Rienk Tamminga

Genotypic and phenotypic characterization of Noonan syndrome : New data and review of the literature

Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, minor facial anomalies, and congenital heart defects. In approximately 50% of cases the condition is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the protein SHP‐2. In this study, PTPN11 mutation analysis was performed in 170 NS patients. In 76 (45%) of them a mutation was identified. We report on the distribution of these mutations, as well as on genotype–phenotype relationships. The benefit of the NS scoring system developed by van der Burgt et al. [( 1994 ); Am J Med Genet 53:187–191] is shown, among physicians who consequently based their diagnosis on the NS scoring system the percentage mutation positive subjects was 54%, whereas this percentage was only 39% among physicians who made less use of the scoring system. In two patients with some uncommon manifestations mutations were found in the C‐SH2 domain, a region in which defects are not often identified in NS. A trend was observed in patients carrying the 922A → G change (Asn308Asp) receiving normal education. In one patient with NS and mild juvenile myelomonocytic leukemia (JMML) the mutation 218C → T (Thr73Ile) was found. This confirms previous findings indicating that individuals with NS with specific mutations in PTPN11 are at risk of developing JMML.

Improved Outcome in Pediatric Relapsed Acute Myeloid Leukemia: Results of a Randomized Trial on Liposomal Daunorubicin by the International BFM Study Group

PURPOSE In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group. PATIENTS AND METHODS Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years). RESULTS The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups. CONCLUSION DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.

Splenectomy in children with idiopathic thrombocytopenic purpura : A prospective study of 134 children from the Intercontinental Childhood ITP Study Group

Splenectomy is an effective procedure for children and adults with severe or refractory idiopathic thrombocytopenic purpura (ITP). Data regarding pediatric patients are limited.

Platelet count, previous infection and FCGR2B genotype predict development of chronic disease in newly diagnosed idiopathic thrombocytopenia in childhood: results of a prospective study

About 25–30% of children with acute idiopathic thrombocytopenia (ITP) develop chronic disease. It is not well known which patient characteristics influence the course of the ITP. A prospective study in 60 children with newly diagnosed ITP was performed. The aim of the study was to identify patient characteristics at the onset of thrombocytopenia that predicts the progression to chronic ITP. Clinical data and blood samples were collected at several time points during the first 6 months of the disease. Variables predicting chronic disease, as calculated in a multivariate logistic regression analysis, were a platelet count >10 × 109/l at the onset [odds ratio (OR) 1·1, 95% confidence interval (CI) 1·01–1·14], the absence of infection shortly before the onset of the disease (OR 4·8, CI 1·16–19·57) and FGR2B‐232I/T genotype (OR 7·9, CI 0·96–65·27). The latter may point at an immune‐modulating role of FcγRIIb in ITP. Although only three patients had serious bleeds, 35 patients received immune‐modulating treatment for low platelet counts only. Seventeen patients were treated with intravenous immunoglobulin (IVIG) and 18 patients received corticosteroids. Patient variables did not differ between these treatment groups. However, patients receiving IVIG had significantly lower risk for chronic disease.

Deep juvenile xanthogranuloma : a lesion related to dermal indeterminate cells

Juvenile xanthogranuloma (JXG) is considered to represent a lesion originating from histiocytes. Three cases of deeply located JXG and one case of cutaneous JXG were studied. One case with extensive mesenteric involvement presented with hypercalcemia and one case with liver involvement had hypergammaglobulinemia. Immunohistochemistry, electron microscopy, karyotyping, and DNA flow cytometry were used to determine the phenotype of the cells involved and to find further clues as to the histogenesis of these lesions. Immunohistochemically, all lesions studied expressed the CD1a antigen but showed no labeling for S-100 protein. The cells did not contain Birbeck granules. From these data it is suggested that the cells involved are of indeterminate dermal histiocyte lineage and that occurrence of deep located lesions of JXG may be due to migration of CD1 a-positive histiocytes.

Possible lower rate of chronic ITP after IVIG for acute childhood ITP an analysis from registry I of the Intercontinental Cooperative ITP Study Group (ICIS)

In children, one‐third of immune thrombocytopenic purpura (ITP) patients follow a chronic course. The present study investigated whether treatment with intravenous immunoglobulin (IVIG) at the time of diagnosis of ITP is of prognostic significance, using data from 1984 children entered in Registry I of the Intercontinental Cooperative ITP Study Group. A matched pairs analysis compared children with thrombocytopenia (platelet count <150 × 109/l) 6 months following diagnosis with children whose platelet count was normal 6 months after diagnosis. It was found that children initially treated with IVIG were more likely to have a normal platelet count 6 months after diagnosis than children not receiving IVIG (odds ratio 1·81; 95% confidence interval: 1·25–2·64). This result was independent of age, gender, country of origin, platelet count at diagnosis or infection preceding the diagnosis of ITP. In a similar analysis, comparing children with a platelet count <50 × 109/l 6 months after diagnosis with children whose platelet count was ≥50 × 109/l at that time point, the former group was less often treated with IVIG than with steroids (P = 0·02). Prospective studies are required to further explore this potential effect of IVIG.

A pilot study on the effects of the transition of paediatric to adult health care in patients with haemophilia and in their parents: patient and parent worries, parental illness-related distress and health-related Quality of Life

Summary.  The aim of this pilot study was to investigate the effects of the transition from paediatric to adult health care services in haemophilia patients and their parents. We compared pretransition children (n = 9) and their parents (n = 18) to posttransition patients (n = 8) and their parents (n = 21). Pre‐ and posttransition patients did not differ in self‐rated health‐related quality of life (QoL) or worries about the transition. Fathers of posttransition patients rated their son’s QoL as poorer than those of pretransition patients (P = 0.034) and indicated higher levels of illness‐related distress than fathers of pretransition patients (P = 0.034). The findings indicate that the transition affects parents more than patients. Moreover, we found gender differences in parental worries about the transition. The findings indicate that programmes designed to facilitate the transition in haemophilic patients should also address the patients’ parents.

Changes in nutritional status in childhood cancer patients: A prospective cohort study

BACKGROUND & AIMS Under- and overnutrition are linked to adverse outcomes during and after childhood cancer treatment. Therefore, understanding the timing of weight loss and weight gain and their contributory factors is essential for improving outcomes. We aimed to determine in which period of treatment changes in nutritional status occurred and which factors contributed to these changes. METHODS A prospective cohort study of 133 newly diagnosed cancer patients with hematological, solid, and brain malignancies was performed. Anthropometric data and related factors were assessed at 0, 3, 6 and 12 months after diagnosis. RESULTS Despite initial weight loss at the beginning of treatment in patients with hematological and solid malignancies, body mass index (BMI) and fat mass (FM) increased within 3 months with 0.13 SDS (P < 0.001) and 0.05 SDS (P = 0.021) respectively. Increase continued during the following months and resulted in a doubling of the number of overnourished patients. Fat free mass (FFM), which was already low at diagnosis, remained low. During the entire study period about 17% of the patients were undernourished on the basis of low FFM. Tube feeding and diminished activity level were related to increases in BMI and %FM respectively. No relationship was found between energy intake or corticosteroids and increase in BMI or %FM. CONCLUSIONS BMI and FM increased during and after the period of intensive treatment, while FFM remained low. Improvement of nutritional status might be accomplished by increasing physical activity from the early phase of treatment.

Treatment with Intravenous Immunoglobulin Does Not Prevent Chronic Immune Thrombocytopenia in Children: Results of a Randomized Controlled Trial

CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) have been shown to effectively prevent graft-versus-host disease (GVHD) when adoptively transferred in murine models of hematopoietic cell transplantation and in phase 1/2 clinical trials. Critical limitations to Treg clinical application are the paucity of cells and limited knowledge of the mechanisms of in vivo function. We hypothesized that inflammatory conditions in GVHD modify Treg characteristics and activity. We found that peripheral blood of recipient animals during acute GVHD (aGVHD) induces Treg activation and enhances their function. The serum contains high levels of tumor necrosis factor-α (TNF-α) that selectively activates Tregs without impacting CD4(+)FoxP3(-) T cells. TNF-α priming induces Treg in vivo proliferation, whereas it limits the ability of CD4 and CD8 conventional T cells (Tcons) to proliferate and induce GVHD. TNF-α-primed Tregs prolong animal survival as compared with unprimed Tregs when used at an unfavorable Treg:Tcon ratio, demonstrating enhanced in vivo efficacy of TNF-α-primed Tregs. Because TNF-α is produced by several immune cells during inflammation, our work elucidates aspects of the physiologic mechanisms of Treg function. Furthermore, TNF-α priming of Tregs provides a new tool to optimize Treg cellular therapies for GVHD prevention and treatment.

Longitudinal anthropometric study in children with acute lymphoblastic leukaemia

In four groups of patients with acute lymphoblastic leukaemia, anthropometric variables were investigated every 3 months for 2 years. Group 1 (n= 7) was treated with a high‐risk protocol, group 2 (n= 13) with a standard‐risk protocol including cranial irradiation, group 3 (n= 13) with a standard‐risk protocol without cranial irradiation and group 4 (n= 8) was followed after completion of treatment. A height retardation of 0.4–0.6 SD was observed during therapy in groups 1–3. A catch‐up of 0.5 SD was found in group 4. The retardation of armspan was significantly larger than the retardation of sitting height when groups 1–3 were taken together. Head circumference was not affected. The anthropometric variables reflecting nutritional status showed a growth above normal during and after treatment. Corticosteroid medication and not cranial irradiation is the most likely explanation for our findings.