Clinical Generics 1976: 10: 77-81

A case of atypical Down’s syndrome with mosaic 46,XX/46,XX=21+t( 21q21q) L. HORN STEIN^

AND

S. SOIJKUP~

1 University

Affiliated Cincinnati Center for Developmental Disorders and Department of Pediatrics, University of Cincinnati, Pavilion Building, and 2 Institute for Developmental Research of Children’s Hospital Research Foundation, and Department of Pediatrics, University of Cincinnati, Elland and Bethesda Avenues Cincinnati, Ohio, U.S.A. A girl with clinically atypical Down’s syndrome was found to be mosaic 46,XX/46,XX, - 21, +t(21q21q) in skin fibroblast and blood lymphocyte preparations. The importance is stressed of repeated and thorough karyotype analysis to prevent these cases being missed. Received 5 December 1975, accepted for publication 30 January 1976

Pediatricians are often called upon to diagnose a patient in whom Down’s syndrome is suspected but where typical features are minimal or lacking. Chromosome findings in these atypical patients range from trisomy 21, to mosaicism of normal and trisomic lines, to apparently normal chromosome constitution (Mikkelsen 1971). We report here a case of a girl with clinically atypical Down’s syndrome in whom chromosome analyses showed a normal number of 46 chromosomes in blood and fibroblast preparations, but karyotype examination showed structural mosaicism for a normal and t(21q21q) chromosome complement. Case History

The proposita, a girl, born on June 10, 1963 was the product of a normal full-term pregnancy of a 37-year-old mother and 39-yearold father; four older siblings were normal. Labor and delivery were uncomplicated; the birth weight was 4338 g (9 Ib, 9 02).

At the age of 9 months she was noted by her physician to have sIanting of the eyes and hypertelorism. Down’s syndrome was suspected, Roentgenograms of skull, chest and pelvis and a chromosome analysis were reported as normal. The parents were told that the child was not mongoloid. A psychological test at age 3 % years showed severe retardation and an I.Q. of 48. At 4 years 3 months, when she was first seen at Cincinnati Center for Developmental Disorders, the major features suggestive of Down’s syndrome were mongoloid slanting of the eyes and facial grimacing. The skull was flattened posteriorly, and the forehead bulging. Epicanthal folds were present, and there were bilateral Brushfield spots. External ears were simplified. She had a long philtrum and a slightly high-arched palate. The fingers were short but there was no clinodactyly. The joints were markedly hypermobile, there was a wide space between the first and second toes, and the tongue was large. The child showed very

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Cytogenetic Studies

Chromosome analysis carried out initially at another hospital was reported as normal. Results of chromosome analyses in our medical center are shown in Table 1. The majority of cells had 46 chromosomes. Mosaicism for a structural abnormality was first noted in the fibroblast culture. Most of the 20 karyotypes were normal 46,XX, but some showed only three normal G chromosomes and an extra F-size chromosome, interpreted as a t(GqGq) chromosome (Fig. 2, A and B). The percent cells with t(GqGq) Flg. 1. Photograph of the patient at age 4 years.

little social responsiveness, Roentgenographic examination of the skull disclosed nasal bones of normal size. The hypoplastic maxilla was well pneumatized, there was no orbital hypotelorism, and the middle phalanges of the fifth digits were normal. The dermatoglyphic patterns on the fingertips were all ulnar loops. The palmar atd angles on the right were 43 and on the left 37 degrees. A loop pattern was present in both fourth interdigital areas. The right and left hallucal patterns were large distal loops. The I.Q. was 34; language and speech were markedly delayed. At the age of 10 years, 4 months, the features were still reminiscent of Down’s syndrome because of slanting of the eyes, grimacing and certain mannerisms; at this time she functioned at the 5 years, 8 months level.

Table 1 Culture Blood 1 Blood 2 Blood 3 Fibroblast 1 Fibroblast 2

No. cells counted

Qh cells

30 50 50 50 100

3

(GqGq)

2 10

27 51

Fig. 2. Chromosomes 1. 19, 20, 21, 22 are shown from four different cells of the patient: (A) unbanded chrornosomes from a normal female cell 46,XX, ( 8 ) from a cell with 46,XX,-G+(GqGq), (C) G banded chrornosomes from a normal female cell, and (D)from a cell showing the (21q21q) chromosome In C and D, the second No. 1 chromosome shows a qh+ region.

A CASE OF ATYPICAL DOWN’S SYNDROME

was estimated from karyotype analyses in the first two blood lymphocyte cultures. In the other cultures the G chromosomes were scored in almost every cell: and an increased percentage of t(GqGq) cells was found. Giemsa (G) banding of normal cells showed normal G chromosomes (Fig. 2C): the abnormal cell line (Fig. 2D) showed one normal No. 21 and a (21q21q) chromosome which could be interpreted either as a translocation (21q21q) or as an isochromosome (21qi). In both cell lines, a No. 1 chromosome with a heterochromatic l q h + region was found. Normal chromosome complements were found in 30 cells examined from each parent. Discussion

From the clinical point of view this patient raises several important considerations. Even though the first impression at 9 months was that of Down’s syndrome, the correct diagnosis could easily have been missed, particularly since the original chromosome findings were reported as normal. Despite the absence of many signs typical of Down’s syndrome, the slanting of eyes, epicanthal folds and grimacing produced a facial gestalt suggestive of the diagnosis. Except for some hypoplasia of the maxilla, the roentgenographic studies failed to demonstrate any of the skeletal stigmata of mongolism. The dermatoglyphic findings, when plotted on the Down’s syndrome dermatogram (1970 Indiana University Foundation), fell between normal and Down’s syndrome, closer to the normal range. Thus only four of the 10 cardinal symptoms of aster (1953) were present in our patient: slanting of the eyes, epicanthi, occipital flattening and hyperextensible joints. Two others, high palate and transitional simian line were only mildly expressed. Although Down’s syndrome is easily re-

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cognized in its typical form, there are children who show only a few of the characteristics, and in some of these chromosomal mosaicism has been found (Mikkelsen 1971). Some earlier studies of patients with mosaicism 46/47, 21 suggested a positive correlation between features of Down’s phenotype, including the degree of mental retardation and the percentage of trisomy 21 cells (Zellweger & Abbo 1963, Shipe et al. 1968, Grosse et al. 1971a). However in other more recent studies there was no correlation (Johnson & Abelson 1969, Kohn et al. 1970). Individuals with mosaicism of a normal and (GqGq) chromosome are rare, but the condition can occur in clinically normal parents of children with Down’s syndrome (Hamerton et al. 1961, Waxman & Arakaki 1966, Schreibenreiter et al. 1968, Yang & Rosenberg 1969), and in persons with clinically typical Down’s syndrome or with atypical Down’s syndrome. These cases represent a variety of cytogenetic types and probably have a different etiology (Richards 1969). Eleven cases of Down’s syndrome with structural mosaicism (GqGq) are summarized in Table 2. The heterogeneity of chromosome findings is apparent. Only the case of Grosse et al. (1971b) is similar to the present case: a blood lymphocyte culture showed 9 % (GqGq) cells; the child had an I.Q. of 80 and the signs of Down’s syndrome were “faintly marked.” Our patient, on the other hand, had an I.Q. found in typical Down’s syndrome. Fibroblast cultures, compared to blood cultures showed a high percentage of abnormal cells in accordance with other studies of mosaics (Day & Wright 1965, Richards et al. 1965, Waxman & Arakaki 1966, Atkins & Bartisocas 1974), although the reverse was true in one case (Hamerton et al. 1961). Thus the lengthy procedure of chromosome analysis from fibroblast cultures is worthwhile in some of these rare cases of Down’s syndrome.

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HORNSTEIN AND SOUKUP Table 2 Summary of Down's syndrome with (GqGq) structural mosaicism

References

Chromosome findings

Comments

Gustavson & Ek (1961) Hamerton et al. (1961) Migeon et al. (1962)

46 normal/47,+(GqGq)/48, +G +(GqGq) 46,Gqil47,Gqi +G 46,(GqGq)/47,(GqGq) +frag/48,(GqGq) +2 frag 46,21qi/48,+G +Gpi 45,(GqGq)tandem/46. (GqGq)tandem

Typical Down's syndrome Typical Down's syndrome Atypical Down's syndrome

Blank et al. (1963) Richards et ai. (1965) Day & Wright (1965) Schreibenreiter et al. (1968) Atkins & Feingold (1969) Grosse et al. (1971b) Atkins & Bartisocas (1974) Present case

Typical Down's syndrome Typical Down's syndrome Mother age 44 46 normal/46,(GqGq)/47,(GqGq)+G Typical Down's syndrome Typical Down's syndrome 46 normal/46,(GqGq)/47+G Mother mosaic Typical Down's syndrome 46,21p -/46,21qi Atypical Down's syndrome 46 normall46,(GqGq) Typical Down's syndrome 45, (DqG W 6 , (Gq Gq) Atypical Down's syndrome 46 norma1/46,(21q21q)

Giemsa banding in our case showed the structural abnormality to be a (21q21q) chromosome. This is the finding in cases of regular sporadic (GqGq) Down's syndrome (Ying 1973), but whether the chromosome is a translocation or an isochromosome is not known. Three cases in Table 2 (Hamerton et al. 1961, Blank et al. 1963, Atkins & Feingold 1969) were thought to be an isochromosome. In our case the formation of an isochromosome in one of the early cell divisions of a normal zygote would seem to be the simplest explanation of the mosaicisrn. However, the (GqGq) chromosome could have arisen in parental meiosis or as a translocation in a trisomic zygote, with subsequent loss of a G chromosome in one line. The finding of a No. 1 chromosome with a l q h + is considered incidental in this case. The importance of cytogenetic analyses in patients with only a few signs of mongolism must be stressed. In some of these individuals the facial gestalt may be the only positive finding. Repeated and careful studies in more than one tissue are recommended if these cases are not to be missed or diagnosed as retardation of unknown etiology. The possibility of missing this type

of structural abnormality in prenatal diagnosis must also be considered. Acknowledgment

This study was supported in part by NIH grant No. HD-05221 and in part by grants No. MCT-000912-08-0 and MCT-0091809-0 awarded by the Bureau of Community Health Services Administration, Public Health Service, DHEW and grant No. 59P-25297103, awarded by Region V, Social and Rehabilitation Service, DHEW, and National Foundation grant No. C-136.

References

Atkins, L. .& C. S. Bartisocas (1974). Down's syndrome associated with 2 Robertsonian t(15q21q) and translocations 45,XX-15-21, 46,XX-21, t(21q21q). J . m e d . G e n e t . 11, 306-309. Atkins, L. #&M. Feingold (1969). 46,XY,21qi/ 46,XY,21p- mosaicism in a child with Down's syndrome. J . med. G e n e t . 6 , 206208. Blank, C. E., P. M. Lord, M. D. Casay .& B. M. Laurance (1963). Chromosome mosaicisrn in a mongo1 boy born to a young mother. Cytogenetics 2, 76-85.

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A CASE OF ATYPICAL DOWN’S SYNDROME

Day, R. W. C S. W. Wright (1965). Down’s syndrome at young maternal ages: chromosomal and family studies. J . Pediat. 66, 764771. Grosse, K. P., G. Grosse, G. Schwanitz & H. D. Rott (1971a). Mosaikmongolismus. 2. Kinderheilk. 110, 332-346. Grosse, K.-P., G. Schwanitz, G. Grosse & H. P, R. Mayer (1971b). G/G-Translokation im Mosaik bei einem Madchen mit schwach ausgepragtem Erscheinungsbild des Mongolismus. Hum. Genet. 13, 315-319. Gustavson, K. H. L J. I. Ek (1961). Triple stem-line mosaicism in mongolism. Lancet ii, 319. Hamerton, J. L., S. Briggs, F. Giannelli L C. 0. Carter (1961). Chromosome studies in detection of parents with high risk of second child with Down’s syndrome. Lancet ii, 788791. Johnson, R. C. L R. B. Abelson (1969). Intellectual behavior and physical characteristics associated with trisomy, translocation, and mosaic types of Down’s syndrome. Amer. J . ment. D e f i c . 73, 852-855. Kohn, G., K. Taysi, T. E. Atkins L W. S. Mellman (1970). Mosaic mongolism: 1. Clinical correlation. J . Pediat. 76, 874-879. Kunze, J . L G. Mau (1975). A1 and Ct, marker chromosomes in children with combined minor and major malformations. Lancet i, 273. Migeon, B. R., B. N. Kautmann L W. J. Young (1962). A chromosome abnormality with centric fragment in a paramongoloid child. Amer. J . Dis. Child. 104, 533. Mikkelsen, M. (1971). Down’s syndrome: current stage of cytogenetic research. Hum. Genet. 12, 1-28. 0ster, G. (1953). Mongolism (Opera ex domo biologiae hereditariae humanae Universitatis

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Hafniensis, vol. 32). Copenhagen, Danish Science Press Ltd. Richards, B. W., A. Stewart L P. E. Sylvester (1965). Reciprocal translocation and mosaicism in a mongol. J . ment. Defic. Res. 9, 118-124. Richards, B. W. (1969). Mosaic mongolism. J . ment. Defic. Res. 13, 66-83. Schreibenreiter, S., 0. Stur L 0. Thalhammer (1968). Chromosomenuntersuchungen an Einer Familie mit drei mongoloiden und zwei gesunden Kindern. Mschr. Kinderheilk. 116, 183. Shipe, D., L. E. Reisman, Y. Chin, Ch. A. Darnell L S. Kelly (1968). The relationship between cytogenetic constitution, physical stigmata and intelligence in Down’s syndrome. Amer. J . Ment. D e f i c . 72, 789-797. Waxman, S. H. L D. Arakaki (1966). Familial mongolism by a G/G mosaic carrier. J . Pediat. 69, 274-278. Yang, S.-J. L H. S. Rosenberg (1969). 21/22 translocation Down’s syndrome: a family with unusual segregating patterns. A m e r . J . hum. Genet. 21, 248-251. Ying, K. L. (1973). Sporadic (GqGq) translocations in Down’s syndrome. Canad. 1. Genet. Cytol. 15, 309-311. Zellweger, H. t G. Abbo (1963). Chromosomal mosaicism and mongolism. Lancet i, 827.

Address: L . Hornstein, M . D . University Affiliated Cincinnati Center f o r Developmental Disorders Children’s Hospital Medical Center Elland and Bethesda Avenues Cincinnati Ohio 45229, U.S.A.