Porth's Essentials of Pathophysiology, 4e

116

Cell and Tissue Function

U N I T 1

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. 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. Numeric Disorders Involving Autosomes

A

Deletion

Lost

Balanced translocation

B

Inversion

C

Pericentric

Paracentric

Robertsonian translocation

D

Lost

Isochromosomal translocation

E

Ring formation

F

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.)