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Chromosome 7 in ataxia-telangiectasia
440
Brief clinical and laboratory observations
The Journal of Pediatrics September 1980
Chromosome 7 in ataxia-telangiectasia J. M. J. C. Seheres, M.D., T. W. J. Hustinx, M. D., and C. M. R. Weemaes, M.D.,
Nijmegen, The Netherlands A T A X I A - T E L A N G I E C T A S I A , or the Louis-Bar syndrome, is a recessive autosomal disorder clinically characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, a n d a predisposition to the d e v e l o p m e n t o f neoplasia. Most often patients die from p u l m o n a r y insufficiency or cancer in the first two decades of life. A T is one of the classical c h r o m o s o m e breakage syndromes; the cells o f the patients usually display a n increased frequency of s p o n t a n e o u s chromosome breaks a n d rearrangements. C h r o m o s o m e 14 a b n o r malities are especially f r e q u e n t a n d very often there is a t a n d e m 14q/14q translocation, a so-called D q + m a r k e r chromosome;, Recently we have detected a n o t h e r c h r o m o s o m a l a b n o r m a l i t y which m i g h t be especially associated with AT: in three s u b s e q u e n t l y studied patients we did not find D q + markers but typical c h r o m o s o m e 7 abnormalities.
84
a
b
cd
Figure. a and b, Normal and inverted chromosomes 7 as found in Patients 2 and 3; b = 7qter--~7q32::7p13---~7q32::7p13--, 7pter. c and d, Abnormal inverted chromosome and normal chromosome 7 of Patient 1; c = 7pter--~ 7p13::7q32 ~ cen--~ 7q32::7p13 --~ 7pter.
CASE REPORTS Patient 1 was born in 1964 as the third child of healthy, unrelated parents. When he started to walk at the age of 14 months the parents noted undue unsteadiness with a tendency to sway, which progressed slowly. After measles at the age of 2 years, frequent episodes of pulmonary infections occurred, Conjunctival telangiectasia was first noticed at 4 years. Progressive deterioration with more severe ataxia and increasing speech involvement was noted. He was admitted to our hospital several times for pulmonary infections. At the age of 14 he died from respiratory failure. Routine laboratory investigations revealed no abnormalities. Quantitative immunoglobulin studies showed absence of secretory and serum IgA, low normal IgG, and normal lgM levels. Anti-lgA antibodies of low affinity were detectable at the age of 10. T cell rosettes were decreased (32%). The proliferative response of blood lymphocytes to stimulation with PHA was normal, but the response to PWM was decreased (60% of normal control value). No proliferative responses to stimulation with tetanus and diphtheria toxoids were measured. Patient 2, brother of Patient 1, was born in 1972 as the fifth child in a sibship of five. He was delivered after a pregnancy of 6.5 months and his birth weight was 1,320 gm. Unsteady gait was noted when he began to walk at the age of 15 months. The diagnosis of cerebellar ataxia was established at 2 years of age. Conjunctival telangiectasia was present at the age of 3. He once had pneumonia and otitis media.
From the Departments of Human Genetics and Pediatrics, Faculty of Medicine, University of Nijmegen.
Routine laboratory investigations revealed no abnormalities. Serum IgM, IgA (141 mg/dl), and lgE values were normal: lgG was low normal. Absolute lymphocyte counts (1,700//xl) and T cell rosettes (46%) were slightly decreased, The blood lymphocytes showed diminished responses to PHA and PWM in vitro (50% as compared with normal controls) and no responses to tetanus and diphtheria toxoids. Patient 3, a boy, was born in 1971. The first symptoms of slowly progressive cerebellar ataxia were noted at the age of 16 months. At the age of 6 years telangiectasias of the conjuntiva were present. He had episodes of otitis media and bronchitiss
Abbreviations used lg: immunoglobulin PHA: phytohemagglutinin PWM: pokeweed mitogen Routine laboratory studies revealed no abnormalities. Serum immunoglobulin studies showed a pronounced IgA deficiency (<1 mg/dl). There was a lymphopenia (600//zl) and T cell rosettes were decreased (26%). In vitro the responses of blood lyrnphocytes to PHA and PWM were decreased and the response to tetanus toxoid was positive: CYTOGENETIC RESULTS AND DISCUSSION C h r o m o s o m e investigations were p e r f o r m e d on cultures o f p e r i p h e r a l lymphocytes stimulated with PHA.
0022-3476/80/090440+ 02500.20/0 9 1980 The C.V. Mosby Co.
Volume 97 Number 3
B r i e f clinical and laboratory observations
The main results are summarized in the Table. As can be expected in AT, all three patients had a relatively high incidence of cells with structural aberrations (gaps, breaks, and rearrangements). A m o n g the rearrangements seen were some typical chromosome 7 abnormalities. Patient 3 had a lymphocyte clone with a pericentric inversion of a chromosome 7, the break points being 7p13 and 7q32 (Figure). We were very surprised when we saw the same chromosome 7 inversion in a cell of Patient 2. In Patient 3 we did not find the inversion itself but an abnormal chromosome which must be derived from it: an isochromosome consisting of twice the long arm of the inversion (Figure). Further, we noticed an identical 7/14 translocation in one cell each of Patients t and 3; the exchanges had taken place at 7 p l 3 - a s in the i n v e r s i o n - a n d at 14ql 1. A similar 7/14 rearrangement has been found in an A T patient of McCaw et al, :~who also described another patient with a 7/14 translocation. These data indicate that not only chromosome 14, but also certain chromosome 7 abnormalities play a role in AT. A chromosome 7 anomaly may not have been noticed previously in A T because this syndrome, which is known to be clinically heterogeneous, 4 also is heterogeneous with respect to the involvement of chromosome 7. Another possibility, however, is that in earlier studies chromosome 7 inversions and translocations have remained undetected when no banding was used, whereas the D q + markers were easily detected even with conventional chromosome staining techniques. In order to gain more insight into the
44 1
Table. Results of repeated cytogenetic studies of the three patients
Patient
3 2 1
Cells with
Cells with structural aberration ~
7 8 4 7 12 14
38 50 45 103 47 " 100
2 8 2 9
7/14 3
--
1
. . . .
4
6
l
1 --
--
1
possible basic significance of specific chromosome abnormalities in this serious disorder, the chromosomes of every patient with A T should be studied extensively with banding techniques, and special attention should be given both to chromosome 14 and to 7, REFERENCES
1. Cohen MM, Kohn G, and Dagan J: Chromosomes in ataxia-telangiectasia, Lancet 2:1500, 1973. 2. Harnden DG: Ataxia telangiectasia syndrome, in German J, editor: Chromosomes in cancer, New York, 1974, John Wiley & Sons, Inc., pp 61%636. 3. McCaw BK, Hecht F, Harnden DG, and Teplitz RL: Somatic rearrangement of chromosome 14 in human lymphocytes, Proc Natl Acad Sci USA 72:2071, 1975. 4. Hecht F, McCaw BK: Chromosome instability syndromes, in Mulvihill JJ, Miller RW, and Fraumeni JF, editors: Genetics of human cancer, New York, 1977, Raven Press, pp 105-123.
Refeeding pancreatitis in malnourished children Joyce Gryboski, M.D.,* Craig Hillemeier, M.D., Samuel Kocoshis, M.D., Walter Anyan, M.D., and John S. Seashore, M.D., New Haven, Conn.
RE v E E D I N G is not mentioned among the major Causes of acute pancreatitis in children. 1-~Acute pancreatitis itself is unusual, with most cases being drug induced, traumatic, or idiopathic; less c o m m o n causes are hyperlipidemia, obstruction of the ampulla of Vater, hereditary pancreatiFrom the Department of Pediatrics, Yale University School of Medicine. Supported in part by National Institutes of Health grant No. RRO0125. *Reprint Address: 333 Cedar St., New Haven, CT 06510.
0022-3476/80/090441 + 03500.30/0 9 1980 The C. V. Mosby Co.
tis, and cystic fibrosis. Pancreatic function has been evaluated in children with protein-calorie malnutrition and, although pancreatic insufficiency was identified and found to persist for weeks to months after improvement of the nutritional status, acute pancreatitis was not noted ?-5 It is the purpose of this report to describe mild pancreatitis which developed during the refeeding of a child with psychosocial dwarfism, and severe disease which followed forced feeding of two patients with anorexia nervosa.
Brief clinical and laboratory observations
The Journal of Pediatrics September 1980
Chromosome 7 in ataxia-telangiectasia J. M. J. C. Seheres, M.D., T. W. J. Hustinx, M. D., and C. M. R. Weemaes, M.D.,
Nijmegen, The Netherlands A T A X I A - T E L A N G I E C T A S I A , or the Louis-Bar syndrome, is a recessive autosomal disorder clinically characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, a n d a predisposition to the d e v e l o p m e n t o f neoplasia. Most often patients die from p u l m o n a r y insufficiency or cancer in the first two decades of life. A T is one of the classical c h r o m o s o m e breakage syndromes; the cells o f the patients usually display a n increased frequency of s p o n t a n e o u s chromosome breaks a n d rearrangements. C h r o m o s o m e 14 a b n o r malities are especially f r e q u e n t a n d very often there is a t a n d e m 14q/14q translocation, a so-called D q + m a r k e r chromosome;, Recently we have detected a n o t h e r c h r o m o s o m a l a b n o r m a l i t y which m i g h t be especially associated with AT: in three s u b s e q u e n t l y studied patients we did not find D q + markers but typical c h r o m o s o m e 7 abnormalities.
84
a
b
cd
Figure. a and b, Normal and inverted chromosomes 7 as found in Patients 2 and 3; b = 7qter--~7q32::7p13---~7q32::7p13--, 7pter. c and d, Abnormal inverted chromosome and normal chromosome 7 of Patient 1; c = 7pter--~ 7p13::7q32 ~ cen--~ 7q32::7p13 --~ 7pter.
CASE REPORTS Patient 1 was born in 1964 as the third child of healthy, unrelated parents. When he started to walk at the age of 14 months the parents noted undue unsteadiness with a tendency to sway, which progressed slowly. After measles at the age of 2 years, frequent episodes of pulmonary infections occurred, Conjunctival telangiectasia was first noticed at 4 years. Progressive deterioration with more severe ataxia and increasing speech involvement was noted. He was admitted to our hospital several times for pulmonary infections. At the age of 14 he died from respiratory failure. Routine laboratory investigations revealed no abnormalities. Quantitative immunoglobulin studies showed absence of secretory and serum IgA, low normal IgG, and normal lgM levels. Anti-lgA antibodies of low affinity were detectable at the age of 10. T cell rosettes were decreased (32%). The proliferative response of blood lymphocytes to stimulation with PHA was normal, but the response to PWM was decreased (60% of normal control value). No proliferative responses to stimulation with tetanus and diphtheria toxoids were measured. Patient 2, brother of Patient 1, was born in 1972 as the fifth child in a sibship of five. He was delivered after a pregnancy of 6.5 months and his birth weight was 1,320 gm. Unsteady gait was noted when he began to walk at the age of 15 months. The diagnosis of cerebellar ataxia was established at 2 years of age. Conjunctival telangiectasia was present at the age of 3. He once had pneumonia and otitis media.
From the Departments of Human Genetics and Pediatrics, Faculty of Medicine, University of Nijmegen.
Routine laboratory investigations revealed no abnormalities. Serum IgM, IgA (141 mg/dl), and lgE values were normal: lgG was low normal. Absolute lymphocyte counts (1,700//xl) and T cell rosettes (46%) were slightly decreased, The blood lymphocytes showed diminished responses to PHA and PWM in vitro (50% as compared with normal controls) and no responses to tetanus and diphtheria toxoids. Patient 3, a boy, was born in 1971. The first symptoms of slowly progressive cerebellar ataxia were noted at the age of 16 months. At the age of 6 years telangiectasias of the conjuntiva were present. He had episodes of otitis media and bronchitiss
Abbreviations used lg: immunoglobulin PHA: phytohemagglutinin PWM: pokeweed mitogen Routine laboratory studies revealed no abnormalities. Serum immunoglobulin studies showed a pronounced IgA deficiency (<1 mg/dl). There was a lymphopenia (600//zl) and T cell rosettes were decreased (26%). In vitro the responses of blood lyrnphocytes to PHA and PWM were decreased and the response to tetanus toxoid was positive: CYTOGENETIC RESULTS AND DISCUSSION C h r o m o s o m e investigations were p e r f o r m e d on cultures o f p e r i p h e r a l lymphocytes stimulated with PHA.
0022-3476/80/090440+ 02500.20/0 9 1980 The C.V. Mosby Co.
Volume 97 Number 3
B r i e f clinical and laboratory observations
The main results are summarized in the Table. As can be expected in AT, all three patients had a relatively high incidence of cells with structural aberrations (gaps, breaks, and rearrangements). A m o n g the rearrangements seen were some typical chromosome 7 abnormalities. Patient 3 had a lymphocyte clone with a pericentric inversion of a chromosome 7, the break points being 7p13 and 7q32 (Figure). We were very surprised when we saw the same chromosome 7 inversion in a cell of Patient 2. In Patient 3 we did not find the inversion itself but an abnormal chromosome which must be derived from it: an isochromosome consisting of twice the long arm of the inversion (Figure). Further, we noticed an identical 7/14 translocation in one cell each of Patients t and 3; the exchanges had taken place at 7 p l 3 - a s in the i n v e r s i o n - a n d at 14ql 1. A similar 7/14 rearrangement has been found in an A T patient of McCaw et al, :~who also described another patient with a 7/14 translocation. These data indicate that not only chromosome 14, but also certain chromosome 7 abnormalities play a role in AT. A chromosome 7 anomaly may not have been noticed previously in A T because this syndrome, which is known to be clinically heterogeneous, 4 also is heterogeneous with respect to the involvement of chromosome 7. Another possibility, however, is that in earlier studies chromosome 7 inversions and translocations have remained undetected when no banding was used, whereas the D q + markers were easily detected even with conventional chromosome staining techniques. In order to gain more insight into the
44 1
Table. Results of repeated cytogenetic studies of the three patients
Patient
3 2 1
Cells with
Cells with structural aberration ~
7 8 4 7 12 14
38 50 45 103 47 " 100
2 8 2 9
7/14 3
--
1
. . . .
4
6
l
1 --
--
1
possible basic significance of specific chromosome abnormalities in this serious disorder, the chromosomes of every patient with A T should be studied extensively with banding techniques, and special attention should be given both to chromosome 14 and to 7, REFERENCES
1. Cohen MM, Kohn G, and Dagan J: Chromosomes in ataxia-telangiectasia, Lancet 2:1500, 1973. 2. Harnden DG: Ataxia telangiectasia syndrome, in German J, editor: Chromosomes in cancer, New York, 1974, John Wiley & Sons, Inc., pp 61%636. 3. McCaw BK, Hecht F, Harnden DG, and Teplitz RL: Somatic rearrangement of chromosome 14 in human lymphocytes, Proc Natl Acad Sci USA 72:2071, 1975. 4. Hecht F, McCaw BK: Chromosome instability syndromes, in Mulvihill JJ, Miller RW, and Fraumeni JF, editors: Genetics of human cancer, New York, 1977, Raven Press, pp 105-123.
Refeeding pancreatitis in malnourished children Joyce Gryboski, M.D.,* Craig Hillemeier, M.D., Samuel Kocoshis, M.D., Walter Anyan, M.D., and John S. Seashore, M.D., New Haven, Conn.
RE v E E D I N G is not mentioned among the major Causes of acute pancreatitis in children. 1-~Acute pancreatitis itself is unusual, with most cases being drug induced, traumatic, or idiopathic; less c o m m o n causes are hyperlipidemia, obstruction of the ampulla of Vater, hereditary pancreatiFrom the Department of Pediatrics, Yale University School of Medicine. Supported in part by National Institutes of Health grant No. RRO0125. *Reprint Address: 333 Cedar St., New Haven, CT 06510.
0022-3476/80/090441 + 03500.30/0 9 1980 The C. V. Mosby Co.
tis, and cystic fibrosis. Pancreatic function has been evaluated in children with protein-calorie malnutrition and, although pancreatic insufficiency was identified and found to persist for weeks to months after improvement of the nutritional status, acute pancreatitis was not noted ?-5 It is the purpose of this report to describe mild pancreatitis which developed during the refeeding of a child with psychosocial dwarfism, and severe disease which followed forced feeding of two patients with anorexia nervosa.