The Principles of Clinical Cytogenetics - Extra Materials - Springer

Sex Chromosomes and Sex Chromosome Abnormalities 207
Sex Chromosomes and Sex Chromosome Abnormalities
INTRODUCTION
From: The Principles of Clinical Cytogenetics, Second Edition
Edited by: S. L. Gersen and M. B. Keagle © Humana Press Inc., Totowa, NJ
207
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Cynthia M. Powell, MD
It can be argued that the sex chromosomes are the most important pair of chromosomes given their
role in determining gender and, therefore, allowing for reproduction and procreation. Considered
together, sex chromosome aneuploidies are the most common chromosome abnormalities seen in
liveborn infants, children, and adults. Physicians in many specialties, including pediatrics, obstetrics
and gynecology, endocrinology, internal medicine, and surgery, commonly encounter individuals
with sex chromosome abnormalities. There has been a great deal of misinformation in the past regarding
outcomes and developmental profiles of these patients, leading to bias and discrimination. This
chapter attempts to provide a summary of information regarding the sex chromosomes, sex chromosome
abnormalities, and disorders of sexual development with normal chromosomes.
THE X AND Y CHROMOSOMES
Role in Sexual Differentiation
Genetic sex is established at the time of fertilization and is dependent on whether an X- or Y-bearing
sperm fertilizes the X-bearing egg. The type of gonads that develop (gonadal sex) is determined by
the sex chromosome complement (XX or XY). Before the seventh week of embryonic life, the gonads
of both sexes appear identical (1). Normally, under the influence of the Y chromosome, the immature
gonad becomes a testis. In the absence of the Y chromosome, the gonad differentiates into an ovary.
The term “phenotypic sex” refers to the appearance of the external genitalia and in some disorders
might not correspond to the genetic or gonadal sex (see the section Sex Reversal).
X Chromosome Inactivation
There are thousands of genes on the X chromosome, but relatively few on the Y chromosome. The
explanation for the fact that males survive quite nicely with only one X chromosome while females
have two involves a concept called “dosage compensation” and is termed the Lyon hypothesis after
its proponent, Dr. Mary Lyon (2).
In somatic cells in females, only one X chromosome is active. X inactivation occurs early in
embryonic life, beginning about 3 days after fertilization, and is completed by the end of the first week
of development. The inactivation is random between the two X chromosomes. Either the maternal or
paternal X can be inactivated and, after one X has become inactive, all the daughter cells from that
original cell have the same inactive X. In female germ cells, the inactive X chromosome is reactivated
as the cells enter meiosis, and in male germ cells, the single X chromosome becomes inactive.
The inactive X has properties characteristic of heterochromatin, with late DNA replication in the
S-phase of the cell cycle and remaining condensed during interphase. Histone proteins associated
with the inactive X are underacetylated, and the cytosines in the CpG islands are methylated (3). A