PURPOSE OF REVIEW: Myelodysplastic and myeloproliferative disorders are clonal myeloid malignancies characterized by the triad of a growth advantage of clonal cells, disturbed differentiation and increased apoptosis. The rarity of these disorders in children and the lack of a widely accepted classification have contributed to the paucity of reports on these malignancies in the pediatric literature. A number of significant advances have been achieved in recent years. The present review will focus on diagnostics and therapy. RECENT FINDINGS: International consensus has been achieved on classifying these disorders into three main groups; myelodysplastic syndrome (MDS), myeloid leukemia of Down syndrome (ML-DS) and juvenile myelomonocytic leukemia (JMML). In the last few years we have witnessed important advances, especially regarding the therapy of these disorders, and we have gained insights into the molecular pathogenesis of ML-DS and JMML. SUMMARY: Classification of myelodysplastic and myeloproliferative disorders has been facilitated. Chemotherapy regimens for ML-DS have been reduced, resulting in fewer toxic deaths and improved survival. The results of stem-cell transplantation for MDS and JMML have improved. Insight into the molecular mechanisms involved may open new therapeutic avenues.

Summary Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders - medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1-18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin-Frankfurt-Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 +/- 5.9% and the INS 98 (n = 43), 83.7 +/- 5.6%(P = 0.12); the cumulative incidence (CI) of any CNS relapse was 5.0 +/- 2.8% and 2.3 +/- 2.3%(P = 0.50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC)>/=100 x 10(9)/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61.9 +/- 5.3% in INS 89 and 72.9 +/- 5.8% in INS 98,(P = 0.21); the CI of any CNS relapse was 7.1 +/- 2.8% and 1.7 +/- 1.7%(P = 0.142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.

Prolidase deficiency (PD) is a rare, pan-ethnic, autosomal recessive disease with a broad phenotypic spectrum. Seventeen causative mutations in the PEPD gene have been reported worldwide. The purpose of this study is to characterize, clinically and molecularly, 20 prolidase deficient patients of Arab Moslem and Druze origin from 10 kindreds residing in northern Israel. All PD patients manifested developmental delay and facial dysmorphism. Typical PD dermatological symptoms, splenomegaly, and recurrent respiratory infections presented in varying degrees. Two patients had systemic lupus erythematosus (SLE), and one a novel cystic fibrosis phenotype. Direct DNA sequencing revealed two novel missense mutations, A212P and L368R. In addition, a previously reported S202F mutation was detected in 17 patients from seven Druze and three Arab Moslem kindreds. Patients homozygous for the S202F mutation manifest considerable interfamilial and intrafamilial phenotypic variability. The high prevalence of this mutation among Arab Moslems and Druze residing in northern Israel, and the presence of an identical haplotype along 500,000 bp in patients and their parents, suggests a founder event tracing back to before the breakaway of the Druze from mainstream Moslem society.(c) 2009 Wiley-Liss, Inc.

Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.

Anaplastic large cell lymphoma (ALCL) is a well-known entity, but there are no data on prognosis according to the age of the patient, especially in infants. A 2-month-old girl was admitted with a 2-week history of coughing, fever, and lymphadenopathy. Physical examination revealed mild respiratory distress, an erythematous macular rash on her trunk, massive cervical lymphadenopathy, splenomegaly, and very mild ascites. Chest radiograph showed bilateral pulmonary infiltrates, pleural effusion, and a mediastinal mass. CBC count showed WBC: 172,000/muL (PMN 40%, lymphocytes 47%, monocytes 3%); hemoglobin concentration: 8.7 g/dL; platelets: 390,000/muL. Cervical lymph node biopsy revealed anaplastic lymphoma with positive staining to ALK 1 and TIA 1. Immunophenotypic analysis of peripheral and bone marrow lymphoid cells showed an aberrant T-cell immunophenotype, including expression of CD3, CD45R0(+), CD43(+), and CD30(+). Cytogenetic analysis performed on blood and bone marrow samples demontrated the translocation t(2;5)(p23;q35), and trisomy 47. After leucophoresis, the child received chemotherapy according to the ALCL-99-EICNHL protocol, and was started on corticosteroids and cyclophosphamide, which resulted in marked improvement. After the second course, WBC decreased to 6000/muL without tumor lysis syndrome, but the child developed bacterial and fungal disseminated infections and died of septic shock with multiorgan failure. This report is of a rare case of infant anaplastic lymphoma and excellent response to treatment. Unfortunately, she did succomb to overwhelming infection. More reports of similar cases may determine the cause and prognosis of such children, helping to tailor therapy according to the age of the child and other prognostic factors, especially bone marrow involvement.

In an attempt to abrogate the deleterious effects of graft-versus-host disease (GVHD), allogeneic transplantation for nonmalignant diseases was performed using high-dose CD34-cell infusion, partial T cell depletion, and no posttransplantation GVHD prophylaxis. Between 1998 and 2004, 16 patients with matched related donors were treated. Median age was 1.5 years (range, 5 months-18 years). The conditioning regimen consisted of busulphan 16 mg/kg, cyclophosphamide 200 mg/kg, antithymocyte globulin (ATG) 25 mg/kg, and fludarabine 200 mg/m(2). No GVHD prophylaxis was given. High doses of CD34 cells, positively selected by immunomagnetic beads, were infused at a median dose of 10.7 x 10(6) CD34/kg (range, 7.4-50 x 10(6)). A total of 1 x 10(5)/kg T cells were given. All patients engrafted, with no graft rejections. All were alive and well at a median of 37 months posttransplantation (range, 18-89 months). Only 1 patient developed chronic GVHD. No episodes of severe infection occurred during or after transplantation. Immunologic reconstitution with CD3/CD4 T cells > 200/muL was observed at a median of 117 days and that with naive T cells (CD4/CD45RA) at a median of 188 days posttransplantation. Our findings suggest that allogeneic transplantation from a matched family donor for nonmalignant disorders can be successfully performed using high doses of CD34 cells, moderate T cell depletion, and no posttransplantation immunosuppression.

We describe a brother and sister with retinitis pigmentosa (RP), growth failure, long eyelashes, and sparse hair. They were born to young healthy consanguineous parents and presented at birth with IUGR. Evolving pigmentary retinopathy was diagnosed at the age of 5 years. A similar condition (Oliver-McFarlane) syndrome was reported previously. Our two sibs confirm the existence of this autosomal recessive syndrome.

Sixteen-slice multidetector CT findings of a case of constrictive pericarditis in a pediatric patient are presented. Multidetector CT depicted a variety of diagnostic findings including dynamic evaluation of interventricular septal motion through the cardiac cycle, documenting a diastolic septal bounce. This case illustrates the full capabilities of multidetector cardiac CT in the evaluation of pericardial pathology.

Blistering disorders in childhood are usually difficult to diagnose and pose complicated management dilemmas. The incidence of herpes zoster in children with malignancy and immunodeficiency is greatly increased compared to normal children of comparable age. Although herpes zoster is known to occur in children with malignancy, the bullous form of herpes zoster is rare; to the authors' knowledge, there was no previous report of this phenomenon in children in general and in children with cancer in particular. The authors describe a 3.5-year-old girl who was diagnosed with acute lymphoblastic leukemia; 7 months after presentation, during chemotherapy treatment, she developed the bullous form of herpes zoster on her right hand. The authors describe the method of diagnosis and provide a review of the literature concerning this rare phenomenon. Recognizing this entity and differentiating it from other bullomatous conditions enable the application of appropriate treatment, without unnecessary delay.

Acquired resistance towards apoptosis is the hallmark of most if not all types of cancer. We have previously identified and characterized ARTS, a broadly expressed protein localized to mitochondria. ARTS was initially shown to mediate TGF-beta induced apoptosis. Recently, we have found that high levels of ARTS induce apoptosis without additional pro-apoptotic stimuli. Further, ARTS promotes apoptosis in response to a wide variety of pro-apoptotic stimuli. Here, we report that the expression of ARTS is lost in all lymphoblasts of more than 70% of childhood acute lymphoblastic leukemia (ALL) patients. The loss of ARTS is specific, as the related non-apoptotic protein H5, bearing 83% identity to ARTS, is unaffected. During remission, ARTS expression is detected again in almost all patients. Two leukemic cell lines, ALL-1 and HL-60 lacking ARTS, were resistant to apoptotic induction by ara-C. Transfection of ARTS into these cells restored their ability to undergo apoptosis in response to this chemotherapeutic agent. We found that methylation process contributes to the loss of ARTS expression. We conclude that the loss of ARTS may provide a selective advantage for cells to escape apoptosis thereby contributing to their transformation to malignant lymphoblasts. We therefore propose that ARTS can function as a tumor suppressor protein in childhood ALL.

The frequencies of chromosome 9 abnormalities in children with hematological neoplasia have constituted: 25/112 in acute lymphoblastic leukemia (ALL), 10/83--in acute myeloid leukemia (AML), 3/20--in refractory anemia (RA). The frequency of deletions was higher than of translocations in ALL. Deletions were found as sole abnormalities as in complexity karyotypes. More often the rearrangements affected bands 9q34 and 9q22. Translocation t (9;22)(q34; q11) occured in 7.1% cases ALL. In AML the translocations were detected with greater frequency than deletions. The long arm bands 9q22 and 9q34 were more often involved in structural rearrangements. Deletions, translocations and duplications were registered in MDS. Comparison with clinical features showed no correlation with age and the main hematological indexes including the amount of blast cells in initial period. Multidrug resistance and disease progression during chemotherapy were noted in t (9;22).

The cases of chromosome 11 abnormalities in leukemic bone marrow cells have constituted 14.0% in acute lymphoblastic leukemia (ALL), 18.7% in acute myeloid leukemia (AML), and 16.7% in refractory anemia (RA). The bands of the short arms 11p13, 11p14, llp15 and the long arms 11q14, 11q21, 11q23 were involved in chromosome rearrangements. The rearrangements of the band 11q23 were detected more often. Reciprocal translocations were found with the highest frequency, while para- and pericentic invertions, terminal and intestitial deletions occured with the lower incidence. Deletions were found in RA cases only. Comparison with the clinical features showed no correlation with the age and the main haematological indexes including the amount of blast cells in the initial period. The results have showed the poor prognosis of the abnormalities not only of 11q21, 11q23 in acute leukemia (AL), but of 11p13, 11p15 in AML as well, while not enough data on this subject is availalbe in the literature.

3-Methylglutaconic aciduria is the biochemical marker of several inherited metabolic diseases. Four types of 3-methylglutaconic aciduria can be distinguished. In the type I form, accumulation of 3-methylglutaconate is due to deficient activity of 3-methylglutaconyl-CoA hydratase, an enzyme of the leucine degradation pathway. In the other forms, 3-methylglutaconic acid is not derived from leucine but is of unidentified origin, possibly derived from other metabolic pathways, such as mevalonate metabolism. We report five patients, all presenting a severe early-onset phenotype characterized by 3-methylglutaconic aciduria, hypertrophic cardiomyopathy, cataract, hypotonia/developmental delay, lactic acidosis, and normal 3-methylglutaconyl-CoA hydratase activity. This peculiar phenotype, for which a primary mitochondrial disorder is hypothesized, identifies a novel subtype of 3-methylglutaconic aciduria.

The Wilms tumor gene was identified as a tumor suppressor gene responsible for a particular type of kidney tumor. Several years ago, it was demonstrated that it is also overexpressed in acute and chronic leukemias. Although the exact role of this gene in the hematopoietic system is still quite completely obscure, it represents a reliable marker for the detection of the presence of leukemic cells. WT1 quantitative assessment may therefore represent a useful tool for the diagnosis and follow up of leukemia patients. In this chapter, we describe the method for the quantification of WT1 transcript by real-time polymerase chain reaction.

A kindred is reported with four members affected with neurodegenerative disorder and 3-methylglutaconic aciduria. Two siblings developed thrombocytopenia heralding a myelodysplastic syndrome; in one patient it evolved into acute myeloid leukemia with monosomy 7 in the marrow. The hematologic complications have hitherto not been previously reported in other cases of 3-methylglutaconic aciduria and are thus thought to represent a new disease entity. This family adds additional evidence to the genetic heterogeneity of Mendelian disorders in which the primary mutation may have a mutator effect that could give origin to myelodysplastic syndrome and acute myeloid leukemia through acquired chromosomal changes.