116
U N I T 1
Cell and Tissue Function
unrestored breaks are eliminated within the next few
mitoses because of deficiencies that may in themselves be
fatal. This is beneficial because it prevents the damaged
cells from becoming a permanent part of the organism
or, if it occurs in the gametes, from giving rise to grossly
defective, nonviable zygotes. Some altered chromosomes,
such as those that occur with translocations, are passed
on to the next generation.
22q11.2 Deletion Syndrome
The 22q11.2 deletion syndrome (22q11.2 DS) is a par-
ticularly common inheritable deletion syndrome.
1
This
autosomal dominant disease is caused by the deletion of
a small piece of chromosome 22 and is characterized by
a wide range of clinical phenotypes. While overall phe-
notypic penetrance for 22q11.2 DS is very high among
deleted individuals, there are often marked phenotypic
differences (variable expressivity) between related indi-
viduals with identical 22q11.2 microdeletions.
2,4,7
Clinical
findings are diverse and include psychosocial abnor-
malities, cognitive abnormalities, developmental delay,
psychiatric illnesses, palatal abnormalities, parathyroid
insufficiency, growth retardation, immune defects, con-
genital heart defects, renal anomalies, and abnormal
craniofacial findings.
1,2,4
Due to its highly variable phe-
notype, 22q11.2 DS has also been known by a variety of
other names, including DiGeorge syndrome, velo-cardio-
facial syndrome, conotruncal anomaly face syndrome,
Shprintzen syndrome, and others. The most widely used
approach to diagnose a patient with suspected 22q11.2
DS relies on the fluorescent
in situ
hybridization (FISH)
cytogenetic test using a probe localized to the
TUPLE1
gene. More recently, clinical cytogenetic reference labs
employ microarrays that carry millions of probes to detect
smaller microdeletions. The early diagnosis of 22q11.2
DS is critically important to effectively treat this disorder.
Numeric Disorders Involving
Autosomes
A change in chromosome number is referred to as
aneu-
ploidy
. Among the causes of aneuploidy is a failure of
the chromosomes to separate during oogenesis or sper-
matogenesis. This can occur in either the autosomes
or the sex chromosomes and is called
nondisjunction
(Fig. 6-9). Nondisjunction gives rise to germ cells that
have an even number of chromosomes (22 or 24). The
products of conception formed from this even number of
chromosomes have an uneven number of chromosomes,
45 or 47.
Monosomy
refers to the presence of only one
member of a chromosome pair. The defects associated
with monosomy of the autosomes are severe and usually
cause abortion. Monosomy of the X chromosome (45,X),
or Turner syndrome, causes less severe defects.
Polysomy
,
or the presence of more than two chromosomes to a set,
occurs when a germ cell containing more than 23 chro-
mosomes is involved in conception. A variety of trisomies
involving autosomal chromosomes 13, 18, 21, and 22
have been described.
2,3
With the exception of trisomy 21,
most of these disorders are quite uncommon.
Deletion
A
B
C
D
E
F
Balanced
translocation
Inversion
Robertsonian
translocation
Isochromosomal
translocation
Ring formation
Pericentric
Paracentric
Lost
Lost
Fragments
FIGURE 6-8.
Structural abnormalities in the human
chromosome.
(A)
Deletion of part of a chromosome leads to
loss of genetic material and shortening of the chromosome.
(B)
A reciprocal translocation involves two nonhomologous
chromosomes, with exchange of the acentric segment.
(C)
Inversion requires two breaks in a single chromosome,
with inversion to the opposite side of the centromere
(pericentric) or with the fragment inverting but remaining on
the same arm (paracentric).
(D)
In robertsonian translocation,
two nonhomologous acrocentric chromosomes break near
their centromeres, after which the long arms fuse to form one
large metacentric chromosome.
(E)
Isochromosomes arise
from faulty centromere division, which leads to duplication
of the long arm and deletion of the short arm, or the reverse.
(F)
A ring chromosome with breaks in both telomeric
portions of a chromosome, deletion of acentric fragments,
and fusion of the remaining centric portion. (Adapted from
Peiper S, Strayer DS. In: Rubin R, Strayer DS, eds. Rubin’s
Pathology: Clinicopathologic Foundations of Medicine. 6th ed.
Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams &
Wilkins; 2012:223.)
