalia ambiguous in the streak testis Ext. genitalia ambiguous in the streak testis Phenotypic females in testicular feminization syndrome Phenotypic females in testicular feminization syndrome  androgen insensitivity synd

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22 FEMALE PSEUDOHERMAPHRODITISM Genetic : 46, XX Genetic : 46, XX Ovaries, internal genitalia normal Ovaries, internal genitalia normal Ext genitalia: ambiguous or virilized Ext genitalia: ambiguous or virilized Excessive androgenic steroids: congenital adrenal hyperplasia or defect in cortisol synthes is Excessive androgenic steroids: congenital adrenal hyperplasia or defect in cortisol synthes is

23 CHROMOSOME INSTABILITY SYNDROMES Autosomal recessive: excessive, randomly broken chromosomes Autosomal recessive: excessive, randomly broken chromosomes Evaluation: SCE (sister chromatid exchange) BRDU, clastogens, UV Evaluation: SCE (sister chromatid exchange) BRDU, clastogens, UV Bloom's syndrome, Fanconi's anemia, ataxia telangiactasia, xeroderma pigmentosum Bloom's syndrome, Fanconi's anemia, ataxia telangiactasia, xeroderma pigmentosum

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