Synchronous occurrence of acute lymphoblastic leukemia and wilms tumor in two patients: underlying etiology and combined treatment plan.

Synchronous cancers are extraordinarily rare in pediatric patients and present a therapeutic challenge. Patient A presented with synchronous unilateral Wilms tumor (WT) and standard-risk (SR) B-precursor acute lymphoblastic leukemia (ALL). Genetic testing revealed bialleleic BRCA2/FANCD1 mutations. Patient B, after SR B-precursor ALL induction therapy, was noted on fever workup to have a renal mass; pathology demonstrated lesion indeterminate between WT and nephrogenic rest. Therapy was customized for each patient to treat both cancers. Both patients have ongoing remission from their cancers, without excessive toxicity. We report two regimens for treating synchronous WT and ALL and recommend screening such patients for cancer predisposition.

SMARCE1 mutations in pediatric clear cell meningioma: case report.

Clear cell meningioma (CCM) is an uncommon variant of meningioma. The authors describe a case of a pediatric CCM localized to the lumbar spine. After resection, sequencing revealed an inactivating mutation in the SWI/SNF chromatin remodeling complex subunit SMARCE1, with loss of the second allele in the tumor. The authors present a literature review of this mutation that is associated with CCM and a family history of spine tumors.

Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas.

We recently reported SMARCE1 mutations as a cause of spinal clear cell meningiomas. Here, we have identified five further cases with non-NF2 spinal meningiomas and six with non-NF2 cranial meningiomas. Three of the spinal cases and three of the cranial cases were clear cell tumours. We screened them for SMARCE1 mutations and investigated copy number changes in all point mutation-negative samples. We identified two novel mutations in individuals with spinal clear cell meningiomas and three mutations in individuals with cranial clear cell meningiomas. Copy number analysis identified a large deletion of the 5' end of SMARCE1 in two unrelated probands with spinal clear cell meningiomas. Testing of affected and unaffected relatives of one of these individuals identified the same deletion in two affected female siblings and their unaffected father, providing further evidence of incomplete penetrance of meningioma disease in males. In addition, we found loss of SMARCE1 protein in three of 10 paraffin-embedded cranial clear cell meningiomas. Together, these results demonstrate that loss of SMARCE1 is relevant to cranial as well as spinal meningiomas. Our study broadens the spectrum of mutations in the SMARCE1 gene and expands the phenotype to include cranial clear cell meningiomas.

Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency.

X-linked lymphoproliferative disease (XLP) is a rare congenital immunodeficiency that leads to an extreme, usually fatal increase in the number of lymphocytes upon infection with EBV. It is most commonly defined molecularly by loss of expression of SLAM-associated protein (SAP). Despite this, there is little understanding of how SAP deficiency causes lymphocytosis following EBV infection. Here we show that T cells from individuals with XLP are specifically resistant to apoptosis mediated by TCR restimulation, a process that normally constrains T cell expansion during immune responses. Expression of SAP and the SLAM family receptor NK, T, and B cell antigen (NTB-A) were required for TCR-induced upregulation of key pro-apoptotic molecules and subsequent apoptosis. Further, SAP/NTB-A signaling augmented the strength of the proximal TCR signal to achieve the threshold required for restimulation-induced cell death (RICD). Strikingly, TCR ligation in activated T cells triggered increased recruitment of SAP to NTB-A, dissociation of the phosphatase SHP-1, and colocalization of NTB-A with CD3 aggregates. In contrast, NTB-A and SHP-1 contributed to RICD resistance in XLP T cells. Our results reveal what we believe to be novel roles for NTB-A and SAP in regulating T cell homeostasis through apoptosis and provide mechanistic insight into the pathogenesis of lymphoproliferative disease in XLP.

Kawasaki disease associated with reactive hemophagocytic lymphohistiocytosis.

We report a case of Kawasaki disease with significant coronary artery aneurysms subsequently associated with reactive hemophagocytic lymphohistiocytosis in a young child with low T-cell perforin expression and NK-cell dysfunction. The patient was treated with a selective T-cell costimulation modulator in an effort to regulate T-cells. This case is unique for several reasons: (1) the severe degree of coronary artery aneurysms; (2) low T-cell perforin and NK-cell values; and (3) treatment with a selective T-cell costimulation modulator, none of which has been described in prior cases.

Aplastic crisis revealing the diagnosis of Hb Evans [alpha62(E11)Val-->Met, GTG-->ATG (alpha2)] in a Hispanic kindred: case report and review.

This report describes a Hispanic girl who presented in aplastic crisis due to parvovirus infection. She was subsequently found to have a chronic hemolytic anemia secondary to an unstable hemoglobinopathy. Genetic testing revealed that the girl and two symptomatic family members had Hb Evans [alpha62(E11)Val-->Met, GTG-->ATG (alpha2)], an unstable hemoglobin (Hb) variant due to a mutation in the alpha2-globin chain. Hb Evans has been described only once previously, in a Caucasian kindred. Literature review indicates aplastic crisis is a rare initial presentation of unstable hemoglobinopathies and that these disorders are infrequent but important causes of hemolytic anemia in Hispanic patients.

Histopathologic verification of acute leukemia (AL) in a cohort of 463 post-Chernobyl patients from Belarus, Russia and Ukraine.

Seven morphologists examined 382 slide and 82 non-slide, post-Chernobyl pediatric acute leukemia (AL) cases in radiation-exposed areas of Belarus, Russia and Ukraine; part of a case-control study by the International Consortium for Research on the Health Effects of Radiation. Among the slide cases, 99% were confirmed as AL: 92% acute lymphoid leukemia (ALL) and 86% acute myeloid leukemia (AMD demonstrating the utility of FAB classification for distinguishing ALL and AML. Among the non-slide cases, 79% were confirmed as AL: 84% ALL, and 71% AML. This study affirms AL diagnostic accuracy during a time of social upheaval in the former Soviet Union.

Treatment of childhood acute lymphoblastic leukemia at a regional non-academic center in Belarus.

The outlook for children with cancer is improving in the less privileged nations of the world. This report from Belarus is representative of results that can be achieved.