J Med Genet: first published as 10.1136/jmg.15.1.73 on 1 February 1978. Downloaded from Case reports 73 References metacentric chromosomes of different sizes. After 1 Caspersson, T., Linstein, J., Zech, L., Buckton, K. E., and Price, autoradiography, the larger of the two was inter- W. H. (1972). Four patients with trisomy 8 identified by the preted as being composed of two long arms of fluorescence and giemsa banding techniques. Journal ofMedical chromosome No. 18. The smaller metacentric Genetics, 9, 1-7. chromosome was assumed to be equivalent to two 2 De Grouchy, J., Josso, F., Beguin, S., Turleau, C., Jalbert, P., and Laurent, C. (1974). Deficit en facteur VII de la coagulation short arms of chromosome No. 18. A similar case is chez trois sujects trisomiques 8. Annals de G&nMtique, 17, presented here in which G and C banding were used 105-108. to confirm the identity of the isochromosomes 3 Fineman, R. M., Ablow, R. C., Howard, R. O., Albright, J., involved. and Breg, R. (1975). Trisomy 8 mosaicism syndrome. Pediatrics, 56, 762-767. 4 Jacobsen, P., Mikkelsen, M., and Rosleff, F. (1974). The trisomy 8 Case report syndrome: report of two further cases. Annales de Genitique, 17,87-94. CLINICAL FINDINGS 5 Kakati, S., Nihill, M., and Sinha, A. K. (1973). An attempt to establish trisomy 8 syndrome. Humangenetik, 19, 293-300. The proposita (Fig. 1) was first seen as a 7-day-old 6 Riccardi, V. M. (1976). Trisomy 8: an international study of 70 infant born to a 23-year-old mother and a 28-year-old patients. In Birth Defects Conference, Vancouver, BC; June 23. father who were not related. She was the product of a 7 Schaumann, B., Cervenka, J., and Gorlin, R. (1974). Dermato- the first ended in glyphics in trisomy 8 mosaicism. Humangenetik, 24,201-205. second pregnancy, having spon- 8 Sperber, M. A. (1975). Schizophrenia and organic brain syndrome taneous abortion. Delivery followed a term preg- with trisomy 8 (group C trisomy 8 [47, XX, 8+1). Biological nancy which was complicated by the cord being Psychiatry, 10, 27-43. wrapped around the neck. Crying was delayed because 'increased mucus' and respiratory distress required administration of oxygen for approxi- Requests for reprints to Dr Marileila Varella-Garcia, mately 10 hours after birth. Birthweight was 2727 g Laborat6rio de Gen&tica, Instituto de Biociencas, and body length was 49*5 cm. Head circumference Letras e Ciencias Exatas, 15100 Sao Jose do Rio was 34 cm and chest 30 cm. The baby had difficulty Preto, Estado de Sao Paulo, Brazil. feeding during thefirst 5 days.

PHYSICAL EXAMINATION AT BIRTH copyright. Physical examination revealed a 'staring appear- ance', low set ears, very small mouth, micrognathia, Trisomy 18 syndrome with an and short neck. There was a poor Moro's reflex, weak cry, no rooting reflex, poor grasp, and fair sucking unusual karyotype: possible double instinct. Genitalia were small with gaping minor and isochromosome major labia. Extremities revealed rockerbottom feet and limited abduction at both hip joints (questionable subluxa- http://jmg.bmj.com/ sumMARY Chromosome analysis of an infant tion). There was an overlapping of the forefinger and with characteristic features of trisomy 18 is ring finger over the middle finger and a short dorsi- toe. were presented. The chromosome complement con- flexed big No simian lines present. A faint systolic murmur was heard at the pulmonary area tained a modal count of47 but there was only one and borderline cardiomegaly was seen on x-ray No. 18. In addition, there were two metacentric examination. two meta- chromosomes of different sizes. The Laboratory tests revealed a haemoglobin of 16-4 on September 28, 2021 by guest. Protected centric chromosomes were identified by G- and g/dl, bilirubin of 114-6 mmol/l (6-7 mg/100 ml) total C-banding to be possible isochromosomes of the and 3-42 mmol/l (0-2 mg/100 ml) direct, sodium of long and short arms of a No. 18 chromosome. 147 mmol/l, and potassium of 3-1 mmol/l. Urinalysis results were normal except for 3 to 4 RBC/hpf.

Trisomy 18 (Edwards' syndrome) is a clinically SUBSEQUENT PHYSICAL DATA recognisable syndrome with an incidence in new- The patient was seen at 1 year, at which timethe karyo- borns of 0-01 % (Jacobs et al., 1974). In most instan- types were repeated and photographs taken. On her ces, it results from nondisjunction in a maternal or most recent visit at the age of 174 months, the patient paternal gamete producing three normal No. 18 was doing remarkably well. Weight at this time was chromosomes in the zygote. Muller et al. (1972) 6556 g, length 73 0 cm, and head circumference 44-6 described a case with the phenotype of trisomy 18 cm. All formula feedings were by the gavage route which had only one No. 18 chromosome and two but solids were taken well from a spoon. Vision and J Med Genet: first published as 10.1136/jmg.15.1.73 on 1 February 1978. Downloaded from 74 Case reports

Fig. 1 Photographs of the proposita at 1 year ofage showingfeatures compatible with trisomy 18 syndrome. copyright.

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F Fig. 2 Complete karyotype of the proposita. The arrows indicate the two abnormal chromosomes. J Med Genet: first published as 10.1136/jmg.15.1.73 on 1 February 1978. Downloaded from Case reports 75 18 '8pi 18qi size to that of the normal No. 18. Karyotypes of both parents were normal.

Discussion The proposita had clinical features common in patients with trisomy 18 syndrome. These included b I K low set ears, small mouth, abnormal genitalia, rocker- bottom feet, limited hip abduction, the characteristic flexion abnormality of the fingers, a short dorsiflexed big toe, and cardiac anomalies. Her karyotype, however, revealed 47 chromosomes with only one chromosome 18 and two metacentric chromosomes of different sizes. By G- and C-band analysis these Fig. 3 Partial karyotypes of three additional cells metacentrics were interpreted to be isochromosomes (a, b, and c) with the normal No. 18, the of the long and short arms of No. 18. The presence of isochromosome ofthe short arms, and the isochromosome the features of the trisomy 18 syndrome can thus be of the long arms. explained by the genetic equivalent of three No. 18 chromosomes. hearing were apparently present. She was extremely Reports of isochromosomes of both arms are ex- hypotonic and reached randomly for objects. She tremely uncommon. In addition to the Muller et al. could raise her head well when prone but could not (1972) report, one other instance was a case described lift it when raised from the supine position. She was by Sinha et al. (1971) in which isochromosomes of able to roll over one way but a sitting position was both arms of a C group chromosome were present, only a slump forward lying on her arms. She could but this occurred as a mosaic in 8 to 10% of the cells smile and laugh. Strabismus and a high palate were with a normal 46,XX cell line. Double isochromo- also apparent at this time. somes of an autosome could probably result in

She was being given Lanoxin for support of a viable birth of a non-mosaic in three chromosomes copyright. borderline cardiovascular compensation. Cardio- of the human complement. These would be the three megaly was present on x-ray film and an atrioven- in which trisomy is associated with live birth, Nos. tricular canal defect was thought to be present. 13, 18, and 21. Thus far it has only been reported in No.18. CYTOGENETIC STUDIES Generally the reports on isochromosomes involve Chromosomal analyses of phytohaemagglutinin only one arm. Mukerjee and Burdette (1966) des- stimulated peripheral blood lymphocytes from whole cribed an extra metacentric chromosome with http://jmg.bmj.com/ blood of the proposita and both parents were done. satellites on both ends which was interpreted as an The proposita was studied at 7 days and again at 1 isochromosome of the short arms on a No. 21 year ofage with identical results. Preparations shown chromosome. Several reports of a supernumerary here were from the latter analysis. Giemsa bands presumptive isochromosome of the short arms of were induced by trypsin treatment (Larson et al., chromosome No. 18 have made possible the descrip- 1977) and C-bands were developed with standard tion of an associated syndrome (Condron et al., procedures. 1974). Borgaonkar (1975) has catalogued a few cases

Study of the baby's chromosomes revealed a of isochromosome or translocation of the long arms on September 28, 2021 by guest. Protected modal count of 47 in 84 cells analysed. Only one ofNos. 13 and 21 as well as the short arms ofNo. 18. structurally normal No. 18 chromosome was identi- Isochromosomes of the long arm of No. 17 are re- fied. In addition, there were two metacentric chromo- ported to be associated with malignancies, par- somes ofunequal sizes. One was the size of a C group ticularly myeloid leukaemias (Engel et al., 1975; and the other smaller than the F group. Giemsa Mitelman et al., 1975). banding identified the larger of the two as the Tlhe origin ofthe metacentrics remains an intriguing equivalent of two long arms of No. 18. The smaller and unresolved subject as the banding analyses do metacentric had no distinct bands but was of similar not give high enough resolution in the centromere size and staining quality to the short arms of the area to pinpoint the break points. Muller et al., normal No. 18. It was interpreted as being composed (1972) considered two possibilities for the origin of of two short arms of chromosome 18 (Fig. 2 and 3). the abnormal chromosomes. First, isochromosomes C-bands revealed one centromere in each meta- may arise as a misdivision of the centromere with centric chromosome that was approximately ofequal both products being passed on to the same gamete of J Med Genet: first published as 10.1136/jmg.15.1.73 on 1 February 1978. Downloaded from 76 Case reports a parent. The products would then be true isochromo- Salamanca-G6mez, F., and Armendares, S. (l975). Identifica- tion of isochromosome 17 in a girl with mental retar- somes by Darlington's (1939) definition. Secondly, a dation and congenital malformations. Annales de Genetique, reciprocal translocation may have occurred as a result 18,235-238. of breaks at or near the centromere during the first Sinha, A. K., Nora, J. J., and Pathak, S. (1971). Isochromo- division of meiosis between two No. 18 chromosomes somes arising from a human 'C'-autosome. Human followed by nondisjunction. In a recent report Heredity, 21,231-237. (Salamanca-Gomez, and Armendares, 1975) an 17 appears Requests for reprints to Professor Walter A. 'isochromosome' of the long arm of No. Wasdahl, Department of Pathology, The University to be caused by this type ofevent. A marker indicated Dakota the non-sister origin ofeach arm. of North Dakota, Grand Forks, North Transverse division of one centromere seems more 58202, U.S.A. likely than breakage and reunion at appropriate positions between two No. 18 chromosomes. With support of the G and C band analysis, we favour isochromosome formation as the mechanism of formation of the two metacentric chromosomes in Partial 18 trisomy (with 47 this report. chromosomes) resulting from a The authors gratefully acknowledge Dr William C. familial maternal translocation Rosen for referral of the patient and providing physical data and photographs. SUMMARY A newborn female infant presented LINDA M. LARSON, WALTER A. WASDAHL, JEAN H. with the classical picture of 18 trisomy syndrome. SAUMUR, MARY L. COLEMAN, AND S. M. JALAL Her karyotype was 47,XX,+der(18)t(12;18)(q24; Department ofPathology, q21)mat. The mother was a balanced reciprocal University ofNorth Dakota Medical School, translocation carrier and so too was one of the Grand Forks, North Dakota 58202; two maternal uncles of the proposita, indicating

and Department ofBiology, University of North that the translocation was already present in onecopyright. Dakota, Grand Forks, North Dakota 58202, U.S.A. of the grandparents who were not available for examination. This family suggests that tripli- cation of the distal part of the long arm of References chromosome 18 is not necessary to produce Edwards' syndrome. Borgaonkar, D. S. (1975). Chromosomal variation in man.

A catalog of variants and anomalies, pp. 100, 135, 148- http://jmg.bmj.com/ 150. The Johns Hopkins University Press, Baltimore. Condron, C. J., Cantwell, R. J., Kaufman, R. L., Brown, S. B., Tertiary trisomy resulting in partial trisomy 18 in a and Warren, R. J. (1974). The supernumary isochromo- child of a balanced D/E translocation carrier mother some 18 syndrome (+18pi). Birth Defects: Original Article has been described by Gleissner et al. (1970), but at Series, X(10), 36-42. that time the break points were not defined. Darlington, C. D. (1939). The origin of iso-chromosomes. Journal ofGenetics, 39, 351-360. Engel, E., McKee, L. C., Flexner, J. M., and McGee, B. J. (1975). 17 long arm isochromosome. A common anomaly in malignant blood disorders. Annales de GMngtique, 18, 56- on September 28, 2021 by guest. Protected 60. Jacobs, P. A., Melville, M., and Ratcliffe, S. (1974). A cyto- genetic survey of 11 680 newborn infants. Annals of Human Genetics, 37,359-376. Larson, L. M., Wasdahl, W. A., and Jalal, S. M. (1977). Partial trisomy 7p associated with familial 7p;22q trans- location. Journal ofMedical Genetics 14, 258-261. Mitelman, F., Panani, A., and Brandt, L. (1975). Isochromo- some 17 in a case of eosinophilic leukaemia. An abnor- mality common to eosinophilic and neutrophilic cells. Scandinavian Journal of Haematology, 14, 308-312. Mukerjee, D., and Burdette, W. J. (1966). A familial minute ® isochromosome. American Journal of Human Genetics, 18, Normal karyotype (.)Translocation 62-69. Not tested QDeceased Muller, Hj., Buhler, E. M., Signer, E., Egli, F., and Stalder, G. R. (1972). Trisomy 18 syndrome caused by trans- Partial 18 trisomy / Proposita location or isochromosome formation. Journal of Medical Genetics, 9,462-467. Fig. 1 Pedigree.