1137 BONE-MARROW TRANSPLANTATION IN OSTEOPETROSIS
SIR,-There is
no
satisfactory
treatment
for
osteopetrosis.
However, in animal models bone resorption has been restored
by temporary parabiosisl.2 and after bone-marrow transplantation in irrad iated gl/gl or mi/mi mice3 and, without preparation, in syngeneic Op/Op rats.4
the bone and haematological abnormalities of this disease by bone-marrow transplantation in an infant girl. The patient was born from Saudi Arabian related parents (common grandfather) after a normal pregnancy and the mother was not known to have taken osteocondensing agents. No other case was recorded in the family; bone X-rays are normal in the parents and the patient’s sister. The disease was diagnosed when she was 2t months old. Severe ocular and haematological symptoms were present-namely, strabismus, random searching eye movement, pale optic discs and enlarged liver, spleen, and glands with anaemia, myelocytosis, erythroblastosis, and profound thrombocytopenia. X-rays revealed a generalised increased bone density and no medullary cavities We have tried
to correct
1. Walker, D. G. Science, 1973, 180, 875. 2. Toyama, K., Moutier, R., Lamendin, H. C.r. Acad. Sci. Paris D, 1974, 278, 115. 3. Walker, D. G. Science, 1975, 190, 784. 4. Milhaud, G., Labat, M. L., Graf, B., Juster, M., Balmain, N., Moutier, R., Toyama, K. C.r. Acad. Sci. Paris, 1975, 280, 2485.
(see figure A). A hyperchloraemic metabolic acidosis consistent with a distal renal tubular defect was also detected. Plasma-calcium (8-5mg/dl) and daily urinary calcium output (5 mg) were low. Calcium kinetic data were typical for osteopetrosis: bone accretion (300 mg/day) and resorption (0 mg/day) were very low and her calcium balance (+300 mg/day) and intestinal absorption rate (53%) were increased.
Plasma-alkaline-phosphatase activity was enhanced (1050 mU/ml, normal 150-550). Serum-immunoglobulins were normal, as were proliferative responses to lectins and allogeneic cells in vitro. A skin test with phytohaemagglutinin was positive. When she was 3 months old the patient, with no previous therapy apart from three blood-transfusions, was given intravenously 2-25xlO9 marrow nucleated cells from her 2-year-old sister, who
was identical for HLA A, B, and D determinants and for all erythrocytic antigens and immunoglobulin allotypes tested. The patient improved, and the improvement is still present 18 months later. 2 weeks after transplantation, immature nucleated cells disappeared from peripheral blood and Hb levels remained around 11-12 g/dl without further transfusion. 2 months after the transplantation, reticulocyte and thrombocyte counts were normal and the hepatosplenomegaly had disappeared. X-rays revealed progressive modifications of bone, mainly the appearance of medullary cavities with distinct cortex and marrow space (see figure, B). Metaphyseal transverse dense bands became visible. The base of the cranium remained dense. The plasma-calcium (9-0 mg/dl) increased. Calcium kinetics indicated a raised bone-accretion rate (594 mg/day) and a higher calcium balance than normal (+594 mg/day); the slowly exchangeable compartment of the calcium pool had fallen from 1100 mg to 430 mg), a finding which can be interpreted as a calcium transfer from the abnormal calcium deposits in the marrow cavity to cortical bone. Plasma alkaline phosphatase activity decreased to 680 mU/ml. Optic atrophy persisted despite an attempt at neurosurgical decompression at 7 months of age. The patient’s renal condition remained unchanged. Her growth and development have progressed but she is still more than 2 S.D. below normal on a growth curve. No evidence of the survival of transplanted cells in the recipient was available, even though their persistence can be anticipated according to the observation made in the Op/Op rat.-I Animal osteopetrosis is genetically heterogeneous and this explains why some mutations are cured by cell transplantation or thymus grafting6 and others are not. Human osteopetrosis is also likely to be genetically heterogeneous; all patients may not respond to bone-marrow but this procedure should be considered because the disease carries a poor prognosis and there is no treatment. .
Groupe de Recherches d’Immunologie et de Rhumatologie Pédiatriques, INSERM U132, Hôpital des Enfants Malades,
J. J. BALLET
75015 Paris, France
C. GRISCELLI
Groupe de Recherches sur l’ Etude des Regulations Hormonales du Métabolisme Phosphocalcique, INSERM U113
C. COUTRIS G. MILHAUD
Unité de Recherches de Génétique Médicale, INSERM U12
P. MAROTEAUX
ATRIAL MYXOMA WITH A PATENT FORAMEN OVALE an
StR,—The diagnosis of atrial myxoma is often difficult. It is unusual cause of stroke in adults, with portions of the myx-
embolising to the brain. I report here a case of proven right atrial myxoma with paradoxical peripheral emboli through a patent foramen ovale.
oma
Milhaud, G., Labat, M. L., Viegas-Pequignot, E., Dutrillaux, B., Moutier, R., Toyama, K. ibid. D, 1975, 281, 1929. 6. Milhaud, G., Labat, M. L., Graf, B., Thillard, J. J. ibid. D, 1976, 283, 531. 5.
1138
The patient, a 63-year-old man, had had atrial fibrillation and progressive congestive heart-failure for 12 years. From 1968 to 1973 he had 4 separate episodes of right or left transient hemiparesis with residual right hemiparesis. He was admitted finally with progressive right heart failure, hepatomegaly and lower extremity lymphoedema. Repeated physical examinations revealed no extracranial vascular disease, but angiography was not done. Only during his final admissions was a mild systolic murmur noted along the left sternal border, apex, and aorta. Neurological findings were unchanged. Routine laboratory tests showed no significant abnormalities except that erythrocyte sedimentation rates ranged from 22 to 40 mm/h. Chest X-ray showed cardiomegaly. An electrocardiogram revealed an old inferior myocardial infarction and atrial fibrillation. Echocardiogram was normal. Diagnosis was finally made by cineangiogram. The right atrial mycoma was removed but the patient died 1 year later due to tricuspid insufficiency and complications of heart surgery. At necropsy, an 8 mm patent foramen ovale of the heart without mural thrombi of the atria or ventricles was found. Old infarctions of the right insular cortex and left frontal cortex were noted without evidence of myxoma in cerebral vessels. There were old bilateral renal infarctions but no pulmonary infarctions and only slight atherosclerosis of the aorta, coronary vessels and cerebral vessels. This case shows that right atrial myxoma can cause peripheral emboli. This diagnosis should thus not be dismissed
when there are unexplained systemic symptoms and stroke syndrome as noted by Duvernoy.’ When atrial myxoma is suspected echocardiography should be done with scanning of the right atrium and tricuspid valve after examination of the left heart. Selected cases may require cineangiography. The clinical features include the signs of right heart failure,2 severe cyanosis and clubbing,3,4 and polycytheemia.1 Ashman et al.5 noted an early, transient pitting oedema of the forehead, while Yufe et a1.6 emphasise the difficulty of diagnosis for the neurologist. National Institutes of Health, Bethesda, Maryland 20014, U.S.A.
ROBERT N. NISHIMURA
COMMON FAMILIAL COMPONENT IN LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE
SIR,-Professor Cohen and her colleagues (Sept. 10, p. 523) report pulmonary-function studies done on first-degree relatives of patients with lung cancer and chronic obstructive pulmonary disease. They found a familial predisposing factor to both diseases. They state that such a component has not been previously reported. In the Scandinavian Journal of Respiratory Diseases (1966, 47, 161) we reported a strongly positive correlation between C.N.S.L.D. (chronic non-specific lung disease) and lung cancer, not dependent solely on smoking. The incidence of C.N.S.L.D. in the childhood of lung-cancer patients and in their family history was very significantly higher than in two neighbourhood control groups matched for sex and age or for sex, age, and cigarette smoking. We consider C.N.S.L.D. to be an independent constitutionbased disease.’ In view of the link between C.N.S.L.D. and lung E.
Duvernoy,
W. F.
independent
Pulmonary Department, University Hospital, Groningen, Netherlands
N. G. M. ORIE H. J. SLUITER A. M. V. D. WAL
TRIMETHOPRIM-RESISTANT SALMONELLA
SIR,-Dr Marks and his colleagues from Bristol (Oct. 8. p. 774) and Professor Brumfitt and his colleagues in London (Oct. 29, p. 926) report chrorriosomally mediated trimethoprim resistance in enterobacteria. We have observed a prolonged outbreak of Salmonella heidelberg infection in Jamaica, in which the epidemic strain appeared to develop non-transferable trimethoprim resistance in vivo. In November, 1972, a baby was admitted to the University Hospital of the West Indies from the Bahamas. He was excreting a strain of S. heidelberg never previously isolated in Jamaica, which was resistant to sulphonamide and six other antibiotics, and partially resistant to trimethoprim (minimum inhibitory concentration [M.I.C.] 2.5 mg/1). This organism was further characterised by delayed dulcitol fermentation, but was otherwise biochemically normal. A prolonged outbreak of hospital infection ensued which later spread into the community : 68 cases were identified, including 5 septicaemias, and 4 patients died. In November, 1973, a strain of S. heidelberg was isolated which was identical in every way to the epidemic strain except that it was fully resistant to trimethoprim (M.LC. 50 mg/1). All isolates of the epidemic strain identified in Jamaica from March, 1975, to December, 1976, have shown this level of resistance to trimethoprim. There have been 23 bacteriologically-confirmed infections with the resistant strain, including 3 patients with septicxmia (1 of whom had meningitis) and 2 deaths. Resistance transfer could not be demonstrated, but the original partially resistant strains (M.l.c. 2.5 mg/1) were readily trained to full resistance (M.l.c. > 1000 mg/1) by exposureto increasing concentrations of trimethoprim in vitro.1.2 It is probable that all these isolates of S. heidelberg were derived from the index case which was imported from the Bahamas. The twenty-fold increase in M.l.c. of trimethoprim that developed 12 months after the introduction of the epidemic strain into the island, seems to have been chromosomally mediated and may have resulted from exposure to trimethoprim in the environment. 70 000 tablets of co-trimoxazole were dispensed at the University Hospital in 1972, and this had risen to 127 000 in 1976.
Sulphonamide-resistant organisms are readily trained to trimethoprim resistance in vitro,1.2 and in these organisms the combination of trimethoprim and sulphamethoxazole may not oe synergistic and may not protect against the emergence of trimethoprim resistance.3.4 However, trimethoprim resistance in enterobacteria other than S. heidelberg remains uncommon in Jamaica, despite widespread sulphonamide resistance.5.6 Departments of Microbiology and Child Health, University of the West Indies, Mona, Kingston 7, Jamaica * Present address: SE1 7EH.
G. L. FRENCH* M. F. LOWRY
Department of Microbiology, St Thomas’ Hospital, London
M.
C., Drake, H., Reddy, S., Karo, J. J. Cardiology, 1975, 60, 206. 2. Harvey, W. P. Am. J. Cardiol. 1968, 30, 328. 3. Goldschlager, A., Popper, R., Goldschlager, N., Gerbode, F., Prozan, G. ibid. 1972, 30, 82. 4. Talley, R. C., Baldwin, B. J., Symbas, P. N., Nutter, D. O. Am. J. Med. 1970, 48, 256. 5. Ashman, N., Zaroff, L. I., Baronofsky, I. ibid. 1960, 28, 487. 6. Yufe, R., Karpati, G., Carpenter, S, Neurology, 1976, 26, 1060. 7. One, N. G. M. Bronchitis; vol. I, p. 43. Assen, 1961. 1.
of smoking, we suggested at that time a factor for lung cancer against a background of genetic C.N.S.L.D., apart from exogenous factors such as smoking. cancer,
1. 2. 3. 4.
Bushby, S. R. Postgrad. med. J. 1969, 45, suppl. no. 10. Darrell, J. H., Garrod, L. P., Waterworth, P. M. J. clin. Path. 1968, 21, 202. O’Grady, F. Can. med. Ass. J.1975, 112, 55 Lacey, R. W., Anderson, J. D., Lewis, E. L., Gillespie, W. A. Lancet, 1973,
5.
ii, 202. French, G. L., King, S. D., Ramachander, N. West, Ind. med. J. 1976, 25,
6.
French, G. L., King, S. D., St. Louis, P. J. Hyg., Camb. 1977, 79, 5.
226.
SIR,-There is
no
satisfactory
treatment
for
osteopetrosis.
However, in animal models bone resorption has been restored
by temporary parabiosisl.2 and after bone-marrow transplantation in irrad iated gl/gl or mi/mi mice3 and, without preparation, in syngeneic Op/Op rats.4
the bone and haematological abnormalities of this disease by bone-marrow transplantation in an infant girl. The patient was born from Saudi Arabian related parents (common grandfather) after a normal pregnancy and the mother was not known to have taken osteocondensing agents. No other case was recorded in the family; bone X-rays are normal in the parents and the patient’s sister. The disease was diagnosed when she was 2t months old. Severe ocular and haematological symptoms were present-namely, strabismus, random searching eye movement, pale optic discs and enlarged liver, spleen, and glands with anaemia, myelocytosis, erythroblastosis, and profound thrombocytopenia. X-rays revealed a generalised increased bone density and no medullary cavities We have tried
to correct
1. Walker, D. G. Science, 1973, 180, 875. 2. Toyama, K., Moutier, R., Lamendin, H. C.r. Acad. Sci. Paris D, 1974, 278, 115. 3. Walker, D. G. Science, 1975, 190, 784. 4. Milhaud, G., Labat, M. L., Graf, B., Juster, M., Balmain, N., Moutier, R., Toyama, K. C.r. Acad. Sci. Paris, 1975, 280, 2485.
(see figure A). A hyperchloraemic metabolic acidosis consistent with a distal renal tubular defect was also detected. Plasma-calcium (8-5mg/dl) and daily urinary calcium output (5 mg) were low. Calcium kinetic data were typical for osteopetrosis: bone accretion (300 mg/day) and resorption (0 mg/day) were very low and her calcium balance (+300 mg/day) and intestinal absorption rate (53%) were increased.
Plasma-alkaline-phosphatase activity was enhanced (1050 mU/ml, normal 150-550). Serum-immunoglobulins were normal, as were proliferative responses to lectins and allogeneic cells in vitro. A skin test with phytohaemagglutinin was positive. When she was 3 months old the patient, with no previous therapy apart from three blood-transfusions, was given intravenously 2-25xlO9 marrow nucleated cells from her 2-year-old sister, who
was identical for HLA A, B, and D determinants and for all erythrocytic antigens and immunoglobulin allotypes tested. The patient improved, and the improvement is still present 18 months later. 2 weeks after transplantation, immature nucleated cells disappeared from peripheral blood and Hb levels remained around 11-12 g/dl without further transfusion. 2 months after the transplantation, reticulocyte and thrombocyte counts were normal and the hepatosplenomegaly had disappeared. X-rays revealed progressive modifications of bone, mainly the appearance of medullary cavities with distinct cortex and marrow space (see figure, B). Metaphyseal transverse dense bands became visible. The base of the cranium remained dense. The plasma-calcium (9-0 mg/dl) increased. Calcium kinetics indicated a raised bone-accretion rate (594 mg/day) and a higher calcium balance than normal (+594 mg/day); the slowly exchangeable compartment of the calcium pool had fallen from 1100 mg to 430 mg), a finding which can be interpreted as a calcium transfer from the abnormal calcium deposits in the marrow cavity to cortical bone. Plasma alkaline phosphatase activity decreased to 680 mU/ml. Optic atrophy persisted despite an attempt at neurosurgical decompression at 7 months of age. The patient’s renal condition remained unchanged. Her growth and development have progressed but she is still more than 2 S.D. below normal on a growth curve. No evidence of the survival of transplanted cells in the recipient was available, even though their persistence can be anticipated according to the observation made in the Op/Op rat.-I Animal osteopetrosis is genetically heterogeneous and this explains why some mutations are cured by cell transplantation or thymus grafting6 and others are not. Human osteopetrosis is also likely to be genetically heterogeneous; all patients may not respond to bone-marrow but this procedure should be considered because the disease carries a poor prognosis and there is no treatment. .
Groupe de Recherches d’Immunologie et de Rhumatologie Pédiatriques, INSERM U132, Hôpital des Enfants Malades,
J. J. BALLET
75015 Paris, France
C. GRISCELLI
Groupe de Recherches sur l’ Etude des Regulations Hormonales du Métabolisme Phosphocalcique, INSERM U113
C. COUTRIS G. MILHAUD
Unité de Recherches de Génétique Médicale, INSERM U12
P. MAROTEAUX
ATRIAL MYXOMA WITH A PATENT FORAMEN OVALE an
StR,—The diagnosis of atrial myxoma is often difficult. It is unusual cause of stroke in adults, with portions of the myx-
embolising to the brain. I report here a case of proven right atrial myxoma with paradoxical peripheral emboli through a patent foramen ovale.
oma
Milhaud, G., Labat, M. L., Viegas-Pequignot, E., Dutrillaux, B., Moutier, R., Toyama, K. ibid. D, 1975, 281, 1929. 6. Milhaud, G., Labat, M. L., Graf, B., Thillard, J. J. ibid. D, 1976, 283, 531. 5.
1138
The patient, a 63-year-old man, had had atrial fibrillation and progressive congestive heart-failure for 12 years. From 1968 to 1973 he had 4 separate episodes of right or left transient hemiparesis with residual right hemiparesis. He was admitted finally with progressive right heart failure, hepatomegaly and lower extremity lymphoedema. Repeated physical examinations revealed no extracranial vascular disease, but angiography was not done. Only during his final admissions was a mild systolic murmur noted along the left sternal border, apex, and aorta. Neurological findings were unchanged. Routine laboratory tests showed no significant abnormalities except that erythrocyte sedimentation rates ranged from 22 to 40 mm/h. Chest X-ray showed cardiomegaly. An electrocardiogram revealed an old inferior myocardial infarction and atrial fibrillation. Echocardiogram was normal. Diagnosis was finally made by cineangiogram. The right atrial mycoma was removed but the patient died 1 year later due to tricuspid insufficiency and complications of heart surgery. At necropsy, an 8 mm patent foramen ovale of the heart without mural thrombi of the atria or ventricles was found. Old infarctions of the right insular cortex and left frontal cortex were noted without evidence of myxoma in cerebral vessels. There were old bilateral renal infarctions but no pulmonary infarctions and only slight atherosclerosis of the aorta, coronary vessels and cerebral vessels. This case shows that right atrial myxoma can cause peripheral emboli. This diagnosis should thus not be dismissed
when there are unexplained systemic symptoms and stroke syndrome as noted by Duvernoy.’ When atrial myxoma is suspected echocardiography should be done with scanning of the right atrium and tricuspid valve after examination of the left heart. Selected cases may require cineangiography. The clinical features include the signs of right heart failure,2 severe cyanosis and clubbing,3,4 and polycytheemia.1 Ashman et al.5 noted an early, transient pitting oedema of the forehead, while Yufe et a1.6 emphasise the difficulty of diagnosis for the neurologist. National Institutes of Health, Bethesda, Maryland 20014, U.S.A.
ROBERT N. NISHIMURA
COMMON FAMILIAL COMPONENT IN LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE
SIR,-Professor Cohen and her colleagues (Sept. 10, p. 523) report pulmonary-function studies done on first-degree relatives of patients with lung cancer and chronic obstructive pulmonary disease. They found a familial predisposing factor to both diseases. They state that such a component has not been previously reported. In the Scandinavian Journal of Respiratory Diseases (1966, 47, 161) we reported a strongly positive correlation between C.N.S.L.D. (chronic non-specific lung disease) and lung cancer, not dependent solely on smoking. The incidence of C.N.S.L.D. in the childhood of lung-cancer patients and in their family history was very significantly higher than in two neighbourhood control groups matched for sex and age or for sex, age, and cigarette smoking. We consider C.N.S.L.D. to be an independent constitutionbased disease.’ In view of the link between C.N.S.L.D. and lung E.
Duvernoy,
W. F.
independent
Pulmonary Department, University Hospital, Groningen, Netherlands
N. G. M. ORIE H. J. SLUITER A. M. V. D. WAL
TRIMETHOPRIM-RESISTANT SALMONELLA
SIR,-Dr Marks and his colleagues from Bristol (Oct. 8. p. 774) and Professor Brumfitt and his colleagues in London (Oct. 29, p. 926) report chrorriosomally mediated trimethoprim resistance in enterobacteria. We have observed a prolonged outbreak of Salmonella heidelberg infection in Jamaica, in which the epidemic strain appeared to develop non-transferable trimethoprim resistance in vivo. In November, 1972, a baby was admitted to the University Hospital of the West Indies from the Bahamas. He was excreting a strain of S. heidelberg never previously isolated in Jamaica, which was resistant to sulphonamide and six other antibiotics, and partially resistant to trimethoprim (minimum inhibitory concentration [M.I.C.] 2.5 mg/1). This organism was further characterised by delayed dulcitol fermentation, but was otherwise biochemically normal. A prolonged outbreak of hospital infection ensued which later spread into the community : 68 cases were identified, including 5 septicaemias, and 4 patients died. In November, 1973, a strain of S. heidelberg was isolated which was identical in every way to the epidemic strain except that it was fully resistant to trimethoprim (M.LC. 50 mg/1). All isolates of the epidemic strain identified in Jamaica from March, 1975, to December, 1976, have shown this level of resistance to trimethoprim. There have been 23 bacteriologically-confirmed infections with the resistant strain, including 3 patients with septicxmia (1 of whom had meningitis) and 2 deaths. Resistance transfer could not be demonstrated, but the original partially resistant strains (M.l.c. 2.5 mg/1) were readily trained to full resistance (M.l.c. > 1000 mg/1) by exposureto increasing concentrations of trimethoprim in vitro.1.2 It is probable that all these isolates of S. heidelberg were derived from the index case which was imported from the Bahamas. The twenty-fold increase in M.l.c. of trimethoprim that developed 12 months after the introduction of the epidemic strain into the island, seems to have been chromosomally mediated and may have resulted from exposure to trimethoprim in the environment. 70 000 tablets of co-trimoxazole were dispensed at the University Hospital in 1972, and this had risen to 127 000 in 1976.
Sulphonamide-resistant organisms are readily trained to trimethoprim resistance in vitro,1.2 and in these organisms the combination of trimethoprim and sulphamethoxazole may not oe synergistic and may not protect against the emergence of trimethoprim resistance.3.4 However, trimethoprim resistance in enterobacteria other than S. heidelberg remains uncommon in Jamaica, despite widespread sulphonamide resistance.5.6 Departments of Microbiology and Child Health, University of the West Indies, Mona, Kingston 7, Jamaica * Present address: SE1 7EH.
G. L. FRENCH* M. F. LOWRY
Department of Microbiology, St Thomas’ Hospital, London
M.
C., Drake, H., Reddy, S., Karo, J. J. Cardiology, 1975, 60, 206. 2. Harvey, W. P. Am. J. Cardiol. 1968, 30, 328. 3. Goldschlager, A., Popper, R., Goldschlager, N., Gerbode, F., Prozan, G. ibid. 1972, 30, 82. 4. Talley, R. C., Baldwin, B. J., Symbas, P. N., Nutter, D. O. Am. J. Med. 1970, 48, 256. 5. Ashman, N., Zaroff, L. I., Baronofsky, I. ibid. 1960, 28, 487. 6. Yufe, R., Karpati, G., Carpenter, S, Neurology, 1976, 26, 1060. 7. One, N. G. M. Bronchitis; vol. I, p. 43. Assen, 1961. 1.
of smoking, we suggested at that time a factor for lung cancer against a background of genetic C.N.S.L.D., apart from exogenous factors such as smoking. cancer,
1. 2. 3. 4.
Bushby, S. R. Postgrad. med. J. 1969, 45, suppl. no. 10. Darrell, J. H., Garrod, L. P., Waterworth, P. M. J. clin. Path. 1968, 21, 202. O’Grady, F. Can. med. Ass. J.1975, 112, 55 Lacey, R. W., Anderson, J. D., Lewis, E. L., Gillespie, W. A. Lancet, 1973,
5.
ii, 202. French, G. L., King, S. D., Ramachander, N. West, Ind. med. J. 1976, 25,
6.
French, G. L., King, S. D., St. Louis, P. J. Hyg., Camb. 1977, 79, 5.
226.
