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BACKGROUND: Essential Thrombocythemia (ET) is an acquired myeloproliferative disorder (MPD) characterized by excessive production of platelets. The disorder is usually affecting adults and is rarely diagnosed in children. PATIENTS AND METHODS: In this retrospective study we describe 12 children aged 5-16 years in whom ET was presumed. RESULTS: Median follow-up was 59 months (range 10-72). At diagnosis 7 patients had clinical symptoms (syncope, poor concentration, fatigue, abdominal pain and mild bleeding), 5 patients were diagnosed accidentally (operation, allergy, enuresis, pneumonia, routine examination). Median platelet count at diagnosis was 1 325 x 10 (9)/L (range 600-3 050). In 11 cases bone marrow morphology was consistent with ET, one patient had chronic idiopathic myelofibrosis. Cytogenetics were normal in all studied cases. Within 6 months after the initial presentation one patient who was diagnosed accidentally developed thrombosis, another patient had mild bleeding. 8 patients were treated with acetylsalicylic acid (in addition, 1 patient received hydroxyurea, 2 patients received anagrelide). On last follow-up all patients were alive, none had developed leukemia. 5 patients experienced hematological remission. 2 of these children had not received any therapy. CONCLUSIONS: Many patients had symptoms attributable to ET. The clinical course is heterogeneous with complete normalization of platelets in the absence of cytoreductive therapy in some children. Due to the low incidence of ET in children indications for therapy are unclear and can only be deduced from findings obtained from studies in adults.

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Main diagnostic criteria of neonatal progeroid syndrome are: failure to thrive and lipoatrophy, old-looking face with hydrocephalic appearance, prominent scalp veins and sparse scalp hair, large hands and feet with long fingers and toes, often neonatal teeth. NPS is usually lethal by 7 months. 5 pairs of siblings with NPS are already published. We present the second report worldwide of two siblings with NPS actually at the age of 5 and 15 years.

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Subacute sclerosing panencephalitis is a rare progressive neurological disorder of childhood and early adolescence caused by persistent measles virus. The diagnosis is based upon characteristic clinical manifestations, periodic EEG discharges, raised antibody titre against measles/SSPE in the plasma and cerebrospinal fluid and increase of gamma-globulins in the cerebrospinal fluid. Histopathological examination shows neuronal loss, astrogliosis, demyelination, infiltration of inflammatory cells, and intranuclear inclusions in neurons, oligodendrocytes and astrocytes. In most cases nucleocapsids are detected by electron microscopy. Although treatment is still undetermined, combination of intrathecal high-dose interferon-alpha and intravenous ribavirin administered at an early stage of SSPE seems to be effective.

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Essential thrombocythemia is a rare myeloproliferative disorder in childhood. For symptomatic patients with platelet counts greater than 1000 x 10(9)/L, cytoreductive treatment is recommended. The authors describe a 5-year-old boy with symptomatic essential thrombocythemia who was treated with anagrelide (Agrylin) for 23 months. He responded well but early on developed anemia. Because anagrelide is thought to specifically inhibit thrombopoesis, anemia is assumed to be a rather rare and late adverse effect. Its early occurence in this patient might indicate an increased vulnerability to anagrelide (Agrylin) in young children.

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BACKGROUND: Early fetal herpes simplex virus (HSV) infection is rarely documented. Only the minority of affected fetuses survive this condition. PATIENT AND METHODS: At 19 weeks of gestation the first episode of a genital HSV-infection of a pregnant woman was treated with local interferon beta. At 34 weeks of gestation hydrocephalus with secondary microcephaly and microphthalmia of both eyes was detected by ultrasonography. In the amniotic fluid HSV type 2 (HSV-2) was isolated and HSV-2-DNA was detected by PCR. The serum of the mother proved positive for HSV-2 (glycoprotein G2)-specific IgG-antibodies. No other infectious causes were apparent on further testing. At 35 + 4 weeks gestation a small-for-gestational-age neonate (2130 g) with microcephaly (29 cm head circumference) was born by spontaneous vaginal delivery. Scarce ulcerative skin lesions and vesicles, hepatosplenomegaly and microphthalmia were diagnosed. Furthermore, encephalomalacia with parenchymal destruction, cataract of both eyes and aplasia of the maculae and papillae were found. HSV-2-PCR was tested positive in chorionic cells and an umbilical segment of the placenta as well as in swabs from both eyes, throat, and a herpetic skin lesion collected during the first 5 days of life. HSV-IgM-antibodies were found in the umbilical cord blood. Local and intravenous treatment with aciclovir was started. The infant exhibited signs of a severely malfunctioning central nervous system. At the age of 4 months the boy suffered from generalised cerebral seizures. He died at the age of 9 months as a consequence of respiratory insufficiency with consecutive circulation failure. RESULTS: The case of an intrauterine HSV-2-infection is presented. The time of onset of fetal infection was most probably at the time of the maternal disease (19 weeks of gestation). Inspite of the very early infection the fetus did not die in utero. CONCLUSIONS: Especially, if a primary genital HSV-2-infection of a pregnant woman is suspected, which can be proven by serological means only several weeks after infection, systemic therapy of the mother with aciclovir should be considered since materno-fetal transmission may occur due to the risk of maternal viraemia.

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The neonatal progeroid syndrome represents a complex of symptoms with unknown cause and pathogenesis. At 37 weeks of uncomplicated pregnancy a boy of non-consanguineous turkish parents was delivered by section. The weight of 1740 g and the length of 43 cm were striking, the circumference of the head was still within normal range. Further on the patient showed the diagnostic criteria of Wiedemann-Rautenstrauch syndrome: Beside growth failure and nearly absence of subcutaneous fat, old-looking face with hydrocephalic appearance, prominent scalp veins and sparse scalp hair, large hands and feet with long fingers and toes were found. Neonatal teeth didn't exist. But neonatal teeth are not always present in this syndrome. Among 19 published cases they were also not described in 6 cases (31.6%). Cataract was not found. A skin biopsy taken at the age of four months revealed an extremely thin dermis with pronounced rarefication of elastic material by light microscopy. On the electron microscopical level, no qualitative morphological aberrations or signs of degeneration were found, but normal although very small elastic fibres. With increasing age the appearance was nearly unchanged. In spite of high-caloric nutrition the increase of weight was not sufficient. The clinical symptoms of this patients were compared with the 19 already published cases of Wiedemann-Rautenstrauch syndrome. This shall be a contribution to the exact description of that extremely rare syndrome. We hope to facilitate, that hereby the differential diagnosis in difficult cases will be more easy. Because of heterogeneity it has to discuss if the Wiedemann-Rautenstrauch syndrome really represents a separate genetic entity within the group of premature aging syndromes.

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Using the Smiley analogue scale we investigated the correlation between the self-assessment of defined pain by children and the estimation of this pain by parents, nurses and physicians. In addition, the correlation was studied between the patient's mood and the pain intensity stated by himself and by others. The results of 111 patients, aged from 2(9)/12 to 17(6)/12 years, exhibited a high correlation between the self-assessments of pain intensity and pain duration by all three observing groups. Between patients and parents the best correlation was observed in the estimation of severe pain. All three observing groups inclined mainly to over- than to underestimate the pain intensity. This behavior pattern was mainly observed in parents. The patient's emotion did not influence the self-assessment of pain intensity and pain duration. But a great correlation was observed between the patient's emotion and the pain assessment by all three observing groups. Using a Smiley analogue scale the pain assessment by children or by others is a helpful tool for an individual pain therapy in the daily clinical routine.

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We report about a premature infant with a De Barsy-Moens-Dierckx-syndrome, which is a rare cutaneo-oculo-cerebral malformation-syndrome. It is defined by the combination of a progeroid aspect, cutis laxa, growth retardation, cornea clouding, mental retardation and athetoid movements. Furthermore, the reported case showed a remarkable thermolability and suffered from generalised seizures resistant to therapy. Despite extensive sonographic examinations the prepartal diagnosis seems to be very difficult.

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Ulcerative colitis is a rare disease in young infants. Less than one per cent of cases occur during the first two years of life. We describe a male child who developed frequent bloody diarrhea at the age of 20 months. More common causes like infections or gastrointestinal food allergy were excluded. Endoscopy and histopathological evaluations revealed ulcerative colitis of the entire colon. Treatment with sulfasalazine and prednisone resulted in a clinical remission after seven weeks. The follow-up of 15 months was complicated by Rotavirus infection. Two relapses were caused by Clostridium difficile infections. The latter were successfully treated with oral vancomycine, but in the last relapse an increased dosage of prednisone was required, too. In relapses of inflammatory bowel disease gastrointestinal infections, especially caused by Clostridium difficile should be considered and treated adequately.

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The clinical course of a 17-year-old patient who suffered from chronic neutropenia without cyclic variation since the age of 2 is presented. The bone marrow showed absent granulopoiesis and yielded very few colony-forming units (CFU-GM) in vitro with maturation up to segmented neutrophils. Incubation with cyclosporin A (CyA) increased CFU-GM markedly. Such an increase was not found after incubation of normal bone marrow with CyA in vitro. The patient also responded to CyA in vivo and maintained adequate granulocyte counts for 7 months when she became neutropenic again. She subsequently responded to high doses of prednisolone. The clinical course and bone marrow studies suggest that the defective granulopoiesis is due to an immunologically mediated mechanism sensitive to CyA and prednisolone. Other findings in this patient, such as impaired natural killer (NK) cell activity and random and chemotactic leukocyte motility, could further point to an imbalance in the regulation of hematopoiesis. Neutropenia, NK cell defect and impaired chemotaxis may be pathogenetically connected.

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Spielmeyer-Vogt-disease (juvenile neuronal ceroid-lipofuscinosis, Batten's disease) is one of a group of severe inherited neurodegenerative disorders called neuronal ceroid-lipofuscinosis, being characterized by accumulation of ceroid-lipofuscin within different organs of the body. A patient is described who developed visual, intellectual and motor deterioration as well as recurrent seizures during an observation period of 21 years. At the age of ten years vacuoles and "fingerprint-profiles" in lymphocytes and "fingerprint-profiles" beside "curvilinear bodies" in dermal cells lead to the diagnosis juvenile neuronal ceroid-lipofuscinosis. Clinical assessment of vision, intellect, language, motor function and epilepsy established a scoring system. The practicability of this scoring system is documented by the particularly poor clinical course of the disease over 21 years in our patient. Since there is no causal therapy the continuous care by the pediatrician for the whole family is of great importance.

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In 1986 and 1987 11 children with TEC (transient erythroblastopenia of childhood) were referred to our hospital. Bone marrow aspirations were performed to exclude haematological malignancy. There was a marked reduction of erythropoiesis in 9 cases (1%-8%), two children had already recovered (33% and 44% erythropoiesis). Eight patients exhibited high percentages of stimulated lymphoid cells. The subsequent immunotyping revealed the expression of CALLA (common acute lymphoblastic leukaemia antigen) on these cells but there was no other sign for malignancy. The patients recovered without any specific treatment except transfusions of packed red cells. Eight patients were followed up 11-18 months after initial presentation and were all found to be in good health. A prominent increase of CALLA-positive stimulated lymphoid cells has also been found in other haematological diseases such as neutropenia and immune thrombocytopenia. The expression of CALLA in bone marrow lymphocytes is a general reactive change to various alterations.

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Nineteen children (median age, 13 years; range 4 to 18 years) with acute lymphoblastic leukemia/lymphoma (ALL) (10 patients) or acute nonlymphoblastic leukemia (ANNL) (9 patients) received allogeneic bone marrow transplants (BMT). Marrow was taken from HLA-identical sibling donors (16 patients) (pts), HLA-identical unrelated donor (1 pt), or one-antigen-missmatched sibling donor (1 pt). Preparatory regimen consisted of fractionated total body irradiation and high-dose VP-16 (50-70 mg/kg body weight). At the time of BMT nine of the pts were not in complete remission (CR): seven pts were refractory to aggressive multiagent chemotherapy and two pts were in first relapse. Six pts were in second CR, one pt in third CR; three pts grafted in first CR carried additional risk factors; e.g. induction failure. Ten out of the nineteen pts are alive and free of disease between one and 53 months (median, 28 months) after BMT. The actuarial disease-free survival rate is 37% for pts with ANLL and 54% for pts with ALL. Six pts have died from BMT-related complications. Only three pts (1 pt with ALL, 2 pts with ANLL) have relapsed between day +106 and day +134 after BMT and subsequently died. The four-year actuarial relapse rates of 29% for ANLL and 14% for ALL, respectively, demonstrate that the combination of fractionated total body irradiation and high-dose VP-16 is an effective antileucemic regimen for children with advanced leukemias.

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As part of the Cooperative Germ Cell Tumors Studies MAKEI 83/86 of the German Society of Pediatric Oncology, 37 patients with intracranial germ cell tumors were registered. Based on histological criteria and tumor markers, 26 were classified as germinomas, 9 as fully malignant non-germinomatous germ cell tumors (2 yolk sac tumors, 1 embryonal carcinoma, 1 choriocarcinoma, 5 mixed type germ cell tumors), and 2 were mature teratomas. Of 26 patients with germinomas, 14 received radiotherapy only, all patients are surviving disease-free, median period of observation: 2 years, 10 patients were treated with both chemotherapy and radiotherapy, 8 of these patients are surviving disease-free. Of the 2 patients who received chemotherapy only, none is surviving. Of 9 patients with fully malignant non-germinomatous germ cell tumors, 4 are surviving following surgery, cisplatinum-based chemotherapy and radiotherapy more than 2 years following diagnosis, 1 of these 4 patients with stable disease. Of 2 patients with mature teratomas, 1 is surviving disease-free. Based on these data, recommendations for diagnostic evaluation and therapy of intracranial germ cell tumors are outlined.

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BMT has gained its place in the treatment of childhood leukaemia. Nevertheless, there are still many questions open. In acute lymphoblastic leukaemia children should normally be grafted in 2nd remission (CR). Some high risk cases, however, should probably be grafted in 1st CR. It is not clear whether children with late relapses benefit more from BMT than from renewed chemotherapy. Children with a relapse during maintenance therapy, however, have a better survival rate with BMT. In acute nonlymphoblastic leukaemia certain high risk patients should be grafted in 1st CR but it has still to be shown that BMT is superior to chemotherapy in such cases. It is not clear whether children with a relapse following intensive chemotherapy (such as the BFM-protocols) will benefit from BMT at all. In chronic myelocytic leukaemia, BMT in chronic phase should be performed. Thus, for the first time cure has become possible for this disease. Waiting for acceleration or even the occurrence of a blast crisis decreases the chance of survival after BMT dramatically. Since complications of BMT such as graft-versus-host reaction or severe infections are less frequent in children, relapses remain the main problem after BMT in childhood leukaemia.

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Neuroblastoma is the third most frequent malignant tumor in childhood. One-third of the patients over one year of age at the time of diagnosis suffer from the disseminated form (stage IV). Despite highly aggressive chemotherapy survival rates are poor. One hundred and eighty-seven patients with neuroblastoma stage IV have been treated according to the German protocol NB 85. The probability of disease free survival is only 15% after 70 months. Treatment strategy in our protocol includes autologous and allogeneic bone marrow transplantation (BMT) for patients with stage IV (and greater than 1 year old). Twenty-two patients were grafted (7 allogeneic and 15 autologous). The conditioning regimen consisted mainly of high-dose melphalan (180 mg/m2) and total body irradiation (TBI) (3.4 Gy). Survival rates are discussed in the context of the chemotherapy protocol. Our own experience with autologous BMT is poor, despite of different purging methods. For this reason we decided to focus on allogeneic BMT. We have grafted five patients within the last 3 years. Three of them are alive and well, on died from veno-occlusive disease 70 days after BMT, and the remaining patient, grafted from a syngeneic donor, died from relapsing tumor. The main problem in neuroblastoma stage IV is resistance to chemotherapy. Intensification of the conditioning regimen or double autografting leads to a rate of toxic deaths close to 20% (Zucker, EBMT 1987) which is not tolerable. New improvements in the conditioning regimen have to be found to increase the effect of BMT.

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Thirty-eight patients (median age, 21 years) with acute nonlymphoblastic leukemia (ANLL) (17 patients), acute lymphoblastic leukemia/lymphoma (ALL) (18 patients), chronic myelogenous leukemia (two patients), and refractory anemia received allogeneic bone marrow transplants from HLA-identical sibling donors or a one-antigen-mismatched brother (one patient) after a preparatory regimen consisting of fractionated total body irradiation and high-dose VP 16-213 (60 to 70 mg/kg body weight). Of the 33 patients with acute leukemia who received grafts from HLA-identical donors, three patients with ANLL received transplants in first remission and one patient with standard-risk ALL received a graft while in second remission. All other patients were in more advanced stages of their disease or exhibited other high-risk features. At the time of analysis, 20 of the 33 patients were alive, with 19 of them remaining in continued complete remission for 6 to 35 months (median, 18 months). The 3-year actuarial disease-free survival rate of 56.6% +/- 9.7% (SE) and the actuarial relapse rate of 11.9% +/- 6.8% (SE) demonstrate that the combination of fractionated total body irradiation and high-dose VP 16 is an effective mode of therapy in patients with advanced leukemias. Preliminary experience cautions against the use of VP 16 instead of cyclophosphamide in any clinical situation carrying an increased risk of graft rejection because the immunosuppressive potency of VP 16 is largely untested but may be inferior to that of cyclophosphamide.

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22 children with metastatic neuroblastoma received myeloablative chemoradiotherapy followed by bone marrow transplantation (BMT). The duration of preceding chemotherapy was 4-30 months and included treatment of recurrences in 10 children. At BMT 12 patients were in CR, 9 in PR and one had tumor progression. 10/15 of autologous bone marrows were purged using immunomagnetic bead method of Kemshead and 2/15 using 4 hydroperoxycyclophosphamide. Myeloablative therapy consisted of melphalan and total body irradiation (TBI) in 13 patients (three each supplemented by vincristine or adriamycin/etoposide), in one child of melphalan and mIBG and in 3 children of melphalan alone. 3 children received double autograft and 2 cyclophosphamide (and TBI). 10 patients survived 0-32 months from BMT and 5-48 months from diagnosis, respectively. 12 patients died including 7/12 of tumor progression and 5/12 of toxicity (venoocclusive disease, gut toxicity, septicemia, pneumonia). We conclude that at this point BMT after conventional high dose chemotherapy may provide the only real chance of survival for a significant number of children with metastatic neuroblastoma.

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