Chromosome Abnormalities and Genetic Counseling , 3rd Edition

10.Autosomal Ring Chromosomes

Ring chromosomes are uncommon, and it is even more uncommon for a person with a ring (or someone on their behalf) to seek genetic advice about reproductive possibilities. The usual physical phenotype comprises major dysmorphogenesis and mental retardation, and procreation is not a relevant issue. But exceptions exist. Remarkably, some persons with a ring chromosome seem to be of entirely normal phenotype. Only mild mental retardation or short stature with minor dysmorphism characterizes some other cases. The ring 20 has a unique association with epilepsy. It is these categories of normal or mildly abnormal phenotype, in other words, of possible reproductive potential, that we particularly consider in this chapter. At the outset, however, we can state that only a few examples of parental transmission of ring chromosomes are known. About 99% of rings arise sporadically (Kosztolányi et al., 1991). The ring X Turner syndrome variant is noted in Chapter 12, and the tiny ring X syndrome on p. 431.

BIOLOGY

There are two types of ring chromosome that can be associated with either a normal phenotype or a clinical picture of relatively mild mental compromise, growth restriction, and absence of major malformation: (1) the full-length or nearly full-length ring that replaces one of the normal homologs, with the karyotype 46,(r); and (2) the very small ring comprising pericentromeric chromatin which exists as a supernumerary chromosome, with the karyotype 47,+(r). Individuals with either of these types of ring may have intact fertility and may present with questions about risks to their offspring. We deal with each category separately, and list some reported cases of individual ring chromosomes.

The “Balanced” (Apparently or Nearly so) Ring Chromosome, 46,(r)

The classic mode of formation of ring chromosomes is breakage in both arms of a chromosome, with fusion of the points of fracture and loss of the distal fragments (Fig. 10-1a). In effect, therefore, the 46,(r) individual has a partial monosomy for the distal short arm and distal long arm. There can be loss of the telomeres, but retention of subtelomeric sequences; nevertheless, even this small genetic loss may contribute to an abnormal phenotype (Vermeesch et al., 2002). Wintle et al. (1995) describe one of the smallest losses in a ring 14 chromosome, comprising no more than 1100 kb of DNA at 14qter, in a phenotypically abnormal r(14) individual.1 The other mode of formation is telomere-to-telomere fusion, with telomeric and subtelomeric sequences being retained, and in this case, in principle, no genetic material would be lost (Sigurdardottir et al., 1999) (Fig. 10-1b). In the 46,(r) heterozygote, the chromosomal constitution may thus be essentially balanced.

Figure 10-1. Formation of a ring chromosome. (a) Classic mechanism with deletions in both arms, and fusion of breakpoints and loss of distal segments. (b) Telomere-to-telomere fusion.

What may then lead to phenotypic abnormality, or exacerbate it, is mechanical disruption of cell division throughout the period of postconceptual growth. This is the consequence of rings becoming entangled, broken, doubled, or otherwise disrupted, following sister chromatid exchange during the cell cycle (Fig. 10-2). Thus, at mitosis daughter cells arise that are partially or totally aneuploid for the chromosome in question, a process termed “dynamic mosaicism.” These cells may die; some, however, survive in the mosaic state and presumably make an unfavorable contribution to the phenotype. This continuous generation and loss of cells seriously undermines the growth rate, although it may not greatly influence the quality of growth. The result is the general ring syndrome—regardless of which autosome is concerned—of marked growth retardation, mild to moderate cognitive impairment, minor dysmorphogenesis, and, perhaps, intact fertility (Kosztolányi, 1987). The mosaicism may leave evidence of its existence in pigmentary skin anomaly (Sigurdardottir et al., 1999). The larger chromosomes (nos. 1–12) may be particularly prone to undergo dynamic mosaicism, and the smaller ones less so; Kosztolányi (1987) refers to labile and stable rings, respectively. Perhaps this is simply a result of their different lengths offering more or less opportunity for sister chromatid exchange to occur. Rings of the smallest chromosomes are largely or wholly immune to ring disruption. Thus, a person heterozygous for a r(21) or r(22) could be almost, or apparently entirely, of normal phenotype.

At gametogenesis in the 46,(r) heterozygote the expectation is, other things being equal, for symmetric disjunction, with 1:1 segregation of the ring and the normal homolog (Fig. 10-3). Thus, half of the conceptuses would be entirely normal karyotypically, and half would carry the ring. If “dynamic mosaicism” then occurred, these latter may be lethal in utero, or those surviving to term might have phenotypic abnormality.

There are tentative grounds for considering that the ring heterozygote might have an increased risk for nondisjunction, resulting in 2:0 segregation. In this event, with respect to chromosome 13, 18, or 21, a child with the respective trisomy might be born. So far, this is on record only in the case of a child with ring Down syndrome, 47,+r(21), born to a 46,r(21) parent (Kosztolányi et al., 1991). The r(21) parent is also at risk of having a child with Down syndrome due to a recombinant duplication 21 (Howell et al., 1984; Fryns and Kleczkowska, 1987; Miller et al., 1987).

Almost all instances of parent-to-child ring transmission involve the mother as the carrier parent (MacDermot et al, 1990). Probably, spermatogenesis is compromised in the presence of a ring chromosome, and infertility is the consequence for most male heterozygotes.

Ring 2

Patients with (apparently) telomere–telomere fusion present a clinical picture in which prenatal and postnatal growth retardation and microcephaly are consistent features. We have seen a case of 46,(r)(2)/46,N mosaicism, a profoundly retarded girl, with dramatic levels of dynamic mosaicism: 22% of cells were tetraploid, and most of the derivative rings were in the tetraploid cells (Sutherland and Carter, 1978). Lacassie et al. (1999) summarize eight published cases and provide a photographic record of their own patient from birth to age 10 years, a microcephalic child with some mild cognitive and behavioral compromise and profoundly growth retarded. Dee et al. (2001) showed a subtle distal 2p deletion in a ring 2 child with a similar phenotype, and suggest that some other cases of r(2) may also have very small deletions. It thus remains an open question whether the phenotype is truly a manifestation of the general ring syndrome or is due, at least in part, to a distal deletion. No parent-to-child transmission has been recorded.

Figure 10-2. Dynamic mosaicism. The single-chromatid ring chromosome replicates during interphase. Sister chromatid exchanges (SCEs) may or may not take place. At meiosis, if there are no SCEs (left), segregation is symmetric (dotted arrows represent spindles drawing homologs to opposite poles). If there is one SCE, a double-sized ring is generated (middle). With each centromere being tugged to opposite poles at anaphase (dotted arrows), the chromosome may break. If there are two SCEs, in the same direction of rotation (right), the two rings become interlocked. Breakage or other mechanical compromise is the consequence. A second SCE in the opposite direction of rotation would restore the situation.

Ring 4

Sigurdardottir et al. (1999) describe a growth-retarded infant with normal developmental progress and whorled areas of hyperpigmentation and hypopigmentation. The r(4) was a true telomere-to-telomere fusion, as demonstrated with FISH using subtelomeric probes. We have seen a man with 46,XY,r(4) manifesting the general ring syndrome: he was considerably shorter than his brothers, and his occupation of warehouse manager differed from the professional qualifications of his siblings. Nevertheless, he could fully appreciate the genetic implications of his condition, and he and his wife chose to have donor insemination.

Figure 10-3. Meiosis with symmetric segregation in the ring heterozygote.

Ring 6

Urban et al. (2002) have undertaken a review, accumulating data on 23 cases. Hydrocephalus was a common observation. At one end of the spectrum, malformations and microcephaly with severe retardation are typical; at the other, a much milder phenotype of growth retardation evokes the general ring syndrome. No case is known of parent-to-child transmission.

Ring 7

Vermeesch et al. (2002) note that 13 examples of r(7) have been recorded. They describe their own patient with microcephaly and height well below the third centile; a few cells had double rings. In this case, they demonstrated a subtelomeric fusion: FISH probes for subtelomeric sequences gave positive signals on the ring chromosome, but no hybridization occurred with telomere probes.

Ring 12

Parmar et al. (2003) review the findings in six cases of 46,r(12). Intellectual compromise of varying degree was a consistent feature. None had had children.

Ring 14

Bowser-Riley et al. (1981) report a 46,XX,r(14) mother “at the lower end of the normal range” of intelligence, who had two retarded 46,XX,r(14) daughters (and a third 46,r(14) pregnancy that was terminated).

Ring 15

Parent-to-child transmission of 46,r(15) is recorded (Horigome et al., 1992). One case was diagnosed prenatally, amniocentesis having been done on the basis of nuchal thickening and growth restriction observed at 20-week fetal ultrasonography (Liu et al., 2001). If the distal breakpoint in a r(15) is just proximal to the subtelomeric region, loss of a growth factor receptor gene IGFR1 in 15q26.1–qter may exacerbate in some but not all the growth deficiency inherent in the general ring syndrome effect (Nuutinen et at., 1995; Peoples et al., 1995).

Ring 18

A mosaic parent can be phenotypically normal, but have a high risk of having an abnormal r(18) child (Fryns et al., 1992b). Yardin et al. (2001) document the history of a woman with the ring 18 syndrome, her karyotype being 46,XX,r(18)(p11.3q23)[32]/45,XX,18[4] on peripheral blood analysis. Six pregnancies all had abnormal outcomes, and the three karyotyped also displayed the same mosaicism. Stankiewicz et al. (2001a) studied seven phenotypically abnormal cases in some detail. Loss of 18q material was consistent, and thus a picture reminiscent of 18q resulted, while loss of 18p was variable.

Ring 19

Flejter et al. (1996) describe a normal mother having ring 19 mosaicism, 46,XX/46,XX,r(19), with only 4% of cells (lymphocytes) having the ring, while her abnormal daughter was 46,XX,r(19) in 98% of cells. A telomeric probe hybridized to the ring, suggesting a telomere-to-telomere fusion format; a small ring might be less likely to undergo dynamic mosaicism, as discussed above.

Ring 20

Mosaicism is typical. Epilepsy is the notable clinical feature, and this may reflect the disruption, haplo-insufficiency, or compromise otherwise of a neuronal gene. The electroencephalogram (EEG) has a characteristic pattern, with trains of theta waves. Any patient with epilepsy who has long runs of epileptiform activity on the EEG in the non-seizing state, which may or may not be associated with confusion or diminished consciousness, should have cytogenetic analysis with this ring chromosome in mind. There may be an earlier period of normal mental development, which arrests following the onset of epilepsy. An unaffected parent with a lower level of mosaicism can have affected children with the ring chromosome in higher proportion (Back et al., 1989). Canevini et al. (1998)studied a mother who had epilepsy with onset at age 11 years and 12% mosaicism on peripheral blood analysis. Her son first had seizures at 5 years of age, and he had a mild intellectual deficiency. He had 83% of chromosomes with the ring. Each showed hybridization with FISH probes for distal 20p and 20q. Both mother and son had a physical appearance that was normal and were only mildly affected intellectually. Thus they likely had only the most minimal genetic loss. Patients with intellectual deficit/dysmor-phism may have larger losses.

Ring 21

The male 46,XY,r(21) heterozygote may be subfertile (Dallapiccola et al., 1986). The cognitive phenotypes can vary from normal to mild retardation (Gardner et al., 1986b). Falik-Borenstein et al. (1992) report a three-gener-ation kindred. One 46,XX,r(21) heterozygote had had seven pregnancies with four early miscarriages, one normal son, one son with Down syndrome, and one 46,XX,r(21) daughter, the latter herself having a 46,XX,r(21) daughter. Most karyotyped cells in these individuals were 46,r(21), but a few were 45,21, and some had a double-size or multisize rings. Short stature but normal IQ/development accompanied the abnormal karyotype in these females; one male heterozygote may have had a low–normal intelligence. Melnyk et al. (1995) discuss the difficulties in counseling relating to uncertainty of the predicted phenotype in a three-generation r(21) family in which the (nonmosaic) r(21) persons were of normal appearance and intelligence. A 46,XX,r(21) mother had a prenatal diagnosis that showed one 46,XY twin and the other with 46,XX,r(21)/45,XX,–21 mosaicism. Both babies were normal, and the girl's postnatal karyotype was nonmosaic 46,XX,r(21), the same as in the mother. The 45,XX,–21 cell line on amniotic fluid culture may have been of extrafetal origin, or it may have arisen as an in vitro artefact. In their review, Muroya et al. (2002) note other instances of a r(21) parent having a child with a rea(21), possibly indicative of a susceptibility within the ring chromosome to undergo further rearrangement. Their own case illustrated the reverse circumstance: a normal mother with a rather complex der(21) had a mildly mentally retarded son with 46,XY,r(21) (and 4/100 cells 45,XY,–21).

Ring 22

Wenger et al. (2000) have reviewed the handful of ring 22 cases. They report their own case of a mother-to-child transmission of a r(22)(p13q13.3). The mother had required special education at high school. Her son had bowel and heart defects, with very little language development by age 20 months. By a strange coincidence he had, on his other no. 22 chromosome, a de novo del(22)(q11.2).

The Supernumerary Small Ring, 47, + (r)

A supernumerary chromosome implies, naturally, a partial trisomy. Daniel and Malafiej (2003) presented six cases of their own and reviewed the literature. Generally, it is only when the ring chromosome is very small or when there is mosaicism with a substantial fraction of normal cells—in other words, where the overall load of genetic imbalance is small—that a question of genetic risk for offspring of the heterozygote will be relevant. Postnatally ascertained cases have naturally presented with an abnormal phenotype, but a fraction of cases come to attention fortuitously, some being phenotypically normal. Mosaicism complicates the interpretation. A few cases are known in which a parent with low-level mosaicism has had an abnormal child with a higher proportion of the cells with the ring.

Small supernumerary rings have been reported for every autosome except no. 17, as listed in Daniel and Malafiej (2003). Brief sketches follow, with particular reference to recorded cases in which a parent with the ring has had offspring.

Supernumerary Ring 1

Callen et al. (1999) presented a series of patients with very small supernumerary r(1) chromosomes ranging in phenotype from normal to abnormal, and showed that the size of the ring was correlated with phenotype. Slater et al. (1999) describe a man who presented with infertility due to oligospermia and was otherwise normal, having an essentially balanced karyotype 47,XY,del(1)(p32p26.1)+r(1)(p32p36.1) (see below, Formation of a Neocentromere). Anderlid et al. (2001) record a phenotypically normal woman with the karyotype 47,XX,+r(1)[5%]/46,XX[95%]. The abnormal chromosome was discovered at placental karyotyping following a fetal death in utero, with no fetal defect being identified at autopsy.

Supernumerary Ring 2

A 47,XX,r(2)/46,XX mother with minor facial dysmorphology and apparently otherwise normal had a son with mosaicism for the same tiny ring chromosome, who presented with mental retardation and a psychotic disorder (Giardino et al., 2002). The ring was present in 54% of cells (peripheral blood) in the mother and in 80% in the son.

Supernumerary Ring 3

A normal mother and her normal infant son had the karyotype 47,r(3)/46 at frequencies of 33% (mother's lymphocytes) and 41% (prenatal diagnosis in the son, amniocyte analysis) (Anderlid et al., 2001).

Supernumerary Ring 7

Tan-Sindhunata et al. (2000) report a family in which the mother of low–normal intelligence and two of her three children had mosaicism for a very small supernumerary ring deriving from the pericentromeric part of chromosome 7, 47,+r(7)/46,N. Although the fractions of mosaicism were similar in the three (about 50%), the children were more severely affected, at least with respect to language acquisition, than their mother. Speculatively, this could reflect in the mother a lesser “ring load” in the brain. Her other child was normal. One other familial example is on record, concerning a normal father, 47,XY,+r(7)[35%]/46,XY[65%], who had a nonmosaic 47,XY,+r(7) son with dysmorphism and neurological compromise (Blennow et al., 1993).

Supernumerary Ring 8

A normal father, a university graduate, with low-level mosaicism for a very small supernumerary r(8) had two nonmosaic 47,XX,r(8) daughters (Rothenmund et al., 1997). They were intellectually handicapped and displayed emotional immaturity, although their physical growth was normal. Daniel and Malafiej (2003)note a normal woman karyotyped because she had had a son with Wolf-Hirschhorn syndrome and she turned out to have a very small r(8) in 27% of lymphocytes. A phenotype suggestive of the MURCS (Müllerian and renal aplasia, cervicothoracic somite dysplasia) association was seen in the patient of Loeffler et al. (2003), a mildly retarded teenage girl, in whom 70% of cells contained a tiny ring 8 chromosome.

Supernumerary Ring 15

An exceptional case is that of a small, bisatellited extra structurally abnormal chromosome (ESAC) derived from chromosome 15 in a grandparent (mosaic) and parent (nonmosaic), evolving into a very small ring 15 in the grandchild. All three and two other siblings with the ESAC were normal (Adhvaryu et al., 1998).

Supernumerary Ring 18

Jenderny et al. (1993) describe a phenotypically normal mother with 47,XX,+r(18) in only 2/100 cells on blood analysis, the remainder being 46,XX, who had a daughter with nonmosaic 47,+r(18).

Supernumerary Ring 22

Mears et al. (1995) report a family in which a phenotypically normal grandfather and father were mosaic for a tiny ring 22 chromosome, 47,XY,+r(22)/48,XY,+r(22),r(22). A grandchild, also 47,+r(22)/48,+r(22),+r(22) but whose ring chromosomes had increased in size, had cat-eye syndrome (see p. 273).

Rare Complexities

More Than One Ring

The formation of the supernumerary ring would be expected to be a sporadic event, unrelated to any particular predisposition. Very rare reports might belie that supposition as a universal truth. Callen et al. (1991) recorded two retarded children, each with two supernumerary small rings: one with a r(6) and an r(X), and the other with an r(3) and another small unidentified ring. Shanske et al. (1999b) described monozygous twins, both of whom had two very small supernumerary rings, with similar proportions of cells in each child: about 60% with 48,XX,+r(1),+r(16), 30% with either 47,XX,+r(1) or 47,XX,+r(16), and 10% with 46,XX.

Formation of a Neocentromere

A fragment of a chromosome not containing a centromere would not normally be able to be transmitted during cell division. But if a neocentromere is generated (p. 273), its survival may be assured. Slater et al. (1999) describe such a scenario in an infertile but otherwise normal man. A segment was deleted from one chromosome 1, and this same segment (1p32p36.1) existed as a tiny supernumerary ring chromosome. This man thus has the karyotype 47,XY,del(1)(p32p26.1)+r(1) (p32p36.1). The ring chromosome was able to activate the formation of certain centromere binding proteins, which presumably enabled its stable transmission. A similar circumstance is recorded in Knegt et al. (2003), in this case a phenotypically normal woman who had presented with recurrent miscarriage, and in whom a tiny ring 13 chromosome was derived from an interstitial deletion of the segment 13q21.31–q22.2. Amniocenteses in her fourth and fifth pregnancies demonstrated normal karyotypes. Multiple tiny rings were identified in a unique case (Vermeesch et al., 1999). In this retarded male, fibroblasts culture showed four tiny rings per cell, and in lymphocytes, six. Each ring had centromeric material.

GENETIC COUNSELING

Parental Karyotype 46,(r)

The great majority of transmitting parents are 46,XX,(r) mothers, which suggests that most male heterozygotes are infertile. The observed risk for the 46,(r) parent to have a child with the same karyotype is a little less than the theoretical 50%, and a figure of about 40% will generally be a fair one to offer. Except, perhaps, for rings of the smallest chromosome, those offspring inheriting the ring could be expected to suffer from the general ring syndrome at least to the same extent as, and quite probably more severely than, their heterozygous parent. In the review of Kosztolányi et al. (1991), about one-third of 46,(r) children were more severely affected mentally than their parent. The 46,(r) parent may be an atypical ring carrier, perhaps with a fortunate pattern of mitotic disruption, who has reached the level of social phenotype that procreation would be likely. An additional risk may apply with respect to imprintable chromosomes, given that mitotic events may lead to mosaicism for a karyotypically normal cell line with uniparental isodisomy of the chromosome concerned; on the other hand, a non-imprinted chromosome might produce “correction” of that cell line.

In the particular case of the 46,r(21) heterozygote, who is often phenotypically normal, there is a small but as yet unquantified risk of having a child with Down syndrome due to an uncommon karyotype: 47,r+(21), 46,rob (21q;21q) or 46,tan dup(21q;21q) (see refs. in Kosztolányi et al., 1991). If in prenatal diagnosis for a pregnancy of a r(21) heterozygote parent the same r(21) karyotype were demonstrated in the fetus, based on the slender evidence thus far available, the chance for phenotypic normality would seem to be substantial, but a (probably mild) degree of abnormality can by no means be excluded. As Kennerknecht et al. (1990) comment, “accurate phenotype–karyotype correlations cannot be made, since there are carriers with a stable ring chromosome who are affected, whereas others with an unstable ring have a normal phenotype and vice versa.”

In a person who is mosaic on somatic analysis, with a 46,(r)/46,(N) karyotype, the mosaicism might extend also into the gonad. This would convey an important risk of having a nonmosaic 46,(r) child.

Parental Karyotype 47, + (r)

Each ring needs to be assessed individually, and careful cytogenetic analysis is urged. Reference to the brief outlines above will give a sense of the range of outcomes. A nonmosaic parent with a very small ring might be expected to transmit the abnormal chromosome with 50% probability, assuming (and this may not necessarily be the case) meiotic and mitotic stability. The parental phenotype would, in principle, predict that of the 47,+r child. Mosaicism in the parent, and potential mosaicism in the child, considerably complicate prediction. A higher-grade mosaicism in the child than in the parent, or complete nonmosaicism in the child, would be expected to produce a more severe phenotype, possibly lethal in utero.

Note

1. More complicated mechanisms of formation have been described in two individuals with Down syndrome (McGinniss et al., 1992). In one, a rob(21;21), or an i(21q), underwent asymmetric breakage and reunion; in the other, a small ring converted by sister chromatid exchange to produce a larger ring.