Mosaic Down's Syndrome with De Novo 45,XX,-21, 22,+T(21Q;22Q)/46, XX,-21 ,+T(21Q;21Q) Rearrangement on September 30, 2021 by Guest

J Med Genet: first published as 10.1136/jmg.21.5.391 on 1 October 1984. Downloaded from

Case reports 391 of partial 4q- suggesting that partial monosomy of the long arm of chromosome 4 was present in this child. Subject IV.15 presented with a beaked nose, pronounced micrognathia, strabismus, and marked hypoplasia of the mandible. Death occurred at 12 years. This appears to be consistent with malfor- FIG 3 Partial karyotypes of the proband showing mations found in partial monosomy of the short centric fission ofchromosome 4 (GTG bandixeg). arm of chromosome 4. In particular, the age of death is similar to the only case reported6 of survival through the first year of life in a subject with partial Discussion 4p monosomy. This appears to be the first published case report of We would like to thank Mr Mario Sanchioni for his transmitted centric fission of chromosome 4 so far. help with the photographs. It is interesting to observe the particular stability of human telocentric chromosomes, which involve References a high risk of transmission of non-balanced gametes. In sibships A and B there are early spontaneous Sinha AK, Pathak S, Nora JJ. A human family suggest- abortions which could be attributed to the un- ing evidence for centric fission and stability of a telocentric chromosome. Hum Hered 1972 ;22 :423-9. balanced form of the aberration. Another point 2 Hansen S. A case of centric fission in man. Hum Genet worthy of attention is the possible clinical inter- 1975 ;26:257-9. pretation of the two children of sibship B, who 3 Fryns JP, Bulcke I, Hens L, Van den Berghe H. Balanced died at 6 months and 12 years, transmission of centromeric fission product in man. Hum respectively. Their Genet 1980;54:127-8. phenotype was deduced from the clinical history and 4 Janke D. Centric fission of chromosome 7 in three copyright. the photographs. generations. Hum Genet 1982;60:200-1. Table 2 lists the symptoms described in cases of 5 Dallapiccola B, Mastroiacovo P, Gandini E. Centric partial aberrations of chromosome 4 and allows fission of chromosome 4 in the mother of two patients with trisomy 4p. Hum Genet 1976;31:121-5. a comparison with those present in the two dead 6 Miller OJ, Breg WR, Warburton D, et al. Partial deletion children as a possible aid to a specific diagnosis. of the short arm of chromosome 4 (4p-): clinical studies Of the various clinical manifestations described in five unrelated patients. J Pediatr 1970;77:792-9. in table 1, subject IV.11 presented with a normal birth weight, flat and wide nasal bridge, mongo- Correspondence and requests for reprints to http://jmg.bmj.com/ loid slant, absence of strabismus, and died at 6 Professor Giuseppe Del Porto, Via San Calepodio 7, months. These symptoms are also found in cases 00152 Rome, Italy.

Mosaic Down's syndrome with de novo 45,XX,-21, 22,+t(21q;22q)/46, XX,-21 ,+t(21q;21q) rearrangement on September 30, 2021 by guest. Protected

A T THARAPEL*, R REDHEENDRANt, C B MANKINENt, AND M K KUKOLICHt *Department ofPediatrics, University of Tennessee Center for the Health Sciences, Memphis, Tennessee; and t the Genetics Screening and Counselling Service, Denton, Texas, USA.

SUMMARY The occurrence of mosaic Down's somes 21 was detected in the majority of cells. syndrome with two independent Robertsonian The patient also revealed a minor cell line with a translocation cell lines is very rare. Such a second Robertsonian translocation involving a patient is reported here, in whom an unbalanced chromosome 21 and a 22. The chromosome Robertsonian translocation between two chromo- translocations detected in this patient were de Received for publication 28 November 1983. Accepted for publication 20 December 1983. novo in origin. J Med Genet: first published as 10.1136/jmg.21.5.391 on 1 October 1984. Downloaded from

392 Case reports Down's syndrome is associated with a remarkable the clinical diagnosis of Down's syndrome by a degree of karyotypic variation. Approximately public school system soon after enrolment, and 92 5% of all patients with this condition have an because she was found to have a scattered IQ additional chromosome 21 resulting in a karyotype between 25 and 50 on a subsequent test. with 47 chromosomes. In about 4 8/%, the extra On physical examination at the age of 6 years, 11 chromosome 21 material is present either in the months the child had a normally shaped head, form of an unbalanced Robertsonian translocation except that the occiput was flat, and the head (Dq;21q or Gq;21q) or as an isochromosome for the circumference was 49 cm (between the 5th and 10th long arm ofchromosome 21. Patients with any of the centile). The eyes were prominent with bilateral above chromosome complements present the char- epicanthic folds and upward slanting palpebral acteristic phenotype of Down's syndrome. The fissures. The ears were small and simple with the remaining 2 7 % have heterogeneous karyotypes helices folded over. The nose was short with a flat such as mosaicisms and double trisomies and often nasal bridge and upturned nostrils. The tongue was exhibit variability in the expression of the pheno- normal and did not protrude from the mouth. The type.' heart was normal. The nipples were widely spaced. A milder Down's syndrome phenotype has been Organomegaly was not present. There was a tiny reported in some patients with tandem duplication umbilical hernia. The external genitalia were normal. of the distal long arm of chromogome 21.2 3 From Arms and legs were symmetrical and proportionate. the hypotheses of Niebuhr2 and Aula et a14 and from The hands were broad and short, with short fifth the information available from the family reported fingers. The palmar creases were normal. Ulnar by Williams et al,5 it is evident that the major loops were present on all fingers except the second features of Down's syndrome phenotype are asso- finger of the left hand. The axial triradii were ciated with the trisomic state for the 21q22->qter distally placed. All joints were hyperextensible. region. By contrast, trisomy for the short arm and Neurologically, no gross defects were seen. the proximal long arm of chromosome 21 (21pter--> The proband was able to dress and undress, to q21) is associated with minor anomalies and mental put on and tie shoes with a neat double knot, buttoncopyright. retardation without the entire clinical spectrum of and unbutton, zip jeans, and thread and buckle her Down's syndrome.5 belt. Fine motor skills appeared to be well developed. Complex balanced translocations involving more She wrote her name in neat printing using both than a single event and more than two chromosomes, capital and small letters correctly, held a pencil though very rare, have been recorded in man. The with no difficulty, and drew animals (cat and dog) reports of Creasy et al,6 Bell and Warburton,7 with all parts appropriately placed. She was able to

Seabright et al,8 Stoll et al,9 Simoni et al,10 Tabor et distinguish her first and last names, state her age, http://jmg.bmj.com/ al,11 and Chewings et al12 provide examples of trans- and indicate the same by holding up the appropriate locations involving more than two autosomes in the number of fingers. In general, she demonstrated same cell. Similarly, different Robertsonian translo- good vocabulary for her age and appeared to have cations leading to at least two cell types in the same normal balance and adequate gait. person are also known.13-'6 To our knowledge there are reports of at least four patients with mosaicism CYTOGENETIC STUDIES for two different Robertsonian translocations, three Karyotype analysis was performed on cultured blood resulting in mosaic Down's syndrome13-'5 and the lymphocytes using GTG, QFQ, and RBA banding on September 30, 2021 by guest. Protected fourth resulting in mosaic trisomy 13.16 An addi- techniques. Of the 304 metaphase spreads analysed tional patient with mosaicism for two cell lines, each from two independent blood samples obtained on with a different Robertsonian translocation, 45,XX, separate occasions, 199 cells contained an un- -21,-22, +t(21q; 22q)/46, XX, -21, +t(21q; 21q), balanced Robertsonian translocation between the is the subject of this report. long arms of two chromosomes 21 (or isochromosome for 21q) resulting in trisomy 21 with a karyo- Case report type 46,XX-21,+t(21q;21q). The remaining 105 cells had a different Robertsonian translocation The proband, a black female, was born to a gravida involving the long arms of a chromosome 21 and a 2, para 1, 34 year old mother and a 35 year old 22 with a karyotype 45,XX,-21,-22, +t(21q;22q). father. The pregnancy and delivery were reported Chromosome analysis from cultured blood lym- to be normal. At birth the infant weighed 3116 g phocytes of both parents revealed normal karyo- (between the 25th and 50th centile) and had a length types. The family refused further investigations of 45 cm (below the 10th centile). She was referred including chromosome analysis from the skin of the for genetic evaluation after the age of 6 because of patient. J Med Genet: first published as 10.1136/jmg.21.5.391 on 1 October 1984. Downloaded from

Case reports 393 Discussion division of this zygote resulted in two cells, one with a normal 46,XX karyotype and the other with a From a cytogenetic standpoint, our patient and Robertsonian translocation, karyotype 45,XX,-21, those reported by Atkins and Bartsocas,13 Lieber -22,+t(21q;22q). The next division of the normal and Shah,14 and Zellweger and Abbo15 contained at cell resulted in two cells with a 46,XX,-21, +t least two different Robertsonian translocation cell (21q;21q) or 46,XX,-21,+i(21q) and with a lines that appeared to have originated independently. 45,XX,-21 karyotype, respectively. The 45,XX,-21 Zellweger and Abbo15 described mosaicism for four cell line was subsequently selected against (fig 1). cell types in their patient. The majority (59 5%) This hypothesis has some deficiencies because it were 45,X,-D,+t(Dq;Gq), 18-5% cells were has to be postulated that the two translocation normal 46,XX, 12-5% were 45,XX,-D,-D,+t events occurred sequentially at the first and second (Dq;Dq), and the remaining were 44,X,-D,-D, zygote divisions. Otherwise, one would expect a -G, +t(Dq;Dq) karyotypes. A D;D translo- normal 46,XX cell line at least in small numbers. cation was also detected in a mosaic state in their Although such a normal cell line was not observed patient's father and paternal grandmother. The speci- in our patient, its existence cannot be ruled out fic origin of the four cell types in the patient remains because chromosome studies from other tissues to be explained. were not performed. It is also presumed that the The two mosaic cell lines noted in our patient 45,XX,-21 cell line was either eliminated totally by were an unbalanced Robertsonian translocation selection or outgrown by the other cell types. between chromosomes 21 with a karyotype 46,XX, A second possibility is chimaerism, where two -21,+t(21q;21q) in 66% of the cells and a Robert- ova or one ovum and a polar body were fertilised sonian translocation between a 21 and a 22 with by sperms carrying t(21q;22q) and t(21q;21q), karyotype 45,XX,-21,-22,+t(21q;21q) in the respectively. The two zygotes later developed into a remaining 34%. No other cell types were noted in single embryo. Heteromorphism studies using QFQ the lymphocyte population. Complex chromosome banding did not reveal conclusive differences be- mosaicism with rearrangements of the above type tween the two cell types. Genotype studies to deter- copyright. requires more than a single cytogenetic event. The mine chimaerism were not possible because of the origin of two independent de novo translocations, lack of cooperation from the parents. involving two different chromosome pairs, is difficult A third explanation is that the zygote had a to determine with certainty. However, the following 47,XX,+21 karyotype. The mother was 34 years hypotheses are advanced to explain the origin of the old at the time of the proband's conception and, chromosome abnormalities in our patient. therefore, maternal age can be considered as a

In the first hypothesis it is assumed that the likely predisposing factor for non-disjunction. It is http://jmg.bmj.com/ zygote had a normal 46,XX karyotype. The first further assumed that Robertsonian translocations

46,XX zygote

Centromere misdivision leading to i[21q1 tl21q;22q1 on September 30, 2021 by guest. Protected

46,XX,-21,+i [21q] 45,XX,-21 45 ,XX,-21,-22+t(21q; 22q]

Chromosomne Cl,hromosome 21 22 FIG 1 Schematic representation ofhypothesis 1. J Med Genet: first published as 10.1136/jmg.21.5.391 on 1 October 1984. Downloaded from

394 Case reports

4 12'

1 2' 5 45,XX,- 21,- 22,+ t[ 21q; 22q]

47,XX,+21 zygote 4' 4 11c

1 1' 2 2 3 3' 4 4' 5 5' 2 2 3 3' 435' 5 1D 2 4 3 5' 46,XX,-21,+t[21q; 21q] 6 Chromosome 21 4 Chromosome 22 Lost due to onaphose log

FIG 2 Schematic representation of hypothesis 3. may occur between single chromatids. Soon after Project 417. The authors acknowledge the secretarial the zygote two the formation of 47,XX, +21 assistance of Barbara Moore. copyright. chromosomes 21 and one 22 were very intimately associated in the formation of the nucleolus when an References apparent 'insult' occurred to that particular region of the cell. Replication was initiated and proceeded de Grouchy J, Turleau C. Clinical atlas ofhuman chromo- from one 21q continuously into one 22q on one somes. New York, Brisbane, Toronto: Wiley, 1977. chromatid and from one 21q to another 21q on the 2 Niebuhr E. Down's syndrome: the possibility of a pathogenetic segment on chromosome no 21. Hum Genet other chromatid. The unaffected chromatids were 1974;21 :99-101. http://jmg.bmj.com/ separated at the centromere and segregated as Schuh BE, Korf BR, Salwen MJ. A 21/21 tandem independent chromosomes while the affected ones translocation with satellites on both long and short arms. segregated as t(21q;22q) and t(21q;21q). During the J Med Genet 1974;11:297-9. same cell division the extra 21 was eliminated Aula P, Leisti J, van Koskull H. Partial trisomy 21. Clin through anaphase lag (fig 2), resulting in two cells Genet 1973;4:241-51. Williams JD, Summitt RL, Martens PR, Kimbrell RA. with 45,XX,-21,-22,+ t(21q;22q) and 46,XX, Familial Down syndrome due to t(10;21) translocation: -21,+t(21q;21q), respectively (U Franke, 1981, evidence that the Down phenotype is related to trisomy personal communication). of a specific segment of chromosome 21. Am J Hum Genet on September 30, 2021 by guest. Protected While all three explanations put forth are pos- 1975 ;27:478-85. 6 JA, Polani PE, Elliott MH. A three we are to favour the last one because Creasy MR, Crolla sible, inclined chromosome translocation involving two homologous it allows us to postulate that a single 'insult' occurred chromosomes in a trisomic abortus. Clin Genet 1976;9: within a single cell leading to two Robertsonian 15-9. translocation cell lines. These hypotheses may also 7Bell EF, Warburton D. Two reciprocal translocations explain the origin of similar chromosome abnor- associated with microcephaly and retardation. J Med Genet 1977;14:141-2. in the 14 malities patients reported previously.'3 8 Seabright M, Gregson N, Pacifico E, et al. Rearrange- ments involving four chromosomes in a child with congenital abnormalities. Cytogenet Cell Genet 1978;20: The authors acknowledge the review of this manu- 150-4. script by Dr Robin M Bannerman of the Division 9Stoll C, Flori E, Macler J, Renaud R. Prenatal diagnosis of Human Genetics, Department of Pediatrics, and postnatal follow-up of an abnormal child with two SUNY at Buffalo. Preparation of the manuscript de novo apparently balanced translocations. Hum Genet 1979 ;47:221-4. was the for publication supported by Department 10 Simoni G, Montali E, Rossella F, Dalpra L, Lo Curto F. of Health and Human Services, Bureau of Maternal A woman carrier of two apparently unrelated reciprocal and Child Health, Human Genetics Program, translocations. Hum Genet 1979 ;46:159-62. J Med Genet: first published as 10.1136/jmg.21.5.391 on 1 October 1984. Downloaded from

Case reports 395 Tabor A, Jensen LK, Lundsteen C, Niebuhr E. A boy with mental retardation. J Med Genet 1982;19: 5;7, 5;12 double reciprocal translocation in a normal 229-32. mother and a 5;7 translocation with a recombinant 15 Zellweger H, Abbo G. Familial mosaicism attributable chromosome 5 in her normal child. J Med Genet 1981 ;18: to a new gene. Lancet 1965;i:455-7. 307-9. 16 Anderson CE, Shulkin JD, Mohandas T. Mosaicism for 12 Chewings WE, Cocks TP, Gardner RJM, Clarkson JE. trisomy 13 with 13/13 translocation and a balanced 13/21 A malformed baby with two separate de novo translo- translocation in a patient with 13p -. Am J Hum Genet cations. J Med Genet 1982;19:70-1. 1979;31:87A. 13 Atkins L, Bartsocas CS. Down's syndrome associated Correspondence and requests for reprints to Dr A T with two Robertsonian translocations, 45,XX,-15,-21, +t(15q;21q) and 46,XX, -21,+t(21q;21q). J Med Genet Tharapel, Department of Pediatrics, UTCHS, 1974;11:306-9. Child Development Center, 711 Jefferson Avenue, 14 Lieber E, Shah P. Two Robertsonian translocations in a Memphis, Tennessee 38163, USA. copyright. http://jmg.bmj.com/ on September 30, 2021 by guest. Protected