American Journal of Medical Genetics 36:391-393 (1990)

Origin of 46,XY/46,XY,r( 19) Mosaicism Jar-Fee Yung, Daniel B. Sobel, and Joe J. Hoo Department of Pathology, Mercy Hospital and Medical Center, (J.F.Y.), and Section of Genetics, Department of Pediatrics, Rush-Presbyterian-St. Luke’s Medical Center (J.J.H.), Chicago; Division of Neonatology, Maine Medical Center, Portland (D.B.S.)

We report on a case of 46,XY/46,XY,r(19) mosa- icism. The patient shows minimal clinical ab- normality and the terminal deletions prereq- uisite for the ring formation are not microscopically discernible. The origin of the mosaicism is discussed. Firstly, the mosaicism may represent chimerism with a prezygotic origin of the ring chromosome; secondly, the ring chromosome could have arisen post- zygotically; and thirdly, the ring could have been of a prezygotic origin with the appar- ently normal cells actually containing re- opened rings. The consequences of these hy- pothesis on genetic counselling are discussed.

KEY WORDS Mosaic 46146,r, prezygotic ori- gin, postzygotic origin, chi- merism, reopened ring

INTRODUCTION Mosaicism is a hallmark of ring chromosome cases. In

most cases, a normal cell line is not part of the mosai- cism. However, there are at least 2 situations where a normal cell line is part of the mosaicism. First is in the cases with the so-called “supernumerary ring chromo- some,” where the karyotype is usually 46/47, + r and the supernumerary chromosome usually is a small ring. The normal cells are most likely of postzygotic origin resulting from anaphase lag of the ring chromosome, whereas the supernumerary ring chromosome is pre- sumed to be of prezygotic origin. Second is in the cases with “a ring chromosome of postzygotic origin,” where the karyotype is usually 46146,r. Since chimerism is a rare event, it is reasonable to assume that the ring chromosome arises postzygotically.

Here, we report a case of 46,XY/46,XY,r(19) (p13.3q13.4) mosaicism and discuss the origin of the ring chromosome.

Received for publication August 5,1988; revision received Janu- ary 22, 1990.

Address reprint requests to Joe J. Hoo, M.D. Section of Genetics, Department of Pediatrics, Rush-Presbyterian-St. Luke’s Medical Center, 1750 W. Harrison, Chicago, IL 60612.

CLINICAL REPORT

Baby F. is a 1,640 g boy born to a 22 year-old G3P2Abl mother at 38 weeks of gestation by a spontaneous vagi- nal delivery. The Apgar scores were 8 at one minute and 9 at 5 minutes. He was small for gestational age with length of 42 cm (below the 5th centile) and head circum- ference of 29 cm (below the 5th centile). Physical exam- ination showed cutaneous syndactyly of the right 1st and 2nd toes and a grade II/VI systolic murmur diag- nosed as mild peripheral pulmonic stenosis. His ECG showed a normal sinus rhythm with -90” axis. His chest film demonstrated normal size of heart and an eventration of the right hemidiaphragm. Results of the ophthalmologic examination and of cranial ultra- sonography were normal. TORCH screening was non- reactive. The placenta was reported as unremarkable.

He was discharged at age 25 days weighing 2,120 g. He was followed at the pediatric clinic up to age one year. He had been thriving well and had shown normal psy- chomotor development. He was lost to follow-up subse- quently and did not reappear until age 3 years. At age 3 years his weight (11.4 kg), height (86.5 cm), and head circumference (47.5 cm) were all below the 5th centile, but were proportionate. Accordingly, he walked alone at 18 months old and was toilet trained at 24 months. He was cooperative and rather talkative. His mental devel- opment appeared to be normal for age. Bilateral clinodactylia were apparent. There was webbing be- tween the fingers. Cutaneous syndactyly between the 1st and 2nd toes of the right foot as well as a small 2nd toe of the left foot were noted. The forefeet appeared narrow. Radiographs of the feet showed that the 2nd, 4th, and 5th toes on the right and 2nd and 5th toes on the left consisted of the proximal and distal phalanges only. The metatarsals were normal.

Chromosome analysis in the neonatal period demon- strated mosaicism: a total of 108 cells were analyzed; 85 cells showed normal 46,XY chromosomes; 21 cells showed a ring chromosome 19 with breakpoints appar- ently at the tips of both arms (Fig. 1). Two cells lacked a chromosome 19. Study of chromosome polymorphisms in both cell lines did not show any difference to suggest the possible presence of chimerism. A repeat chromo- some study from peripheral lymphocytes at 3 years of age showed 84 cells of 46,XY and 16 cells of 46,XY,r(19). Skin fibroblast culture was also obtained. Of 86 cells

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392 Yung et al.

a

b

C

Fig. 1. Partial karyotypes showing 6 pairs of chromosome 19 at 550- band stage. a: From 2 normal cells. b From 2 ring-containing cells. c: From 2 ring-containing cells with the ring chromosomes showing com- plete banding patterns of chromosome 19.

analyzed, all cells were normal 46,XY; no ring was noted.

DISCUSSION Ring chromosome 19 is rare. Uchida and Lin 119721

reported on a 12 year-old healthy girl with a ring chro- mosome 19 in 22% of her lymphocytes. The cytogenetic study on her was initiated as part of a family study on Down syndrome, as her youngest sib had trisomy 21. Jacobs et al. [1978] found a profoundly retarded, deaf- mute male with ring 19 in 50% of his lymphocytes. The patient did not show any obvious anomalies except for a club foot. This patient had a brother with similar clini- cal manifestations but with normal chromosomes. Thus, the mental retardation and deaf-mutism did not appear to have any causal relationship with the ring 19. Judg- ing from the size of the ring, Jacobs et al. [ 19781 thought that very little material of chromosome 19 was lost during its formation. Recently, Sybert et al. 119881 re- ported on a patient with mosaic ring 19 in about 10% of cultured lymphocytes and fibroblasts, who showed a complex and unusual cardiac malformation, mild micro- cephaly, and subtle dymorphic features, but whose de- velopmental milestones had been normal up to age 27 months.

The above 3 ring chromosome 19 cases and our own case appear to suggest that mosaic ring 19 cases do not cause any specific clinical manifestations. The reason that 3 of the four 46/46,r(19) cases are abnormal is likely ascertainment bias. If they are clinically normal there is no reason to study them and they would not come to our attention. Perhaps, the terminal deletions were so small as not to cause any noticeable clinical abnormality. The morphology of chromosome 19, which consists almost entirely of euchromatic material, suggests that any sub- stantial or discernible deletion of either arm is likely not compatible with life. In fact, we are unaware of any patients with either constitutional 19p - or 19q - . In

his review on ring chromosome syndromes, KosztolAnyi [ 19871 revived the idea of end-to-end fusion as the mech- anism of ring formation without preceding deletion.

Mosaic ring cases containing a normal cell line (46/46r) have been reported and involved various chro- mosomes [Petit and Koulischer, 1971; Parker et al., 1974; Hamers and Van Kemper, 1977; Pfeiffer et al., 1977; Herva et al., 1977; Sutherland and Carter, 1978; Kini et al., 1979; Vigfusson et al., 1980; Hata et al., 19821. Most cases were clinically abnormal with a mini- mal loss of chromosome material during ring formation. In 2 cases [Sutherland and Carter, 1978; Kini et al., 19793, the indiscernible terminal deletions of both arms were nicely demonstrated on elongated and banded ring chromosomes. The percentage of normal cells varies widely from case to case. No longitudinal study was performed in most cases.

Assuming that the ring had arisen before the forma- tion of the zygote, the presence of normal cells would lead to the conclusion that chimerism was the cause of mosaicism. Chimerism can be easily verified by study- ing the chromosome polymorphism in both cell lines and by studying other genetic markers including that of the parents, if necessary. However, since chimerism is a relatively rare event, it is reasonable to assume that the ring chromosome, in most cases, is of postzygotic origin as has been suggested [Petit and Koulischer, 1971; Parker et al., 1974; Hamers and Van Kemper, 1977; Pfeiffer et al., 1977; Herva et al., 1977; Sutherland and Carter, 1978; Kini et al., 1979; Vigfusson et al., 1980; Hata et al., 19821.

A prezygotic origin with chimerism or a postzygotic origin of the ring chromosome does not explain the fol- lowing intriguing results of longitudinal studies in some cases of 46/46r mosaicism. The case of Sutherland and Carter [1978] showed a substantial difference of normal cell percentage, from 50% of the normal diploid cells at early infancy to only 14% at age 7 years. Like- wise, Parker et al. [19741 reported a child with 46,XX/46,XX,r(4) mosaicism in which the proportion of cells with the ring rose from 9% to 72% over a period of 7 years. These results prompted Sutherland and Carter [19781 to speculate that cells containing a ring are prob- ably at a selective advantage in vivo in some cases. However, this contradicts the general assumption that normal cells have a selective advantage against ring- containing cells, which are abnormal and labile to ge- netic imbalance with self-destruction of the ring. An- other hypothesis on the origin of mosaicism appears necessary to explain the above phenomena.

%opening of a ring chromosome has been demon- strated or suggested previously. Hoo et al. [1974] studied the case of a telocentric chromosome 13 in a patient with ring 13, suggesting a reopening of the ring chromosome 13 at its junction. Niikawa and Tamura [1980] des- cribed a case of 46,XX,de1(13)(q22)/46,XX,r(13)(p13q22), which also suggested the reopening of ring chromosome 13 at its junction. Most recently, Leung and Rudd [19881 reported a case of mosaic 9p- and r(9); here also the 9p- chromosome was likely a reopened ring 9. In the cases where the deletions required for a ring formation are not discernible under the microscope, a reopened

Mosaic 46146,r 393

ring will hardly be different from a normal chromosome except in acrocentrics which have lost satellite stalks and short arms. If the fusion site of a ring is labile then the ring may reopen during cell culture and slide prepa- ration. Therefore, the number of reopened rings may vary from one study to another with randomly variable percentages of reopened rings. The rather unusual change of normal cell percentages in longitudinal studies of Sutherland and Carter [1978] and of Parker et al. [19741 could be explained by the assumption that their “normal” cells actually contained reopened ring chromosomes.

The assumption that the normal cells in 46/46,r cases with minimal telomeric deletions are actually cells with reopened ring chromosomes affects genetic counselling. When the apparently normal 46/46,r individual, such as the patient of Uchida and Lin 119721, reaches childbear- ing age, prenatal diagnosis may not be necessary or indicated. The offspring will likely be normal, whether they inherit the normal chromosome, the ring chromo- some, or the reopened ring chromosome. But, assuming a postzygotic origin of the ring suggests that prenatal diagnosis is indicated. The phenotypically normal indi- vidual with 46f46,r may have a low percentage of ring- containing cells in her body other than the lymphocytes, which accounts for the scarcity of clinical manifesta- tions. However, if a fetus inherits the ring chromosome and has it in all body cells, then the fetus may be clini- cally abnormal.

Likewise, if the patient with 46/46,r and minimal terminal deletions is clinically abnormal (as is true in most cases of 461467) genetic counselling must take into account the assumption of the origin of mosaicism. The assumption of a postzygotic origin of the ring chromo- some is associated with a recurrence risk for sibs no greater than the risk in the general population. How- ever, the recurrence risk will be slightly higher than the general population risk if the ring is assumed to be of prezygotic origin and the normal cells are assumed to contain a reopened ring. This is because germinal mosa- icism cannot be totally ruled out in parents with appar- ently normal chromosomes in their peripheral lympho-

cytes. Perhaps studies of the recently described human telomeric DNA sequences [Roberts, 19881 may be useful in detecting telomeric deletion in this connection in the future.

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