Evaluation of NSD2 and NSD3 in overgrowth syndromes

Sotos syndrome is an overgrowth condition predominantly caused by truncating mutations, missense mutations restricted to functional domains, or deletions of NSD1. NSD1 is a member of a protein family that includes NSD2 and NSD3, both of which show 70-75% sequence identity with NSD1. This strong sequence similarity suggests that abrogation of NSD2 or NSD3 function may cause non-NSD1 Sotos cases or other overgrowth phenotypes. To evaluate this hypothesis, we mutationally screened NSD2 and NSD3 in 78 overgrowth syndrome cases in which NSD1 mutations and deletions had been excluded. Additionally, we used microsatellite markers within the vicinity of the genes to look for whole gene deletions. No truncating mutations or gene deletions were identified in either gene. We identified two conservative missense NSD2 alterations in two non-Sotos overgrowth cases but neither was within a functional domain. We identified three synonymous and two intronic variants in NSD2 and two synonymous base substitutions in NSD3. Our results suggest that despite strong sequence similarity between NSD1, NSD2 and NSD3, the latter genes are unlikely to be making a substantial contribution to overgrowth phenotypes and thus may operate in distinct functional pathways from NSD1.     

Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura

Controversy exists regarding management of children newly diagnosed with immune thrombocytopenic purpura (ITP). Drug treatment is usually administered to prevent severe hemorrhage, although the definition and frequency of severe bleeding are poorly characterized. Accordingly, the Intercontinental Childhood ITP Study Group (ICIS) conducted a prospective registry defining severe hemorrhage at diagnosis and during the following 28 days in children with ITP. Of 1106 ITP patients enrolled, 863 were eligible and evaluable for bleeding severity assessment at diagnosis and during the subsequent 4 weeks. Twenty-five children (2.9%) had severe bleeding at diagnosis. Among 505 patients with a platelet count less than or equal to 20 000/mm(3) and no or mild bleeding at diagnosis, 3 (0.6%), had new severe hemorrhagic events during the ensuing 28 days. Subsequent development of severe hemorrhage was unrelated to initial management (P = .82). These results show that severe bleeding is uncommon at diagnosis in children with ITP and rare during the next 4 weeks irrespective of treatment given. We conclude that it would be difficult to design an adequately powered therapeutic trial aimed at demonstrating prevention of severe bleeding during the first 4 weeks after diagnosis. This finding suggests that future studies of ITP management should emphasize other outcomes.     

American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis

Objective

To prospectively validate the preliminary criteria for clinical inactive disease (CID) in patients with select categories of juvenile idiopathic arthritis (JIA).

Methods

We used the process for development of classification and response criteria recommended by the American College of Rheumatology Quality of Care Committee. Patient‐visit profiles were extracted from the phase III randomized controlled trial of infliximab in polyarticular‐course JIA (i.e., patients considered to resemble those with select categories of JIA) and sent to an international group of expert physician raters. Using the physician ratings as the gold standard, the sensitivity and specificity were calculated using the preliminary criteria. Modifications to the criteria were made, and these were sent to a larger group of pediatric rheumatologists to determine quantitative, face, and content validity.

Results

Variables weighted heaviest by physicians when making their judgment were the number of joints with active arthritis, erythrocyte sedimentation rate (ESR), physician's global assessment, and duration of morning stiffness. Three modifications were made: the definition of uveitis, the definition of abnormal ESR, and the addition of morning stiffness. These changes did not alter the accuracy of the preliminary set.

Conclusion

The modified criteria, termed the “criteria for CID in select categories of JIA,” have excellent feasibility and face, content, criterion, and discriminant validity to detect CID in select categories of JIA. The small changes made to the preliminary criteria set did not alter the area under the receiver operating characteristic curve (0.954) or accuracy (91%), but have increased face and content validity.     

School readiness

School readiness includes the readiness of the individual child, the school's readiness for children, and the ability of the family and community to support optimal early child development. It is the responsibility of schools to be ready for all children at all levels of readiness. Children's readiness for kindergarten should become an outcome measure for community-based programs, rather than an exclusion criterion at the beginning of the formal educational experience. Our new knowledge of early brain and child development has revealed that modifiable factors in a child's early experience can greatly affect that child's learning trajectory. Many US children enter kindergarten with limitations in their social, emotional, cognitive, and physical development that might have been significantly diminished or eliminated through early identification of and attention to child and family needs. Pediatricians have a role in promoting school readiness for all children, beginning at birth, through their practices and advocacy. The American Academy of Pediatrics affords pediatricians many opportunities to promote the physical, social-emotional, and educational health of young children, with other advocacy groups. This technical report supports American Academy of Pediatrics policy statements "Quality Early Education and Child Care From Birth to Kindergarten" and "The Inappropriate Use of School 'Readiness' Tests."     

The Texas Children's Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder

OBJECTIVE: In 1998, the Texas Department of Mental Health and Mental Retardation developed algorithms for medication treatment of attention-deficit/hyperactivity disorder (ADHD). Advances in the psychopharmacology of ADHD and results of a feasibility study of algorithm use in community mental health centers caused the algorithm to be modified and updated. METHOD: We convened a consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families to revise the algorithms for the pharmacotherapy of ADHD itself as well as ADHD with specific comorbid disorders. New research was reviewed by national experts, and rationales were provided for proposed changes and additions to the algorithms. The changes to the algorithms were discussed and approved both by the national experts and experienced clinicians from the Texas public mental health system. RESULTS: The panel developed consensually agreed-upon algorithms for ADHD with and without comorbid disorders. The major changes included elimination of pemoline as a treatment option, adding atomoxetine to the algorithm, and refining guidelines for treating ADHD with comorbid depression, aggressive behaviors, and tic disorders. CONCLUSIONS: Medication algorithms for ADHD can be modified to keep abreast of developments in the field. Although these evidence- and consensus-based treatment recommendations may be a useful approach to guide the treatment of ADHD in children, additional research is needed to determine how these algorithms can be used to maximally benefit child outcomes.     

Safety assessment of intensive induction therapy in childhood anaplastic large cell lymphoma: report of the ALCL99 randomised trial

Background

ALCL99 protocol including six courses of chemotherapy derived from the NHL‐BFM protocol is widely used for the treatment of paediatric anaplastic large‐cell lymphoma. In the ALCL99 trial, patients were randomised to receive MTX 1 g/m² in 24 hr with intrathecal injection (MTX1) versus MTX 3 g/m² in 3 hr without intrathecal (MTX3); then to receive or not vinblastine (high‐risk patients). The present study provides information about the acute adverse reactions (ARs) during the six courses of the ALCL99 treatment, assesses risk factors for ARs and evaluates the risk of overweight related to treatment.

Methods

Data concerning ARs were assessed using CTCv2 and analysed overall and according to the type of course.

Results

Between 1999 and 2005, 352 patients were recruited. Toxicity assessed after 2050 courses included grade 4 neutropaenia (70% of courses), grade 3–4 stomatitis (13%), grade 3–4 transaminase elevation (10%) and grade 3–4 infection (5%). Four patients (1%) died of toxicity. The toxicity profile differed between courses‐A (significantly more haematological toxicity) and courses‐B (significantly more stomatitis). The percentage of ARs was higher after the first course than after subsequent courses. Severe toxicity was more frequent after MTX1 than after MTX3 courses but did not differ between courses with or without vinblastine. Overall 20% of patients had a weight gain exceeding 20%.

Conclusions

The high rate of acute toxicity should be considered when using the ALCL99 protocol. Chemotherapy including MTX 3 g/m² in 3 hr was less toxic than the same regimen with MTX 1 g/m² in 24 hr. Adding vinblastine did not increase the risk of toxicity. Pediatr Blood Cancer 2011;56:1071–1077. © 2011 Wiley‐Liss, Inc.     

Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer Survivor Study

BACKGROUND: Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML). METHODS: This analysis included 272 5-year AML survivors who participated in the Childhood Cancer Survivor Study (CCSS). All patients were diagnosed at age < or =21 years between the years 1970 and 1986, and none underwent stem cell transplantation. Rates of survival, relapse, and late outcomes were analyzed. RESULTS: The average follow-up was 20.5 years (range, 5-33 years). The overall survival rate was 97% at 10 years (95% confidence interval [95%CI], 94%-98%) and 94% at 20 years (95% CI, 90%-96%). Six survivors reported 8 recurrences. The cumulative incidence of recurrent AML was 6.6% at 10 years (95% CI, 3.7%-9.6%) and 8.6% at 20 years (95% CI, 5.1%-12.1%). Ten subsequent malignant neoplasms (SMN) were reported, including 4 with a history of radiation therapy, for a 20-year cumulative incidence of 1.7% (95% CI, 0.02%-3.4%). Six cardiac events were reported, for a 20-year cumulative incidence 4.7% (95% CI, 2.1%-7.3%). Half of the survivors reported a chronic medical condition and, compared with siblings, were at increased risk for severe or life-threatening chronic medical conditions (16% vs 5.8%; P < .001). Among those aged > or =25 years, the age-adjusted marriage rates were similar among survivors and the general United States population (57% for both) and lower compared with siblings (67%; P < .01). Survivors' college graduation rates were lower compared with siblings but higher than the general population (40% vs 52% vs 34%, respectively; P < .01). Employment rates were similar between survivors, siblings, and the general population (93%, 97.6%, and 95.8%, respectively). CONCLUSIONS: Long-term survival from childhood AML > or =5-years after diagnosis was favorable. Late-occurring medical events remained a concern with socioeconomic achievement lower than expected within the individual family unit, although it was not different from the general United States population.