Chromosome Abnormalities and Genetic Counseling , 3rd Edition

19.Chromosome Instability Syndromes

A defect of DNA repair underlies the chromosome instability syndromes, also known as chromosome breakage syndromes (Brewer et al., 1997; Michelson and Weinert, 2000; Taylor, 2001). Thus, they can be described as mu-tagen-hypersensitivity syndromes. The “instability” refers to the predisposition of the chromosomes to undergo rearrangement or to display other abnormal cytogenetic behavior. Their inclusion in this book is warranted in that special cytogenetic techniques have a role in clinical diagnosis and prenatal diagnosis.

The classic chromosome instability syndromes are Fanconi pancytopenia syndrome, Bloom syndrome, and ataxia-telangiectasia. The main cytogenetic features are listed in Table 19-1. They are Mendelian conditions, and in each the mode of inheritance is autosomal recessive. There is genetic heterogeneity in Fanconi syndrome, with cells homozygous for one mutation able to correct in vitro cells homozygous for another mutation (complementation). We briefly note two other rare mutagen-hypersensitivity syndromes—the Nijmegen breakage syndrome and the immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome. Proneness to cancer is a common concomitant of several of the breakage syndromes (Duker, 2002). Some of the genes have in common their interaction with the breast cancer susceptibility gene BRCA1, their protein products forming a “BRCA1-associated genome surveillance complex” (Futaki and Liu, 2001). Roberts syndrome also rates mention in this chapter, since a cytogenetic anomaly (heterochromatin repulsion) may be useful in its diagnosis, although no defect of DNA repair is known.

Rare or even unique families with various clinical presentations have been associated with chromosomal instability, and some representatives are mentioned below. Chromosome instability has been reported as an occasional observation in quite a number of known conditions. This list includes, among others, Cockayne syndrome, xeroderma pigmentosum, Riyadh chromosome breakage syndrome, Rothmund-Thomson syndrome, radial-renal syndrome, craniostenosis-microcephaly syndrome, Dubowitz syndrome, and alacrima-achalasia-adrenal insufficiency. But in several cases the associations are not clear and the relevance for genetic counseling is uncertain (other than in supporting a diagnosis), thus we do not consider them here. The interesting concept of “chromatin modification disorders” (Johnson, 2000) does not quite fit into the purview of this chapter, and we do not consider these disorders either.


The three classic chromosomal breakage syndromes, as well as Roberts syndrome, Nijmegen breakage syndrome, and the ICF syndrome, are of autosomal recessive inheritance, and the recurrence risk for parents who have had one affected child is 1 in 4. In those rare instances in which parenthood is achievable, the risk for the affected child him or herself will in most cases be very low. Two of the very rare syndromes are dominantly inherited.

Table 19.1. Three Classic Chromosome Instability Syndromes


Cytogenetic features

Fanconi pancytopenia

Increased spontaneous and inducible chromosome breakage


Increase in chromosome breaks, presence of clones with translocations having specific breakpoints in 7, 14, and X

Bloom syndrome

Increased spontaneous and inducible sister chromatid exchange; increase in spontaneous chromatid breakage with production of symmetrical quadriradials

Fanconi Pancytopenia Syndrome

This uncommon disorder of protean manifestation (also known simply as Fanconi anemia [FA]) is the least rare of the breakage syndromes (Tischkowitz and Hodgson, 2003). Originally described as a disorder of short stature, characteristic facies, and certain malformations along with progressive bone marrow failure, the picture has now widened. In one-third of FA cases there are no major congenital malformations, although many of these will have minor anomalies, skin pigmentary abnormalities, microophthalmia, and growth indices below the fifth centile (Giampietro et al., 1997). Acute myeloid leukemia is a common complication. The syndrome of vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects with hydrocephalus (VACTERL-H) is due, at least in some cases, to a Fanconi mutation (Cox et al., 1996).

Chromosomes show a range of abnormalities, including an increase in chromosome breakage, both spontaneously and, in particular, upon exposure to DNA cross-linking agents (Fig. 19-1). There is little or no hypersensitivity to radiation damage. The increase in chromosome breakage after exposure of cells to the cross-linking agent diexpoxybutane (DEB) provides, when it is observed, a reliable diagnostic test (Auerbach, 1993). As Joenje et al. (1998) note, most cytogenetic laboratories will see a case of true FA only very infrequently, and it may be difficult to maintain technical expertise in the practice of clastogen-challenge test protocols. Thus, a negative result might not absolutely exclude the diagnosis. Another reason for a misleading negative result is in vivo “correction” of the functional defect in blood-forming tissue by intragenic homologous recombination, with proliferation of the corrected stem cell population. Joenje et al. refer to patients with typical FA who converted from a positive test result on blood sampling to apparent false-negative status over a period of years. Skin fibroblasts maintain the clastogensensitive phenotype, and diagnosis following fibroblast study should be reliable.

There is genetic heterogeneity in FA, with six loci identified. The gene products from these different loci contribute to the control of cellular DNA repair (Grompe and D'Andrea, 2001; Tischkowitz and Hodgson, 2003). One of these genes is the breast cancer susceptibility gene BRCA2, although this is in fact an uncommon basis for FA (Howlett et al., 2002).

Prenatal diagnosis by mutation detection will be possible in those cases with a known mutation (Kwee et al., 1996). Preimplantation diagnosis has been successfully applied, not only to select an unaffected embryo but also to choose a donor on the basis of HLA typing for blood stem cell donation to a preexisting affected sibling, an approach not without controversy (Verlinsky et al., 2001b). Otherwise, DEB-induced chromosome breakage in amniotic fluid or chorionic villus cells provides a satisfactory approach (Auerbach et al., 1986). We have seen a case in which, at routine fetal ultrasonography, upper limb defects were identified, and the couple chose to terminate the pregnancy; subsequent analysis of fetal tissue showed the characteristic cytogenetics of FA. This same cytogenetic testing is being offered in subsequent pregnancies.

Figure 19-1. Metaphase from (a) a control and (b) a patient with Fanconi anemia after exposure to diepoxybutane. Note the high level of chromatid breakage in the patient metaphase. One chromatid break is shown (straight arrow), and a quadriradial figure is indicated (curved arrow).

Bloom Syndrome

Bloom syndrome (BS) is a rare disorder that has its highest prevalence in Ashkenazi Jews but occurs in many other ethnic groups. It is characterized clinically by proportionate short stature, a characteristic facies, sun-sensitive skin rash, immunodeficiency, and a marked susceptibility to cancer (German, 1993). Infertility seems to be invariable in the male; females have difficulty conceiving, but a few have given birth (Martin et al., 1994). The Bloom gene, BLM, was originally mapped to 15q25–qter by the elegant approach of determining the region of isodisomy in a child with BS and concomitant Prader-Willi syndrome due to uniparental disomy 15 (Woodage et al., 1994). BLM codes for a recQ DNA helicase that monitors DNA integrity during S phase (German and Ellis, 2000). (Other members of this gene family are the basis of Werner and Rothmund-Thomson syndromes.)

The diagnostic cytogenetic finding in BS is a markedly increased level of spontaneous sister chromatid exchange (SCE). The normal amount is 6 to 10 exchanges per cell; in BS, it is more than 50 per cell (Fig. 19-2), although some normal cells may be present in BS patients. Similarly to FA, there may have been a “correcting” genetic event occurring in a bone marrow cell, and which then led to a heterozygous cell line having a normal in vitro phenotype. The correcting event may be either a somatic recombination between the two sites of BLM mutation in the homologs in the BS individual with compound heterozygosity, or a back mutation in a homozygote (Ellis et al., 2001). The other cytogenetic abnormality is an increased incidence of spontaneous chromatid aberrations, giving the classic symmetrical quadriradial configuration. Intriguingly, this effect can manifest in the haploid state, with the heterozygous male producing an excess of sperm with chromosome breaks and rearrangements (Martin et al., 1994).

Prenatal diagnosis may be based on observation of increased SCEs in chorionic villus cells (Howell and Davies, 1994). Specific mutation analysis would be applicable if the family mutations were known. For the affected woman's reproductive outlook (in those few surviving to adulthood), the standard Mendelian advice, with consideration of the likelihood of the spouse being heterozygous, applies (Chisholm et al., 2001). The male is infertile.

Roberts Syndrome

Roberts syndrome (RS) is a syndrome of craniofacial abnormalities and limb defects that are often severe. Cases from as far back as 1672, 1737, 1829, and 1898, before Roberts' description of 1919, have been reported (Bates, 2001, 2003). Intellect is normal. The syndrome has been interpreted as a human mitotic mutation syndrome that leads to secondary developmental defects (Van Den Berg and Francke, 1993). Most affected individuals (about 80%) exhibit a chromosomal phenomenon known as premature centromere separation (PCS) (also referred to as “heterochromatin repulsion” [HR]). These patients represent a common complementation group, presumably due to a single locus, with the cytogenetic defect correctable in vitro by fusion with control cells (McDaniel et al., 2000). Those not showing PCS likely represent a different complementation group (Allingham-Hawkins and Tomkins, 1995). There is an abnormality of sister chromatid apposition around the centromeres, which is particularly noticeable for those chromosomes with large blocks of heterochromatin (Fig. 19-3). It is best seen in plain-stained or C-banded chromosomes; G-banding obscures the phenomenon (Van Den Berg and Francke, 1993).

Prenatal diagnosis based upon the presence or absence of PCS at chorionic villus sampling and abnormality or normality of limbs on first trimester fetal ultrasonography should be valid in at least the majority. It would be prudent to follow up an interpretation of normality at second trimester ultrasonography (Otaño et al., 1996).


Ataxia-telangiectasia (AT) is the archetype of a group in which the basic pathogenetic process is a failure in one of the monitoring and repair systems that keep watch for DNA damage. The group includes AT itself, Nijmegen breakage syndrome (NBS), and AT-like disorder (ATLD), all of which exhibit chromosome instability, and possibly some of the variant forms of these conditions such as AT without telangiectasia. The genes for AT (ATM), NBS (NBS1), and ATLD (MRE11) encode proteins that are part of a complex sensing abnormal DNA structures and monitoring post-replication DNA repair (Michelson and Weinert, 2000).

Figure 19-2. Metaphase from (a) a control and (b) a patient with Bloom syndrome, showing very high sister chromatid exchange (SCE) in the latter. Three points of SCE are indicated (arrows) on the control metaphase.


This disorder is a rare brain/immune/cancer syndrome. It is characterized by cerebellar ataxia and oculomotor apraxia (difficulty in performing voluntary eye movements), oculocutaneous telangiectasia, immunodeficiency, and increased cancer predisposition, with hypersensitivity to ionizing radiation and radiomimetic chemicals. The cytogenetic hallmarks of AT include frequent nonrandom rearrangements of chromosomes 7, 14, and occasionally X, in T lymphocytes; nonspecific chromosome breakage in fibroblasts; and normal chromosomes in bone marrow. The breakpoints in the lymphocyte rearrangements are at 7p14, 7q35, 14q12, and 14q32, involving the T-cell receptor and immunoglobulin heavy-chain genes. Clones with rearrangements may be harbingers of a T-cell malignancy, and these clones evolve as the disease progresses. Ataxia-telangiectasia and NBS (see below) homozy gotes have markedly increased rates of nonspecific spontaneous translocations, as Stumm et al. (2001) have demonstrated using whole chromosome painting, and it may be that genome instability is greater than previously thought. Other cytogenetic hallmarks are telomeric fusions in some patients (these are not tissue specific), and increased vulnerability of chromosomes when cells are exposed to ionizing radiation and radiomimetic chemicals such as bleomycin (Kojis et al., 1991).

Figure 19-3. Unusual appearance of the chromosomes in Roberts syndrome: puffing at the centromeres (a,b); a C-banded preparation showing separation of the heterochromatic segments (c) is compared with a C-banded preparation from a control showing the normal centromere appearance (d). (Reproduced from Mann et al., 1982, with the permission of the British Medical Association.)

Ataxia-telangiectasia is due to homozygosity or compound heterozygosity for a recessive gene ATM (AT mutated), whose locus is at 11q22.3 (Savitsky et al., 1995). The ATM gene has a key role in responding to double-stranded DNA (dsDNA) damage, by halting the cell cycle until the damage is corrected. When this surveillance fails, chromosome breaks are not fixed, and lymphocytes (which are normally undergoing dsDNA breaks and rejoinings, as part of the immune process) accumulate rearrangements (Wang, 2000). The cancer risk presumably has this same molecular basis, whereas the cerebellar defect may reflect disordered apoptosis. Most ATM mutations are null, but missense and splicing mutations that allow a limited amount of functional product to be produced may lead to milder clinical and cytogenetic phenotypes. Some of these milder mutations may, on the other hand, promote an increased cancer risk, including breast cancer in the female heterozygote (Stankovic et al., 1998: Gatti et al., 1999; Chenevix-Trench et al., 2002).

Prenatal diagnosis of classic AT, originally approached cytogenetically on amniocytes, is now achievable using flanking markers or by direct mutation analysis of the ATM gene on chorionic villus tissue (Llerena et al., 1989; Gatti et al., 1993; Chessa et al., 1999). Preimplantation genetic diagnosis may be successful (Hellani et al., 2002).

Nijmegen Breakage Syndrome

This is another brain/immune/cancer syndrome, and is rare indeed. The clinical picture includes microcephaly with brain dysgenesis, immune deficiency, and risk for lymphoreticular malignancy. It shares with AT certain cytogenetic features (preferential involvement of chromosomes 7 and 14 in rearrangements) and radiation hypersensitivity (van der Burgt et al., 1996). The causative gene, NBS1, is on chromosome 8q21, and it interacts with the ATM gene, as noted above (Wang, 2000).

Prenatal diagnosis has been undertaken using an assay for radioresistant DNA synthesis (Kleijer et al., 1994); this is a sophisticated approach that only a reference laboratory with a specialist interest should perform. The discovery of the gene itself now enables direct mutation analysis to be exploited.

Ataxia-Telangiectasia Without Telangiectasia, or AT-Like Syndromes

Some syndromes of ataxia resemble AT, but lack certain features, notably the telangiectasia, and may or may not manifest chromosome breakage. The genetic separateness of one of these has been proven, with the demonstration of mutation in the MRE11 gene at 11q21 (Stewart et al., 1999). One syndrome of cerebellar ataxia with oculomotor apraxia does not show chromosomal breakage, and its locus is elsewhere (9q34) (Németh et al., 2000). Some milder AT-like cases, however, are indeed due to mutation at the ATM locus; the type of mutation is the presumed basis of the phenotypic variation, as noted above.

Very Rare Syndromes

Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) Syndrome

The ICF syndrome is characterized by immunodeficiency, an unusual facies, growth and developmental retardation; and a most remarkable tendency of chromosome nos. 1, 9, and 16 to form “windmill” multiradials by interchange within heterochromatic regions (Fig. 19-4). This instability of the pericentromeric heterochromatin reflects hypomethylation of satellites II and III, which are important components of its structure. Franceschini et al. (1995) document the variability of the phenotypic range. The phenotype, physical and cytogenetic, can be considered to be secondary to a failure of methylation. Most cases are due to mutation in the DNA methyltransferase 3B gene, although locus heterogeneity is presumed to exist (Wijmenga et al., 2000). Linked marker analysis on chorion villi is the appropriate means for prenatal diagnosis (Björck et al., 2000; Ehrlich et al., 2001).

Figure 19-4. A “windmill” or “starburst” multiradial chromosome 1 in the ICF syndrome. (From Sawyer, J. R., Swanson, C. M., Wheeler, G., and Cunniff, C. Chromosome instability in ICF syndrome: formation of micronuclei from multibranched chromosomes 1 demonstrated by fluorescence in situ hybridization. Am. J. Med. Genet. 56, 203–209, © 1995 Am. J. Med. Genet., courtesy J. R. Sawyer. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Variegated Aneuploidy with Premature Centromere Separation

The core phenotype of this recessively inherited syndrome comprises microcephaly with functional neurological abnormality, growth retardation, and susceptibility to childhood malignancy, with most of the lymphocytes and about half of skin fibroblasts showing premature centromere separation (PCS). Many cells are aneuploid, with trisomies, double trisomies, and monosomies, and almost every chromosome is represented, sometimes referred to “mosaic variegated aneuploidy” (Limwongse et al., 1999; Kajii et al., 2001; Plaja et al., 2001; Jacquemont et al., 2002). The basic defect in the cell cycle likely involves one of the checkpoint proteins that control progression through the mitotic process; genetic heterogeneity is quite possible. The heterozygote may display the tendency in a proportion of lymphocytes, and some mitotic cells may present the striking observation of a 92-chromosome count. Patients without PCS, and those without the physical phenotype, may represent different loci. Alternatively, the randomness with which aneuploidies were generated in time (embryonic, fetal, postnatal life) and place (differing tissue distributions) may underlie the inconsistency of the observed clinical patterns. Prenatal diagnosis has been reported, based on conventional cytogenetics, the abnormalities being very obvious (Plaja et al., 2003)

Syndromes Reported in Only One Family (Examples)

Ishikawa et al. (2000) reported a single family with a new chromosome instability syndrome, in which the inheritance is autosomal dominant. The major clinical observations are mild to moderate mental retardation, depression, and a spastic ataxia, with striking abnormalities of cerebral white matter and the basal ganglia, and an atrophic spinal cord, demonstrable on magnetic resonance imaging. All three affected individuals having a cytogenetic analysis showed a low frequency of a t(7;14), with a common 14q11.2 breakpoint in each, and a hypersensitivity to radiation and radiomimetic drugs.

A unique Austrian family appears to present a chromosome breakage syndrome with ovarian failure, although it is difficult to apply the word syndrome when two of the “affected” brothers of the index case were normal and healthy (Duba et al., 1997). The index case presented with primary hypogonadism, and karyotyping showed a high proportion of cells with breaks, acentric fragments, triradial rearrangements, and dicentric chromosomes. Two brothers had essentially the same chromosome findings. The cytogenetic picture most closely resembled that of FA, although the three siblings also demonstrated an elevation in α-fetoprotein, which is a feature of AT. This may represent a private recessively inherited syndrome; the ovarian failure in the index case may have been coincidental, and merely the route that led to a chromosome study being done.

Yamada et al. (2001) describe a girl with a number of abnormalities, along with chromosomal instability. She had immunodeficiency with susceptibility to infections, microcephaly, growth retardation, and polydactyly. She was the only affected person in the family; there was no known parental consanguinity.

While not a breakage syndrome, the novel disorder reported by Neitzel et al. (2002) deserves a mention. The cytogenetic observation is that of chromosomes prematurely entering mitosis: in metaphase lymphocytes (without colcemid exposure) and fibroblasts, an excess of cells showed chromosomes appearing to be in prophase. The two affected children were severely retarded in growth and mental development. The condition is presumed autosomal recessive.