Hum. Genet. 49,283--289 (1979) © by Springer-Verlag1979

Partial Trisomy for the Long Arm of Chromosome 7 Due to Familial Balanced Translocation M. Schmid*, J. Wolf, H. Nestler, and W. Krone Abteilung Humangenetik, Universit/it Ulm, P. O. Box 4066, D-7900 Ulm, Federal Republic of Germany

Summary. A partial trisomy for the distal segment of the long arm of chromosome 7 (bands q32--'qter) was observed in a severely retarded child with somatic and CNS anomalies. The phenotypically normal father and paternal grandmother had a balanced reciprocal translocation between the long arm of a chromosome 2 and the long arm of a chromosome 7: 46,XX-XY,t(2;7) (q37;q32). The clinical features of the child at birth and at the ages of 5 months and 2 years are compared with those previously reported in cases of partial trisomy 7q.

Introduction Seventeen cases of partial trisomy of the long arm of chromosome 7 have been described since the introduction of banding techniques in human cytogenetics (Carpentier et al., 1972; Alfi et al., 1973; Bass et al., 1973; Berger et al., 1974, 1977; Grace et al., 1972, 1973; Vogel et al., 1973; Vogel, 1977; Serville et al., 1975; A1 Saadi and Moghadan, 1976; Mori6-Petrovi6 et al., 1976; Turleau et al., 1976; Winsor et al., 1978). All these cases were the result of reciprocal or insertion translocations. Some of the clinical features of partial trisomy 7q are common to all 17 cases, independent of the size of the duplicated segment or of the recipient chromosomes to which the 7q material is translocated. There are, conversely, some clinical features which are specific for very defined regions of the long arm of chromosome 7 (see review by Vogel, 1977). A further case of partial trisomy for the distal segment of 7q (bands @2-*@6) is reported in this paper. Together with the five partial trisomies of the same chromosome segment already described (Newton et al., 1972 cited by Vogel, 1977; Mori6-Petrovi6 et al., 1976; Winsor et al., 1978), a clinically recognizable malformation pattern can be deliniated. * To whom offprint requests should be sent: Institut ftir Humangenetik, Universitfit G6ttingen, Nikolausberger Weg 5a, D-3400 G6ttingen

0340-6717/79/0049/0283/$ 01.40

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Case Report

Family History. The father was 20 years old, the mother 22 at the time of birth of the patient (IV1, Fig. 1). The mother had a miscarriage 5 years before (3rd month). The parents are not related. The mother is undersized (149 cm). Several conspicuous dermatoglyphic patterns were observed in the patient's family (Table 1). The paternal grandmother of the patient (II-5) had 2 miscarriages in the 7th and 8th month of pregnancy, respectively.

Patient History (up to the Age of 51/2Months). The pregnancy was uneventful and birth took place without complications 10 days after term. There is no history of diagnostic irradiation or of any unusual form of medication during pregnancy. Weight 2560 g (3rd percentile), length 48 cm (3rd--10th percentile), head circumference 31 cm (4cm below 3rd percentile). The newborn showed several dysplastic traits: asymmetric skull with broadly projecting ossa parietalia; a weakly expressed pterygium colli; the position of the eyelid axis was horizontal to slightly mongoloid; bilateral epicanthus; deep-seated, dysplastic auricles; auditory canal difficult to inspect; single transverse palmar crease; hollow feet with remarkably large hallux; periodic athetoid movements of the hands; mewling cries. The head circumference increased from 31 cm to 35.5 cm during the first two postnatal weeks. Hydrocephalus was excluded by ventriculography. During the first 4 months the child needed almost constant hospital treatment due to frequent infections (Salmonellosis, a. o.). The parents reported one possible convulsive fit.

t

¢

12(

II.1 ( ~

7

5

III 1[~ 2~) r~46,XY 046,XX ~]46, XY,t(2q+;7q-)~)46, XX,t(2q+;7q-)

IV

146,XY, 2q+ [77 (~)Not examined • Abortus Fig. 1. Pedigree of the family. II-5 and III-4 are carriers of the balanced translocation t(2q+;7q-). IV-1 is the patient who has a partial trisomy of the distal long arm of chromosome 7 (46,XY, 7q+pat)

Fig. 2 (a, b) Physical appearance of the patient at age 5~2 months. (e, d) Appearance at age 2~12years. (e) Q-banded chromosome pairs 2 and 7 of the father (II-5). (f) G-banded chromosome pairs 2 and 7 of the grandmother (II-5). (g) Chromosome pairs 2 and 7 of the patient, showing replication patterns of the middle S-phase (6h thymidine incorporation). (h) Diagrammatic representation of the balanced translocation t(2q+;7q-) according to the G-band idiogram of the Paris Conference (1971)

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Clinical Findings at the Age of 5t/2 Months (Fig. 2a, b). Weight 5.8 kg (200g below the 3rd percentile); length 63 cm (10th percentile); the head circumference had increased to 43 cm by the 3rd month (97th percentile), but was within the normal range in the 5th month with 43.5 cm (50th percentile). The child had a high, arching forehead and broadly protruding ossa parietalia, rendered prominent by indentations above and lateral to the eyebrows. The neck was abnormally short with a fold at the nape. The nose was flattened, revealing a tendency toward hypertelorism. An inspiratory stridor was found to be caused by a soft epiglottis. Further findings: epicanthus, short upper lip; deep-seated, dysplastic ears; hydrocele testis (right); hollow feet. Neurological findings: no control of head positioning; diminished reflexes; no ascertainable pathological findings on the EEG; severe psychomotor retardation. Clinical Findings at the Age of 2~/12 Years (Fig. 2c, d). The patient's weight, size and head circumference had remained within normal limits since the age of 592 months. The head was distinguished by a high forehead, protruding ossa parietalia, wide nasal bone, short upper lip and deep seated ears, as observed previously. The inspiratory stridor had distinctly improved. Convergent strabismus, the absence of an optokinetic nystagmus (as in central disorders), but oscillating nystagmus were now observed. A slight left-convex kyphoscoliosis was noticed. There was general muscular hypotonia; head control and static reflex of the legs were missing. Muscular reflexes were bilaterally diminished; bilateral tendency to hollow feet. Neurological findings: sudden jerking movements accompanied by flexion had suggested cerebral convulsions (myoclonic convulsions), and the patient had accordingly been treated with Primidon since the age of 13/12 years. Repeated EEG and echoencephalographic examinations revealed no certain pathologic signs, except for the increase in fl-spindles characteristic of early brain damage or Primidon consumption. The peripheral nerve impulse velocity was normal. The behavioural development of the patient corresponded to that of a 9-month old child. Biochemical Tests. The following laboratory tests were made postnatally: blood sedimentation rate, erythrocyte-, leukocyte- and thrombocyte-counts, differential blood count, urine glucose and protein, thyroid parameters (FTE, T3, T4). At the age of 51/2 months diagnostic measures were extended to include: serum electrolytes, alkaline phosphatase, y-glutamyl transferase, creatinine-phosphokinase, immunoglobulins, aminoacid-thinlayer-chromatography of serum, tests for cytomegaly, toxoplasmosis, listeriosis, lues venerera, aryl sulfatase, urine mucopolysaccharides, hemoglobin electrophoresis. All laboratory tests listed yielded normal results. Salmonella panama and Staphylococcus aureus were found in the stool (51/2 months). After the assignment of the fl-glucuronidase structural gene to chromosome 7 by several groups of investigators, Knowles et al. (1977) provided preliminary evidence for the location of

I

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Fig. 3. Dermatoglyphic patterns of the patient. In the original fingerprinting the fingertip patterns could not be reproduced distinctly enough; they are therefore only presented schematically

287

Partial Trisomy 7q Table 1. Dermatoglyphics Finger I

Patient Left Right

Palm

II

III

IV

V

W cp . W cp . W

. W

. W cp

W

. W

. W cp

. WC p . W

Mother Left Right

W d! W . W cp . W . W W dl W dl . L u . W cp " L u

Father Left Right

Lu tu

Lu . L u . L u . W cp t u . t u . W cp . L u

1 1 . 9 .7 . 5 ' . 7 . 5 " . 5 " 3(11).

--fit')---tt u~

V/A u. O . O . L Lr 0 . 0. 0

11.9 11.9

--tt't"t~

W

0. L

.V

--tt't"--

LU/L~ . W . 0 . L

.D

7.9

.7 .7

1. 1.

. 5". 3(11).

7.5".5".4.

- - t t u-----

Lr

--t--

Au

. W.

0 . 0. L/D. L . 0. 0.0

this gene on the long arm of this chromosome. We compared the specific activity of flglucuronidase in fibroblast cultures from the patient with that of cultures derived from agematched healthy male individuals. Although corresponding stages of the growth cycle and passage number were used throughout these studies, the high variability of the fl-glucuronidaseactivities, also observed by other authors (Gehler et al., 1974; Hultberg et al., 1973) eliminated any possibility of detecting a gene dosage effect. Relating the specific activity of fl-glucuronidase to that of acid phosphatase did not improve the results. On the basis of the recent assignment of the fl-glucuronidase locus to the region 7pter~q22 (Benn et al., 1977) an increased amount of this enzyme in the cells of our patient is not to be expected.

Dermatoglypkics (Fig. 3 and Table 1). Both the patient and his mother exhibit brachydactyly. The patient has a single transverse palmar crease on his left hand, a variant of a single transverse palmar crease as well as a missing thenar crease on his right hand. Whorl patterns with extralimital triradii and at least five central pockets are found on the fingertips. There are large hypothenar patterns.

Cytogenetic

.d .L

Studies

C h r o m o s o m e p r e p a r a t i o n s w e r e m a d e f r o m the p e r i p h e r a l b l o o d l y m p h o c y t e s ( p a t i e n t a n d p a r e n t s ) a n d f r o m f i b r o b l a s t s ( p a t i e n t ) , a c c o r d i n g to the m e t h o d s o f P f e i f f e r (1974) a n d W o l f (1974). Q - b a n d i n g ( C a s p e r s s o n et al., 1970) a n d G b a n d i n g ( S e a b r i g h t , 1971) w e r e p e r f o r m e d f o r the m e t a p h a s e c h r o m o s o m e s f r o m l y m p h o c y t e cultures. T h e m e t h o d o f E p p l e n et al. (1975) was u s e d f o r t h e analysis o f the late r e p l i c a t i o n p a t t e r n s o f c h r o m o s o m e s f r o m f i b r o b l a s t s . T h e k a r y o t y p e o f t h e p a t i e n t ( I V - I ) is 4 6 , X Y , 2 q + in all the m e t a p h a s e s a n a l y s e d (Fig. 2 g). In the k a r y o t y p e s o f the f a t h e r (III-4) a n d the p a t e r n a l g r a n d m o t h e r (II-5) t h e l o n g a r m s o f a c h r o m o s o m e 2 a n d 7 are i n v o l v e d in a r e c i p r o c a l t r a n s l o c a t i o n (Fig. 2e, f). T h e b r e a k a g e p o i n t s are l o c a t e d at 2q37 a n d 7q32 ( F i g . 2 h ) . T h e r e c o m m e n d e d d e s i g n a t i o n o f this t r a n s l o c a t i o n (Paris C o n f e r e n c e , 1971) w o u l d be t(2;7)(q37;q32) in t h e s h o r t s y s t e m a n d t ( 2 ; 7 ) ( 2 p t e r - , 2 q 3 7 : : 7 q 3 2 ~ 7 q t e r ; 7 p t e r 7 q 3 2 : : 2 @ 7 ~ 2qter) in the d e t a i l e d system. T h e p a t i e n t is t h e r e f o r e t r i s o m i c f o r the b a n d s 7 q 3 2 ~ 7 q t e r a n d his k a r y o t y p e c a n be d e s i g n a t e d as 4 6 , X Y , - 2 ; + d e r ( 2 ) ,

.L

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t(2;7)(q37;q32)pat. Since this is a reciprocal translocation between two terminal chromosome regions, the patient must additionally be a monosomic for the telomeric region of 2q. At its greatest extent, this m o n o s o m y would include the entire band 2q37, because the band 2q36 is still detectable on the translocation chromosome 2 (Fig. 2f). The karyotypes of the mother (III-5) and the other patients examined (II-1, II-3, II-6, II-7, and II-8) are unconspicuous.

Discussion

Of the 17 cases of partial trisomy 7q described in the literature to date, five had the same duplicated segment (7q32~7qter) as in the present case (Newton et al., 1972 cited by Vogel, 1977; Mori6-Petrovi6 et al., 1976; Winsor et al., 1978). The features c o m m o n to these cases were found to be: low birth weight, growth and mental retardation, high forehead with broadly protruding ossa parietalia, wide and flattened nasal bone, very short neck, deep-seated ears, tendency towards hypertelorism, epicanthus. The same characteristics were also seen in the case discussed in this paper. Micrognathia and cleft palate occurred in none of these cases, though they did in five patients with partial trisomy for the segment 7q31~7qter (Alfi et al., 1973; Bass et al., 1973; Vogel et al., 1973; A1 Saadi and Moghadan, 1976; Berger et al., 1977) and in 1 patient with partial trisomy for the segment 7q22~7qter (Carpentier et al., 1972). Furthermore micrognathia and cleft palate were not seen in partial trisomies of the distal segment 7q33~7qter (Turleau et al., 1976) and the interstitial segments 7q22-~7q32 (Grace et al., 1972, 1973) and 7q22~7q31 (Berger et al., 1974; Serville et al., 1975). It therefore seems possible to separate the clinical syndrome for trisomy of the segment 7q32~7qter from the malformation patterns occurring in other partial trisomies 7q, and to establish it as a distinct entity.

Acknowledgement. We thank Miss Christine Klett and Mrs. Sybille Z6rlein for skilful technical assistance.

References

Alfi, O. S., Donnel, G. N., Kramer, S. L.: Partial trisomy of the long arm of chromosome No. 7. J. Med. Genet. 10, 187--189 (1973) A1 Saadi, A., Moghadan, H. A.: Partial trisomy of the long arm of chromosome 7. Clin. Genet. 9, 250--254 (1976) Bass, H. N., Crandall, B. F., Marcy, S. M.: Two different chromosome abnormalities resulting from a translocation carrier father. J. Pediat. 83, 1034--1038 (1973) Benn, P., Chern, C. J., Bruns, G., Craig, I. W., Croce, C. M.: Assignment of the genes for human fl-glucuronidase and mitochondrial malate dehydrogenase to the region pter-*q22 of chromosome 7. Cytogenet. Cell Genet. 19,273--280 (1977) Berger, R., Derre, J., Ortiz, M. A.: Les trisomies partielles du bras long du chromosome 7. Nouv. Presse M6d. 3, 1801--1804 (1974) Berger, R., Turc, C., Wachter, H., Begue, G.: Partial 7q trisomy. Clin. Genet. 11, 39-42 (1977) Carpentier, S., Rethor6, M.-O., Lejeune, J.: T'risomie partielle 7q par translocation familiale t(7;12)(q22;q24). Ann. Gbn~t. 15, 283--286 (1972)

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Caspersson, T., Zech, L., Johannsson, C., Modest, E. J.: Identification of human chromosomes by DNA binding fluorescent agents. Chromosoma 30, 215--227 (1970) Epplen, J. T., Siebers, J.-W., Vogel, W.: DNA replication patterns of human chromosomes from fibroblasts and amniotic fluid cells revealed by a Giemsa staining technique. Cytogenet. Cell Genet. 15, 177--185 (1975) Gehler, J., Cantz, M., Tolksdorf, M., Spranger, J., Gilbert, E., Drube, H.: Mucopolysaccharidosis VII: fl-glucuronidase deficiency. Humangenetik 23, 149--158 (1974) Grace, E., Sutherland, G. R,, Bain, A. D.: Familial insertional translocation. Lancet II, 231 (1972) Grace, E., Sutherland, G. R., Stark, G. O., Bain, A. D.: Partial trisomy of 7q resulting from a familial translocation. Ann. G~n6t. 16, 51--54 (1973) Hultberg, B., Si6blad, S., ()ckerman, P. A.: Properties of five acid hydrolases in human skin fibroblast cultures. Acta Paediat. Scan. 62,474--480 (1973) Knowles, B. B., Solter, D., Trinchieri, G., Maloney, K. M., Ford, S. R., Aden, D. P.: Complement-mediated antiserum cytotoxic reactions to human chromosome 7 coded antigens: immunoselectionof rearranged human chromosome 7 in human-mouse somatic cell hybrids. J. Exp. Med. 145, 314--326 (1977) Mori6-Petrovi6, S., La6a, Z., Krajgher, A.: Translocation r6ciproque dans la famille de deux proposants avec une trisomie partielle du chromosome 7q. Ann. G6n6t. 19,133--136 (1976) Newton, M. S., Cunningham, C., Jacob, P. A., Price, W. H., Fraser, I. A.: Chromosome survey of a hospital for the mentally subnormal. Part II: autosomal abnormalities. Clin. Genet. 3, 226--248 (1972) Paris Conference (1971): Standardization in human cytogenetics. Birth defects: Original article series, VIII: 7. New York: The National Foundation 1972 Pfeiffer, R. A.: Cell cultures from blood and bone marrow. In: Methods in human cytogenetics, H. G. Schwarzacher, U. Wolf, eds., pp. 1--37. Berlin-Heidelberg-New York: Springer 1974 Seabright, M.: A rapid banding technique for human chromosomes. Lancet II, 971--972 (1971) Serville, F., Broustet, A., Sandler, B., Bourdeau, M,-J., Leloup, M,: Trisomie 7q partielle. Ann. G6n6t. 18, 67--70 (1975) Turleau, C., Rossier, A., Montis, G. de, Roubin, M., Chavin-Colin, F., Grouchy, J, de: Trisomie partielle 7q. Un ou deux syndromes? Apropos d'une nouvelle observation. Ann. G6nbt. 19, 37--42 (1976) Vogel, W.: Partial duplication 7q. In: New chromosomal syndromes, J. Yunis, ed., pp. 185--195. New York-San Francisco-Lojadon: Academic Press 1977 Vogel, W., Siebers, J.-W., Reinwein, H.: Partial trisomy 7q. Ann. G6n6t. 16, 277--280 (1973) Winsor, E. J. T., Palmer, C. G., Ellis, P. M., Hunter, J. L. P., Ferguson-Smith, M. A.: Meiotic analysis of a pericentric inversion, inv(7)(p22q32), in the father of a child with a duplicationdeletion of chromosome 7. Cytogenet. Cell Genet. 20, 169--184 (1978) Wolf, U.: Cell cultures from tissue explants. In: Methods in human cytogenetics, H. G. Schwarzacher, U. Wolf, eds., pp. 39--58. Berlin-Heidelberg-New York: Springer 1974 Received January 1, 1979