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Classification of disorders of sex development

Classification of disorders of sex development
The sex chromosomes initiate the process of genetic programming of sex determination, but the
subsequent differentiation of the internal and external genitalia is controlled by locally secreted and
circulating sex hormones
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In spite of a normal sex chromosomal complement, disruption in
the timing or malfunction of one or more of the myriad downstream elements in sex differentiation
can produce a DSD
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This category embraces patients with defects in testicular development or
in the production and/or action of androgens), and 46XX DSD, (originating from a number of
deficiencies, including among others flawed ovarian development, fetal androgen excess, SRY positivity,
and duplication of the SOX9 gene
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An abnormal/pathologic combination of sex chromosomes in cells produces abnormalities in
both internal and external genitalia
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16 Not only the reproductive system is involved,
in fact, the anatomy and physiology of other organs and systems are also affected to a degree that
depends on the total population of abnormal cells in the propositus and the precise nature of the
distortion of sex chromosome content
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The
constellation of abnormalities, not all of which are confined to the reproductive system, attests to the
importance of the sex chromosomes not only in the formation, development, and maintenance of the
gonads and genitalia but also in the structure and function of other organs and tissues in the body
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Although the abnormalities in the external genitalia at delivery are the first
signal of an abnormal sex chromosome distribution, as development proceeds anomalies in other body
systems become apparent
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Certainly, there
is no comprehensive survey of the consequences in all body organs and tissues of sex chromosome
abnormalities in the literature
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summarize some of the difficulties in diagnosing intersex
disorders, maintaining that only about 20% of cases have a specific molecular diagnosis
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Ford reviews the types and
probable mechanisms of formation of chimeras and makes a distinction between them and mosaics
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) The partial chimera is the result of one of
several phenomena: crossfertilization between dizygotic twins, transfusion, or maternal fetal placental
exchange
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The mechanism whereby chimeric forms exist throughout the whole body is not clear;
presumably, it results from the fusion of two embryos, fertilization of an ovum and polar body by
two different sperm, or fusion of an ovum with a diploid sperm
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The simultaneous existence of cells that contain different
combinations of the sex chromosomes, that is, XXY/XX mosaic, infers a defect in the process of
allocation (disjunction during mitosis) of the appropriate number of sex chromosomes to daughter
cells
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When the abnormality of sex chromosome distribution (now categorized as sex chromosome
DSDs) is a property of all or almost all cells, the resulting syndrome is quite characteristic
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These individuals have small
or undescended testicles, hypospadias, delayed or incomplete puberty, and infertility and are unusually
tall
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In patients with Turner syndrome (45,X0 individuals) there are characteristic anatomical features,
including a short webbed neck, low hairline at the back of the neck, and low set ears
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When pregnancy is achieved by
egg donation, it can have its own unique hazards; aortic dissection is a hazard for these patients
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Some single reports of mosaic configurations in humans are particularly illuminating; for example, Ford
and Polani’s group described a human XXY/XX mosaic, pointing out that the presence of sex chromatin
19
(Barr body) in cells is not diagnostic of an XX individual
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The investigators postulated that the
abnormal cells developed from an XXY zygote arising from fertilization of a nondisjunctional XX egg by a
normal Y sperm or of a normal X ovum by a nondisjunctional XY sperm
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20 Hirschhorn et al
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16 The child had ambiguous external genitalia, including a
penis-sized phallus (without a foreskin) and a urethral opening at its base (hypospadias)
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Interestingly, this
individual had five siblings one of whom was a brother with hypospadias
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)
Laparotomy at 4 months of age revealed a normal uterus and gonads in the position of ovaries with histologic
features of both ovarian and testicular tissue
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Another group reported an XX/XY
hermaphrodite with mosaicism in all tissues sampled and which was felt to be an example of double
fertilization of two eggs by two genetically different sperm that fused to form a single organism
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Interestingly, one eye was hazel and the
right brown
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Another
report postulated the same mechanism of double fertilization of an ovum by one sperm and the

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