Clinical Genetics 1975: 8: 213-217

A girl with 46,XX,t(l;l5) karyotype. Cytogenetic and clinical observations J . 0. VAN HEMEL,J. P. VAN BIERVLIET,AND P. W. DE JAGER-VAN DER GRIFT Cytogenetics Laboratory, Institute of Genetics and Wilhelmina Children’s Hospital, State University Utrecht, The Netherlands

Results are presented of karyotype analysis with autoradiography and Q-banding of a mentally retarded dwarf. A reciprocal ( l p - ;15q+), de-novo translocation was observed. Received 29 November 1974, revised 27 February, accepted f o r publication 3 April 1975

Routine chromosome analysis was performed on a mentally retarded girl with dwarfism. Blood culture metaphases showed a 46,XX karyotype, in which an abnormally long D chromosome was present. Orceinstained slides permitted no definitive identification of the elements involved in the rearrangement. A report on the results of tritium-thymidine autoradiography and quinacrine mustard fluorescence studies is presented. The possibilities and limitations of both chromosome identification methods are discussed. The patient has been described in a preliminary note (van Heme1 1968). Methods

Leucocyte metaphases of the patient and her closest relatives (father, mother, one sister, one brother) were obtained from peripheral blood cultures (Arakaki & Sparkes 1963). For skin fibroblast cultures the perforated cellophane method (Hienz 1971) was applied. Autoradiography and fluorescence studies were done as described by Schmid (1965) and Caspersson et al. (1971). Growth hormone (G.H.) was measured dur-

ing the insulin tolerance test as described by Croughs et al. (1968). Case Report

A.Y., a female child, was born on 21 September 1959. Her birth weight was 1880 g. Her length was not recorded. No X-ray examination of the parents was performed around the time of conception and no clinical signs of viral infections were present. There is no consanguinity between the parents, and no known hereditary disease in their families. Two other children are normal. Besides dwarfism and mental retardation the most striking phenomena were the oldlooking face, microcephaly, wide sutures, enlarged fontanelle, abundant hair with abnormal implantation over the head and forehead, bushy eyebrows and long eyelashes. At 6 years of age the patient was referred to the Wilhelmina Children’s Hospital, Utrecht. Clinical examination revealed a normally proportioned, severely mentally retarded dwarf. Her length was 92.5 cm, weight 11.9 kg and skull circumference 46 cm (Fig. 1). Mild hypertelorism, flattened

VAN HEMEL. VAN BlERVLlET AND DE JAGER

214

Flg. 1. The patient at 14 years of age.

occiput, hypernasal voice with insufficiency of the velum, cubiti valgi, pronounced clinodactyly in the fifth finger and bilateral membranous syndactyly of basal phalanx of second and third toes were also seen. We observed stiffness of all joints and severe limitation of pronation-supination movements of the elbow. The patient did not have a webbed neck, but her posterior hair-

line was low. Other organs were normal. Her mental age at 6 years was 2.3 years (range 1.6-2.6 years) and her Stuttsman intelligence quotient was 46. Radiologic examination of the skull revealed microcephaly and short palatum durum. Her bone age according to Tanner and Whitehouse was 2 years. On the pharyngogram the velum did not touch the posterior pharyngeal wall. Minerals, acid-base metabolism, liver and kidney functions, carbohydrate and aminoacid metabolism and gastrointestinal functions were all normal. Thyroid and adrenal function was normal. We observed an abnormal elevated growth hormone excretion during the insulin tolerance test (0.05 U insulin/kg body weight i.v.) and pronounced hypoglycaemia (Fig. 2). Growth hormone measurements were as follows: 0 min - 23.0 ng/ml plasma; 30 min - 64.5 ng/ml; 45 min - 74.0 ng/ml; 90 min - 41.0 ng/ml (mean maximal G.H. level in small normal children 35.1 ng/ml plasma; Croughs et al. 1968). Reexamination in 1973 at age 14 revealed no important new features. There was still

GLUCOSE

10

0

,

0

M'

60'

do,

Fig. 2. Growth hormone response to intravenous insulin induced hypoglycaernia. G.H. levels are high. Mean level in a control group of non-endocrine growth retardation was 29.5 nglrnl plasma.

5-

i

'

'

*

;3

' 1;'

Flg. 3. Height curve of the proband A.Y.

( 7 ,

19

A (lp-;

1 5 q f ) TRANSLOCATION

extreme dwarfism, but a minimal pubertal growth increase and secondary sexual characteristics were seen. The height chart is given in Fig. 3. Blood typing of the patient and her parents showed the following phenotypes: ABO, MNS, P, Lutheran, Kell, Duffy, Group specific component, Haptoglobin, Gm factors and Inv. factors. No irregularities in expression or mode of inheritance were detected. In cells of buccal smears X-chromatin frequency and morphology were normal.

215

terns (Fig. 4). In all metaphases one very late replicating X-chromosome was present. The fluorescence patterns in the proband karyotypes (Fig. 5 ) showed that the part of chromosome no. 1 distal from band p22 had been translocated to the long arm of a no. 15 element and attached to band q26 (Fig. 6). Aside from a minor aneuploidy in the complements of the mother of the proband, no numerical or morphological abnormalities were observed in the karyotypes or fluorescence banding patterns of the parents or sibs.

Cytogenetic Studies

In all leucocyte metaphases of the patient 46 chromosomes were counted. One Dgroup element attracted attention because of its abnormal length. Patterns of late S-labeling were studied in 142 cells. The marker D-chromosome appeared unambiguously as an early replicating element; it labeled (lightly) in all cells. In 12 out of 19 cells studied in detail labeling was seen halfway along the long arm in the satellite region. In three cells the element was totally unlabeled. The A- and D-chromosomes from one cell were sorted in pairs on the basis of their replication pat-

Discussion

The abnormal D-chromosome appears as an early replicating element in all cells with the exception of a late replicating zone in the long arm of the presumed chromosome 15. This suggests a relation between points of attachment of translocated elements and late replication. Support for this suggestion is not found in the literature. The late replicating X chromosome in all cells points to a normal XX sex chromosome constitution in this girl. The fluorescence studies show that the 15q+ part is a segment of chromosome 1,

Fig. 4. Late-S 3H-thymidine labeling patterns of group A and D chromosomes of the 46,XX,t(lp-;15q+)

patient.

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VAN HEMEL. VAN BlERVLlET AND D E JAGER

Fig. 5. Q-banding patterns of group A and D chromosomes of the 46,XX,t(lp-;l5q+) banding pattern permits identification of the chromosome 1.

distal to the p22 band. It appears to be attached to the 15 q26 band, which suggests a balanced reciprocal translocation. From the normal karyotypes of the parents and her sibs it can be concluded that a de-nova translocation is present in this patient. No definite conclusions can be drawn as to the possible relationship between the

patient. The specific

chromosomal and clinical abnormalities in this case. An abnormal growth hormone level may have caused the dwarfism. Acknowledgmenta

We are indebted to Prof. dr. H. A. w. M. Tiddens (Maastricht) who referred the pa-

Flg. 6. Diagrammatic representations of breakage points in chromosomes 1 and 15 (white arrows) and point of attachment in the translocated chromosome (black arrow).

A ( l p - ;

15q-t) TRANSLOCATION

tient t o us, and Dr. L. E. Nijenhuis (Amsterdam) for bloodgroup typing. Miss Marijke Overbeeke and Miss Corry Verhoef cooperated in the fibroblast cultures and fluorescence studies.

References

Arakaki, D. T. & R. S. Sparkes (1963). Microtechnique for culturing leukocytes from whole blood. Cytogenetics 2, 57-60. Caspersson, T., G. Lomakka & L. Zech (1971). The 24 fluorescence patterns of the human metaphase chromosomes - distinguishing characters and variability. Hereditas (Lund) 67, 89-102. Croughs, W., W. Schopman & H. A. W. M. Tiddens (1968). Plasma-Growth Hormone response to insulin induced hypoglycaemia. Helv. paediat. Acta 23, 464-477.

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Hemel, J. 0. van (1968). Twee bijzondere chromosoomafwijkingen bij de mens. Genen Phaenen 12, 1-2. Hienz, H. A. (1971). Chromosorrien Fibel. Stuttgart, Thiemen Verlag. Paris Conference 1971 (1972). Standardization in human cytogenetics. Birth Defects: Original Article Series V l l l No. 7. Schmid, W. (1965). Autoradiography of human chromosomes. Human Chromosome Methodology, ed. Yunis, J. J. London and New York, Academic Press, pp. 91-110. Address: D r . J . 0. van Hemel Cytogenetics Laboratory Institute of Genetics State University Transitorium 3 Padualaan 8 Utrecht, the Netherlands