- Email: [email protected]
Genetic influences on pulmonary severity in cystic fibrosis
294
The need for more consultant participation in emergency work and in the training of junior surgical staff was very clearly stated in the Royal College of Surgeons’ report on the composition of the surgical team, published in January, 1988.3 So far this authoritative statement seems to have had little effect. It is time to remind local and national manpower committees and the health ministries of its recommendations.
CLINICAL FEATURES OF PROBAND (111-1), MOTHER MATERNAL AUNT (11-3)
(11-2)
AND
7 Park Road,
Cults,
PETER
Aberdeen AB19HR, UK
F. JONES *=normal range, t=at age 18, FEV,=forced expiratory volume IRT= immunoreactive trypsm.
1. Buck N, Devlin HB, Lunn JN. Report of a confidential enquiry into perioperative deaths. London: Nuffield Provincial Hospitals Trust and King’s Fund, 1988. 2. Steele RJC, Logie JRC, Munro A. Technical training m surgery: the trainee’s view. Br J Surg 1989; 76: 1291-93. 3. Commission on the Provision of Surgical Services. Report of the working party on the composition of the surgical team, general surgery, orthopaedics and otolaryngology. London: Royal College of Surgeons of England, 1988.
Genetic influences on pulmonary severity in
cystic fibrosis SiR,—The recent discovery of the cystic fibrosis (CF) gene and the identification of the most common mutation (&bgr;F 508) indicates that patients with pancreatic insufficiency carry two copies of &bgr;F 508 or other severe mutations, whereas pancreatic sufficient patients bear a severe allele on only one or on neither chromosome.’ We report a family in whom differences in the severity of pulmonary disease in the presence of pancreatic sufficiency may be accounted for by genetic differences. The family pedigree and clinical features are shown in the figure and table, respectively. The proband (III-1) was diagnosed at age 12 years having had respiratory infections for 5 years. She had progressive severe pulmonary disease and at age 18 died of respiratory failure. Throughout she remained pancreatic sufficient. The mother (11-2) and maternal aunt (11-3) were diagnosed only after the diagnosis was established in the proband. Neither has severe pulmonary disease nor has needed hospital treatment for respiratory problems within the past three years. Both remain pancreatic sufficient. The fact that all affected individuals in our family were pancreatic sufficient supports the concordance of pancreatic sufficiency within families.2 The genetic data are also in accord with the hypothesis that pancreatic sufficient patients are either compound heterozygotes or homozygotes for mild mutations and confirms that
in
1
s,
pancreatic sufficiency is genetically dominant. The proband inherited the severe 4FSOg allele from her father, and a mild as yet unspecified mutation from the mother. The CF alleles in the mother and her sister are unknown and therefore whether they are homozygous or heterozygous for a mild mutation cannot be established. However, the pronounced discrepancy in the severity of pulmonary disease between the proband and her mother and aunt, in the absence of other pulmonary complications, would suggest that both maternal alleles are milder than the F 508 allele. This patient offers further evidence that different CF mutations determine the clinical manifestations of the disease, including not only pancreatic sufficiency or insufficiency but also the severity of pulmonary disease. Identification of the mild mutations would be very important in the understanding of the pathophysiology of CF. We suggest that individuals who have inherited two mild alleles may have few clinical problems and may remain undiagnosed in the absence of a family history of CF. The prevalence of CF in the population may therefore be underestimated. We thank Ms C. Williams and Prof R. Williamson for advice and help and the Shearer Ball Appeal for generous financial support.
London SW3 6HP, UK
G. SANTIS L. OSBORNE R. KNIGHT M. E. HODSON
Molecular Genetics Department, St Mary’s Hospital Medical School, London
M. RAMSAY
Department of Cystic Fibrosis, Brompton Hospital,
1. Kerern B-S, Rommens JM, Buchanan JA, et al. Identification of the CF gene: genetic analysis. Science 1989; 245: 1073-80. 2. Corey M, Durie P, Moore D, et al. Familial concordance of pancreatic function in
Cystic Fibrosis. J Pediatr 1989; 115: 274-77.
TNF-induced cardiomyopathy SiR,—Tumour necrosis factor (TNF), now being tested in phase I and II clinical studies in cancer patients,1,2 has the following dose-dependent side-effects: fever and chills, hepatotoxicity, nausea and vomiting, tachycardia, hypertension and hypotension, and increased serum trigylcerides. These adverse effects are reversible, within 30 days of treatment ending, and chronic toxicity has not been reported. A 44-year-old man with renal cell carcinoma and spread to the lungs was given TNF postoperatively, consisting of 2 h intravenous infusions daily x 5 every 3 weeks. Seventeen courses were
Pedigree, CF allele, and linked * proband =
marker haplotypes.
adminstered. The dose was increased from 20 to 40, 80, 120,160 and 200 ug/m2 daily (this, the maximum tolerated dose, being given for the last twelve courses). Chills and fever up to 39 4°C developed within 2 hours of the start of TNF infusions. During the last five courses he had a substemal pressure and from the eleventh cycle ST-segment depression was seen on the ECG. On day 2 of the fifteenth cycle TNF was discontinued because of severe chest pain and a non-transmural myocardial infarction was diagnosed. Arteriography revealed no significant signs of coronary artery disease. Two more cycles were then administered, substemal pressure appearing whenever TNF was infused. The lung metastases have remained unchanged. The patient presented 3 months after TNF therapy had been discontinued with respiratory distress, increase in weight, severe
The need for more consultant participation in emergency work and in the training of junior surgical staff was very clearly stated in the Royal College of Surgeons’ report on the composition of the surgical team, published in January, 1988.3 So far this authoritative statement seems to have had little effect. It is time to remind local and national manpower committees and the health ministries of its recommendations.
CLINICAL FEATURES OF PROBAND (111-1), MOTHER MATERNAL AUNT (11-3)
(11-2)
AND
7 Park Road,
Cults,
PETER
Aberdeen AB19HR, UK
F. JONES *=normal range, t=at age 18, FEV,=forced expiratory volume IRT= immunoreactive trypsm.
1. Buck N, Devlin HB, Lunn JN. Report of a confidential enquiry into perioperative deaths. London: Nuffield Provincial Hospitals Trust and King’s Fund, 1988. 2. Steele RJC, Logie JRC, Munro A. Technical training m surgery: the trainee’s view. Br J Surg 1989; 76: 1291-93. 3. Commission on the Provision of Surgical Services. Report of the working party on the composition of the surgical team, general surgery, orthopaedics and otolaryngology. London: Royal College of Surgeons of England, 1988.
Genetic influences on pulmonary severity in
cystic fibrosis SiR,—The recent discovery of the cystic fibrosis (CF) gene and the identification of the most common mutation (&bgr;F 508) indicates that patients with pancreatic insufficiency carry two copies of &bgr;F 508 or other severe mutations, whereas pancreatic sufficient patients bear a severe allele on only one or on neither chromosome.’ We report a family in whom differences in the severity of pulmonary disease in the presence of pancreatic sufficiency may be accounted for by genetic differences. The family pedigree and clinical features are shown in the figure and table, respectively. The proband (III-1) was diagnosed at age 12 years having had respiratory infections for 5 years. She had progressive severe pulmonary disease and at age 18 died of respiratory failure. Throughout she remained pancreatic sufficient. The mother (11-2) and maternal aunt (11-3) were diagnosed only after the diagnosis was established in the proband. Neither has severe pulmonary disease nor has needed hospital treatment for respiratory problems within the past three years. Both remain pancreatic sufficient. The fact that all affected individuals in our family were pancreatic sufficient supports the concordance of pancreatic sufficiency within families.2 The genetic data are also in accord with the hypothesis that pancreatic sufficient patients are either compound heterozygotes or homozygotes for mild mutations and confirms that
in
1
s,
pancreatic sufficiency is genetically dominant. The proband inherited the severe 4FSOg allele from her father, and a mild as yet unspecified mutation from the mother. The CF alleles in the mother and her sister are unknown and therefore whether they are homozygous or heterozygous for a mild mutation cannot be established. However, the pronounced discrepancy in the severity of pulmonary disease between the proband and her mother and aunt, in the absence of other pulmonary complications, would suggest that both maternal alleles are milder than the F 508 allele. This patient offers further evidence that different CF mutations determine the clinical manifestations of the disease, including not only pancreatic sufficiency or insufficiency but also the severity of pulmonary disease. Identification of the mild mutations would be very important in the understanding of the pathophysiology of CF. We suggest that individuals who have inherited two mild alleles may have few clinical problems and may remain undiagnosed in the absence of a family history of CF. The prevalence of CF in the population may therefore be underestimated. We thank Ms C. Williams and Prof R. Williamson for advice and help and the Shearer Ball Appeal for generous financial support.
London SW3 6HP, UK
G. SANTIS L. OSBORNE R. KNIGHT M. E. HODSON
Molecular Genetics Department, St Mary’s Hospital Medical School, London
M. RAMSAY
Department of Cystic Fibrosis, Brompton Hospital,
1. Kerern B-S, Rommens JM, Buchanan JA, et al. Identification of the CF gene: genetic analysis. Science 1989; 245: 1073-80. 2. Corey M, Durie P, Moore D, et al. Familial concordance of pancreatic function in
Cystic Fibrosis. J Pediatr 1989; 115: 274-77.
TNF-induced cardiomyopathy SiR,—Tumour necrosis factor (TNF), now being tested in phase I and II clinical studies in cancer patients,1,2 has the following dose-dependent side-effects: fever and chills, hepatotoxicity, nausea and vomiting, tachycardia, hypertension and hypotension, and increased serum trigylcerides. These adverse effects are reversible, within 30 days of treatment ending, and chronic toxicity has not been reported. A 44-year-old man with renal cell carcinoma and spread to the lungs was given TNF postoperatively, consisting of 2 h intravenous infusions daily x 5 every 3 weeks. Seventeen courses were
Pedigree, CF allele, and linked * proband =
marker haplotypes.
adminstered. The dose was increased from 20 to 40, 80, 120,160 and 200 ug/m2 daily (this, the maximum tolerated dose, being given for the last twelve courses). Chills and fever up to 39 4°C developed within 2 hours of the start of TNF infusions. During the last five courses he had a substemal pressure and from the eleventh cycle ST-segment depression was seen on the ECG. On day 2 of the fifteenth cycle TNF was discontinued because of severe chest pain and a non-transmural myocardial infarction was diagnosed. Arteriography revealed no significant signs of coronary artery disease. Two more cycles were then administered, substemal pressure appearing whenever TNF was infused. The lung metastases have remained unchanged. The patient presented 3 months after TNF therapy had been discontinued with respiratory distress, increase in weight, severe