Hum. Genet. 50, 285--289 (1979) © by Springer-Verlag 1979
Terminal 7p Deletion and 1;7 Translocation Associated with Craniosynostosis R. K. Dhadial 1 and M. F. Smith 2. Department of Anatomy, St. Thomas' Hospital Medical School 2Paediatric Department, The Rayne Institute, St. Thomas' Hospital, London, SE17EH, England
Summary. A female infant with presumptive deletion of the 7p2 region and an unusual translocation between a part of the short arm of chromosome 1 and a deleted chromosome 7 is described. The patient showed congenital craniosynostosis of the coronal and metopic sutures; marked turricephaly; hypotelorism; deeply cleft palate; shallow orbits with prominent bulging eyes; a depressed nasal bridge; anteverted nostrils; short hands with broad thin fingers and elongated thumbs; a mild talipes calcaneovalgus deformity of the feet; a systolic m u r m u r due to a small VSD; and psychomotor retardation. The child died of bronchopneumonia at 10 weeks of age. The parents are chromosomally normal.
Introduction To our knowledge only three cases of short-arm terminal deletion of chromosome 7 have been reported (Wilson et al., 1973; Friedrich et al., 1975; McPherson et al., 1976). There is a further report by Zackai and Breg (1973), describing two patients with a ring chromosome abnormality of chromosome 7, where presumably the terminal ends of both the short and the long arms were deleted to form the ring. In four of these patients premature craniosynostosis was the characteristic feature considered to be associated with the loss of genetic material from the terminal region of the short arm of chromosome 7 (McPherson et al., 1976); the fifth had microcephaly. We report here another case with congenital craniosynostosis and other phenotypic abnormalities; the karyotype revealed translocation between chromosomes 1 and 7 and terminal short-arm deletion of the latter.
Case Report The patient was born to healthy unrelated caucasian parents, both aged 18 years, following an uneventful first pregnancy and normal delivery at 40 weeks gestation. The birth weight was * To whom offprint requests should be sent
0340-6717/79/0050/0285/$ 01.00
286
R.K. Dhadial and M. F. Smith
Fig. 1. a The patient at 6 weeks. There is marked turricephaly, shallow orbits with protuberant eyes and hypotelorism, b The hand is short and broad with slender, tapering fingers. The thumb is extended
2.36 kg, placental weight 425 g. The OFC was 29 cm and the body length 48 cm. The infant showed marked hypotelorism With shallow orbits and prominent eyes. Epicanthic folds were present, as was an inability to abduct the left eye from the midline. There was marked turricephaly with flattening of the occiput, a 2-cm posterior fontanelle, and synostosis of the metopic and coronal sutures (Fig. 1 a). The nose was short, with a low bridge and anteversion of the nostrils. There was a central cleft of the palate with prominent lateral palatal ridges. The ears appeared to be posteriorly rotated. The hands were short and broad, with thin fingers and extended thumbs (Fig. 1 b). There was mild talipes calcaneo-valgus deformity of the feet. A systolic murmur was considered to be due to a small VSD; the chest X-ray and ECG were normal. Feeding was difficult to establish, and gavage was frequently necessary. The infant did not gain weight satisfactorily and at 10 weeks weighed only 3.0 kg, at this stage she rapidly developed broncbopneumonia and died. Prior to this she was able to fix but would not follow. She had not smiled and there was considerable head lag when she was pulled to a sitting position or held in ventral suspension.
Cytogenetie Studies Chromosome preparations were obtained from lymphocyte cultures by standard m e t h o d s a n d e x a m i n e d u s i n g c o n v e n t i o n a l A S G - ( S u m n e r et al., 1971), C ( S u m n e r , 1972), a n d R - b a n d i n g (Sehesled, 1974) t e c h n i q u e s w i t h slight m o d i f i c a tions. T h e R - b a n d i n g results w e r e i n c o n c l u s i v e . In the 38 m e t a p h a s e s a n a l y s e d , t h e m o d a l n u m b e r o f c h r o m o s o m e s was 46. T h e k a r y o t y p e r e v e a l e d t w o s t r u c t u r a l l y a b n o r m a l c h r o m o s o m e s (Fig. 2). B r e a k a g e a n d r e j o i n i n g b e t w e e n c h r o m o s o m e s 1 a n d 7 is c o n s i d e r e d to be
Terminal 7p Deletion and 1;7 Translocation with Craniosynostosis
287
Fig. 2. Partial karyotype showing chromosome pairs 1 and 7. Note two structurally abnormal chromosomes, one in each pair. A r r o w s point to the presumptive breakpoints
Fig. 3. The idiogram (Paris Conference, 1971) demonstrates the presumptive breakpoints shown by a r r o w s and the translocation
1
Ip-
t(I;7)
7
responsible for this abnormal karyotype. Presumably one break occurred in chromosome 1 at the level of band p22 and another in chromosome 7 at about band p15 (Fig. 3). Subsequently a part of the short arm of chromosome 1, distal to its presumptive break, had become attached to 7 at its breakpoint, giving rise to a structurally abnormal chromosome: t(1;7)(p22;p15). The major portion of chromosome 1 (a part of the short arm of which is involved in translocation) was represented by the second abnormal chromosome, l p - . Nothing seems to be missing from this chromosome, but the p2 region of chromosome 7 distal to its presumptive break appears to be lost. The prominent, easily detectable, band 7p21 of this region was not observed in any sample of either of the two abnormal
288
R.K. Dhadial and M. F. Smith
chromosomes. The karyotype of the child could be written as 46,XX,t(1;7) (p22;p15),del(7)(pter--*p15:). Both parents are chromosomally normal (studied at the Paediatric Research Unit, Guy's Hospital Medical School).
Discussion The clinical symptoms in our patient resemble those found in five published cases with terminal 7p deletion (McPherson et al., 1976). Most of these symptoms are c o m m o n in patients with chromosome aberrations, but the characteristic feature of these cases, except for one (Zackai and Breg, 1973), is the congenital craniosynostosis, which is considered to be associated with the deletion involving the 7p2 region (Friedrich et al., 1975; McPherson et al., 1976). Our case gives further support to this view. However, our patient differs from others in having a terminal 7p deletion and translocation between a part of the short a r m of chromosome 1 and the deleted chromosome 7. To our knowledge this is only the second case of translocation and deletion occurring simultaneously. Recently Fried et al. (1978) have described a patient with de novo reciprocal translocation and deletion involving chromosomes 18 and 21. The extreme rarity of simultaneous occurrence of these two aberrations occurring simultaneously may be due to the impossibility of detecting small deletions in cases of apparently balanced translocation. Analysis of the G-banded preparations did not reveal the usually darkly stained prominent band p21 of chromosome 7 involved in translocation in any sample of the two structurally abnormal chromosomes. We presume there is only one break in chromosome 7, and the interstitial deletion of 7p21 band a n d the presence of distal 7p22 band therefore seems to be unlikely. Therefore, bands 7p21 and 7p22 of the 7p2 region are considered to have been deleted in our case. In two other cases (Wilson et al., 1973; Friedrich et al., 1975) bands 7p21 and 7p22 are missing, although Wilson et al. (1973) speculated on the possibility of the 7p21 band being translocated onto the short arm of chromosome 13 and being represented by the 'giant' satellites observed in their case. They were also uncertain about the identification of 7p22 band. The 'giant' satellites are now considered to be only a minor variant (Therapel et al., 1978). The prominent dark G band 7p21 has been seen in two patients with a no. 7 ring chromosome (Zackai and Breg, 1973), and only band 7p22 is considered to be absent. Only one case (McPherson et al., 1976) has been reported where the interstitial deletion of band 7p21 was observed and the terminal 7p22 was present. In all these cases, whether band 7p21 or 7p22 or both were absent, the c o m m o n feature is the early closure of cranial sutures, resulting in abnormal head configuration. We agree with Friedrich et al. (1975) and McPherson et al. (1976) that whole or partial deletion of 7p2 is associated with early closure of the cranial sutures. The minor clinical variations in the extent of premature synostosis may be related to the proportion of genetic material lost from the 7p2 region. The establishment of defined clinical characteristics for the 7p terminal deletion syndrome has to await further reports. The predominant features
Terminal 7p Deletion and 1;7 Translocation with Craniosynostosis
289
r e p o r t e d thus far include the following: synostosis o f cranial sutures resulting in t u r r i c e p h a l y , p r o m i n e n c e o f the f o r e h e a d a n d flattening o f the occiput; shallow o r b i t s with p r o m i n e n t eyes; h y p e r t e l o r i s m ; d e p r e s s e d nasal bridge, m e d i a n cleft palate; m a l f o r m a t i o n o f the h a n d s , feet, a n d ears; a n d p s y c h o m o t o r r e t a r d a t i o n . Studies o f the p a r e n t s o f these children have n o t revealed a n y a b n o r m a l i t y .
Acknowledgements. The authors wish to thank Prof. M. H. Day for advice and Dr. G. S. Clayden for allowing them to study his patient.
References Fried, K., Mundel, G., Rosenblatt, S.: De novo simultaneous reciprocal translocation and deletion. J. Med. Genet. 15, 152--164 (1978) Friedrich, W., Eyngbye, T., Oster, J.: A girl with karyotype (46,XX,del(7)qter~p15:). Hum. Genet. 26, 161--165 (1975) McPherson, E., Hall, J. G., Hickman, R.: Chromosome 7 short arm deletion and craniosynostosis: a 7p syndrome. Hum. Genet. 35, 117--123 (1976) Paris Conference (1971): Standardization in Human Cytogenetics. Birth Defects: Original Article Series, VIII: 7. New York: The National Foundation 1972 Sehesled, J.: A simple method for R-banding of human chromosomes, showing a pH-dependent connection between R and G bands. Hum. Genet. 21, 55--58 (1974) Sumner, A. T.: A simple technique for demonstrating centromeric heterochromatin. Exp. Cell Res. 75, 304---306 (1972) Sumner, A. T., Evans, H. J., Buckland, R. K.: A new technique for distinguishing between human chromosomes. Nature New. Biol. 232, 31--32 (1971) Tharapel, A. T., Summitt, R. L.: Minor chromosome variations and selected heteromorphisms in 200 unclassified mentally retarded patients and 200 normal controls. Hum. Genet. 41,121-130 (1978) Wilson, M. G., Jujimoto, A., Shinno, N. W., Tourner, J. W.: Grant satellites or translocation? Cytogenet. Cell Genet. 12,209--214 (1973) Zackai, E. H., Breg, W. R.: Cytogenet. Cell Genet. 12, 40---48 (1973) Received March 12, 1979
Terminal 7p Deletion and 1;7 Translocation Associated with Craniosynostosis R. K. Dhadial 1 and M. F. Smith 2. Department of Anatomy, St. Thomas' Hospital Medical School 2Paediatric Department, The Rayne Institute, St. Thomas' Hospital, London, SE17EH, England
Summary. A female infant with presumptive deletion of the 7p2 region and an unusual translocation between a part of the short arm of chromosome 1 and a deleted chromosome 7 is described. The patient showed congenital craniosynostosis of the coronal and metopic sutures; marked turricephaly; hypotelorism; deeply cleft palate; shallow orbits with prominent bulging eyes; a depressed nasal bridge; anteverted nostrils; short hands with broad thin fingers and elongated thumbs; a mild talipes calcaneovalgus deformity of the feet; a systolic m u r m u r due to a small VSD; and psychomotor retardation. The child died of bronchopneumonia at 10 weeks of age. The parents are chromosomally normal.
Introduction To our knowledge only three cases of short-arm terminal deletion of chromosome 7 have been reported (Wilson et al., 1973; Friedrich et al., 1975; McPherson et al., 1976). There is a further report by Zackai and Breg (1973), describing two patients with a ring chromosome abnormality of chromosome 7, where presumably the terminal ends of both the short and the long arms were deleted to form the ring. In four of these patients premature craniosynostosis was the characteristic feature considered to be associated with the loss of genetic material from the terminal region of the short arm of chromosome 7 (McPherson et al., 1976); the fifth had microcephaly. We report here another case with congenital craniosynostosis and other phenotypic abnormalities; the karyotype revealed translocation between chromosomes 1 and 7 and terminal short-arm deletion of the latter.
Case Report The patient was born to healthy unrelated caucasian parents, both aged 18 years, following an uneventful first pregnancy and normal delivery at 40 weeks gestation. The birth weight was * To whom offprint requests should be sent
0340-6717/79/0050/0285/$ 01.00
286
R.K. Dhadial and M. F. Smith
Fig. 1. a The patient at 6 weeks. There is marked turricephaly, shallow orbits with protuberant eyes and hypotelorism, b The hand is short and broad with slender, tapering fingers. The thumb is extended
2.36 kg, placental weight 425 g. The OFC was 29 cm and the body length 48 cm. The infant showed marked hypotelorism With shallow orbits and prominent eyes. Epicanthic folds were present, as was an inability to abduct the left eye from the midline. There was marked turricephaly with flattening of the occiput, a 2-cm posterior fontanelle, and synostosis of the metopic and coronal sutures (Fig. 1 a). The nose was short, with a low bridge and anteversion of the nostrils. There was a central cleft of the palate with prominent lateral palatal ridges. The ears appeared to be posteriorly rotated. The hands were short and broad, with thin fingers and extended thumbs (Fig. 1 b). There was mild talipes calcaneo-valgus deformity of the feet. A systolic murmur was considered to be due to a small VSD; the chest X-ray and ECG were normal. Feeding was difficult to establish, and gavage was frequently necessary. The infant did not gain weight satisfactorily and at 10 weeks weighed only 3.0 kg, at this stage she rapidly developed broncbopneumonia and died. Prior to this she was able to fix but would not follow. She had not smiled and there was considerable head lag when she was pulled to a sitting position or held in ventral suspension.
Cytogenetie Studies Chromosome preparations were obtained from lymphocyte cultures by standard m e t h o d s a n d e x a m i n e d u s i n g c o n v e n t i o n a l A S G - ( S u m n e r et al., 1971), C ( S u m n e r , 1972), a n d R - b a n d i n g (Sehesled, 1974) t e c h n i q u e s w i t h slight m o d i f i c a tions. T h e R - b a n d i n g results w e r e i n c o n c l u s i v e . In the 38 m e t a p h a s e s a n a l y s e d , t h e m o d a l n u m b e r o f c h r o m o s o m e s was 46. T h e k a r y o t y p e r e v e a l e d t w o s t r u c t u r a l l y a b n o r m a l c h r o m o s o m e s (Fig. 2). B r e a k a g e a n d r e j o i n i n g b e t w e e n c h r o m o s o m e s 1 a n d 7 is c o n s i d e r e d to be
Terminal 7p Deletion and 1;7 Translocation with Craniosynostosis
287
Fig. 2. Partial karyotype showing chromosome pairs 1 and 7. Note two structurally abnormal chromosomes, one in each pair. A r r o w s point to the presumptive breakpoints
Fig. 3. The idiogram (Paris Conference, 1971) demonstrates the presumptive breakpoints shown by a r r o w s and the translocation
1
Ip-
t(I;7)
7
responsible for this abnormal karyotype. Presumably one break occurred in chromosome 1 at the level of band p22 and another in chromosome 7 at about band p15 (Fig. 3). Subsequently a part of the short arm of chromosome 1, distal to its presumptive break, had become attached to 7 at its breakpoint, giving rise to a structurally abnormal chromosome: t(1;7)(p22;p15). The major portion of chromosome 1 (a part of the short arm of which is involved in translocation) was represented by the second abnormal chromosome, l p - . Nothing seems to be missing from this chromosome, but the p2 region of chromosome 7 distal to its presumptive break appears to be lost. The prominent, easily detectable, band 7p21 of this region was not observed in any sample of either of the two abnormal
288
R.K. Dhadial and M. F. Smith
chromosomes. The karyotype of the child could be written as 46,XX,t(1;7) (p22;p15),del(7)(pter--*p15:). Both parents are chromosomally normal (studied at the Paediatric Research Unit, Guy's Hospital Medical School).
Discussion The clinical symptoms in our patient resemble those found in five published cases with terminal 7p deletion (McPherson et al., 1976). Most of these symptoms are c o m m o n in patients with chromosome aberrations, but the characteristic feature of these cases, except for one (Zackai and Breg, 1973), is the congenital craniosynostosis, which is considered to be associated with the deletion involving the 7p2 region (Friedrich et al., 1975; McPherson et al., 1976). Our case gives further support to this view. However, our patient differs from others in having a terminal 7p deletion and translocation between a part of the short a r m of chromosome 1 and the deleted chromosome 7. To our knowledge this is only the second case of translocation and deletion occurring simultaneously. Recently Fried et al. (1978) have described a patient with de novo reciprocal translocation and deletion involving chromosomes 18 and 21. The extreme rarity of simultaneous occurrence of these two aberrations occurring simultaneously may be due to the impossibility of detecting small deletions in cases of apparently balanced translocation. Analysis of the G-banded preparations did not reveal the usually darkly stained prominent band p21 of chromosome 7 involved in translocation in any sample of the two structurally abnormal chromosomes. We presume there is only one break in chromosome 7, and the interstitial deletion of 7p21 band a n d the presence of distal 7p22 band therefore seems to be unlikely. Therefore, bands 7p21 and 7p22 of the 7p2 region are considered to have been deleted in our case. In two other cases (Wilson et al., 1973; Friedrich et al., 1975) bands 7p21 and 7p22 are missing, although Wilson et al. (1973) speculated on the possibility of the 7p21 band being translocated onto the short arm of chromosome 13 and being represented by the 'giant' satellites observed in their case. They were also uncertain about the identification of 7p22 band. The 'giant' satellites are now considered to be only a minor variant (Therapel et al., 1978). The prominent dark G band 7p21 has been seen in two patients with a no. 7 ring chromosome (Zackai and Breg, 1973), and only band 7p22 is considered to be absent. Only one case (McPherson et al., 1976) has been reported where the interstitial deletion of band 7p21 was observed and the terminal 7p22 was present. In all these cases, whether band 7p21 or 7p22 or both were absent, the c o m m o n feature is the early closure of cranial sutures, resulting in abnormal head configuration. We agree with Friedrich et al. (1975) and McPherson et al. (1976) that whole or partial deletion of 7p2 is associated with early closure of the cranial sutures. The minor clinical variations in the extent of premature synostosis may be related to the proportion of genetic material lost from the 7p2 region. The establishment of defined clinical characteristics for the 7p terminal deletion syndrome has to await further reports. The predominant features
Terminal 7p Deletion and 1;7 Translocation with Craniosynostosis
289
r e p o r t e d thus far include the following: synostosis o f cranial sutures resulting in t u r r i c e p h a l y , p r o m i n e n c e o f the f o r e h e a d a n d flattening o f the occiput; shallow o r b i t s with p r o m i n e n t eyes; h y p e r t e l o r i s m ; d e p r e s s e d nasal bridge, m e d i a n cleft palate; m a l f o r m a t i o n o f the h a n d s , feet, a n d ears; a n d p s y c h o m o t o r r e t a r d a t i o n . Studies o f the p a r e n t s o f these children have n o t revealed a n y a b n o r m a l i t y .
Acknowledgements. The authors wish to thank Prof. M. H. Day for advice and Dr. G. S. Clayden for allowing them to study his patient.
References Fried, K., Mundel, G., Rosenblatt, S.: De novo simultaneous reciprocal translocation and deletion. J. Med. Genet. 15, 152--164 (1978) Friedrich, W., Eyngbye, T., Oster, J.: A girl with karyotype (46,XX,del(7)qter~p15:). Hum. Genet. 26, 161--165 (1975) McPherson, E., Hall, J. G., Hickman, R.: Chromosome 7 short arm deletion and craniosynostosis: a 7p syndrome. Hum. Genet. 35, 117--123 (1976) Paris Conference (1971): Standardization in Human Cytogenetics. Birth Defects: Original Article Series, VIII: 7. New York: The National Foundation 1972 Sehesled, J.: A simple method for R-banding of human chromosomes, showing a pH-dependent connection between R and G bands. Hum. Genet. 21, 55--58 (1974) Sumner, A. T.: A simple technique for demonstrating centromeric heterochromatin. Exp. Cell Res. 75, 304---306 (1972) Sumner, A. T., Evans, H. J., Buckland, R. K.: A new technique for distinguishing between human chromosomes. Nature New. Biol. 232, 31--32 (1971) Tharapel, A. T., Summitt, R. L.: Minor chromosome variations and selected heteromorphisms in 200 unclassified mentally retarded patients and 200 normal controls. Hum. Genet. 41,121-130 (1978) Wilson, M. G., Jujimoto, A., Shinno, N. W., Tourner, J. W.: Grant satellites or translocation? Cytogenet. Cell Genet. 12,209--214 (1973) Zackai, E. H., Breg, W. R.: Cytogenet. Cell Genet. 12, 40---48 (1973) Received March 12, 1979
