Page 253 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

and cardiac defects. In addition to these malformations,
patients with 22q11.2 deletion are at particularly high risk for
psychoses such as schizophrenia and bipolar disorder. The
molecular basis for this syndrome is not fully understood.
The affected region of chromosome 11 encodes many
genes. Among these, a transcription factor gene called
TBX1 is suspected to be responsible, since its loss seems to
correlate with the occurrence of DiGeorge syndrome.
The diagnosis of this condition may be suspected on
clinical grounds but can be established only by detection
of the deletion by fluorescence in situ hybridization (FISH)
(Fig. 6–37, B).
S U M M A RY
Cytogenetic Disorders Involving Autosomes
• Down syndrome is associated with an extra copy of genes
on chromosome 21, most commonly due to trisomy 21
and less frequently from translocation of extra chromo-
somal material from chromosome 21 to other chromo-
somes or from mosaicism.
• Patients with Down syndrome have severe mental retar-
dation, flat facial profile, epicanthic folds, cardiac malforma- of sex chromosomes.
tions, higher risk of leukemia and infections, and premature
development of Alzheimer disease.
• Deletion of genes at chromosomal locus 22q11.2 gives
rise to malformations affecting the face, heart, thymus, and
parathyroids.The resulting disorders are recognized as (1)
DiGeorge syndrome (thymic hypoplasia with diminished T
cell immunity and parathyroid hypoplasia with hypocalce-
mia) and (2) velocardiofacial syndrome (congenital heart
disease involving outflow tracts, facial dysmorphism, and
developmental delay).
Cytogenetic Disorders Involving
Sex Chromosomes
A number of abnormal karyotypes involving the sex chro-
mosomes, ranging from 45,X to 49,XXXXY, are compatible
with life. Indeed, phenotypically normal males with two
and even three Y chromosomes have been identified. Such
extreme karyotypic deviations are not encountered with
the autosomes. In large part, this latitude relates to two
factors: (1) lyonization of X chromosomes and (2) the small
amount of genetic information carried by the Y chromo-
some. The consideration of lyonization must begin with
Mary Lyon, who in 1962 proposed that in females, only one
X chromosome is genetically active. X inactivation occurs
early in fetal life, about 16 days after conception: Either the
paternal or the maternal X chromosome is randomly inac-
tivated in each of the primitive cells representing the devel-
oping embryo. Once inactivated, the same X chromosome
remains genetically neutralized in all of the progeny of
these cells. Moreover, all but one X chromosome is inacti-
vated, and so a 48,XXXX female has only one active X
chromosome. This phenomenon explains why normal
females do not have a double dose (compared with males)
of phenotypic attributes encoded on the X chromosome.
The Lyon hypothesis also explains why normal females are
in reality mosaics, containing two cell populations: one
Cytogenetic Disorders 239
with an active maternal X, the other with an active
paternal X.
Although essentially accurate, the Lyon hypothesis sub-
sequently has been somewhat modified. Most important,
the initial presumption that all of the genes on the inactive
X are “switched off” has been revised as more recent
studies suggest that 21% of genes on Xp, and a smaller
number (3%) on Xq, escape X inactivation. This possibility
has implications for monosomic X chromosome disorders,
or Turner syndrome, as discussed later on.
Extra Y chromosomes are readily tolerated because the
only information known to be carried on the Y chromo-
some seems to relate to male differentiation. Of note, what-
ever the number of X chromosomes, the presence of a Y
invariably dictates the male phenotype. The gene for male
differentiation (SRY, sex-determining region of Y chromo-
some) is located on the short arm of the Y.
Described briefly next are two disorders, Klinefelter syn-
drome and Turner syndrome, that result from aberrations
Klinefelter Syndrome
Klinefelter syndrome is best defined as male hypogonadism that
develops when there are at least two X chromosomes and one or
more Y chromosomes. Most affected patients have a 47,XXY
karyotype. This karyotype results from nondisjunction of
sex chromosomes during meiosis. The extra X chromosome
may be of either maternal or paternal origin. Advanced
maternal age and a history of irradiation in either parent
may contribute to the meiotic error resulting in this condi-
tion. Approximately 15% of the patients show mosaic
patterns, including 46,XY/47,XXY, 47,XXY/48,XXXY,
and variations on this theme. The presence of a 46,XY line
in mosaics usually is associated with a milder clinical
condition.
Klinefelter syndrome is associated with a wide range of
clinical manifestations. In some persons it may be expressed
only as hypogonadism, but most patients have a distinctive
body habitus with an increase in length between the soles and
the pubic bone, which creates the appearance of an elongated
body. Also characteristic is eunuchoid body habitus.
Reduced facial, body, and pubic hair and gynecomastia also are
frequently seen. The testes are markedly reduced in size,
sometimes to only 2 cm in greatest dimension. In keeping
with the testicular atrophy, the serum testosterone levels are
lower than normal, and urinary gonadotropin levels are
elevated.
Klinefelter syndrome is the most common cause of hypogonad-
ism in males. Only rarely are patients fertile, and presum-
ably such persons are mosaics with a large proportion of
46,XY cells. The sterility is due to impaired spermatogen-
esis, sometimes to the extent of total azoospermia. Histo-
logic examination reveals hyalinization of tubules, which
appear as ghostlike structures on tissue section. By con-
trast, Leydig cells are prominent, as a result of either hyper-
plasia or an apparent increase related to loss of tubules.
Although Klinefelter syndrome may be associated with
mental retardation, the degree of intellectual impairment
typically is mild, and in some cases, no deficit is detectable.
The reduction in intelligence is correlated with the number
of extra X chromosomes. Klinefelter syndrome is associ-
ated with a higher frequency of several disorders, includ-
ing breast cancer (seen 20 times more commonly than in