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EARLY DIAGNOSIS OF MUCOPOLYSACCHARIDOSIS
1300 conditions present as bloody diarrhoea, abdominal pain, and but without significant fever; and in both barium enema vomiting,10,12 features are compatible with acute ischaemic colitis and characterised by the descriptions "thumbprinting", "pseudotumour", and "transverse ridging". This suggests that HUS and haemorrhagic colitis belong in a spectrum of clinical manifestations of the same underlying disease process. The radiological thumbprinting pattern has been reproduced experimentally by reversible vascular occlusion of the colon and represents submucosal haemorrhage and oedema. Evidence that Shiga toxin acts on the bowel in this manner again comes from the work of Cavanagh et al6 who, in 1956, showed that rats injected with this toxin acquire a haemorrhagic enterocaecitis characterised by submucosal haemorrhage and oedema. We propose that verotoxin is of direct aetiological importance in the pathogenesis of both HUS and haemorrhagic colitis. For this hypothesis to be valid, it would need to be shown that the pathological picture in HUS and haemorrhagic colitis is the direct result of circulating cytotoxin. Although circulating verotoxin has not yet been demonstrated in human cases, indirect evidence from animal work suggests that "toxaemia" may be important in the pathogenesis. "Oedema disease" is a naturally occurring illness of pigs that resembles HUS and haemorrhagic colitis. 14,15 The natural disease follows enteric infection by cytotoxin-producing E coli whose serotypes are different from those of strains associated with human disease. The cytotoxin of the porcine strains has the same biological activity as verotoxin, but the relation between these toxins remains to be established.16 Natural oedema disease of pigs can be reproduced by the parenteral administration of the toxin:15 this is strong evidence for involvement of "cytotoxaemia" in this disease and suggests that the human disease may have a similar basis. Additional evidence that verotoxin has a direct role in HUS is the fact that patients mounted significant serological responses to the
toxin.2
If verotoxin is of direct pathogenic significance in HUS and haemorrhagic colitis, these diseases might be by immunisation. Almost thirty years ago Howard showed that injection of Shiga toxoid into laboratory animals gives rise to neutralising antibodies and protects them from the lethal effects of Shiga toxin. The role of pre-existing immunity in the development of verotoxin-associated HUS and haemorrhagic colitis remains to be established. However, the age distribution of the endemic variety of HUS suggests that susceptibility to this disease, as to other specific infections of childhood, is probably related to the absence of specific antibodies.
preventable
Departments of Bacteriology and Virology, Hospital for Sick Children, Toronto, Ontario, Canada M5G IXG; and Department of Microbiology, University of Toronto
M. A. KARMALI M. PETRIC C. LIM P. C. FLEMING
Department of Paediatrics, McMaster University, Hamilton, Ontario
B. T. STEELE
EARLY DIAGNOSIS OF MUCOPOLYSACCHARIDOSIS marrow transplantation is to be offered as a for mucopolysaccharidosis, as we believe it should, early referral before mental deterioration has gone too far, is important. No child with Hurler’s disease who has had a successful bone marrow transplant has subsequently shown any further mental deterioration. Our first patient, treated in June, 1980, aged 11I
SIR,-If bone
treatment
12. Peterson RB, Meseroll WP, Shrago GG, Gooding CA. Radiographic features of colitis associated with the hemolytic-uremic syndrome. Radiol 1976; 118: 667-71. 13. Schwartz S, Boley S, Lash J, Sternhill V. Roentgenologic aspects of reversible vascular occlusion of the colon, and its relationship to ulcerative colitis. Radiol 1963; 80: 625-35. 14. Timoney JF. Oedema disease of swine. Irish Vet J 1950; 62: 748-55. 15. Clugston RE, Nielsen NO, Smith DLT. Experimental edema disease of swine (E coli enterotoxemia) III: Pathology and pathogenesis. Can J Comp Med 1974; 38: 34-43. 16. Dobrescu L. New biological effect of edema disease principle (Escherichia colineurotoxin) and its use as an in-vitro assay for this toxin. Am J Vet Res 1983; 44: 31-34. 17. Howard JG. Observations on the intoxication produced in mice and rabbits by the neurotoxm of Shigella shigae. Br J Exp Pathol 1955; 36: 439-46.
months,
nearly 41/z years old. He has, if anything, progressed according to Griffith’s developmental assessments. The same applies to the next two cases who have now been followed-up is
now
for 21f2 and 21/4 years. In four cases the mother noticed the lumbar gibbus within the first few months of life but the significance of this was not appreciated by the doctors to whom she pointed it out. Most of these children had been operated on for inguinal or umbilical hernias by the age of 6 months. Surely the need for surgery is unusual in cases of simple umbilical hernia. The other important alternative diagnosis (hypothroidism) will in many centres now be excluded by neonatal
screening. INCIDENCE OF HERNIAS BY AGE SIX MONTHS IN CHILDREN WITH MUCOPOLYSACCHARIDOSIS
*I=Hurler, ll=Hunter; III=Sanfilippo; IV=Morquio.
The accompanying table shows the very high incidence of hernias before the age of 6 months in cases of mucopolysaccharidosis associated with mental deterioration, except for Sanfilippo’s disease. May I ask paediatricians and community doctors screening young babies, and surgeons who repair hernias in children, to exclude the rare but now treatable disease of mucopolysaccharidosis. A lateral X-ray of the lumbar spine will almost certainly be diagnostic in Hurler’s and Hunter’s disease (but not in Sanfilippo’s). Testing a random urine for glycosaminoglycan: creatinine ratio will always exclude these diagnoses. This test, which is not expensive and can be done in regional centres, is essential because the hepatosplenomegaly of mucopolysaccharidosis is not necessarily obvious at the time that the baby has its hernia. Bone Marrow Transplant Unit, Westminster Children’s Hospital, London SW1P 2NS
KENNETH HUGH-JONES
PENTAMIDINE OR CO-TRIMOXAZOLE FOR PNEUMOCYSTIS CARINII PNEUMONIA
1109) describe diffuse erythematous maculopapular eruptions eight of eighteen homosexual men with acquired immunodeficiency syndrome (AIDS) treated with co-trimoxazole (trimethoprim/sulfamethoxazole, TMP/SMZ). They suggest that this type of adverse reaction is immunologically mediated and that pentamidine rather than TMP/SMZ be considered for the initial therapy of Pneumocystis carinii pneumonia (PCP) in this grouup of patients. Until their randomised trial of pentamidine against TMP/SMZ is complete we would caution against this suggested replacement. A 26-year-old homosexual man with a 3-month history of fever, cough, and weight loss was admitted to hospital. His haemoglobin was 11-2 2 g/dl, the white blood cell count 6000/1 and the platelet count 114 OOOIIAI. Chest X-ray was normal. Bronchoscopy revealed PCP, and oral co-trimoxazole was started (TMP 20 and SMZ 100 mg/kg daily). After 9 days of therapy, during which the patient was afebrile and almost free of symptoms, a diffuse, itchy, maculopapular eruption developed. His haemoglobin was 10-66 g/dl, the white cell count 2600/1, and the platelet count 135 000/(1. TMP/SMZ was discontinued for 2 days after which the rash had almost disappeared. Since we were reluctant to start pentamidine therapy the patient was rechallenged with one double-strength SiR.—Dr Jaffe and colleagues (Nov 12,
p
in
no reaction occurred. The white blood cell returned to normal and the haemoglobin and platelet count remained as before. 4 months after this rechallenge the patient is
tablet of TMP/SMZ; count
JR, et al Reversal of clinical features of Hurler’s disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet 1981; ii:
1. Hobbs
709-12.
toxin.2
If verotoxin is of direct pathogenic significance in HUS and haemorrhagic colitis, these diseases might be by immunisation. Almost thirty years ago Howard showed that injection of Shiga toxoid into laboratory animals gives rise to neutralising antibodies and protects them from the lethal effects of Shiga toxin. The role of pre-existing immunity in the development of verotoxin-associated HUS and haemorrhagic colitis remains to be established. However, the age distribution of the endemic variety of HUS suggests that susceptibility to this disease, as to other specific infections of childhood, is probably related to the absence of specific antibodies.
preventable
Departments of Bacteriology and Virology, Hospital for Sick Children, Toronto, Ontario, Canada M5G IXG; and Department of Microbiology, University of Toronto
M. A. KARMALI M. PETRIC C. LIM P. C. FLEMING
Department of Paediatrics, McMaster University, Hamilton, Ontario
B. T. STEELE
EARLY DIAGNOSIS OF MUCOPOLYSACCHARIDOSIS marrow transplantation is to be offered as a for mucopolysaccharidosis, as we believe it should, early referral before mental deterioration has gone too far, is important. No child with Hurler’s disease who has had a successful bone marrow transplant has subsequently shown any further mental deterioration. Our first patient, treated in June, 1980, aged 11I
SIR,-If bone
treatment
12. Peterson RB, Meseroll WP, Shrago GG, Gooding CA. Radiographic features of colitis associated with the hemolytic-uremic syndrome. Radiol 1976; 118: 667-71. 13. Schwartz S, Boley S, Lash J, Sternhill V. Roentgenologic aspects of reversible vascular occlusion of the colon, and its relationship to ulcerative colitis. Radiol 1963; 80: 625-35. 14. Timoney JF. Oedema disease of swine. Irish Vet J 1950; 62: 748-55. 15. Clugston RE, Nielsen NO, Smith DLT. Experimental edema disease of swine (E coli enterotoxemia) III: Pathology and pathogenesis. Can J Comp Med 1974; 38: 34-43. 16. Dobrescu L. New biological effect of edema disease principle (Escherichia colineurotoxin) and its use as an in-vitro assay for this toxin. Am J Vet Res 1983; 44: 31-34. 17. Howard JG. Observations on the intoxication produced in mice and rabbits by the neurotoxm of Shigella shigae. Br J Exp Pathol 1955; 36: 439-46.
months,
nearly 41/z years old. He has, if anything, progressed according to Griffith’s developmental assessments. The same applies to the next two cases who have now been followed-up is
now
for 21f2 and 21/4 years. In four cases the mother noticed the lumbar gibbus within the first few months of life but the significance of this was not appreciated by the doctors to whom she pointed it out. Most of these children had been operated on for inguinal or umbilical hernias by the age of 6 months. Surely the need for surgery is unusual in cases of simple umbilical hernia. The other important alternative diagnosis (hypothroidism) will in many centres now be excluded by neonatal
screening. INCIDENCE OF HERNIAS BY AGE SIX MONTHS IN CHILDREN WITH MUCOPOLYSACCHARIDOSIS
*I=Hurler, ll=Hunter; III=Sanfilippo; IV=Morquio.
The accompanying table shows the very high incidence of hernias before the age of 6 months in cases of mucopolysaccharidosis associated with mental deterioration, except for Sanfilippo’s disease. May I ask paediatricians and community doctors screening young babies, and surgeons who repair hernias in children, to exclude the rare but now treatable disease of mucopolysaccharidosis. A lateral X-ray of the lumbar spine will almost certainly be diagnostic in Hurler’s and Hunter’s disease (but not in Sanfilippo’s). Testing a random urine for glycosaminoglycan: creatinine ratio will always exclude these diagnoses. This test, which is not expensive and can be done in regional centres, is essential because the hepatosplenomegaly of mucopolysaccharidosis is not necessarily obvious at the time that the baby has its hernia. Bone Marrow Transplant Unit, Westminster Children’s Hospital, London SW1P 2NS
KENNETH HUGH-JONES
PENTAMIDINE OR CO-TRIMOXAZOLE FOR PNEUMOCYSTIS CARINII PNEUMONIA
1109) describe diffuse erythematous maculopapular eruptions eight of eighteen homosexual men with acquired immunodeficiency syndrome (AIDS) treated with co-trimoxazole (trimethoprim/sulfamethoxazole, TMP/SMZ). They suggest that this type of adverse reaction is immunologically mediated and that pentamidine rather than TMP/SMZ be considered for the initial therapy of Pneumocystis carinii pneumonia (PCP) in this grouup of patients. Until their randomised trial of pentamidine against TMP/SMZ is complete we would caution against this suggested replacement. A 26-year-old homosexual man with a 3-month history of fever, cough, and weight loss was admitted to hospital. His haemoglobin was 11-2 2 g/dl, the white blood cell count 6000/1 and the platelet count 114 OOOIIAI. Chest X-ray was normal. Bronchoscopy revealed PCP, and oral co-trimoxazole was started (TMP 20 and SMZ 100 mg/kg daily). After 9 days of therapy, during which the patient was afebrile and almost free of symptoms, a diffuse, itchy, maculopapular eruption developed. His haemoglobin was 10-66 g/dl, the white cell count 2600/1, and the platelet count 135 000/(1. TMP/SMZ was discontinued for 2 days after which the rash had almost disappeared. Since we were reluctant to start pentamidine therapy the patient was rechallenged with one double-strength SiR.—Dr Jaffe and colleagues (Nov 12,
p
in
no reaction occurred. The white blood cell returned to normal and the haemoglobin and platelet count remained as before. 4 months after this rechallenge the patient is
tablet of TMP/SMZ; count
JR, et al Reversal of clinical features of Hurler’s disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet 1981; ii:
1. Hobbs
709-12.