J Med Genet: first published as 10.1136/jmg.15.5.395 on 1 October 1978. Downloaded from

Case reports 395 well be that, in this family, 18q- is unable to segre- mosaicism. Chromosome 18 trisomy was found gate properly during gametogenesis and early post- only in 18% of lymphocytes and not in skin zygotic , leading to an unbalanced state and fibroblasts. A likely interpretation is double non- +(18q-). disjunction in a single lymphocyte precursor HAROLD N. BASs, FELICE WEBER-PARISI, AND of a trisomy 21 embryo. A brief review of other ROBERT S. SPARKES cases of mitotic multiple nondisjunction and Department ofPediatrics (Genetics), Kaiser- double aneuploid mosaicism is presented. Permanente Medical Center, Panorama City, California 91402; and Division ofMedical Genetics, Chromosomal mosaicism occurs in a small percentage Departments ofMedicine, Pediatrics, andPsychiatry, of patients with Down's syndrome. The vast majority UCLA Centerfor the Health Sciences, Los Angeles, of these mosaics have a normal cell line in addition to California 90024, USA the trisomy 21 cell line. This report describes the first reported instance, to our knowledge, of an unusual References type of double trisomy mosaicism in lymphocytes Castel, Y., Riviere, D., Nawrocki, T., Le Fur, J-M., and Toudic, involving chromosomes 18 and 21. L. (1975). Trisomie partielie 18q par translocation familiale t(l8q-;13q+). Lyon Medical, 233, 211-217. Francke, U. (1972). Quinacrine mustard fluorescence of human chromosomes: characterization of unusual translocations. Case report American Journal ofHuman Genetics, 24, 189-213. Fujita, K., and Fujita, H. M. (1974). An extra small submetacentric The proposita was referred for chromosome analysis chromosome: possible partial trisomy 18. Japanese Journal of at age 20 years because of numerous signs of trisomy Huinani Genetics, 19,371-374. Lejeune, J., Berger, R., Rethore, M. D., and Attal, C. (1970). Sur un 21. Her facial appearance was typical of Down's cas 47,XY(?18q-)+. Annales de Genetique, 13,47-5 1. syndrome, with a flat nasal bridge, oblique palpebral Marcelli, A., Benajam, A., Poirier, J. C., Dausset, J., Rethore, fissures, and epicanthal folds. There was a high arched M. D., Prieur, M., and Lejeune, J. (1974). Modification of the palate and a furrowed tongue. The patient was 140 cm expression of the ABO locus in a subject with 47,XY,(? 18q-)+. Humangenetik, 22, 223-24 1. tall (less than 3rd centile), obese (weight 50-5 kg), and Muller, H., Buhler, E. M., Signer, E., Egli, F., and Stalder, G. R. her head circumference was 50.5 cm (less than 2nd (1972). Trisomy 18 syndrome caused by translocation or centile). Her hands were broad and short with bilateral isochromosome formation. Journal of Medical Genetics, 9, 462- simian lines and laterally displaced axial triradii. Her 467. Steele, M. W., Pan, S., Mickell, J., and Senders, V. (1974). Trisomy fingers, wrists, and elbows were hyperextensible. There for the distal half of chromosome no. 18: a report of two affected was muscle hypotonia, and her co-ordination was sibs. Journal ofPediatrics, 85, 827-829. poor. No focal deficits were noted on neurological Stern, L. M., and Murch, A. R. (1975). Pseudohermaphroditism examination. Her electroencephalogram was inter- http://jmg.bmj.com/ with clinical features of trisomy 18 in an infant trisomic for parts of chromosome 16 and 18: 47,XY,der(18), t(16;18)(p12;q11)- preted as moderately abnormal because of excessive mat. Journal ofMedical Genetics, 12, 305-307. posterior slowing and had a background alpha rhythm Taylor, K. M., Wolfinger, H. L., Brown, M. G., and Chadwick, of 8 to 9 Hz moderate voltage activity. D. L. (1975). Origin of a small metacentric chromosome: familial Psychometric examination indicated the patient to and cytogenetic evidence. Clinical Genetics, 8, 364-369. be mildly retarded (WAIS: verbal IQ, 64; perfor- Requests for reprints to Dr Harold N. Bass, Depart- mance IQ, 63; full scale IQ, 61). Academic skills assessed by PIAT were as follows: mathematics, 1.4 ment of Pediatrics (Genetics), Kaiser-Permanente on October 2, 2021 by guest. Protected copyright. Medical Center, Panorama City, California 91402, grade equivalent; reading recognition, 3.9 grade USA. equivalent; and general information, 3*2 grade equiva- lent. In her subjective evaluation she showed a strong tendency towards inappropriate responses and fantasy activities. The proposita was the 3rd child of unrelated parents. Her mother and father were aged 45 years Trisomy 21 with 47,+ 18 and 52 years, respectively, at the time of her birth. Her sibs were normal and there was no family history of lymphocyte cell line: double mental retardation. mitotic nondisjunction CHROMOSOME STUDIES Of a total of 100 cultured lymphocytes analysed from SUMMARY A patient with Down's syndrome two blood samples, 82 cells were 47,XX,+21 and 18 was found to have 47,XX,+18/47,XX,+21 were 47,XX,+ 18. Giemsa banded E and G groups are J Med Genet: first published as 10.1136/jmg.15.5.395 on 1 October 1978. Downloaded from

396 Case reports

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Fig. Giemsa bandedE and G groupsfrom two lymphocytes showing trisomy 18 (upper) and trisomy 21 (lower). shown in the Fig. Examination of 100 cultured skin line is much more widely distributed, the patient fibroblasts revealed only trisomy 21. has typical Down's syndrome. The report of Marks The patient's parents are deceased; there is no et al. (1967) describes a very similar case involv- record of chromosome analysis being performed on ing chromosomes 18 and 21, but only leucocyte them. chromosomes were analysed. Reports by Zellweger and Abbo (1965) and Warren and Keith (1971) Discussion describe similar situations involving D and E group chromosomes. Double trisomy, with or without mosaicism, has been The Table lists cases of double aneuploid mosaicism reported in numerous instances. The majority of these where more than one mitotic nondisjunction and/or cases has either full double trisomy (resulting from 2 lag is the most likely explanation for the nondisjunctions in gametogenesis or a single nondis- observed relatively complex mosaicisms. In addition,http://jmg.bmj.com/ junction in a trisomic zygote) or, less often, mosaicism single aneuploid mosaics have been reported where based on a single missegregation in a tri- two missegregations are required (Ribas-Mundo and somic zygote (Ebbin et al., 1972; Wilson et al., 1974). Prats, 1965). Thus, it seems clear that multiple mitotic The same chromosomes are usually involved that are segregational errors occurring early in embryo- most often found in the single trisomies. A single genesis, while rare, should be expected from time to postzygotic nondisjunction of a sex chromosome can time, as should full double trisomies resulting from two rise to double with errors in The also give multiple cell segregational gametogenesis.1 separation on October 2, 2021 by guest. Protected copyright. lines, exemplified by such trisomy/monosomy - of such sporadic occurrences from familial instances isms as XO/XXX, XO/XY/XXX, and XO- (discussed below) is not possible unless multiple /XX/XXX (Hamerton, 1971), or even double mono- cases are found in one family. somy mosaicism (Weber et al., 1971). The genetic control over disjunction has been We feel that the most probable events leading to the reviewed by Hamerton (1971) and is well known in present instance of 'double' trisomy mosaicism are Drosophila and in some plant species. In man, meiotic chromosome 18 nondisjunction and chromosome 21 nondisjunction occurs in some families at an increased anaphase lag (or nondisjunction) in a haematopoietic rate, as evidenced by the increase in risk of recurrence precursor of a trisomy 21 embryo. This seems likely for trisomy (Mikkelsen and Stene, 1970), and by the because of the mother's advanced age at pregnancy, much more frequent occurrence of double trisomies because trisomy 21 is much more prevalent in the than is predicted by chance (Hamerton et al., 1965). patient's blood and is the only abnormality detected in skin, and because no normal or doubly trisomic cells 'Multiple errors in gametogenesis are best exemplified by multisomy X and Y cases; in fact, pentasomy X has been reported (Mulchay and Stevens, 1975), were seen among 200 . Thus, two mitotic probably resulting from successive oogenic nondisjunction at both meioses missegregations are probable. Since the trisomy 21 cell (Race and Sanger, 1969). J Med Genet: first published as 10.1136/jmg.15.5.395 on 1 October 1978. Downloaded from

Case reports 397 Table Cases ofdouble aneuploid mosaicism requiring more than one unequal mitotic segregation Report Karyotype Probable explanation Fraccaro et al. (1962) 45, X/46, XY/48, XXXY Nondisjunction and anaphase lag in XXY zygote Baikie et al. (1965) 47, XX, +D/47, XX, +E/48, XX, +D, +E Nondisjunction and/or anaphase lag in doubly trisomic zygote (blood) Hsu et al. (1965) 46, XX/48, XX, + 18, +21 (blood) Two nondisjunctions in normal zygote Zellweger and Abbo (1965) (Case 2) 47, XY, +E/47, XY, +G/48, XY, +E, +G Nondisjunction and/or anaphase lag in doubly trisomic zygote (blood) (Case 3) 47, XY, +D/47, XY, +E (skin) Nondisjunction and anaphase lag in trisomic zygote Marks et aL (1967) 47, XY, +G/47, XY, +E (blood) Nondisjunction and anaphase lag in trisomic zygote or 2 nondisjunctions at 2 cell stage in euploid zygote Garson et aL (1969) 47, XX, +D/47, XX, + 18/48, XX, +D, +E Nondisjunction and/or anaphase lag in doubly trisomic zygote* (blood) Porter et al. (1969) 47, XY, +D/47, XY + G/48, XY, +D, +G Nondisjunction and/or anaphase lag in doubly trisomic zygote* (blood) Warren and Keith (1971) 47, XY, +D/47, XY, +E Two nondisjunctions at 2 cell stage ofeuploid zygote or nondisjunction and anaphase lag in trisomic zygote Cohen and Davidson (1972) 47, XX, +21 (skin) Nondisjunction (2) or anaphase lag (2) in lymphocyte 47, XX, +21/45, X (blood) precursor; trisomic zygote Weber et al. (1973) 47, XX, +21 (skin) Translocation and nondisjunction in lymphocyte precursor; 47, XX, +21/47, XX, +mar (blood) trisomic zygote Schinzel et al. (1974) 45, X/47, XY, + 18 (blood and skin) Nondisjunction and/or anaphase lag ofY and 18 in trisomic zygote Gafter et al. (1976) 45, X/46, XX/47, XXX/47, XX, +8 Two nondisjunctions in euploid embryo Present case 47, XX, +21 (skin) Nondisjunction and anaphase lag in lymphocyte precursor: 47, XX, +21/47, XX, + 18 (blood) trisomic zygote * Explained also by nondisjunction and lag in a trisomic zygote. In addition, mosaicism in man is familial in a number References of instances, as reviewed by Hsu et al. (1970) for 10 Baikie, A. G., Garson, D. M., and Birrell, R. G. (1965). Mosaicism families, and reported more recently by Zdansky et al. for trisomy 17-18 and trisomy 13-15 in man. Nature, 207, 1419- (1971), Siegelman (1972), Shih et al. (1974), and 1420. DeBault and Halmi (1975). It is that Cohen, M. M., and Davidson, R. G. (1972). Double aneuploidy probable (47,XX,+21/45,X) arising through simultaneous double nondis- apparent instances of increased nondisjunction in junction. Journal ofMedical Genetics, 9, 242-244. humans have various causes, including dominant and DeBault, L., and Halmi, K. (1975). Familial trisomy 7 mosaicism. http://jmg.bmj.com/ recessive inheritance of factors affecting normal Journal ofMedical Genetics, 12, 200-203. disjunction. These causes encompass mutant genes, Ebbin, A. J., Lim, R. C., Tawner, J. W., and Wilson, M. G. (1972). A double aneuploid mosaic: trisomy 13 and XXY. Journal of chromosome structural variants, and environmental Medical Genetics, 9,365-367. agents and, except for a few chromosome trans- Fraccaro, M., Bott, M. G., Salzeno, F. M., Russell, R. W. R., and locations, remain unidentified. For counselling, no Evanston, W. I. (1962). Triple chromosome mosaic in a woman increase in risk can be related in cases of sporadic with clinical evidence ofmasculinisation. Lancet, 1, 1379-138 1. Gafter, M., Shabtai, F., Kahn, Y., Halbrecht, I., and Djaldetti, M. mitotic double aneuploidy. Where multiple mitotic (1976). Aplastic anemia followed by leukemia in congenital nondisjunctions have apparently occurred in a triso- trisomy 8 mosaicism. Clinical Genetics, 9, 134-142. on October 2, 2021 by guest. Protected copyright. mic zygote the recurrence risk is for practical purposes Garson, D. M., Baikie, A. G., Ferguson, J., and Greer, C. H. (1969). the same as that for the primary Double autosomal trisomy and mosaicism for three cell lines in trisomy. man. Journal ofMedical Genetics, 6, 209-215. Hamerton, J. L. (1971). Human Cytogenetics, Vol. II. Academic We thank Glenna Swanda and Ruth Klefsas for their Press, New York. expert assistance. Hamerton, J., Gianelli, F., and Polani, P. E. (1965). Cytogenetics of Down's syndrome (mongolism). Cytogenetics, 4, 171-185. M. B. JENKINS', R. L. L. Hsu, L. Y. F., Hirschhorn, K. Goldstein, A., and Barcinski, M. KRIEL2, BOYDI, (1970). Familial chromosomal mosaicism, genetic aspects. AND A. BARNWELL2 Annals ofHuman Genetics, 33, 343-349. Hsu, L. Y. F., Schwager, A. J., Newhauser, I., and Sobel, E. H. 'Human Genetics Unit, Minnesota Department of (1965). A case of double autosomal trisomy with mosaicism: Health, 48/XX (trisomy 18+21) and 46/XX. Journal of Pediatrics, 66, Minneapolis, MN 55440, USA 1055-1060. 2Department Marks, J. F., Wiggins, K. M., and Spector, B. J. (1967). Trisomy 21- ofPediatrics, St. Paul Ramsey Hospital, trisomy 18 mosaicism in a boy with clinical Down's syndrome. St. Paul, MN55101, USA Journal ofPediatrics, 71, 126-128. J Med Genet: first published as 10.1136/jmg.15.5.395 on 1 October 1978. Downloaded from

398 Case reports Mikkelsen, M., and Stene, J. (1970). Genetic counselling in Down's red cells grouped as B, but no anti-A was detected in syndrome. Human Heredity, 20,457-464. his serum. He had a brother and sister still living and Mulchay, M. T., and Stevens, J. B. (1975). Pentasomy X. Lancet, 2, 1213. also had a stillborn twin, sex unknown. His karyotype Porter, I. H., Peterson, W., and Brown, C. D. (1969). Double auto- was 46,XY and all cells analysed showed a normal somal trisomy (trisomy D+G) with mosaicism. Journal of male pattern. His white cells typed as HLA Al 1, Medical Genetics, 6,347-348. AW30: BW21, BW40. Race, R. R., and Sanger, R. (1969). Xg and sex-chromosome abnormalities. British MedicalBulletin, 25, 99-103. Ribas-Mundo, M., and Prats, J. (1965). Hermaphrodite with mosaic Serological findings XX/XY/XXY. Lancet, 2,494. Schinzel, A., Schmid, W., and Prader, A. (1974). Turner phenotype Standard blood grouping methods were used mosaic 45,X/47,XY,+ 18. Journal ofMedical Genetics, 11, 101- 104. throughout. Elution was carried out by the Shih, L. Y., Hsu, L. Y. F., Sujansky, E., and Kushnick, T. (1974). Landsteiner-Miller technique (as described by Duns- Trisomy 18 mosaicism in two siblings. Clinical Genetics, 5, 420- ford and Bowley, 1967). In the ABO absorption and 427. elution expernments, 0-5 ml packed cells were incu- Siegelman, M. (1972). XO/XX and XO/XY mosaicism: a study of a family. Obstetrics and Gynecology, 39, 510-514. bated with 2 ml anti-A for 2 hours at 40C and the Warren, R. J., and Keith, J. I. (1971). Trisomy D/trisomy E antibody was eluted into 1 ml physiological saline. In mosaicism in an infant male. Journal ofMedical Genetics, 8, 384- the anti-Fya absorption and elution experiments, 4 ml 386. packed cells were incubated with 8 ml anti-Fya for 2 Weber, F. M., Sparkes, R. S., and Muller, H. (1971). Double mono- somy mosaicism (45,X/45,XX,21-) in a retarded child with hours at 370C and the antibody eluted into 1 ml multiple congenital malformations. Cytogenetics, 10, 404--412. antibody-free serum. Weber, F. M., Sparkes, R. S., and Muller, H. (1973). Down's syndrome with 47,XX,+21/47,XX,+mar mosaicism. Journal of Results Medical Genetics, 10, 177-179. Wilson, M. G., Fujimoto, A., and Affi, 0. S. (1974). Double auto- somal trisomy and mosaicism for chromosomes no. 8 and no. The blood groups of the propositus and his family are 21. Journal ofMedical Genetics, 11,96-101. as follows: Zdansky, R., Retl, A., Madl, W., and Piperger, A. (1971). Erbliche chromosomale mosaik-Konstitution und ihre Bedeutung fir die Propositus, AciB Rh CcDEe, M, S+s-, P1+, belastete Familie. Weiner Medizinische Wochenschrift, 121, 59- Lu(a-), K-, Le(a-b+), 63. Fy(a-b+), Jk(a-b+). Zellweger, H., and Abbo, G. (1965). Familial mosaicism attribut- Father, A B Rh CcDee, M, S+s-, P -, able to a new gene. Lancet, 1, 455-457. Lu(a-), K-, Le(a-b+), Requests for reprints to Dr M. B. Jenkins, Human Fy(a+b+), Jk(a-b+). Genetics Unit, Minnesota Department of Health, 717 Mother, Al Rh CcDEe, M, S+s-, PI+, S.E. Delaware Street, Minnesota Lu(a-), K-, Le(a-b-), Minneapolis, 55440, Fy(a+b+), Jk(a-b+). USA. http://jmg.bmj.com/ Brother, B Rh ccDEe, M, S+s-, P1+, Lu(a-), K-, Le(a-b+). Fy(a+), Jk(a-b+). Sister, Al Rh CcDEe, M, S+s-, Pi+, The phenotype Ae,B: a probable Lu(a-), K-, Le(a-b+), result of chimerism Fy(a+), Jk(a-b+).

The red cells of the propositus were not agglutinated on October 2, 2021 by guest. Protected copyright. by 10 different anti-A reagents or with a high titre SUMMARY An apparently normal healthy adult anti-A+B that had been absorbed for anti-B. How- with the blood group phenotype AeiB is de- ever, anti-A could be eluted from his red cells after scribed. The unusual ABO group is apparently the they had been sensitised with anti-A. No anti-A was result of chimerism, the proportion of the minor detected in his serum; however, on 2 occasions a weak population of cells being so small as to be only anti-A, active at 40C was found in his serum. He was detectable by absorption and elution tech- a secretor of B and H substances, but not of A sub- stance. His plasma contained B and H transferases niques. within the normal range, but no A transferase was detected. The H antigen strength was similar to that of normal group B cells. Case report The blood groups of the family show that the only The propositus was an apparently normal healthy other antigen the propositus lacked, but his stillborn blood donor, aged 24 years. During routine testing his twin might have possessed, was Fya. In view of this,