Sialic acid storage 315

Sialic acid concentrations in urine and cultured fibroblasts free sialic acid in cells and urine. The infant reported here displayed all these features, and Patient Controls respiratory she also showed a more pronounced Arch Dis Child: first published as 10.1136/adc.65.3.315 on 1 March 1990. Downloaded from Mean Range impairment. Cardiac failure was also pro- Urine (iLmol/mmol minent, suggesting either a storage disorder of creatinine) Free 994 93, 78 the myocardium, or a response to the respira- Bound 109 71, 52 tory problems. The presence of multiple wide- Fibroblasts (nmol/mg spread telangiectasias, presumably related to protein) liver disease, is also a new finding. Free 25 2-6 1-5-67 (n=9) The exact role of sialic acid in cellular func- Bound 17 8-6 6-5-10-7 (n=5) tion is unclear, but it is known to be an impor- Sialic acid concentrations were measured by the thiobarbituric tant constituent of many glycolipids and glyco- acid method4 before and after hydrolysis. proteins. It has been suggested that the under- lying defect is impaired transport of free sialic mus and a pale retina. Blood smears showed acid across the lysosomal membranes, but the vacuolated lymphocytes, monocytes, and neu- precise defect has yet to be identified.5 Ante- trophils. A bone marrow specimen also showed natal diagnosis is available by assaying free sialic vacuolated cells and an excess of eosinophils. acid in amniotic fluid or by chorionic villus The free sialic acid concentration of cultured biopsy.6 Severe infantile sialic acid storage fibroblasts and urine was raised (table), and a disease should be considered in a child present- diagnosis of severe infantile sialic acid storage ing with coarse facial features, growth and disease was made. developmental delay, hepatosplenomegaly, and Subsequent clinical progress was poor. She evidence of abnormal storage in cells. remained extremely hypotonic and was socially unresponsive. Oxygen requirement persisted, We are grateful to Dr AW Boon for allowing us to report his and she eventually died with bronchopneu- patient. monia at 13 months. Permission for necropsy was refused. I Lowden JA, O'Brien JS. Sialidosis: a review ofhuman neura- minidase deficiency. Am J Hum Genet 1979;31:1-18. 2 Aula P, Autio S, Raivio KO, et al. Salla disease - a new lyso- somal storage disorder. Arch Neurol 1979;36:88-94. Discussion 3 Wilcken B, Don N, Greenaway R, et al. Sialuria: a second Stevenson et al described two unrelated cases of case. J Inherited Metab Dis 1987;10:97-102. 4 Stevenson RE, Lubinsky M, Taylor HA, et al. Sialic acid severe infantile sialic acid storage disease and storage disease with sialuria: clinical and biochemical fea- reviewed five other cases in 1983.4 The main tures in the severe infantile type. 1983;72:441-9. 5 Renlund M, Kovanen PT, Raivio KO, et al. Studies on the features he identified were coarse facies, growth defect underlying the lysosomal storage of sialic acid in delay, appreciable mental retardation, hepato- Salla disease. J Clin Invest 1986;77:568-74. 6 Lake BD, Young EP, Nicholaides K. Prenatal diagnosis of splenomegaly, recurrent pneumonias, and in infantile sialic acid storage disease in a twin pregnancy. five, evidence of lysosomal storage with raised J Inherited Metab Dis 1989;12:152-6. http://adc.bmj.com/

Acute liver failure induced by carbamazepine

N Hadzic, B Portmann, E T Davies, A P Mowat, G Mieli-Vergani on September 30, 2021 by guest. Protected copyright.

Abstract but in only one of these was carbamazepine the Two children developed acute liver failure sole hepatotoxin. We describe two children while taking carbamazepine. Clinical and receiving carbamazepine who developed life laboratory findings suggested an immunoal- threatening liver disease. lergic reaction, but only one child improved King's College School of and on steroids. Determination of liver function , London during the first few weeks of treatment and Case reports Department of early detection of signs of idiosyncrasy may CASE 1 N Hadzic prevent this rare but severe complication. A girl aged 11 6 years developed a severe E T Davies maculopapular rash, intermittent fever, arthral- Liver Unit gia, cough, anaemia, anorexia, diarrhoea, and B Portmann Since 1970, 14-5 million adults and children vomiting four weeks after starting carbamaze- Department of are estimated to have taken carbamazepine. pine (16 mg/kgl24 hours) for focal epilepsy. Her Child Health Unwanted effects mainly or exclusively affect- medical history was negative. Carbamazepine A P Mowat ing the liver have been reported in 499 in- was stopped, the blood concentration being 32 G Mieli-Vergani stances, but often other causes of liver damage 16-50 Two Correspondence to: imol/l (therapeutic range: ,tmol/l). Dr G Mieli-Vergani, were not excluded. In about half of these cases weeks later she developed jaundice. On Department of Child Health, alteration in the results of liver function tests admission, six days later, she was pale and jaun- King's College Hospital, Denmark Hill, was the only abnormality reported (Ciba-Geigy, diced, with a generalised exfoliative rash, London SE5 8RX. personal communication). There have been 17 periorbital oedema, generalised lymphadeno- Accepted 5 October 1989 deaths from liver disease, five in children,' 2 pathy, and stomatitis. Firm liver and spleen 316 Hadzic, Portmann, Davies, Mowat, Mieli-Vergani

Prednisolone edges were palpable 6 and 7 cm below the costal I -40 margin. Temperature was 38-5°C. Her haemo- 300- a,) D globin concentration was 76 g/l; red cell indices, Arch Dis Child: first published as 10.1136/adc.65.3.315 on 1 March 1990. Downloaded from i.-- 0 reticulocyte, white cell, platelet, and differential E -30 counts were normal, with no eosinophilia; 200- cu

prothrombin time was 20 seconds (control 13 c seconds). , £:._\\~- 20 EE0 c ioo- Biochemical investigations were as follows -0 :3 (reference range in parentheses). Total bilirubin cE vf m concentration was 212 (<20) with a con- -10 [tmol/l U-nJ jugated fraction of 198. Activities of enzymes 0 1 2 3 4 were: aspartate aminotransferase 165 IU/l Weeks after admission (<50); y glutamyl transpeptidase 299 IU/l Figure 2 Effect of prednisolone treatment on serum (<50); and alkaline phosphatase 407 IU/l aminotransferase, bilirubin, andprothrombin time in case 1. (<300). Albumin concentration was 31 g/l (35-50) and concentrations of plasma sodium and proteins were normal. Concentration of IgA marrow aspirate contained many plasmocytoid was normal but IgG, IgM, and IgE were lymphocytes and moderate erythrophagocytosis increased (22-3 g/l, 5 g/l, and 30 kU/l (<18, by macrophages. A specimen taken at liver <2-2, and <10) respectively). C3 and C4 com- biopsy, performed 12 days after admission, plement components were decreased (0 35 g/l showed an acute hepatitis, with both portal and and 0-13 g/l (0-55-1-2 and 0-20-0 60) respec- parenchymal cell infiltrates rich in plasma cells tively). Autoantibodies were negative. A 99mTc (fig IA). After 10 days of supportive treatment colloid liver scan showed reduced liver uptake, (blood and albumin transfusions, oral iron, with increased bone and spleen uptake. Bone Ketovite (Paines and Byrne), and intravenous vitamin K) without improvement, she was given prednisolone (0-7 mg/kg/24 hours). This was followed by a dramatic symptomatic and biochemical improvement, although the prothrombin time had already returned to nor- mal before starting steroid treatment (fig 2). She was discharged one week later after complete resolution of symptoms. Her serum bilirubin concentration was 31 [imol/l, y glutamyl trans- peptidase 214 IU/1, and aspartate aminotrans- ferase, alkaline phosphatase, albumin, and prothrombin time were normal. Prednisolone was stopped after 18 days. Three years later the girl is well with normal liver function. http://adc.bmj.com/

CASE 2 A girl aged 7-8 years presented with fever, gen- eralised maculopapular rash, arthralgia, and lymphadenopathy four weeks after starting

carbamazepine (16-5 mg/kg/24 hours). Seven- on September 30, 2021 by guest. Protected copyright. teen days later she developed jaundice, ascites, and generalised oedema. She had had convul- sions from the age of 8 months. At 3 years grand mal epilepsy was diagnosed. She received sodium valproate for two months at the age of 7 years, but she had been on no anticonvulsant treatment for four months before starting carba- mazepine. On admission she was jaundiced, with generalised peeling maculopapular rash, oedema, and ascites. A firm liver was palpable 3 cm below the costal margin; her spleen was not palpable. Concentrations of carbamazepine in the blood was 28 [tmol/l. Her haemoglobin concentration was 105 g/l with normal white cell, platelet, and differential counts; there was no eosinophilia, and the prothrombin time was 24 seconds (control 15 seconds). Total bilirubin concentra- tion was 236 ,umol/l and activities of aspartate aminotransferase 946 IU/1, y glutamyl trans- Figure Liver histology. A: sectionfrom case showing prominent perivenular cell loss peptidase 206 IU/1, and alkaline phosphatase andplasma cell infiltration (hv, hepatic vennule). B: section from case 2 showing submassive 151 IU/I. Ammonia was 94 ,tmol/l (10-47), total parenchymal loss with widespread inflammation, scattered bile duct like structures, and only occasional islands ofsurviving, pale staining hepatocytes. Haemotoxylin and eosin protein 43 g/l, albumin 24 g/l, and plasma stain: A x 180, B x45. sodium 126 [tmol/l. IgG was 5-9 g/l (6-5-18), Acute liverfailure induced by carbamazepine 317

IgA and IgM were normal, and IgE was raised midone. The mechanism of liver injury in car- at 550 kU/l. Autoantibodies were negative. C3 bamazepine hepatitis remains poorly under-

and C4 were 1 5 and 0-19 g/l. She was treated stood, although it is presumed to be an idiosyn- Arch Dis Child: first published as 10.1136/adc.65.3.315 on 1 March 1990. Downloaded from with fluid restriction, vitamin K, cimetidine, cratic hypersensitivity,5 possibly deriving from albumin and, three days after admission, pred- genetically determined inability to inactivate nisolone 1 mg/kg/24 hours. Four days after toxic metabolites.6 Consistent with reports from admission grade III hepatic encephalopathy other authors, we found that clinical presenta- developed and prothrombin time lengthened to tion and laboratory tests in our two patients sug- 70 seconds. Because of further deterioration, gest an immunoallergic mechanism. Thus both orthotopic liver transplantation was performed had onset of symptoms four weeks after starting 24 hours later when prothrombin time was 120 treatment, fever, rash, arthralgia, and raised seconds. The excised liver was shrunken with IgE with carbamazepine concentrations within evidence of submassive necrosis. On histology the therapeutic range. In addition, case 1 had a there was widespread inflammation comprised heavy plasma cell infiltrate found on histology, of lymphocytes, pigmented macrophages, neu- decreased complement concentration with trophils, and fewer plasma cells (fig iB). The increased IgG and IgM, and her recovery has child died of infectious complications three been aided by the administration of steroids. In months after transplant. case 2 these features were absent and no In both cases hepatitis A and B, cytomegalo- response to steroid was observed, possibly sug- virus, Epstein-Barr, measles, and leptospira gesting another mode of hepatocyte injury. infections were excluded; a, antitrypsin pheno- Liver function tests performed routinely in type and caeruloplasmin, plasma and urine the first weeks of carbamazepine treatment, and copper, serum potassium, calcium, phosphate, in the presence of other idiosyncratic reactions glucose, cholesterol, creatinine, and urea con- to the drug, may help to detect patients at risk centrations, and urinalysis were normal. of developing this rare complication.

We thank Dr TK Hanid and Dr DM Cook for referring the patients. NH is a Bristish Council Research Fellow, GMV is Discussion supported by the M McGough Foundation Against Liver Disease The diagnosis of liver injury induced by drugs in Children. rests on the exclusion of other aetiological factors. In the two children described no other 1 Zucker P, Daum F, Cohen MI. Fatal carbamazepine hepati- cause of liver damage or drug exposure could be tis. J Pediatr 1977;91:667-8. 2 Smith DW, Cullity GJ, Siberstein EP. Fatal hepatic necrosis identified. associated with multiple anticonvulsant . Aust NZJ Hepatic side effects of carbamazepine are Med 1988;18:575-81. 3 Horowitz S, Patwardhan R, Marcus E. Hepatotoxic reactions very rare. Among them, changes in results of associated with carbamazepine therapy. Epilepsia 1988; liver function tests, jaundice, and granu- 29:149-54. 4 Pellock JM. Carbamazepine side effects in children and lomatous or cholestatic hepatitis are the most adults. Epilepsia 1987;28(suppl 3):S64-70. 5 Stricker BHC. Hepatic injury by drugs and environmental common.3 In a study of children, a clinically http://adc.bmj.com/ toxins. In: Arias IM, Frenkel M, Wilson JHP, eds. The insignificant rise in results of liver function tests liver annual/6. Amsterdam: Elsevier, 1987:538-92. was found in 6% of 220 patients. We have iden- 6 Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest tified only three reported cases of fatal acute 1988;82: 1826-32. liver failure directly attributable to carbamaze- pine, one being a child.' Recently four children Addendum with fatal fulminant hepatitis while on carbama- Since this paper was accepted we have admitted zepine were reported.2 All were taking several and successfully transplanted a 3 year old child drugs, with three receiving other potentially who had fulminant hepatic failure due to on September 30, 2021 by guest. Protected copyright. hepatotoxic drugs, such as phenytoin and pri- carbamazepine toxicity. Contractural arachnodactyly with mitral regurgitation and iridodonesis

I C Huggon, J P Burke, J F Talbot Paediatric Unit, Northern General Hospital Abstract Beals and Hecht described an autosomal domi- I C Huggon An infant girl with arachnodactyly, spontane- nant syndrome of congenital contractural Department of ously resolving contractures, dolichosteno- arachnodactyly distinct from classical Marfan's , Royal melia, iridodonesis, and mitral and tricuspid syndrome.' It is characterised by multiple Haliamshire Hospital, incompetence died in cardiac failure. We contractures at birth Sheffield that resolve spontaneously J P Burke confirm that congenital contractural arachno- (in 94%), dolichostenomelia, arachnodactyly (in J F Talbot dactyly may exhibit serious cardiovascular 85%), abnormalities of the external ears (in Correspondence to: and ophthalmic complications like Marfan's 65%),2 and the absence of the eye and cardio- Mr J P Burke, Department of syndrome. The presence of iridodonesis vascular abnormalities typical of Marfan's syn- Ophthalmology, Royal Hallanshire Hospital, further obscures the differentation between drome. Since then, however, serious eye and Sheffield S10 2JF. classical Marfan's syndrome and congenital cardiac abnormalities that lessen the distinction Accepted 9 October 1989 contractural arachnodactyly. from Marfan's syndrome have been described.`5