919

Interferon alpha-2a therapy of consumptive coagulopathy in Kasabach-Merritt syndrome

eration and angiogenesis are inhibited by interferon alpha-2a. The mechanism of decreased thrombocyte aggregation may be explained by a reduction in platelet adherence and trapping, resulting from increased endothelial prostacyclin synthesis [1] or by a change in the vascular blood flow characteristics [7]. Hypothetically, the sudden coagulopathy in our patient may have been induced by a change in the metabolism of endothelial cells disturbing the balance of coagulation and fibrinolysis that could be reversed by interferon alpha-2a.

C. Klein 1, M. Hauser 2, and H. B. Hadorn 2 IUnitd d'Immunologieet d'Hdmatologie, H6pital Necker Enfants Malades, 149, rue de S~vres, F-75743 Paris Cddex 15, France 2Dr. yon Hauner'sches Kinderspital, Ludwig MaximilianUniversit~itMtinchen,Lindwurmstrasse4, W-8000 Mtinchen2, Federal Republic of Germany

References

Sir: We report the case of a 15-year-old boy with disseminated vascular dysplasia involving the spleen, thoracic vessels and skeletal system. He suddenly developed a consumptive coagulopathy which could be controlled by interferon alpha-2a. After obtaining informed consent we administered daily subcutaneous injections of interferon alpha-2a (Roferon, Hoffman La Roche), initially at a dose of 1 x 106 units/m 2, gradually increasing over the following 3 days to 3 • 106units/m2. During this therapy no further platelet transfusions were required. The platelet count rose to 70.000/mm 3 and coagulation parameters normalised. After an interruption of the treatment a relapse of the consumptive coagulopathy could be controlled by reinitiating interferon alpha-2a injections (Fig. 1). Finally a curative splenectomy was performed, proving that a splenic dysplasia caused the bleeding disorder.

thrombocytes

1. Eldor A, Fridman R, VlodvaskyI, Hy-Am E, Fuks Z, Panet A (1984) Interferon enhances prostacyclinproduction by cultured vascularendothelial cells. J Clin Invest 73 :251-257 2. Ezekowitz RAB, Mulliken JB, Folkman J (1992) Interferon Alfa-2a Therapy for Life-ThreateningHemangiomasof Infancy. N Engl J Med 326 : 1456-1464 3. FolkmanJ (1989) Successfultreatment of an angiogenicdisease. N Engl J Med 320:1211-1212 4. Larson EC, Zinkham WH, Eggleston JC, Zitelli BJ (1987) KasabachMerritt syndrome:therapeutic considerations.Pediatrics79 : 971-980 5. Ozsoylu S, frken G, GfirgeyA (1989) High dose intravenous methylprednisolone for Kasabach-Merritt syndrome. Eur J Pediatr 148:403405 6. Warrei1RP, KempinSJ (1985) Treatment of severe coagulopathyin the Kasabach-Merrittsyndromewith aminocaproicacid and cryoprecipitate. N Engl J Med 313 :309-312 7. White CW, Wolf SJ, Korones DN, SondheimerHM, Tosi MF, Yu A (1991) Treatment of childhood angiomatousdiseases with recombinant interferon alfa-2a. J Pediatr 118:59-66

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160

Preaxial polydactyly in the fetal valproate syndrome

140 120

I. M. Buntinx

100 80

Department of Medical Genetics, Universityof Antwerp-U.I.A., Universiteitsplein1, B-2610Wilrijk,Belgium

60

Received January 7, 1992/ Accepted after revisionApril 24, 1992

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Fig. 1. Response to interferon alpha-2a

The standard of therapy of Kasabach-Merritt syndrome consists of surgical removal of the haemangiomatous dysplasia [4]. In disseminated vascular dysplasias this might not be possible. Corticosteroids [5], and fibrinolytic inhibitors [6] have been proposed as alternative treatments. A new strategy for control of severe coagulopathy might be offered by interferon alpha-2a that has previously been reported to exhibit antiproliferative effects in angiomatous diseases, including reversal of secondary bleeding disorders [2, 3, 7]. The pharmacological effects of interferon alpha-2a remain unclear. It has been shown in-vitro that endothelial cell prolif-

Sir: Recently we saw an ll-month-old girl with facial dysmorphism suggestive of the fetal valproate syndrome: prominent forehead with bitemporal hollowing, short nose with anteverted nostrils, upstanted palpebral fissures, epicanthus, flat philtrum, small vermillion border of upper lip, pronounced nasolabial folds, downturned corners of the mouth, low-set ears and short neck. Her motor milestones were delayed since she could not sit unsupported at this age. Neurological examination revealed axial and peripheral hypotonia. She had hyperlaxity of all joints. Her mother took valproic acid 3 • 500 mg/day during pregnancy. Repeated ultrasound examination and alpha-fetoprotein level in maternal serum at 17 weeks gestation were normal. The child was born with a preaxial polydactyly on the right hand, which was the main reason for referral. The supernumerary finger, containing bony elements on X-ray, was surgically removed at the age of 5 months. We did not find any case report of fetal valproate syndrome with this kind of limb defect. Verloes et al. [2] recently reviewed all limb defects in fetal valproate syndrome. Limb anomalies described in such patients and also in animal studies are reduction defects: radial aplasia, aplasia of the 1st and 2nd ray, hypoplasia of phalanges and nails. The only exception is a triphalangeal thumb.

920 Martinez-Frias, however, reported two cases of postaxial polydactyly as result of valproic acid m o n o therapy (one) and valproic acid in combination with carbomazepine (one) [1]. It is not clear whether these children had associated anomalies. Polydactyly must be added to the spectrum of limb defects caused by valproic acid. In our patient as in most patients also the preaxial side of the upper limb is involved. The mechanism of this predilection is unclear.

References 1. Martinez-Frias ML (1990) Clinical manifestation of prenatal exposure to valproic acid using case reports and epidemiologic information. Am J Med Genet 37 : 277-282 2. Verloes A, Frikiche A, Gremiltet C, Paquay T, Decortis T, Rigo J, Senterre J (1990) Proximal phocomelia and radial ray aplasia in fetal valproic syndrome. Eur J Pediatr 149 : 266-267

Asymptomatic lesions of the basal ganglia in a patient with methylmalonic aciduria S. St6ckler 1, I. Slave 1, F. Ebner 2, and R. Baumgartner 3 Departments of tPaediatrics and 2Radiology, University of Graz, Auenbruggerptatz 3, A-8036 Graz, Austria 3Department of Paediatrics, University of Basel, Switzerland Received May 27, 1992 / Accepted August 8, 1992 Sir: Methylmalonic aciduria (MMA) is an i n b o r n error of metabolism affecting the degra,dation of the aminoacids valine, isoleucine, methionine and threonine, of cholesterol and of odd-numbered long-chain fatty acids ( O L C F A ) . Acute episodes of metabolic decompensation manifest with vomiting, drowsiness, ketoacidosis and hyperammonaemia. Persistent neurological signs, mainly extrapyramidal, have been reported in some patients with M M A [3, 4-6]. We observed a patient with M M A diagnosed at the age of 3 weeks by highly elevated urinary concentrations of methylmalonic acid (11 tool/tool creat). Enzyme studies in cultured flbroblasts indicated a rout 0 genotype. His dietary intake of natural protein was 0.8-1.2g/kg per day and carnitine was supplemented in doses of 50-100 mg/kg per day. During metabolic equilibrium urinary methylmalonic acid excretion ranged between 0.5 and 22 mol/mol creatinine (mean value = 10.5 tool/ mol creatinine, n = 14). Until 7 years of age he had nine episodes of metabolic decompensation characterised by vomiting, refusal to take oral fluids and metabolic acidosis. Laboratory findings during these episodes included mildly decompensated metabolic acidosis, plasma concentrations of a m m o n i a and lactic acid were mildly elevated on one occasion. Urinary methylmalonic acid excretion ranged b e t w e e n 12 a n d 23 m o l / m o l creatinine (mean value = 17.6mol/mol creat, n = 7). A n episode at the age of 36 months was the only one to be accompanied by reduced consciousness without neurological signs. Methylmalonic acid excretion was 20mol/mol creatinine. Brain M R I at the age of 4.5 and 6.5 years revealed symmetrical lesions within the central parts of the basal ganglia (globus pallidus) (Fig. 1), These lesions were never complicated by corresponding neurological signs. There is evidence of intellectual Abbreviations: MMA = methylmalonic aciduria; OLCFA = odd num-

bered long-chain fatty acids

Fig. 1. MR image (1.5 Teslar superconductive magnet system) of a 4.5-yearold boy with MMA: left demonstrating symmetrical areas of low signal intensity within the central portions of the basal ganglia (globuls pallidns) on Tl-weighted partial saturation spin echo and inversion recovery pulse sequences; right demonstrating high signal intensity areas, isointense to cerebrospinal fluid on proton density and T2-weighted images develomental delay: A t the age of 6.5 years his IQ (SnijdersO o m e n [P]) was 68. Lesions of the basal ganglia with corresponding neurological, mainly extrapyramidal signs have been demonstrated in other patients with M M A [1, 3-6]. So far they were thought to result from acute, stroke-like events during episodes of metabolic decompensation. However, our patient never demonstrated extrapyramidal signs and there has been no clinical evidence of a stroke-like event during the episodes of metabolic decompensation. This suggests that the damage to the basal ganglia results from a chronic process rather than from an acute one. Accumulation of O L C F A within the basal ganglia was demonstrated in a patient with a vitamin B12-dependent type of M M A [5]. In our patient high urinary excretion of M M A occurring even during states of metabolic equilibrium reflects poor metabolic control. This should lead to accumulation of O L C F A [7] which might be a reason for the chronic damage to the basal ganglia. We conclude that M R I should be performed in all patients with M M A even if there are no signs of neurological involvement. In patients with lesions, metabolic control should be carefully re-evaluated. Aggressive treatment monitored by additonal parameters such as quantitative determination of urinary M M A and of O L C F A in blood lipids should be initiated in order to avoid neurological deterioration caused by further progression of these lesions.

References 1. Dayan AD, Ramsey RB (1974) An inborn error of vitamin B12 metabolism associated with cellular deficiency of coenzyme forms of the vitamin. J Neurol Sci 23 : 117-128 2. Gompertz D (1971) The distribution of 17 carbon fatty acids in the liver of a child with propionicacidemia. Lipids 6 : 576-580 3. Heidenreich R, Natowicz M, Halline E, Berman P, Kelley RI, Hillman R, Berry GT (1988) Acute extrapyramidal syndrome in methylmalonic acidemia: "metabolic stroke" involving the globus pallidus. J Pediatr 113 : 1022-1027 4. Korf B, Wallman JK, Levy HL (1986) Bilateral lucency of the globus pallidus complicating methylmalonic acidemia. Ann Neurol 20:364-366 5. Roodhooft AM, Baumgartner ER, Martin JJ, Blom W, Van Acker KJ (1990) Symmetrical necrosis of the basal ganglia in methlymalonic acidemia. Eur J Pediatr 149 : 582-584 6. Thompson GN, Christodoulou J, Danks DM (letter) (1989) Metabolic stroke in methylmalonic acidemia. J Pediatr 115(3):499-500 7. Wendel U (1989) Abnormalityof odd-numbered long-chain fatty acids in erythrocyte membrane lipids fi'om patients with disorders of propionate metabolism. Pediatr Res 25 : 147-150