Hum. Genet. 51,231--235 (1979) © by Springer-Verlag 1979
A Girl with Karyotype 46,XX,del(7)(pter-~ q32 :) Ursula Friedrich 1., Ole Osterballe 2, Stener Stenbjerg 3, and J a n Jorgensen 3 ~Institute of Human Genetics, University of Aarhus, Bartholin Building, DK-8000 Arhus C, Denmark 2Department of Pediatrics, Aalborg Hospital, Aalborg, Denmark 3The Coagulation Laboratory and Blood Grouping Laboratory, University Hospital, DK-8000 Aarhus C, Denmark
Introduction P r o m p t e d by Uta Francke's note (1978), we report another case with distal 7q deletion, where factor X I I determinations have been carried out. The patient was the first child of healthy parents, both 26 years old. Pregnancy and delivery were uncomplicated. The gestational age was 37 weeks and the birthweight 2279 g, length 46 cm. Abnormalities included microcephaly with flattened occiput, cheilo-gnathopalato-schisis, m o n g o l o i d eye slant, large poorly modulated ears, overlapping third and fifth toes bilaterally, deep furrows on the sole. There was redundant subcutaneous tissue, especially on the back of the feet and the hands (Fig. 1). H e a d circumference at birth was 27 cm (below the 3rd centile) and at t h e age of six months 32 cm (below the 3rd centile). Examination o f the eyes revealed atrophia nervi optici and c o l o b o m a o f the optical nerve on the left side. X-ray examination of the skull showed very narrow sutures and microcephaly, but no real craniosynostosis; otherwise X-ray examination was normal. L a b o r a t o r y examinations were normal, including screening for congenital infection and abnormalities in amino acid metabolism. The only a b n o r m a l findings in dermatoglyphics were a radial loop on the fourth finger and an axial triradius in position t" on the right hand. On the left h a n d an abortive C-line was seen. The m a x i m u m atd angle was enlarged, measuring 139 ° .
Case Report From the age of two months she had convulsions every day in spite of treatment with phenobarbital and diphenylhydantoin. Her psychomotor development was retarded. She died when eight months old of septicemia caused by a generalized candida albicans infection. * To whom offprint requests should be sent
0340-6717/79/0051/0231/$01.00
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U. Friedrich et al.
Fig. 1. The proband at the age of 6 months
Fig. 2. Chromosomes no. 7 from the proband and her parents, Q banding and C banding, showing that the deleted chromosome no. 7, in which the heterochromatin is located towards the short arm side of the centromere, is inherited from the father and not from the mother
A Girl with Karyotype 46,XX,del(7)(pter~q32 :)
233
Table 1. Coagulation factors. Specific assays of coagulation factors were performed on two blood samples obtained on different days. Each factor was determined in quadruplicate Proband Sample No.
Father Sample No.
Mother Sample No.
1
1
1
2
2
Normal % + 2 SD
2
F XII
54
67
41
41
99
96
F XI
108
78
105
95
90
82
65--135
F VIII act.
158
143
92
67
49
49
60--140
F VIII R-ag.
65--135
260
125
105
98
73
F IX F X
95 88
72 103
84 100-
74 122
84 75
84
35--175 60--140
87
70--150
F V F II
68 52
108 73
40 80
94 68
60 64
102 58
> 65 55--115
133
160
110
105
85
79
60--150
F VII
Table 2. Phenotypes of the proband and her parents Marker system
Father
Mother
Proband
Hp GPT
2-1 2-1
2 2-1
2-1 l
AcP
BA
CB
CB
AK ADA
1 1
1 1
1 l
6PGD
A
A
A
C'3 Gc
2 1
2-1 2-1
2-1 2-1
Tf
C
C
C
AB0
0
0
0
Rhesus
ccDEe
CcDee
ccDee
MNS
MNSs
MMSs
MMss
Lewis Duffy
Le(a-b+) Fy(a+b+)
Le(a-b+) Fy(a+b-)
Le(a+b-) Fy(a+b-)
Lutheran Kell
Lu(a-) K-
Lu(a-) K-
Lu(a-) K-
Kidd
Jk (a +b+)
J k (a+b+)
Jk (a+b+)
P
P2
P1
P2
234
U. Friedrich et al.
Pathological findings: All organs were infiltrated with candida albicans. She had microcephaly, a small and spherical cerebrum, arhinencephaly with the hemispheres abnormally closed in front, horse-shoe shaped. The olfactory nerve was lacking. The ventriculi cerebri formed one common chamber. Chromosome examinations of the proband, her parents and paternal grandparents were done on 72 h-lymphocyte cultures and fibroblast cultures. In Q-banding all 66 cells analyzed in the proband showed a terminal deletion of one chromosome no.7, distal to band q32, The karyotype was 46,XX,del(7)(pter~q32:). Both parents and the paternal grandparents had normal karyotypes. With C-banding, on the deleted chromosome no.7 of the proband the centromeric heterochromatin appeared towards the short arms, similar to that in one chromosome no. 7 of the father, whereas in both chromosomes no. 7 of the mother it was placed on the long arms. Therefore the deleted chromosome no. 7 most probably was of paternal and not of maternal origin (Fig. 2). For coagulation studies a sample of 9 ml venous blood was drawn in plastic tubes containing one ml of 3.8% trisodium citrate. Platelet poor plasma was stored at -60°C until assayed. F XI was measured on fresh plasma. Specific factor assays were performed as described earlier (Stenbjerg et al., 1975). F VIII related antigen (F VIII R-ag.) was determined by rocket immune electrophoresis with antibody obtained from Behringwerke, W.Germany. Reduced F XII activity was revealed in the proposita and her father (Table i). The father's parents were available for study, but F XII levels were within normal limits (104% in the father and 80% in his mother). F VIII activity and F VIII R-ag. were slightly raised in the proposita, and a subnormal level of F VIII activity was recorded in the mother. The other genetic markers were not informative. Activity of beta-glucuronidase in the proband and her parents was within the normal range.
Discussion The clinical findings in o u r p a t i e n t fit quite well with the p r o p o s e d deletion s y n d r o m e (Harris et al., 1977). A l t h o u g h F X I I levels in our patient were below the n o r m a l range (based o n the study of 100 healthy persons), the F VIII activity, F V I I I related a n t i g e n a n d F VII activity were raised. This suggests that the observed F XII level was n o t at the patient's m i n i m u m , which is further s u p p o r t e d by the c o n s t a n t l y lower level of F X I I (41%) f o u n d in the father. V e l t k a m p et al. (1968) f o u n d two groups of carriers of F X I I deficiency. O n e group had an average F X I I level of 60% while the lower group averaged a r o u n d 20%. The F X I I deficiency in the present family m a y belong to either group. A p p a r e n t l y the defect arose in the father since n o r m a l F X I I levels were f o u n d in both of his parents. S u p p o s i n g the gene for F X I I is located on the distal segment of the long arm of c h r o m o s o m e no. 7 as p r o p o s e d by d e G r o u c h y et al. (1974), the findings in o u r study can be explained in the following way: The m u t a t i o n a l event in the father has caused a small interstitial deletion or a p o i n t m u t a t i o n in b a n d q32 in one c h r o m o s o m e no. 7 with s i m u l t a n e o u s increase of a t e n d e n c y to break in this region. Such a breakage has occurred in the c h r o m o s o m e no. 7 inherited by the p r o b a n d , who w o u l d also have the deletion described as the F X I I deficiency. If this i n t e r p r e t a t i o n is correct the locus for F X I I can be assigned to b a n d q32 of c h r o m o s o m e no. 7. I f however the m u t a t i o n in the father a n d the deletion of c h r o m o s o m e no. 7 in the child are i n d e p e n d e n t events, no i n f o r m a t i o n is given a b o u t the location of the locus for F XII.
A Girl with Karyotype 46,XX,de1(7)(pter~q32!)
235
Acknowledgement. We thank Professor Dr. med. A.J. Therkelsen, chief of the Institute of Human Genetics, for his fruitful discussion. We are grateful to Bente Falkenberg, Sonja Rou Jensen, G. Krog, L. Norengaard, P. Sharma, S. Christiansen, and Bodil Schmidt for excellent technical assistance and to Dorte Laursen for preparing the manuscript.
References DeGrouchy, J., Turleau, C.: Tentative localization of a Hageman (Factor XII) locus on 7q, probably the 7q35 band. Humangenetik 24, 197--200 (1974) Francke, U.: Hageman (Factor XII) locus on 7q? Report of a second case with del(7)q35 and normal factor XII level. Hum. Genet. 45, 363--367 (1978) Harris, E. L., Wappner, R. S., Palmer, C. G.0 Hall, B., Dinno, N., Seashore, M. R., Breg, W. R.: 7q deletion syndrome (7q32--*7qter). Clin. Genet. 12, 233--238 (1977) Veltkamp, J. J., Drion, E. F., Loeliger, E. A.: Detection of the carrier state in hereditary coagulation disorders. Thromb. Diath. Haemorrh. 19, 403--422 (1968)
Received March 26, 1979
A Girl with Karyotype 46,XX,del(7)(pter-~ q32 :) Ursula Friedrich 1., Ole Osterballe 2, Stener Stenbjerg 3, and J a n Jorgensen 3 ~Institute of Human Genetics, University of Aarhus, Bartholin Building, DK-8000 Arhus C, Denmark 2Department of Pediatrics, Aalborg Hospital, Aalborg, Denmark 3The Coagulation Laboratory and Blood Grouping Laboratory, University Hospital, DK-8000 Aarhus C, Denmark
Introduction P r o m p t e d by Uta Francke's note (1978), we report another case with distal 7q deletion, where factor X I I determinations have been carried out. The patient was the first child of healthy parents, both 26 years old. Pregnancy and delivery were uncomplicated. The gestational age was 37 weeks and the birthweight 2279 g, length 46 cm. Abnormalities included microcephaly with flattened occiput, cheilo-gnathopalato-schisis, m o n g o l o i d eye slant, large poorly modulated ears, overlapping third and fifth toes bilaterally, deep furrows on the sole. There was redundant subcutaneous tissue, especially on the back of the feet and the hands (Fig. 1). H e a d circumference at birth was 27 cm (below the 3rd centile) and at t h e age of six months 32 cm (below the 3rd centile). Examination o f the eyes revealed atrophia nervi optici and c o l o b o m a o f the optical nerve on the left side. X-ray examination of the skull showed very narrow sutures and microcephaly, but no real craniosynostosis; otherwise X-ray examination was normal. L a b o r a t o r y examinations were normal, including screening for congenital infection and abnormalities in amino acid metabolism. The only a b n o r m a l findings in dermatoglyphics were a radial loop on the fourth finger and an axial triradius in position t" on the right hand. On the left h a n d an abortive C-line was seen. The m a x i m u m atd angle was enlarged, measuring 139 ° .
Case Report From the age of two months she had convulsions every day in spite of treatment with phenobarbital and diphenylhydantoin. Her psychomotor development was retarded. She died when eight months old of septicemia caused by a generalized candida albicans infection. * To whom offprint requests should be sent
0340-6717/79/0051/0231/$01.00
232
U. Friedrich et al.
Fig. 1. The proband at the age of 6 months
Fig. 2. Chromosomes no. 7 from the proband and her parents, Q banding and C banding, showing that the deleted chromosome no. 7, in which the heterochromatin is located towards the short arm side of the centromere, is inherited from the father and not from the mother
A Girl with Karyotype 46,XX,del(7)(pter~q32 :)
233
Table 1. Coagulation factors. Specific assays of coagulation factors were performed on two blood samples obtained on different days. Each factor was determined in quadruplicate Proband Sample No.
Father Sample No.
Mother Sample No.
1
1
1
2
2
Normal % + 2 SD
2
F XII
54
67
41
41
99
96
F XI
108
78
105
95
90
82
65--135
F VIII act.
158
143
92
67
49
49
60--140
F VIII R-ag.
65--135
260
125
105
98
73
F IX F X
95 88
72 103
84 100-
74 122
84 75
84
35--175 60--140
87
70--150
F V F II
68 52
108 73
40 80
94 68
60 64
102 58
> 65 55--115
133
160
110
105
85
79
60--150
F VII
Table 2. Phenotypes of the proband and her parents Marker system
Father
Mother
Proband
Hp GPT
2-1 2-1
2 2-1
2-1 l
AcP
BA
CB
CB
AK ADA
1 1
1 1
1 l
6PGD
A
A
A
C'3 Gc
2 1
2-1 2-1
2-1 2-1
Tf
C
C
C
AB0
0
0
0
Rhesus
ccDEe
CcDee
ccDee
MNS
MNSs
MMSs
MMss
Lewis Duffy
Le(a-b+) Fy(a+b+)
Le(a-b+) Fy(a+b-)
Le(a+b-) Fy(a+b-)
Lutheran Kell
Lu(a-) K-
Lu(a-) K-
Lu(a-) K-
Kidd
Jk (a +b+)
J k (a+b+)
Jk (a+b+)
P
P2
P1
P2
234
U. Friedrich et al.
Pathological findings: All organs were infiltrated with candida albicans. She had microcephaly, a small and spherical cerebrum, arhinencephaly with the hemispheres abnormally closed in front, horse-shoe shaped. The olfactory nerve was lacking. The ventriculi cerebri formed one common chamber. Chromosome examinations of the proband, her parents and paternal grandparents were done on 72 h-lymphocyte cultures and fibroblast cultures. In Q-banding all 66 cells analyzed in the proband showed a terminal deletion of one chromosome no.7, distal to band q32, The karyotype was 46,XX,del(7)(pter~q32:). Both parents and the paternal grandparents had normal karyotypes. With C-banding, on the deleted chromosome no.7 of the proband the centromeric heterochromatin appeared towards the short arms, similar to that in one chromosome no. 7 of the father, whereas in both chromosomes no. 7 of the mother it was placed on the long arms. Therefore the deleted chromosome no. 7 most probably was of paternal and not of maternal origin (Fig. 2). For coagulation studies a sample of 9 ml venous blood was drawn in plastic tubes containing one ml of 3.8% trisodium citrate. Platelet poor plasma was stored at -60°C until assayed. F XI was measured on fresh plasma. Specific factor assays were performed as described earlier (Stenbjerg et al., 1975). F VIII related antigen (F VIII R-ag.) was determined by rocket immune electrophoresis with antibody obtained from Behringwerke, W.Germany. Reduced F XII activity was revealed in the proposita and her father (Table i). The father's parents were available for study, but F XII levels were within normal limits (104% in the father and 80% in his mother). F VIII activity and F VIII R-ag. were slightly raised in the proposita, and a subnormal level of F VIII activity was recorded in the mother. The other genetic markers were not informative. Activity of beta-glucuronidase in the proband and her parents was within the normal range.
Discussion The clinical findings in o u r p a t i e n t fit quite well with the p r o p o s e d deletion s y n d r o m e (Harris et al., 1977). A l t h o u g h F X I I levels in our patient were below the n o r m a l range (based o n the study of 100 healthy persons), the F VIII activity, F V I I I related a n t i g e n a n d F VII activity were raised. This suggests that the observed F XII level was n o t at the patient's m i n i m u m , which is further s u p p o r t e d by the c o n s t a n t l y lower level of F X I I (41%) f o u n d in the father. V e l t k a m p et al. (1968) f o u n d two groups of carriers of F X I I deficiency. O n e group had an average F X I I level of 60% while the lower group averaged a r o u n d 20%. The F X I I deficiency in the present family m a y belong to either group. A p p a r e n t l y the defect arose in the father since n o r m a l F X I I levels were f o u n d in both of his parents. S u p p o s i n g the gene for F X I I is located on the distal segment of the long arm of c h r o m o s o m e no. 7 as p r o p o s e d by d e G r o u c h y et al. (1974), the findings in o u r study can be explained in the following way: The m u t a t i o n a l event in the father has caused a small interstitial deletion or a p o i n t m u t a t i o n in b a n d q32 in one c h r o m o s o m e no. 7 with s i m u l t a n e o u s increase of a t e n d e n c y to break in this region. Such a breakage has occurred in the c h r o m o s o m e no. 7 inherited by the p r o b a n d , who w o u l d also have the deletion described as the F X I I deficiency. If this i n t e r p r e t a t i o n is correct the locus for F X I I can be assigned to b a n d q32 of c h r o m o s o m e no. 7. I f however the m u t a t i o n in the father a n d the deletion of c h r o m o s o m e no. 7 in the child are i n d e p e n d e n t events, no i n f o r m a t i o n is given a b o u t the location of the locus for F XII.
A Girl with Karyotype 46,XX,de1(7)(pter~q32!)
235
Acknowledgement. We thank Professor Dr. med. A.J. Therkelsen, chief of the Institute of Human Genetics, for his fruitful discussion. We are grateful to Bente Falkenberg, Sonja Rou Jensen, G. Krog, L. Norengaard, P. Sharma, S. Christiansen, and Bodil Schmidt for excellent technical assistance and to Dorte Laursen for preparing the manuscript.
References DeGrouchy, J., Turleau, C.: Tentative localization of a Hageman (Factor XII) locus on 7q, probably the 7q35 band. Humangenetik 24, 197--200 (1974) Francke, U.: Hageman (Factor XII) locus on 7q? Report of a second case with del(7)q35 and normal factor XII level. Hum. Genet. 45, 363--367 (1978) Harris, E. L., Wappner, R. S., Palmer, C. G.0 Hall, B., Dinno, N., Seashore, M. R., Breg, W. R.: 7q deletion syndrome (7q32--*7qter). Clin. Genet. 12, 233--238 (1977) Veltkamp, J. J., Drion, E. F., Loeliger, E. A.: Detection of the carrier state in hereditary coagulation disorders. Thromb. Diath. Haemorrh. 19, 403--422 (1968)
Received March 26, 1979
