Case Reports J Med Genet: first published as 10.1136/jmg.2.2.131 on 1 June 1965. Downloaded from J. med. Genet. (I965). 2, I31. Mosaicism in an Indian Child with Down's AMALA CHAUDHURI and K. C. CHAUDHURI From The Chaudhuri Centre for Medical , Calcutta-I4, India Since the first report by Lejeune, Gautier, and 46, 47, 48, 49, 50, and SI in varying Turpin in 1959 of the findings of 2I and a proportions; one is a trisomic 2I/pentasomic 2I chromosome number of 47 in Down's syndrome (Piazzi and Rondinini, I96I); and one (mongolism), several different chromosomal pat- is a mosaic of normal cells and of cells carrying terns have been described in patients with this dis- a I3-I5/2I translocation (Franceschini, Volante, order. One of these is chromosome mosaicism. In Ceppellini, De Carli, Nuzzo, and Torricelli, such cases, the patient may lack some of the I963). This paper reports another case ofmosaicism features characteristic of the syndrome-and in- in a patient with Down's syndrome, whose leuco- deed some subjects with mosaicism are hardly dis- cytes on culture revealed two different comple- tinguishable phenotypically from normal people ments, a normal one with 46 chromosomes and (Fraccaro, Kaijser, and Lindsten, I960; Hamerton, an abnormal one with 47 chromosomes, the Briggs, Giannelli, and Carter, I96I; Blank Gem- extra chromosome belonging to the G group. mell, Casey, and Lord, I962; Smith, Therman, As expected, the chromosome number in the

Patau, and Inhorn, I962; Tonomura, Honda, and normal Indian has previously been reported to copyright. Kurita, I962; Weinstein and Warkany, I963). be 46 (Chaudhuri and Chaudhuri, i963a, b). Several cases of mosaicism in Down's syndrome are now on record and 24 are listed in Table I: i6 Methods possess two types of cells containing 46 and 47 chro- Chromosomal investigation was done by a modifica- mosomes respectively, i.e. are mosaics of normal tion of the technique of Moorhead, Nowell, Mellman, and 2I trisomic cells (Aula, Hjelt, and Kauhtio, I96I; Battips, and Hungerford (I960) (Chaudhuri, I963). Clarke, Edwards, and Smallpeice, I96I; Hayashi, Smears from the oral mucosa were stained with 2 % http://jmg.bmj.com/ Hsu, and Chao, I962; Lindsten, Alvin, Gustavson, aceto-orcein and examined for the presence of Barr and Fraccarro, I962; Nichols, Coriell, Fabrizio, bodies. The percentage of Barr bodies in normal males Bishop, and Boggs, I962; Richards and Stewart, found in this laboratory varies from 0-2 %. I962; Giraud, Bernard, Stahl, Giraud, Hartung, and Lebeuf, I963; Hayashi, I963; Verresen, Case Report Van Den Berghe, and Van Den Berghe, I963; A 4-year-old Hindu boy from a vegetarian Marwari family in Indore came to the Centre because of mental

Zellweger and Abbo, I963; Gustavson, I964; on September 24, 2021 by guest. Protected Stearns, Droulard, and Sahhar, I960; Warkany, backwardness. He was born normally at term to a healthy 22-year-old mother and 24-year-old , who Weinstein, Soukup, Rubinstein and Curless, I964; were not related to each other. He was the last in a Zellweger and Abbo, I964); 2 have also two cell sibship of three and the previous sibs were alive and types but carry a possible for the well. long arm of No. 21 (iSo-1-2I) (Hamerton et al., The infant did not cry at birth and the skull was soft I96I; Blank, Lord, Casey, and Laurance, I963); both anteriorly and posteriorly. He was unable to suck 3 show triple cell lines with 46, 47, and 48 chromo- at the breast and was fed expressed breast milk for 20 somes, 2 of them with a probable isochromosome days. All the developmental milestones were delayed. (Fitzgerald and Lycette, I96I; Gustavson and He sat up at I2 months, started waLking at 2j years, Ek, I96I; Gustavson, Mauer and Noe, cut his first tooth at 12 months, and did not learn to 1964; speak. I964). One, reported by Valencia, de Lozzio, The facial appearance had some features of mon- and de Coriat (I963), has several cell lines with golism (Fig. I). The head circumference was i8-5 in. (46-2 cm.), there was slight epicanthus, and the nasal Received August 5, I964. bridge was broad and flat. The lips were thick, the I3' J Med Genet: first published as 10.1136/jmg.2.2.131 on 1 June 1965. Downloaded from I32 Amala Chaudhuri and K. C. Chaudhuri TABLE I SOME DATA FROM REPORTED CASES OF MOSAICISM IN DOWN'S SYNDROME

Maternal Sex Chromosome Type of Age at Complement % of Mosaicism Birth and Hyperdiploid Author Phenotype Intelligence (yr.) Chromosome No. Cells PartiI Normal/trisomy 2I 25 XX 46/47 Bone marrow 32 Aula et al. (I96I) I Partial D.Q. 43 I mongolism Normal/trisomy 2I 26 XX 46/47 Skin i 47 Skin 2 62 Clarke et al. (I96I) Mongol I.Q. I00 Blood 0 Normal/trisomy 2I/ XY 46/47/48 53 and 5 Fitzgerald and Mongol features Severe 2I Lycette (I96I) mental defect 'Trisomy' 2I/ 2I Xy 46/47 Blood Few} 'tetrasomy' 2I Skin Hamerton et al. (I96I) Mongol (both cell lines with a presumptive iso-1-2i) Trisomy 21/ 28 XX 47/49 Bone marrow 711 Piazzi and Mongol pentasomy 2I and 295 Rondinini (I96I) Normal/trisomy 2I I7 XY 46/47 Blood 45 Hayashi et al. (I962) Mongol Fair Normal/trisomy 2I 38 Xy 46/47 Blood 6i et Skin 31 Lindsten al. (I962) Mongol features Average Normal/trisomy 21 I9 XX 46/47 Blood 17 Nichols et al. (I962) Mongol Normal/trisomy 21I Young XX 46/47 Blood 52 Richards and Mongol Imbecile Stewart (1962) Is0-1-2I/trisomy 2I + Young XX 46/48 Blood Blank et al. (I963) Mongol fragment Normal/13-I5/21 XY 46/46 Blood 96 translocation trisomy (abnormal line) Franceschini et al. ' Fascia lata 57 (Ic963) phenotype' (abnormal line) Normal/trisomy 2I 39 XX 46/47 34 Giraud et al. (1963) Some features of |I.Q. 85 mongolism Normal/trisomy 21 46/47 Blood 52 Hayashi (I963) Mongol Normal/variable XY 46/47/48, etc. Blood 30 21 and 32 Valencia et al. (I963) Bone marrow 23 Mongol I.Q. 75 and 47 Normal/trisomy 21 XX 46/47 Blood 56 Verresen et al. (I963) Mongol D.Q. 40 copyright. Normal/trisomy 21 40 XY 46/47 Blood 67 Zellweger and Abbo Mongol Retarded (1963, 1964) Normal/trisomy 21/ 24 XY 46/47/48 Blood 100 trisomy 21 + and o Gustavson (I964) Typical mongol I.Q. 36 probable iso-1-21 Skin i 42 Gustavson and Ek and 46 (I96I) Skin 2 32 and 28 Normal/trisomy 21 38 XX 46/47 Blood I 71 Blood 2 5Il Gustavon and Ek Not completely D.Q. 89 Skin I 421 (I96I) typical http://jmg.bmj.com/ Skin 2 12 mongol Skin 3 27 Normal/trisomy 2I/ 38 XY 46/47/48 69} Mauer and Noe (I964) Some features of I.Q. 23 ? tetrasomy 2I and IS} mongolism Normal/trisomy 21 XY 46/47 62 Stearns et al. (I960) Mongolism Average develop- ment Normal/trisomy 21 XX 46/47 50 Stearns et al. (I960) Mongolism I.Q. 72 Normal/trisomy 21 25 XY 46/47 60 Warkany et al. (I964) Typical mongol Normal/trisomy 21 23 XY 46/47 Blood, 2 cultures Warkany et al. (r964) IAtypical I.Q. 8I Skin I 23 mongol I on September 24, 2021 by guest. Protected Skin 2 I I Normal/trisomy 2I 22 Xy 46/47 Blood 59 Present case features Severely IMongol retarded mouth was kept open, and the tongue protruded. He distal interphalangeal joint, with the toe-nails in an had a high-arched narrow palate and small irregular, abnormal position. There was a wide space between the malaligned teeth, some of which were peg-shaped, with first and second toes. He was flat-footed, walked with diastasis. The hands were short with square palms and an unsteady gait, and dragged his feet. short broad fingers, but there were no single transverse The heart, gastro-intestinal system, and external palmar lines. Detailed analysis of the dermatoglyphic genitalia were normal. There was only a mild degree of changes was not done and only the following data are hyperextensibility of the joints and of . available. The axial triradius was near the centre of The child's attempt at language resulted in an inar- the palm, there was absence of pattern in the thenar ticulate vocalization, but he was able to understand a area, and the digital loop was present between digits few simple commands and to execute some of them. III and IV. The fifth fingers were short and bent. The Routine haematological examination was normal. second toe on each foot was curved medially at the Radiographs of the pelvis showed reduced acetabular J Med Genet: first published as 10.1136/jmg.2.2.131 on 1 June 1965. Downloaded from Chromosome Mosaicism in an Indian Child with Down's Syndrome I33 TABLE II CHROMOSOME COUNTS IN THE PATIENT AND HIS MOTHER

Type ofo ______Number of Chromosomes TotalCells CutypeCulture < 45 45 46 47 > 47 Counted Blood (patient) 2 I 20 38 3 64 Blood (mother) 2 2 37 - 2 43

keeping with the patient's phenotype the extra chromo- some was probably a No. 2I (Fig. 2). of the cells with 46 chromosomes were normal. A single sex chromatin mass was seen in 3 % of the resting nuclei, a value higher than that usually found in this laboratory. Chromosomal analysis of the mother's leucocytes revealed 46 chromosomes in 37 out of 43 cells. Karyo- types of four metaphase plates were all normal. The cells with chromosome counts varying from 44 to 48 were accounted for by random loss. FIG. I. The 4-year-old patient with incomplete mongolism. Discussion angles. There was hypoplasia of the middle phalanges of the fifth fingers. Autosomal mosaicism of the numerical types described in the cases of Down's syndrome now Chromosomal Studies on record could originate from mitotic non- disjunction after the first cleavage division of a Sixty-four cells in mitotic metaphase with well-spread normal zygote, from anaphase lagging in a zygote copyright. chromosomes were examined: of these, 20 (31 %) contained 46 and 38 (59 %) had 47 chromosomes originally trisomic, or from a trisomic zygote if (Table II). non-disjunction took place after the first cleavage Karyotypes prepared from enlarged photomicro- division. graphs of seven metaphase plates containing 47 chromo- The predominance of trisomic cells in this somes showed six small acrocentric chromosomes. In patient might favour the hypothesis of an originally http://jmg.bmj.com/

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FIG. 2. with six small acrocentrics. J Med Genet: first published as 10.1136/jmg.2.2.131 on 1 June 1965. Downloaded from 134 Amala Chaudhuri and K. C. Chaudhuri trisomic zygote. However, the proportions of the over 50 % trisomic cells. The various cell types may differ in different tissues was not determined in our patient, but he was and in different areas from the same tissue, and apparently severely mentally retarded with 59% furthermore change with time. trisomic cells. On the other hand, the mother of our patient It is apparent from the data available at present was only 22 years old at the time of the patient's on mosaicism in Down's syndrome that it is not birth, and we can assume that non-disjunction yet possible to establish a definite relation between in a normal zygote was the more likely cause of the proportions of the various cell lines and either the mosaicism. Meiotic non-disjunction producing the type of zygote responsible for the mosaicism a trisomic zygote is usually associated with advanc- or the physical features and level of intellectual ing maternal age. It is a remarkable fact that of attainment. As more data become available on the the I7 mothers with mosaic offsprings whose ages proportions of the cell-lines in several tissues of are recorded, I2 (71 %) are below 28 years of age the same patient with mosaicism, the differences, (Table I). As pointed out by Polani (I963), if any, will become more apparent, which might mosaicism may be of two types when considered then allow proper correlation to be made between in relation to maternal age, the one arising from these proportions and phenotypic expression. normal zygotes and the other from trisomic 2I zygotes. Summary The presence of mosaicism in our patient may Mosaicism with two cell lines consisting of account for the incompleteness of the mongoloid 46 and 47 (with an extra G) chromosomes respec- state. While possessing several of the features of tively in a 4-year-old Indian boy with Down's Down's syndrome, the patient lacked such stigmata syndrome is described. as Brushfield's spots, slanting palpebral fissures, The question of the correlation between the and furrowed tongue. Though some correlation proportions of the cell-types and the phenotype appears to exist between the proportion of abnormal in mongols with mosaicism is briefly discussed. stem-lines and the physical features ofthe syndrome

-the higher the proportion of abnormal cells, The authors wish to thank Professor Paul E. Polani,copyright. the greater the severity of the mongoloid condition ofthe Paediatric Research Unit, Guy's Hospital Medical to School, London, for very kindly reading through the -so far no definite relationship with respect manuscript, and for his valuable suggestions and particular physical characters has yet been estab- additions to the paper. lished. The authors also thank Dr. H. P. Klinger of the Zellweger and Abbo (I963), from an analysis Department of Anatomy (Genetics), Albert Einstein of the eight mosaics with Down's syndrome on College of Medicine, New York, for his many helpful suggestions during the establishment of their cyto- http://jmg.bmj.com/ record at that time, found a correlation between genetics unit where the above investigation was carried the level of intelligence and the proportions of the out. cell types-over 50 % of abnormal cells being We are also grateful to Ciba (Basle) Ltd., Switzerland, associated with severe mental retardation, while for the supply of Colcemid used in the investigation. intelligence was fair to normal where normal cells predominated. This correlation may change with further reports on mosaics and with the accumu- REFERENCES

lation of data on the proportions of the cell types Aula, P., Hjelt, L., and Kauhtio, J. (i96i). Chromosomal investi- on September 24, 2021 by guest. Protected gation in congenital malformations. Ann. Paediat. Fenn., 7, 206. between and within the tissues of the same patient. Blank, C. E., Gemnmell, E., Casey, M. D., and Lord, M. (i962). One of the recent cases reported (Valencia et al., Mosaicism in a mother with a mongol child. Brit. med. J., 2, 378. over and abnormal cells -, Lord, P. M., Casey, M. D., and Laurance, B. M. (I963). 1963) had 62 % 70 % Chromosome mosaicism in a mongol born to a young mother. in blood and bone-marrow respectively, with six , 2, 76. cell lines in the tissues, yet the I.Q. was as high Chaudhuri, A. (I963). Simplified method for obtaining leucocytes for culture from peripheral blood. Hum. Chromos. Newsl., No. ii, as 75. The mongol of Lindsten et al. (I962), i8. who was of average intelligence, had 6i % trisomic -, and Chaudhuri, K. C. (x963a). The chromosome number in A mother man. Indian J. Pediat., 30, 75. cells in one of two tissues examined. - and - (963b). The karyotype in normal Indians. Hum. with the stigmata of Down's syndrome who had Chromos. Newsl., No. I1, 2. described Clarke, C. M., Edwards, J. H., and Smallpeice, V. (I961). 21- a child with classical mongolism, by Trisomy/normal mosaicism in an intelligent child with some Blank et al. (I962), had only I4% and II% cells mongoloid characters. Lancet, I, 1028. with 2i-trisomy in two separate leucocyte cultures, Fitzgerald, F. H., and Lycette, R. R. (I96I). Mosaicism in man involving the associated with mongolism. ibid., 2, 212. and her I.Q. was only 60; whereas Richards and Fraccaro, M., Kaiiser, K., and Lindsten, J. (i96o). Chromosomal Stewart's (I962) mosaic was an imbecile with just abnormalities in father and mongol child. ibid., I, 724. J Med Genet: first published as 10.1136/jmg.2.2.131 on 1 June 1965. Downloaded from Chromosome Mosaicism in an Indian Child with Down's Syndrome I35

Franceschini, P., Volante, G., Ceppellini, R., De Carli, L., Nuzzo, Piazzi, G., and Rondinini, B. (I96I). Double mosaic in mongolism. F., and Torricelli, C. (I963). Mosaico cromosomico traslocazione (In Italian.) Clin. Pediat. (Bologna), 43, 934. 21 su I3-15 normale in un individuo mongoloide. Atti Ass. Polani, P. E. (1 963). Cytogenetics of Down's syndrome (mongolism). genet. ital., 8, IOI. Pediat. Clin. N. Amer., 10, 423. Giraud, P., Bernard, R., Stahl, A., Giraud, F., Hartung, N., and Richards, B. W., and Stewart, A. (I962). Mosaicism in a mongol. Lebeuf, M. (I963). Mosaique chromosomique chez une mongo- Lancet, I, 275. lienne avec un Q.I. A Pidiatrie, I8, 753. o,85. Smith, D. W., Therman, E. M., Patau, K. A., and Inhorn, S. L. Gustavson, K.-H. (I964). Down's Syndrome, a Clinical and Cyto- genetical Investigation. Institute for of the (I962). Mosaicism in mother of two . Amer. Dis. University of Uppsala. Almquist and Wiksell, Uppsala. Child., 104, 534. Stearns, P. E., Droulard, K. E., and Sahhar, F. H. (I960). Studies , and Ek, J. I. (I96I). Triple stem-line mosaicism in mongolism. Lancet, 2, 3I9. bearing on of male and female mongoloids. Amer. J. Hamerton, J. L., Briggs, S. M., Giannelli, F., and Carter, C. 0. ment. Defic., 65, 37. (196I). Chromosome studies in detection of parents with high Tonomura, A., Honda, T., and Kurita, T. (I962). Chromosome risk of second child with Down's syndrome. ibid., 2, 788. abnormalities in a child with Down's syndrome and in its father. Hayashi, T. (I963). Karyotypic analysis of 83 cases of Down's Proc. J7ap. Acad., 38, 526. syndrome in Harris County, Texas. Tex. Rep. Biol. Med., 21, 28. Valencia, J. I., de Lozzio, C. B., and de Coriat, L. F. (I963). -, Hsu, T. C., and Chao, D. (I962). A case of mosaicism in Heterosomic mosaicism in a mongoloid child. Lancet, 2, 488. mongolism. Lancet, I, 2I8. Verresen, H., Van Den Berghe, H., and Van Den Berghe, G. Lejeune, J., Gautier, M., and Turpin, R. (I959). Etude des (I963). Considerations sur l'expression clinique du mongolisme- chromosomes somatiques de neuf enfants mongoliens. C.R. mosaicisme (46 normal, 47 trisomie 2I, avec presentation d'un Acad. Sci. (Paris), 248, 1721. cas). Acta paediat. belg., 17, 137. Lindsten, J., Alvin, A., Gustavson, K. H., and Fraccarro, M. Warkany, J., Weinstein, E. D., Soukup, S. W., Rubinstein, J. H., (I962). Chromosomal mosaicism in a girl with some features and Curless, M. C. (I964). Chromosome analyses in a children's of mongolism. Cytogenetics, I, 20. hospital. , 33, 290. Mauer, I., and Noe, 0. (1964). Triple stem-line chromosomal mosaicism in Down's syndrome (mongolism). Lancet, I, 666. Weinstein, E. D., and Warkany, J. (I963). Maternal mosaicism Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., and Down's syndrome (mongolism). J. Pediat., 63, 599. and Hungerford, D. A. (I960). Chromosome preparations of Zellweger, H., and Abbo, G. (I963). Chromosomal mosaicism leukocytes cultured from human peripheral blood. Exp. Cell and mongolism. Lancet, I, 827. Res., 20, 613. -, and (I964). Moderne Mongolismus-Probleme: Mon- Nichols, W. W., Coriell, L. L., Fabrizio, D. P. A., Bishop, H. C., golismus, Paramongolismus und mongoloide Stigmatisierung in and Boggs, T. R., Jr. (I962). Mongolism with mosaic chromo- klinischer und zytogenetischer Betrachtung. Dtsch. med. Wschr.,

some pattern. J. Pediat., 6o, 69. 89, 405. copyright. http://jmg.bmj.com/ on September 24, 2021 by guest. Protected