Structural Chromosomal Abnormalities

I. DELETIONS are a loss of chromatin from a chromosome. The following are clinical examples caused by deletions.

A. Chromosome 4p deletion (Wolf-Hir schhor n syndrome)

1. Cause. Wolf-Hirschhorn syndrome is caused by a deletion in the short arm of chromosome 4 (4p); the specific region involved is 4pl6.

2. Characteristics include a prominent forehead and broad nasal root (Greek "warrior helmet"), short philtrum, down-turned mouth, congenital heart defects, growth retardation, and severe mental retardation.

B. Chromosome 5p deletion (cri du chat or cat's cry syndrome)

1. Cause. Cri du chat syndrome is caused by a deletion in the short arm of chromosome 5 (5p); the specific region involved is 5pl5.

2. Characteristics include a round facies, a cat-like cry, congenital heart defects, microcephaly, and mental retardation.

C. Ring chromosome 14

1. Cause. Ring chromosome 14 occurs when chromosome 14 forms a ring structure with breakpoints at 14pl 1 and 14q32.

2. Characteristics include mild dysmorphic features, frequent seizures, and variable mental retardation.

II. MICRODELETIONS are a loss of chromatin from a chromosome, which can be detected only by high-resolution banding. The following are clinical examples of syndromes caused by microdeletions.

A. Prader-Willi syndrome

1. Cause. Prader-Willi syndrome is caused by a microdeletion in the long arm of chromosome 15 (15q) derived from the father (i.e., paternal imprinting); the specific region involved is 15ql 1—13.

2. Characteristics include hyperphagia (insatiable appetite), hypogonadism, hypotonia, obesity, short stature, small hands and feet, behavior problems (rage, violence), and mild-to-moderate mental retardation.

3. This syndrome is an example of parental imprinting, whereby the expression of certain genes derived from the father differs from the expression of the same genes derived from the mother. Parental imprinting occurs during gametogenesis due to

DNA methylation of cytosine nucleotides. Other examples of parental imprinting include hydatidiform mole (paternal imprinting) and Beckwith-Wiedemann syndrome (paternal imprinting).

4. The counterpart of Prader-Willi syndrome is Angelman's syndrome.

B. Angelman's syndrome (happy puppet syndrome)

1. Cause. Angelman's syndrome is caused hy a microdeletion in the long arm of chromosome 15 (15q) derived from the mother (i.e., maternal imprinting); the specific region involved is 15qll-13.

2. Characteristics include gait ataxia (stiff, jerky, unsteady, upheld arms), seizures, happy disposition with inappropriate laughter, and severe mental retardation (only a 5-10 word vocabulary.)

3. This syndrome is another example of parental imprinting (see A 3).

4. The counterpart of Angelman's syndrome is Prader-Willi syndrome.

C. DiGeorge syndrome (DS)

1. Cause. DS is caused by a microdeletion in the long arm of chromosome 21 (21q); the specific region involved is 21qll [also called the DGCR (DiGeorge chromosomal region)].

2. Characteristics include congenital heart defects in the conotruncal region, immunodeficiency due to the absence of the thymus gland, hypocalcemia due to the absence of the parathyroid glands, hypertelorism, low-set prominent ears, and micrognathia.

3. DS has a phenotypic and genotypic similarity to velocardiofacial syndrome (VCFS), that is, both DS and VCFS are manifestations of a microdeletion at 21 q 11.

4. The following genes have been mapped to 21qll or the DGCR (although their role is far from clear): catechol-O-methyltransferase (COMT; an enzyme used in catecholamine metabolism), Gplbb (receptor for von Willebrand factor), DGCR3 (a leucine zipper transcription factor), and citrate transport protein (CTP).

D. Miller-Dieker syndrome (agyria, lissencephaly)

1. Cause. Miller-Dieker syndrome is caused by a microdeletion in the short arm of chromosome 17; the specific region is 17pl3.3.

2. Characteristics include lissencephaly (smooth brain, i.e., no gyri), microcephaly, and a high and furrowing forehead. Death occurs at an early age.

3. Miller-Dieker syndrome should not be mistakenly diagnosed in the case of premature infants whose brains have not yet developed an adult pattern of gyri (gyri begin to appear normally at about week 28).

III. TRANSLOCATIONS result from breakage and exchange of segments between chromosomes. The following are clinical examples.

A. Robertsonian translocation t( 13q 14q)

1. Cause. This is a translocation between the long arms (q) of chromosomes 13 and 14 where the breakpoints are near the centromere; the short arms (p) of chromosomes 13 and 14 are generally lost.

2. Characteristics. Carriers of this Robertsonian translocation are clinically normal because 13p and 14p, which are lost, contain only inert DNA and some rRNA (ri-bosomal RNA) genes that occur in multiple copics on other chromosomes.

3. This translocation is the most common translocation found in humans.

B. Robertsonian translocation t(14q21q)

1. Cause. This is a translocation between the long arms (q) of chromosomes 14 and 21 where the breakpoints are near the centromere; the short arms (p) of chromosomes 14 and 21 are generally lost.

2. Characteristics. Carriers of this Robertsonian translocation are clinically normal.

3. The clinical issue in this translocation concerns reproduction. Depending on how the chromosomes segregate during meiosis, conception can produce offspring with trisomy 21 (livebirth), trisomy 14 (early miscarriage), monosomy 14 or 21 (early miscarriage), nonnal chromosome complement (live birth), or a t(14q21q) carrier (live birth). Consequently, in a couple where one member is a t(14q21q) carrier, the offspring may present with trisomy 21 (Down syndrome) or the woman may have recurrent miscarriages.

C. Acute promyelocytic leukemia t( 15; 17)(q21 ;q21)

1. Cause. This disorder is caused by a reciprocal translocation between band q21 on chromosome 15 and band q21 on chromosome 17.

2. Result. The result is a fusion of the promyelocyte gene (PML gene) on chromosome 15q21 with the retinoic acid receptor gene (RARa gene) on chromosome 17q21, thus forming the pml/raroL oncogene. The PML/RARa oncoprotein (a transcription factor) blocks the differentiation of promyelocytes to mature granulocytes such that there is continued proliferation of promyelocytes.

3. Characteristics include coagulopathy and severe bleeding.

D. Chronic myeloid leukemia t(9;22)(q34;q 11)

1. Cause. This disorder is caused by a reciprocal translocation between band q34 on chromosome 9 and band ql 1 on chromosome 22; this is referred to as the Philadelphia chromosome.

2. Result. The result is a fusion of the ABL gene on chromosome 9q34 with the BCR gene on chromosome 22ql 1, thus forming the abl/bcr oncogene. The ABL/BCR oncoprotein (a tyrosine kinase) has enhanced tyrosine kinase activity, which transforms hematopoietic precursor cells.

3. Characteristics include an increased number of granulocytes in all stages of maturation and many mature neutrophils.

IV. FRAGILE SITES are gaps or breaks in chromosomes that can be visualized if cell cultures are exposed to specific culture conditions. Fragile X syndrome (Martin-Bell syndrome), described below, is one clinical example.

A. Cause. Fragile X syndrome is caused by a fragile site on chromosome X; the specific region involved is Xq27.

B. Characteristics include macroorchidism, speech delay, behavioral problems (e.g., hyperactivity, attention deficit), prominent jaw, and large, dysmorphic ears.

C. The fragile site is observed when cells are cultured in a folate-depleted medium. The fragile site is produced by a trinucleotide (CGG) repeat mutation in the FMR1 gene. The FMR1 gene encodes for a protein called FMRP, whose exact function is unknown but has RNA-binding capability.

D. This syndrome is the leading cause of inherited mental retardation (most severe in males).

V. IS0CHR0M0S0MES occur when the centromere divides transversely (instead of longitudinally) such that one of the chromosome arms is duplicated and the other arm is lost. Isochromosome Xq, described below, is one clinical example.

A. Cause. Isochromosome Xq is a duplication of the long arm(q) and loss of the short arm (p) of chromosome X.

B. This isochromosome is found in 20% of females with Turner's syndrome (see Chapter 22 II E).

C. The occurrence of isochromosomes within any of the autosomes is generally lethal.

VI. INVERSIONS are the reversal of the order of DNA between two breaks in a chromosome.

A. Pericentric inversions occur on both sides of the centromere; paracentric inversions occur on the same side of the centromere.

B. Carriers of inversions are normal.

C. Diagnosis is generally a coincidental finding during prenatal testing or the repeated occurrence of spontaneous abortions or stillbirths.

VII. BREAKAGE. Breaks in chromosomes are caused by sunlight or ultraviolet irradiation, ionizing irradiation, DNA cross-linking agents, or DNA-damaging agents. These insults may cause depurination of DNA, deamination of cytosine to uracil, or pyrimidine dimerization, which must be repaired by DNA repair enzymes. The clinical importance of DNA repair enzymes is illustrated by some rare inherited diseases that involve genetic defects in DNA repair enzymes, such as the following.

A. Xeroderma pigmentosum (XP) is a genetic skin disease in which the affected individuals are hypersensitive to sunlight (ultraviolet radiation).

1. Cause. XP is caused by a genetic defect in one or more of the enzymes involved in the removal of pyrimidine dimers, which in humans have been shown to require at least eight different gene products.

2. Characteristics include severe skin lesions and malignant skin cancer; most affected individuals die by 30 years of age.

B. Ataxia-telangiectasia is a genetic disease in which the affected individual is hypersensitive to ionizing radiation.

1. Cause. Ataxia-telangiectasia is caused by genetic defects in enzymes involved in DNA repair.

2. Characteristics include cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency.

C. Fanconi's anemia is a genetic disease in which affected individuals are hypersensitive to DNA cross-linking agents.

1. Cause. Fanconi's anemia is caused by genetic defects in enzymes involved in DNA repair.

2. Characteristics include leukemia and progressive aplastic anemia.

D. Bloom's syndrome is a genetic disease in which affected individuals are hypersensitive to a wide variety of DNA-damaging agents.

1, Cause. Blooms syndrome is caused by widespread genetic defects in enzymes involved in DNA repair.

2. Characteristics include immunodeficiency, growth retardation, and predisposition to several types of cancers.

E. Hereditary nonpolyposis colorectal cancer (HNPCC). Although most colorectal cancers are not genetic diseases, HPNCC accounts for 15% of all cases of colorectal cancer.

1. The genes involved in HPNCC have been identified as MSH2 genes. The MSH2 genes are the human homologues to the Escherichia coli mutS and mutL genes that code for DNA repair enzymes.

2. Identification of the genes responsible for HPNCC allows individuals at risk for this inherited cancer to be identified by genetic testing. Early diagnosis greatly improves the chances of patient survival, because the early stage of rhis disease is the outgrowth of small benign polyps that can be removed easily by surgery before malignancy.

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