Hum Genet (1991) 87 : 320-324
9 Springer-Verlag1991
Inherited ring chromosomes: an analysis of published cases GySrgy Kosztoldnyi I, KMoly M6hes I, and Ernest B.Hook 2 1Department of Pediatrics, University Medical School, H-7623 Pdcs, Hungary 2Department of Social and Administrative Health Sciences, University of California, School of Public Health, Berkeley, CA 94 720, USA Received January 28, 1991 / Revised February 27, 1991
Summary. A review of case reports on patients with ring c h r o m o s o m e revealed 30 individuals (plus two fetuses) who inherited the ring from a total of 23 carrier parents (21 mothers and 2 fathers). The proportion of cases with inherited rings, a m o n g all patients with a ring, was calculated to be 5.6% as an u p p e r limit. However, because of a propable difference in survival and fertility between individuals with transmitted and de novo rings, and because of the preferential publication of cases involving inherited rings (and thus a publication bias), the proportion of inherited rings should in reality be no m o r e than 1%. Out of 30 transmitted rings, there were 9 where parent and child were both mosaics, suggesting an inherited instability of the c h r o m o s o m e involved leading to de novo re-formation of the ring in the second generation. The relatively mild clinical manifestations of ring chrom o s o m e s , in general, was found to be even m o r e striking in familial cases. In half of the offspring the phenotype was very similar to that of the parent. However, in about a third of cases the offspring were m o r e severely (mentally) affected. This fact should be considered in genetic counseling of clinically normal w o m e n who carry a ring chromosome.
Introduction Inheritance of a ring c h r o m o s o m e has rarely been reported. Possible reasons for this include: (1) the unstable nature of a ring c h r o m o s o m e during cell division, which m a y lead to loss of the ring during meiosis, or (2) the infertility of ring carriers, a phenotypic consequence of a change in gene dosage or of some other alteration in the genetic material associated with ring formation. An earlier p a p e r analyzed aspects of patients with ring chromosomes from the literature, the vast bulk of the cases reviewed being sporadic (Kosztol~nyi 1987a). This p a p e r extends that review and specifically considers inherited ring chromosomes.
Offprint requests to: G. Kosztol~inyi
Materials and methods The study group was collected from published reports and, as far as we know, includes all patients in the literature with a familial ring chromosome. We use the term ,,dysmorphism" below to indicate the presence of at least three significant minor anomalies or morphogenetic variants. We use the term ,,malformation" for a major or minor congenital defect of an organ. Since some reports did not contain a detailed description of phenotype, we could not analyze these manifestations in all instances.
Results and discussion Epidemiology The review of case reports revealed 30 individuals with a ring (plus two fetuses detected at prenatal diagnosis) who were the offspring of a total of 23 transmitting parents (Back et al. 1989; Bowser Riley et al. 1981; Burden et al. 1973; Christensen et al. 1970; Dallapiccola et al. 1980; Donlan and Dolan 1986; Fagan et al. 1988; Fryns and Van den Berghe 1979; Fujimaki et al. 1987; Hertz 1987; Howell et al. 1984; Ikeuchi et al. 1990; Kennerknecht et al. 1990; Kosztolfinyi et al. 1985; Matalon et al. 1980; Matsubara et al. 1982; Miller et al. 1987; Palmer et al. 1977; Schmidt et al. 1983; Stoll and Roth 1983; Zdansky et al. 1969). An earlier review included reports of 191 nuclear families in which at least one affected offspring with a presumptive deleted karyotype associated with a ring was present and in which both parents were known to have been investigated (Kosztohinyi 1987a). In 7 of the families (3.7%) the ring was transmitted to at least one offspring. Of the total of 195 children with a ring in these 191 families, 184 (94.4%) showed an apparent de novo mutation, while 11 (5.6%) had inherited the ring. The latter represents the upper limit of the true proportion of inherited rings, for two reasons. Transmitted rings, by their very nature, must be compatible not only with survival but also with the achieved fertility of at least one individual, i.e., the carrier parent. D e novo mutant rings,
321 on the other hand, may well result in so severe a deletion that the affected conceptus is either aborted or expires in early life before cytogenetic detection is possible. Secondly, there is almost certainly a preferential publication of diagnosed cases with an inherited, rather than a de novo, ring c h r o m o s o m e and hence a publication bias. The observed proportion inherited, 5.6%, thus constitutes an u p p e r limit for the fraction of infants with rings that have been inherited. If an inherited ring is five to ten-times m o r e likely to be reported than a de novo ring, then the true proportion of inherited rings in those surviving to live birth, a m o n g all rings cytogenetically investigated, is about 1 - 2 % . If we adjust for the likelyhood of the preferential survival of conceptuses with an inherited, rather than a de novo, ring, then the true proportion inherited is even smaller. While some c h r o m o s o m e s are preferentially involved in inherited rings, the proportion inherited will, of course, vary with the particular c h r o m o s o m e involved. A m o n g the 191 nuclear families referred to above, all the inherited tings involved c h r o m o s o m e s 14, 21, or 22. The proportion of offspring with an inherited ring by type were 4/22 (18%) with ring 14 chromosomes, 3/11 (27.3%) with ring 21 chromosomes, and 4/9 (44%) with ring 22
Table 1. Ascertained ring chromosome segregation published in
the literature Chromo- No. of some no families
References
Cytogenetics
Maternal ring transmission 11 1 Fagan et al. 1988 14 2 Bowser Riley et al. 1981; Matalon et al. 1980 15 1 Fujimaki et al. 1987 18 2 Cbristensen et al. 1970; Donlan and Dolan 1986 20 1 Back et al. 1989 21 10 Palmer et al. 1982; Matsubara et al. 1982; Schmid et al. 1983 (two families); Howel et al. 1984; Kosztol~inyiet al. 1985; Hertz 1987; Miller et al. 1987; Ikeuchi et al. 1990; Kennerknecht et al. 1990 22 2 Fryns and Van den Berghe 1979; Stoll and Roth 1983 G 1 Zdansky et al. 1969 X 1 Dallapiccola et al. 1980 Paternal ring transmission 17 1 Burden et al. 1973 22 1 Stoll and Roth 1983
Table 2. Familial ring chromosomes and other chromosomal aberrations in the same patient
chromosomes. Again, because of the biases discussed above, these proportions are likely to be u p p e r limits of the true proportions of these types of inherited rings. The differences a m o n g c h r o m o s o m e s m a y result from variation in the mutation rate, or else in the stability of, or the phenotype associated with, rings of particular chromosomes. Analysis of the parental origin of ring inheritance showed a strong maternal dominance. In the 23 families, there were only two cases of paternal transmission (Table 1). Yet there is no significant sex difference in the prevalence of ring chromosomes in general (Kosztol~inyi 1987a). Most of the patients reported have been below reproductive age, so that their reproductive ability cannot be assessed (Fujimaki et al. 1987). Nevertheless, ring chrom o s o m e s a p p e a r to impair male meiosis but not female gametogenesis (Dallapiccola et al. 1986; Bowser Riley et al. 1981). In the 21 families with maternal transmission of a ring, c h r o m o s o m e 21 was involved preferentially (Table 1). Out of the 21 mothers with a ring c h r o m o s o m e , 14 had only one child with a ring, while 5 and 2 w o m e n had two and three offspring, respectively, who also carried the ring. Thus, the 21 mothers had 30 affected offspring altogether (28 liveborn children and two fetuses in which a ring was observed in amniotic culture). If we consider also the two children of paternal transmission, the overall sex ratio is 1 : 1.
Because of the mitotic instability of the ring chromosome, various ring derivatives m a y be formed, or the ring m a y be lost during cell division. The presence in a ring carrier of h y p o m o d a l cells without the ring, or cells with various types of derivative aneuploidy, is interpreted by some authors as evidence of a "constitutive" type of mosaicism. Nevertheless, these h y p o m o d a l or derivative aneuploid cells, rather than being descendants of a ,,constitutive" cell line present f r o m early embryonic stages, m a y have been generated de novo at recent cell divisions (Kosztol~inyi 1987b). In any event, myxoploidy in patients with a ring c h r o m o s o m e m a y result f r o m different mechanisms. In the discussion below we use the t e r m "mosaicism" only to refer to the coexistence of cells with a ring c h r o m o s o m e (or its derivative) and cells with 46 normal chromosomes. In 15 out of 30 (28 maternal and 2 paternal) ring transmissions both the parent and the offspring were nonmosaic, i.e., every cell analyzed contained the ring or a derivative of it. Five offspring, who were non-mosaic, in-
Mother
Offspring
References
45,t(14;21)/46,r(14)
46,XY,r(14) 46,XY,r(14) 46,XY,r(22) 47,XXX,r(21) 47,XY,+r(21) 46,XX/47,XX, + r(21)
Matalon et al. 1980
45,t(15;22)/46,r(22)/46,XX 46,r(21) 46,r,(21) 46,r(21)
Fryns and Van den Berghe 1979 Palmer et al. 1977 Matsubara et al. 1982 Schmid et al. 1983
322 Table 3. Ring formation and other aberrations of the same chromosome in different family members Mother
Offspring
References
45,t(13;14) 45,t(15;15) 46,r(21) 46,r(21) 46,r(21)
46,XY,r(13) 46,XY,r(15) 45,XX,t(21;21) 46,XX,tandup(21;21) 46,XX,tandup(21;21)
Niebuhr 1973 Neri et al. 1983 Fryns and Kleczkowska 1987 Howellet al. 1984 Milleretal. 1987
Proband
Sibling
46,XX,r(13)
45,XY,t(13;15)
Muleset al. 1983
herited the ring f r o m a mosaic parent. (There were nine families in which b o t h the p a r e n t and the child were mosaic, while in one family the child was a normal/ring mosaic but the p a r e n t was r e p o r t e d to have no n o r m a l cell line.) Five families are k n o w n where, in addition to the ring c h r o m o s o m e , either the p a r e n t or the offspring had a n o t h e r cytogenetic a b n o r m a l i t y (Table 2). A l t h o u g h the coexistence of cells with a R o b e r t s o n i a n translocation and cells with a ring involving one m e m b e r of a c h r o m o s o m e involved in the translocation is not readily explained, their association m a y be m o r e than coincidental (Fryns and V a n den B e r g h e 1979). A particular vulnerability of the c h r o m o s o m e involved in ring formation is also suggested by a few families in which a firstdegree relative of the p e r s o n with a ring had a R o b e r t s o nian translocation or i s o - c h r o m o s o m e of the same chrom o s o m e involved in the ring of the p r o b a n d (Table 3).
Table 4. Main phenotypic characteristics of patients with a familial ring chromosome
Phenotype In Table 4, both parents and viable offspring with a familial ring c h r o m o s o m e , i.e., 53 individuals in all (excluding the fetuses), are analyzed according to their clinical manifestations. As with all r e p o r t e d individuals with a ring c h r o m o s o m e (Kosztolgnyi 1987a), patients with a familial ring were also r e p o r t e d to have few p h e n o t y p i c abnormalities. M o r e than one-third of the cases were normal, b o t h somatically and mentally. N o patients had a m a j o r congenital m a l f o r m a t i o n and the majority of those with mental retardation were r e p o r t e d to be only m o d e r a t e l y or slightly affected. A m o n g the 9 patients with dysmorphism, in 3 children with D o w n s y n d r o m e the p h e n o t y p e was related to trisomy 21, rather than to the ring itself. A more-or-less specific manifestation was reported in 2 further patients: a m o t h e r and her daughter with 45,X/46,XX/46,X,r(X) mosaicism, b o t h of w h o m had some features of T u r n e r syndrome. A l t h o u g h in 11 cases the height was below the 3rd centile, the specific manifestation of what has b e e n defined as the ,,ring synd r o m e " (severe somatic retardation, no m a l f o r m a t i o n , no or only a few minor anomalies), which was f o u n d in 40 of 194 subjects with a sporadic ring c h r o m o s o m e (20.6%) (Kosztolfinyi 1987a), was n o t e d in only five of the 53 with a familial ring (9.4%). H o w e v e r , this comparison is certainly biased by the fact that 20 of the 53 cases analyzed here had a ring 21 c h r o m o s o m e which is k n o w n to have relatively little effect on p h e n o t y p e (Dallapiccola et al. 1986). In 15 offspring the p h e n o t y p e , w h e t h e r n o r m a l or abnormal, was in general the same as that of the p a r e n t f r o m w h o m the ring segregated (Table 5). In 11 families
Patients
No.
Non-mosaic parent Mosaic parent Non-mosaic offspring Mosaic offspring
15 8 20 10
8 4 5 3
Totals
53
20
-
Clinically normal
Malformation
Dys motphism
-
2 la
-
4 b
-
Height below the 3rd centile
Mental retardation
2c
2 2 5 2
4 4 14 3
9
11
25
a One case: some features of Turner syndrome with mosaic r(X) b One case: Down syndrome with dic r(21); one case: Down syndrome with 47,XY,+r(21) c One case: some features of Turner syndrome with mosaic r(X); one case: some features of Down syndrome with 47,X,+r(21)
Table 5. Comparison of the phenotype of parents and their offspring
Clinical abnormalities
Offspring more affected Parent and offspring similarly affected Offspring less affected
Non-mosaic parent Non-mosaic child
Mosaic parent Non-mosaic child
Mosaic parent Mosaic child
Non-mosaic parent Mosaic child
4
4
3
-
11 -
1 -
3 3
1
323 Table 6. The reproductive histories of families with a segregating ring chromosome
References
Offspring Cytogenetically normal
Ring carrier Male Female
Male Female
Offspring with other chromosome anomaly
Spontaneous abortion
Maternal ring transmission Fagan et al. 1988 Bowser Riley et al. 1981 Matalon et al. 1980 Fujimaki et al. 1987 Christensen et al. 1970 Donlan and Dolan 1986 Back et al. 1989 Palmer et al. 1977 Matsubara et al. 1982 Schmid et al. 1983 Howell et al. 1984 Kosztol~inyi et al. 1985 Hertz 1987 Miller et al. 1987 Ikeuchi et al. 1990 Kennerknecht et al. 1990 Fryns and Van den Berghe 1979 Stoll and Roth 1983 Zdansky et al. 1969 Dallapiccola et al. 1986
2 3b
ia
2 2b'c 1 2r
1 1
2c 1 1 1 1 1
2
2 2
1 1 1 id
1 1 1 1 1 2
2 (twins) 1
Paternal ring transmission Stoll and Roth 1983 Burden et al. 1973
2
4
1 1
a 46,XY/47,XXY b One of the offspring was karyotyped in utero; pregnancy terminated Sex unpublished d Tan dup(21;21)
Table 7. Outcome of pregnancies of 24 womena with a ring chromosome No. Offspring with ring chromosome 30 Offspring with chromosome anomaly other than ring 4 Spontaneous abortion 12 Normal child 12 Total
58
% 51.7 6.9 20.7 20.7 100
a One woman had three spontaneous abortions only, i.e., no child with a ring; one woman had two spontaneous abortions, one normal child and one child with a 21/21 translocation only, i.e., no child with a ring; one woman had one normal child and one child with a tan dup(21q) only, i.e., no child with a ring
the child was m o r e severely affected ( m a i n l y m e n t a l l y ) t h a n the p a r e n t carrying the s a m e ring c h r o m o s o m e , while in 4 families the s o m a t i c a n d / o r m e n t a l a b n o r malities w e r e m i l d e r in the offspring. I n all of the latter, the p a t i e n t s were mosaics, a fact which m a y e x p l a i n the differences in expressivity b e t w e e n g e n e r a t i o n s . C o n s i d -
e r i n g the n o n - m o s a i c cases only, 11 c h i l d r e n h a d a b o u t the s a m e m a n i f e s t a t i o n of p h e n o t y p i c a b n o r m a l i t y as their p a r e n t s while four were m o r e severely affected t h a n their p a r e n t s
Familial ring chromosome and reproduction T h e r e p r o d u c t i v e histories of families with a segregating ring are p r e s e n t e d in T a b l e 6. I n a d d i t i o n to the 21 w o m e n w h o t r a n s m i t t e d a ring, 3 o t h e r w o m e n with ring c h r o m o s o m e were r e p o r t e d who, w i t h o u t t r a n s m i t t i n g the ring to offspring, h a d p r e g n a n c i e s . T h e o u t c o m e s of a total of 58 p r e g n a n c i e s of these 24 w o m e n are summ a r i z e d in T a b l e 7.
Conclusions 1. P a r e n t a l t r a n s m i s s i o n of a ring c h r o m o s o m e is possible, d e p e n d i n g o n the n u m b e r a n d k i n d of crossover events ( P a l m e r et al. 1977). T h o u g h c r o s s i n g - o v e r bet w e e n the ring a n d its h o m o l o g u e can lead to g a m e t i c in-
324 stability, as a r e s u l t o f c h r o m o s o m e lagging at m e i o s i s , it is p o s s i b l e to r e c o v e r a ring a f t e r c r o s s i n g - o v e r if, for e x a m p l e , a t w o - s t r a n d d o u b l e c r o s s o v e r occurs. 2. A l t h o u g h t r a n s m i s s i o n o f a ring c h r o m o s o m e f r o m p a r e n t to o f f s p r i n g m a y a c c o u n t for its i n h e r i t a n c e , an alt e r n a t i v e m e c h a n i s m c a n also b e i n f e r r e d f r o m t h e fact t h a t in 9 families b o t h t h e p a r e n t s a n d the offspring h a d n o r m a l cells in a d d i t i o n to t h e ring cells. This familial ring c h r o m o s o m e m o s a i c i s m suggests an inherited instability o f t h e c h r o m o s o m e i n v o l v e d l e a d i n g to de n o v o ref o r m a t i o n o f t h e ring in t h e s e c o n d g e n e r a t i o n ( Z d a n s k y et al. 1969; Stoll a n d R o t h 1983; B a c k et al. 1989). T h e p r e s e n c e o f a n o r m a l cell line in an offspring with a ring, b o r n to a ring c a r r i e r , s u p p o r t s t h e c o n c l u s i o n t h a t in s o m e i n s t a n c e s it is a c h r o m o s o m e p r e d i s p o s e d to t e r m i n a l d e l e t i o n t h a t is t r a n s m i t t e d f r o m t h e p a r e n t to the o f f s p r i n g r a t h e r t h a n a ring p e r se. 3. T h e r e l a t i v e l y less s e v e r e clinical m a n i f e s t a t i o n s o f ring c h r o m o s o m e s in g e n e r a l , c o m p a r e d with o t h e r struct u r a l c h r o m o s o m e a b n o r m a l i t i e s , is e v e n m o r e striking in cases with a f a m i l i a l ring c h r o m o s o m e . W h i l e 92 o f 194 ( 4 7 . 4 % ) p a t i e n t s w i t h a s p o r a d i c ring a u t o s o m e h a d major malformation(s) and/or three or more minor anomalies ( K o s z t o l ~ n y i 1987a), n o i n d i v i d u a l in the p r e s e n t study g r o u p h a d a m a l f o r m a t i o n and t h e r e w e r e only 6 out o f 48 p a t i e n t s w h o h a d t h r e e o r m o r e insignificant m i n o r a n o m a l i e s ( e x c l u d i n g cases with c o i n c i d e n t a l t r i s o m y 21). 4. T h e fact t h a t t h e clinical m a n i f e s t a t i o n o f a familial ring c h r o m o s o m e is r e l a t i v e l y m i l d suggests that signific a n t d e l e t i o n s o f c h r o m o s o m a l m a t e r i a l a r e n o t necess a r y e v e n t s for r i n g f o r m a t i o n . T h e cases a s s o c i a t e d with i n h e r i t e d c h r o m o s o m a l i n s t a b i l i t y suggest t h a t s i m p l e fusion o f c h r o m o s o m e e n d s ( t e l o m e r i c fusion) r a t h e r t h a n d e l e t i o n s a n d j o i n i n g m a y b e m o r e likely in at least s o m e i n s t a n c e s o f ring f o r m a t i o n . 5. T h e f i n d i n g t h a t , in s o m e cases, t h e p h e n o t y p i c m a n i f e s t a t i o n o f t h e s a m e ring was m o r e s e v e r e in t h e offs p r i n g t h a n t h e p a r e n t s h o u l d b e c o n s i d e r e d in t h e g e n e t ic c o u n s e l i n g o f clinically n o r m a l w o m e n w h o c a r r y a ring c h r o m o s o m e .
References Back E, Voiculescu I, Brtinger M, Wolff G (1989) Familial ring (20) chromosomal mosaicism. Hum Genet 83 : 148-154 Bowser Riley S, Buckton KE, Ratcliffe SG, Syme J (1981) Inheritance of a ring 14 chromosome. J Med Genet 18 : 209-213 Burden M, Lupascu E, Margineanu L (1973) A familial case of I7R ring shaped chromosome of group E with transmission from father to son. Rev Med Chit Soc Med Nat Iasi 77:353357 Christensen KR, Friedrich U, Jacobsen P, Jensen K, Nielsen J (1970) Ring chromosome 18 in mother and daughter. J Ment Defic Res 14: 49-67 Dallapiccola B, Bruni L, Boscherini B, Pasquino AM, Chessa L, Vignetti P (1980) Segregation of an X ring chromosome in two generations. J Med Genet 17 : 306-308
Dallapiccola B, De Filippis V, Notarangelo A, Perla G, Zelante L (1986) Ring chromosome 21 in healthy persons: different consequencies in females and in males. Hum Genet 73:218-220 Donlan MA, Dolan CR (1986) Ring chromosome 18 in a mother and son. Am J Med Genet 24:171-174 Fagan K, Suthers GK, Hardacre G (1988) Ring chromosome 11 and caf6-au-lait spots. Am J Med Genet 30:911-916 Fryns JP, Kleczkowska A (1987) Ring chromosome 21 in the mother and 21/21 translocation in the fetus: karyotype 45,XX,-21, -21,t(21;21)(pll;q11). Ann G6n6t (Paris) 30:109-110 Fryns JP, Van den Berghe H (1979) Ring chromosome 22 in a mentally retarded child and mosaic 45,XX, - 15, -22, +t (15;22) (p11;qll)/46,XX,r(22) karyotype in the mother. Hum Genet 47 : 213-216 Fujimaki W, Baba K, Tatara K, Umezu R, Kusakawa S, Mashima Y (1987) Ring chromosome 15 in a mother and her children. Hum Genet 76 : 302 Hertz JM (1987) Familial transmission of a ring chromosome 21. Clin Genet 32 : 35-39 Howell RI, McDermott A, Gardner A, Dickinson V (1984) Down's syndrome with a recombinant tandem duplication of chromosome 21 derived from a maternal ring. J Med Genet 21 : 310314 Ikeuchi I, Yamamoto K, Quiao F, Hayakawa K, Migita T, Nishikawa Y (1990) Ring chromosome 21 transmitted from mother to daughter: its stability in a lymphoblastoid cell line. Ann G6n6t (Paris) 33 : 32-35 Kennerknecht I, Barbi G, Vogel W (1990) Maternal transmission of ring chromosome 21. Hum Genet 86 : 99-101 Kosztol~inyi G (1987a) Does a "ring syndrome" exist? An analysis of 207 case reports on patients with a ring autosome. Hum Genet 75 : 174-179 Kosztolfinyi G (1987b) Decreased cell viability of fibroblasts from two patients with a ring chromosome: an in vitro reflection of growth failure? Am J Med Genet 28 : 181-184 Kosztolfinyi G, Osztovics M, T6th S, Kiss P, Nagy A, Pap M, Timer L, Dobos M, KOrner H, Degen D, Prtitz D, Federlein F, Hickman G (1985) Sixteen cases with ring autosomes. Phenotype and karyotype. Clin Genet 28 : 443 Matalon R, Michals K, Thompson F, Rosenthal IM (1980) Ring chromosome 14 in two brothers, with mosaicism for ring 14 and translocation t(14q;21q) in the mother. Pediatr Res 14:525 Matsubara I, Nakagome Y, Ogasawara N, Oka S, Yokochi T (1982) Maternally transmitted extra ring (21) chromosome in a boy with Down syndrome. Hum Genet 60 : 78-79 Miller K, Reimer A, Schulze B (1987) Tandem duplication chromosome 21 in the offspring of a ring chromosome 21 carrier. Ann G6n6t 30 : 180-182 Mules EH, Stamberg J, Jabs EW, Leonard CO (1983) Two different structural abnormalities of chromosome 13 in offspring of chromosomally normal parents with two fragile sites. Clin Genet 23 : 380-385 Neri G, Ricci R, Pelino A, Bova R, Tedeschi B, Serra A (1983) A boy with ring chromosome 15 derived from a t(15q;15q) Robertsonian translocation in the mother: cytogenetic and biochemical findings. Am J Med Genet 14 : 307-314 Niebuhr E (1973) Reexamination of a family with a t(13q14q) and a ring D(13) child. Ann G6n6t (Paris) 16:199-202 Palmer CG, Hades ME, Reed T, Kajetin J (1977) Four new cases of ring 21 and 22 including familial transmission of ring 21. J Med Genet 14 : 54-60 Schmid W, Tenconi R, Baccichetti C, Caufin D, Schinzel A (1983) Ring chromosome 21 in phenotypically apparently normal persons: report of two families from Switzerland and Italy. Am J Med Genet 16 : 323-329 Stoll C, Roth MP (1983) Segregation of a 22 ring chromosome in three generations. Hum Genet 63 : 294-296 Zdansky R, Biihler EM, Vest M, B0hler UK, Stalder G (1969) Famili~res Mosaik mit G-Ring. Humangenetik 7 : 275-286
9 Springer-Verlag1991
Inherited ring chromosomes: an analysis of published cases GySrgy Kosztoldnyi I, KMoly M6hes I, and Ernest B.Hook 2 1Department of Pediatrics, University Medical School, H-7623 Pdcs, Hungary 2Department of Social and Administrative Health Sciences, University of California, School of Public Health, Berkeley, CA 94 720, USA Received January 28, 1991 / Revised February 27, 1991
Summary. A review of case reports on patients with ring c h r o m o s o m e revealed 30 individuals (plus two fetuses) who inherited the ring from a total of 23 carrier parents (21 mothers and 2 fathers). The proportion of cases with inherited rings, a m o n g all patients with a ring, was calculated to be 5.6% as an u p p e r limit. However, because of a propable difference in survival and fertility between individuals with transmitted and de novo rings, and because of the preferential publication of cases involving inherited rings (and thus a publication bias), the proportion of inherited rings should in reality be no m o r e than 1%. Out of 30 transmitted rings, there were 9 where parent and child were both mosaics, suggesting an inherited instability of the c h r o m o s o m e involved leading to de novo re-formation of the ring in the second generation. The relatively mild clinical manifestations of ring chrom o s o m e s , in general, was found to be even m o r e striking in familial cases. In half of the offspring the phenotype was very similar to that of the parent. However, in about a third of cases the offspring were m o r e severely (mentally) affected. This fact should be considered in genetic counseling of clinically normal w o m e n who carry a ring chromosome.
Introduction Inheritance of a ring c h r o m o s o m e has rarely been reported. Possible reasons for this include: (1) the unstable nature of a ring c h r o m o s o m e during cell division, which m a y lead to loss of the ring during meiosis, or (2) the infertility of ring carriers, a phenotypic consequence of a change in gene dosage or of some other alteration in the genetic material associated with ring formation. An earlier p a p e r analyzed aspects of patients with ring chromosomes from the literature, the vast bulk of the cases reviewed being sporadic (Kosztol~nyi 1987a). This p a p e r extends that review and specifically considers inherited ring chromosomes.
Offprint requests to: G. Kosztol~inyi
Materials and methods The study group was collected from published reports and, as far as we know, includes all patients in the literature with a familial ring chromosome. We use the term ,,dysmorphism" below to indicate the presence of at least three significant minor anomalies or morphogenetic variants. We use the term ,,malformation" for a major or minor congenital defect of an organ. Since some reports did not contain a detailed description of phenotype, we could not analyze these manifestations in all instances.
Results and discussion Epidemiology The review of case reports revealed 30 individuals with a ring (plus two fetuses detected at prenatal diagnosis) who were the offspring of a total of 23 transmitting parents (Back et al. 1989; Bowser Riley et al. 1981; Burden et al. 1973; Christensen et al. 1970; Dallapiccola et al. 1980; Donlan and Dolan 1986; Fagan et al. 1988; Fryns and Van den Berghe 1979; Fujimaki et al. 1987; Hertz 1987; Howell et al. 1984; Ikeuchi et al. 1990; Kennerknecht et al. 1990; Kosztolfinyi et al. 1985; Matalon et al. 1980; Matsubara et al. 1982; Miller et al. 1987; Palmer et al. 1977; Schmidt et al. 1983; Stoll and Roth 1983; Zdansky et al. 1969). An earlier review included reports of 191 nuclear families in which at least one affected offspring with a presumptive deleted karyotype associated with a ring was present and in which both parents were known to have been investigated (Kosztohinyi 1987a). In 7 of the families (3.7%) the ring was transmitted to at least one offspring. Of the total of 195 children with a ring in these 191 families, 184 (94.4%) showed an apparent de novo mutation, while 11 (5.6%) had inherited the ring. The latter represents the upper limit of the true proportion of inherited rings, for two reasons. Transmitted rings, by their very nature, must be compatible not only with survival but also with the achieved fertility of at least one individual, i.e., the carrier parent. D e novo mutant rings,
321 on the other hand, may well result in so severe a deletion that the affected conceptus is either aborted or expires in early life before cytogenetic detection is possible. Secondly, there is almost certainly a preferential publication of diagnosed cases with an inherited, rather than a de novo, ring c h r o m o s o m e and hence a publication bias. The observed proportion inherited, 5.6%, thus constitutes an u p p e r limit for the fraction of infants with rings that have been inherited. If an inherited ring is five to ten-times m o r e likely to be reported than a de novo ring, then the true proportion of inherited rings in those surviving to live birth, a m o n g all rings cytogenetically investigated, is about 1 - 2 % . If we adjust for the likelyhood of the preferential survival of conceptuses with an inherited, rather than a de novo, ring, then the true proportion inherited is even smaller. While some c h r o m o s o m e s are preferentially involved in inherited rings, the proportion inherited will, of course, vary with the particular c h r o m o s o m e involved. A m o n g the 191 nuclear families referred to above, all the inherited tings involved c h r o m o s o m e s 14, 21, or 22. The proportion of offspring with an inherited ring by type were 4/22 (18%) with ring 14 chromosomes, 3/11 (27.3%) with ring 21 chromosomes, and 4/9 (44%) with ring 22
Table 1. Ascertained ring chromosome segregation published in
the literature Chromo- No. of some no families
References
Cytogenetics
Maternal ring transmission 11 1 Fagan et al. 1988 14 2 Bowser Riley et al. 1981; Matalon et al. 1980 15 1 Fujimaki et al. 1987 18 2 Cbristensen et al. 1970; Donlan and Dolan 1986 20 1 Back et al. 1989 21 10 Palmer et al. 1982; Matsubara et al. 1982; Schmid et al. 1983 (two families); Howel et al. 1984; Kosztol~inyiet al. 1985; Hertz 1987; Miller et al. 1987; Ikeuchi et al. 1990; Kennerknecht et al. 1990 22 2 Fryns and Van den Berghe 1979; Stoll and Roth 1983 G 1 Zdansky et al. 1969 X 1 Dallapiccola et al. 1980 Paternal ring transmission 17 1 Burden et al. 1973 22 1 Stoll and Roth 1983
Table 2. Familial ring chromosomes and other chromosomal aberrations in the same patient
chromosomes. Again, because of the biases discussed above, these proportions are likely to be u p p e r limits of the true proportions of these types of inherited rings. The differences a m o n g c h r o m o s o m e s m a y result from variation in the mutation rate, or else in the stability of, or the phenotype associated with, rings of particular chromosomes. Analysis of the parental origin of ring inheritance showed a strong maternal dominance. In the 23 families, there were only two cases of paternal transmission (Table 1). Yet there is no significant sex difference in the prevalence of ring chromosomes in general (Kosztol~inyi 1987a). Most of the patients reported have been below reproductive age, so that their reproductive ability cannot be assessed (Fujimaki et al. 1987). Nevertheless, ring chrom o s o m e s a p p e a r to impair male meiosis but not female gametogenesis (Dallapiccola et al. 1986; Bowser Riley et al. 1981). In the 21 families with maternal transmission of a ring, c h r o m o s o m e 21 was involved preferentially (Table 1). Out of the 21 mothers with a ring c h r o m o s o m e , 14 had only one child with a ring, while 5 and 2 w o m e n had two and three offspring, respectively, who also carried the ring. Thus, the 21 mothers had 30 affected offspring altogether (28 liveborn children and two fetuses in which a ring was observed in amniotic culture). If we consider also the two children of paternal transmission, the overall sex ratio is 1 : 1.
Because of the mitotic instability of the ring chromosome, various ring derivatives m a y be formed, or the ring m a y be lost during cell division. The presence in a ring carrier of h y p o m o d a l cells without the ring, or cells with various types of derivative aneuploidy, is interpreted by some authors as evidence of a "constitutive" type of mosaicism. Nevertheless, these h y p o m o d a l or derivative aneuploid cells, rather than being descendants of a ,,constitutive" cell line present f r o m early embryonic stages, m a y have been generated de novo at recent cell divisions (Kosztol~inyi 1987b). In any event, myxoploidy in patients with a ring c h r o m o s o m e m a y result f r o m different mechanisms. In the discussion below we use the t e r m "mosaicism" only to refer to the coexistence of cells with a ring c h r o m o s o m e (or its derivative) and cells with 46 normal chromosomes. In 15 out of 30 (28 maternal and 2 paternal) ring transmissions both the parent and the offspring were nonmosaic, i.e., every cell analyzed contained the ring or a derivative of it. Five offspring, who were non-mosaic, in-
Mother
Offspring
References
45,t(14;21)/46,r(14)
46,XY,r(14) 46,XY,r(14) 46,XY,r(22) 47,XXX,r(21) 47,XY,+r(21) 46,XX/47,XX, + r(21)
Matalon et al. 1980
45,t(15;22)/46,r(22)/46,XX 46,r(21) 46,r,(21) 46,r(21)
Fryns and Van den Berghe 1979 Palmer et al. 1977 Matsubara et al. 1982 Schmid et al. 1983
322 Table 3. Ring formation and other aberrations of the same chromosome in different family members Mother
Offspring
References
45,t(13;14) 45,t(15;15) 46,r(21) 46,r(21) 46,r(21)
46,XY,r(13) 46,XY,r(15) 45,XX,t(21;21) 46,XX,tandup(21;21) 46,XX,tandup(21;21)
Niebuhr 1973 Neri et al. 1983 Fryns and Kleczkowska 1987 Howellet al. 1984 Milleretal. 1987
Proband
Sibling
46,XX,r(13)
45,XY,t(13;15)
Muleset al. 1983
herited the ring f r o m a mosaic parent. (There were nine families in which b o t h the p a r e n t and the child were mosaic, while in one family the child was a normal/ring mosaic but the p a r e n t was r e p o r t e d to have no n o r m a l cell line.) Five families are k n o w n where, in addition to the ring c h r o m o s o m e , either the p a r e n t or the offspring had a n o t h e r cytogenetic a b n o r m a l i t y (Table 2). A l t h o u g h the coexistence of cells with a R o b e r t s o n i a n translocation and cells with a ring involving one m e m b e r of a c h r o m o s o m e involved in the translocation is not readily explained, their association m a y be m o r e than coincidental (Fryns and V a n den B e r g h e 1979). A particular vulnerability of the c h r o m o s o m e involved in ring formation is also suggested by a few families in which a firstdegree relative of the p e r s o n with a ring had a R o b e r t s o nian translocation or i s o - c h r o m o s o m e of the same chrom o s o m e involved in the ring of the p r o b a n d (Table 3).
Table 4. Main phenotypic characteristics of patients with a familial ring chromosome
Phenotype In Table 4, both parents and viable offspring with a familial ring c h r o m o s o m e , i.e., 53 individuals in all (excluding the fetuses), are analyzed according to their clinical manifestations. As with all r e p o r t e d individuals with a ring c h r o m o s o m e (Kosztolgnyi 1987a), patients with a familial ring were also r e p o r t e d to have few p h e n o t y p i c abnormalities. M o r e than one-third of the cases were normal, b o t h somatically and mentally. N o patients had a m a j o r congenital m a l f o r m a t i o n and the majority of those with mental retardation were r e p o r t e d to be only m o d e r a t e l y or slightly affected. A m o n g the 9 patients with dysmorphism, in 3 children with D o w n s y n d r o m e the p h e n o t y p e was related to trisomy 21, rather than to the ring itself. A more-or-less specific manifestation was reported in 2 further patients: a m o t h e r and her daughter with 45,X/46,XX/46,X,r(X) mosaicism, b o t h of w h o m had some features of T u r n e r syndrome. A l t h o u g h in 11 cases the height was below the 3rd centile, the specific manifestation of what has b e e n defined as the ,,ring synd r o m e " (severe somatic retardation, no m a l f o r m a t i o n , no or only a few minor anomalies), which was f o u n d in 40 of 194 subjects with a sporadic ring c h r o m o s o m e (20.6%) (Kosztolfinyi 1987a), was n o t e d in only five of the 53 with a familial ring (9.4%). H o w e v e r , this comparison is certainly biased by the fact that 20 of the 53 cases analyzed here had a ring 21 c h r o m o s o m e which is k n o w n to have relatively little effect on p h e n o t y p e (Dallapiccola et al. 1986). In 15 offspring the p h e n o t y p e , w h e t h e r n o r m a l or abnormal, was in general the same as that of the p a r e n t f r o m w h o m the ring segregated (Table 5). In 11 families
Patients
No.
Non-mosaic parent Mosaic parent Non-mosaic offspring Mosaic offspring
15 8 20 10
8 4 5 3
Totals
53
20
-
Clinically normal
Malformation
Dys motphism
-
2 la
-
4 b
-
Height below the 3rd centile
Mental retardation
2c
2 2 5 2
4 4 14 3
9
11
25
a One case: some features of Turner syndrome with mosaic r(X) b One case: Down syndrome with dic r(21); one case: Down syndrome with 47,XY,+r(21) c One case: some features of Turner syndrome with mosaic r(X); one case: some features of Down syndrome with 47,X,+r(21)
Table 5. Comparison of the phenotype of parents and their offspring
Clinical abnormalities
Offspring more affected Parent and offspring similarly affected Offspring less affected
Non-mosaic parent Non-mosaic child
Mosaic parent Non-mosaic child
Mosaic parent Mosaic child
Non-mosaic parent Mosaic child
4
4
3
-
11 -
1 -
3 3
1
323 Table 6. The reproductive histories of families with a segregating ring chromosome
References
Offspring Cytogenetically normal
Ring carrier Male Female
Male Female
Offspring with other chromosome anomaly
Spontaneous abortion
Maternal ring transmission Fagan et al. 1988 Bowser Riley et al. 1981 Matalon et al. 1980 Fujimaki et al. 1987 Christensen et al. 1970 Donlan and Dolan 1986 Back et al. 1989 Palmer et al. 1977 Matsubara et al. 1982 Schmid et al. 1983 Howell et al. 1984 Kosztol~inyi et al. 1985 Hertz 1987 Miller et al. 1987 Ikeuchi et al. 1990 Kennerknecht et al. 1990 Fryns and Van den Berghe 1979 Stoll and Roth 1983 Zdansky et al. 1969 Dallapiccola et al. 1986
2 3b
ia
2 2b'c 1 2r
1 1
2c 1 1 1 1 1
2
2 2
1 1 1 id
1 1 1 1 1 2
2 (twins) 1
Paternal ring transmission Stoll and Roth 1983 Burden et al. 1973
2
4
1 1
a 46,XY/47,XXY b One of the offspring was karyotyped in utero; pregnancy terminated Sex unpublished d Tan dup(21;21)
Table 7. Outcome of pregnancies of 24 womena with a ring chromosome No. Offspring with ring chromosome 30 Offspring with chromosome anomaly other than ring 4 Spontaneous abortion 12 Normal child 12 Total
58
% 51.7 6.9 20.7 20.7 100
a One woman had three spontaneous abortions only, i.e., no child with a ring; one woman had two spontaneous abortions, one normal child and one child with a 21/21 translocation only, i.e., no child with a ring; one woman had one normal child and one child with a tan dup(21q) only, i.e., no child with a ring
the child was m o r e severely affected ( m a i n l y m e n t a l l y ) t h a n the p a r e n t carrying the s a m e ring c h r o m o s o m e , while in 4 families the s o m a t i c a n d / o r m e n t a l a b n o r malities w e r e m i l d e r in the offspring. I n all of the latter, the p a t i e n t s were mosaics, a fact which m a y e x p l a i n the differences in expressivity b e t w e e n g e n e r a t i o n s . C o n s i d -
e r i n g the n o n - m o s a i c cases only, 11 c h i l d r e n h a d a b o u t the s a m e m a n i f e s t a t i o n of p h e n o t y p i c a b n o r m a l i t y as their p a r e n t s while four were m o r e severely affected t h a n their p a r e n t s
Familial ring chromosome and reproduction T h e r e p r o d u c t i v e histories of families with a segregating ring are p r e s e n t e d in T a b l e 6. I n a d d i t i o n to the 21 w o m e n w h o t r a n s m i t t e d a ring, 3 o t h e r w o m e n with ring c h r o m o s o m e were r e p o r t e d who, w i t h o u t t r a n s m i t t i n g the ring to offspring, h a d p r e g n a n c i e s . T h e o u t c o m e s of a total of 58 p r e g n a n c i e s of these 24 w o m e n are summ a r i z e d in T a b l e 7.
Conclusions 1. P a r e n t a l t r a n s m i s s i o n of a ring c h r o m o s o m e is possible, d e p e n d i n g o n the n u m b e r a n d k i n d of crossover events ( P a l m e r et al. 1977). T h o u g h c r o s s i n g - o v e r bet w e e n the ring a n d its h o m o l o g u e can lead to g a m e t i c in-
324 stability, as a r e s u l t o f c h r o m o s o m e lagging at m e i o s i s , it is p o s s i b l e to r e c o v e r a ring a f t e r c r o s s i n g - o v e r if, for e x a m p l e , a t w o - s t r a n d d o u b l e c r o s s o v e r occurs. 2. A l t h o u g h t r a n s m i s s i o n o f a ring c h r o m o s o m e f r o m p a r e n t to o f f s p r i n g m a y a c c o u n t for its i n h e r i t a n c e , an alt e r n a t i v e m e c h a n i s m c a n also b e i n f e r r e d f r o m t h e fact t h a t in 9 families b o t h t h e p a r e n t s a n d the offspring h a d n o r m a l cells in a d d i t i o n to t h e ring cells. This familial ring c h r o m o s o m e m o s a i c i s m suggests an inherited instability o f t h e c h r o m o s o m e i n v o l v e d l e a d i n g to de n o v o ref o r m a t i o n o f t h e ring in t h e s e c o n d g e n e r a t i o n ( Z d a n s k y et al. 1969; Stoll a n d R o t h 1983; B a c k et al. 1989). T h e p r e s e n c e o f a n o r m a l cell line in an offspring with a ring, b o r n to a ring c a r r i e r , s u p p o r t s t h e c o n c l u s i o n t h a t in s o m e i n s t a n c e s it is a c h r o m o s o m e p r e d i s p o s e d to t e r m i n a l d e l e t i o n t h a t is t r a n s m i t t e d f r o m t h e p a r e n t to the o f f s p r i n g r a t h e r t h a n a ring p e r se. 3. T h e r e l a t i v e l y less s e v e r e clinical m a n i f e s t a t i o n s o f ring c h r o m o s o m e s in g e n e r a l , c o m p a r e d with o t h e r struct u r a l c h r o m o s o m e a b n o r m a l i t i e s , is e v e n m o r e striking in cases with a f a m i l i a l ring c h r o m o s o m e . W h i l e 92 o f 194 ( 4 7 . 4 % ) p a t i e n t s w i t h a s p o r a d i c ring a u t o s o m e h a d major malformation(s) and/or three or more minor anomalies ( K o s z t o l ~ n y i 1987a), n o i n d i v i d u a l in the p r e s e n t study g r o u p h a d a m a l f o r m a t i o n and t h e r e w e r e only 6 out o f 48 p a t i e n t s w h o h a d t h r e e o r m o r e insignificant m i n o r a n o m a l i e s ( e x c l u d i n g cases with c o i n c i d e n t a l t r i s o m y 21). 4. T h e fact t h a t t h e clinical m a n i f e s t a t i o n o f a familial ring c h r o m o s o m e is r e l a t i v e l y m i l d suggests that signific a n t d e l e t i o n s o f c h r o m o s o m a l m a t e r i a l a r e n o t necess a r y e v e n t s for r i n g f o r m a t i o n . T h e cases a s s o c i a t e d with i n h e r i t e d c h r o m o s o m a l i n s t a b i l i t y suggest t h a t s i m p l e fusion o f c h r o m o s o m e e n d s ( t e l o m e r i c fusion) r a t h e r t h a n d e l e t i o n s a n d j o i n i n g m a y b e m o r e likely in at least s o m e i n s t a n c e s o f ring f o r m a t i o n . 5. T h e f i n d i n g t h a t , in s o m e cases, t h e p h e n o t y p i c m a n i f e s t a t i o n o f t h e s a m e ring was m o r e s e v e r e in t h e offs p r i n g t h a n t h e p a r e n t s h o u l d b e c o n s i d e r e d in t h e g e n e t ic c o u n s e l i n g o f clinically n o r m a l w o m e n w h o c a r r y a ring c h r o m o s o m e .
References Back E, Voiculescu I, Brtinger M, Wolff G (1989) Familial ring (20) chromosomal mosaicism. Hum Genet 83 : 148-154 Bowser Riley S, Buckton KE, Ratcliffe SG, Syme J (1981) Inheritance of a ring 14 chromosome. J Med Genet 18 : 209-213 Burden M, Lupascu E, Margineanu L (1973) A familial case of I7R ring shaped chromosome of group E with transmission from father to son. Rev Med Chit Soc Med Nat Iasi 77:353357 Christensen KR, Friedrich U, Jacobsen P, Jensen K, Nielsen J (1970) Ring chromosome 18 in mother and daughter. J Ment Defic Res 14: 49-67 Dallapiccola B, Bruni L, Boscherini B, Pasquino AM, Chessa L, Vignetti P (1980) Segregation of an X ring chromosome in two generations. J Med Genet 17 : 306-308
Dallapiccola B, De Filippis V, Notarangelo A, Perla G, Zelante L (1986) Ring chromosome 21 in healthy persons: different consequencies in females and in males. Hum Genet 73:218-220 Donlan MA, Dolan CR (1986) Ring chromosome 18 in a mother and son. Am J Med Genet 24:171-174 Fagan K, Suthers GK, Hardacre G (1988) Ring chromosome 11 and caf6-au-lait spots. Am J Med Genet 30:911-916 Fryns JP, Kleczkowska A (1987) Ring chromosome 21 in the mother and 21/21 translocation in the fetus: karyotype 45,XX,-21, -21,t(21;21)(pll;q11). Ann G6n6t (Paris) 30:109-110 Fryns JP, Van den Berghe H (1979) Ring chromosome 22 in a mentally retarded child and mosaic 45,XX, - 15, -22, +t (15;22) (p11;qll)/46,XX,r(22) karyotype in the mother. Hum Genet 47 : 213-216 Fujimaki W, Baba K, Tatara K, Umezu R, Kusakawa S, Mashima Y (1987) Ring chromosome 15 in a mother and her children. Hum Genet 76 : 302 Hertz JM (1987) Familial transmission of a ring chromosome 21. Clin Genet 32 : 35-39 Howell RI, McDermott A, Gardner A, Dickinson V (1984) Down's syndrome with a recombinant tandem duplication of chromosome 21 derived from a maternal ring. J Med Genet 21 : 310314 Ikeuchi I, Yamamoto K, Quiao F, Hayakawa K, Migita T, Nishikawa Y (1990) Ring chromosome 21 transmitted from mother to daughter: its stability in a lymphoblastoid cell line. Ann G6n6t (Paris) 33 : 32-35 Kennerknecht I, Barbi G, Vogel W (1990) Maternal transmission of ring chromosome 21. Hum Genet 86 : 99-101 Kosztol~inyi G (1987a) Does a "ring syndrome" exist? An analysis of 207 case reports on patients with a ring autosome. Hum Genet 75 : 174-179 Kosztolfinyi G (1987b) Decreased cell viability of fibroblasts from two patients with a ring chromosome: an in vitro reflection of growth failure? Am J Med Genet 28 : 181-184 Kosztolfinyi G, Osztovics M, T6th S, Kiss P, Nagy A, Pap M, Timer L, Dobos M, KOrner H, Degen D, Prtitz D, Federlein F, Hickman G (1985) Sixteen cases with ring autosomes. Phenotype and karyotype. Clin Genet 28 : 443 Matalon R, Michals K, Thompson F, Rosenthal IM (1980) Ring chromosome 14 in two brothers, with mosaicism for ring 14 and translocation t(14q;21q) in the mother. Pediatr Res 14:525 Matsubara I, Nakagome Y, Ogasawara N, Oka S, Yokochi T (1982) Maternally transmitted extra ring (21) chromosome in a boy with Down syndrome. Hum Genet 60 : 78-79 Miller K, Reimer A, Schulze B (1987) Tandem duplication chromosome 21 in the offspring of a ring chromosome 21 carrier. Ann G6n6t 30 : 180-182 Mules EH, Stamberg J, Jabs EW, Leonard CO (1983) Two different structural abnormalities of chromosome 13 in offspring of chromosomally normal parents with two fragile sites. Clin Genet 23 : 380-385 Neri G, Ricci R, Pelino A, Bova R, Tedeschi B, Serra A (1983) A boy with ring chromosome 15 derived from a t(15q;15q) Robertsonian translocation in the mother: cytogenetic and biochemical findings. Am J Med Genet 14 : 307-314 Niebuhr E (1973) Reexamination of a family with a t(13q14q) and a ring D(13) child. Ann G6n6t (Paris) 16:199-202 Palmer CG, Hades ME, Reed T, Kajetin J (1977) Four new cases of ring 21 and 22 including familial transmission of ring 21. J Med Genet 14 : 54-60 Schmid W, Tenconi R, Baccichetti C, Caufin D, Schinzel A (1983) Ring chromosome 21 in phenotypically apparently normal persons: report of two families from Switzerland and Italy. Am J Med Genet 16 : 323-329 Stoll C, Roth MP (1983) Segregation of a 22 ring chromosome in three generations. Hum Genet 63 : 294-296 Zdansky R, Biihler EM, Vest M, B0hler UK, Stalder G (1969) Famili~res Mosaik mit G-Ring. Humangenetik 7 : 275-286
