Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11

We report a patient with a clinical and molecular diagnosis of LEOPARD syndrome (LS) associated with multiple granular cell tumors (MGCT). Bidirectional sequencing of exons 7, 12, and 13 of the PTPN11 gene revealed the T468M missense mutation in exon 12. This mutation has been previously reported in patients with LS. To our knowledge, this is the first report of MGCT associated with molecularly characterized LS and provides the first molecular evidence linking granular cell tumors (GCT) to the Ras/mitogen-activated protein (MAP) kinase pathway. We propose that MGCT can be associated with LS. Analysis of GCT from this case tested negatively for loss of heterozygosity (LOH) at the PTPN11 and NF1 loci and did not show deletions of the PTEN gene. The absence of LOH of PTPN11 supports published functional data that T468M is a dominant-negative mutation.     

C/EBPalpha binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment

The PU.1 gene contains a 237-base pair distal enhancer located 14 kilobases upstream of its promoter. We have identified 2 sites within the PU.1 enhancer that strongly bind C/EBPalpha in a gel shift assay, and interaction with endogenous C/EBPalpha was confirmed by chromatin immunoprecipitation. Mutation of these DNA elements reduced activity of a distal enhancer-promoter construct 2- or 5-fold in a myeloid cell line, while mutation of a weaker C/EBPalpha-binding site located in the promoter minimally reduced activity in this context. These findings strengthen the link between C/EBPalpha and PU.1 expression. Reduction of C/EBPalpha activity in cases of acute myeloid leukemia may therefore contribute to transformation by reducing PU.1 levels. In addition, induction of PU.1 by C/EBPalpha during normal hematopoiesis may contribute to stem cell commitment to the myeloid lineages and further commitment to monopoiesis. Consistent with a requirement for C/EBPalpha induction of PU.1 during myeloid development, we demonstrate that C/EBPalpha induces monocytic development when expressed in PU.1(+/+), PU.1(+/-), or PU.1(+/kd) marrow myeloid progenitors but induces granulocyte lineage commitment in PU.1(kd/kd) cells lacking the PU.1 distal enhancer and does not induce either lineage in PU.1(-/-) cells.     

Occult malignant breast lesions in 114 patients: relationship to age and the presence of microcalcifications

This study evaluates the mammographic findings in 352 patients, aged 30-85 years, who underwent spot localization and biopsy for evaluation of nonpalpable breast abnormalities. Malignancy was found at biopsy in 114 cases. The mammographic appearance (specifically, whether grouped microcalcifications, mass, or both were present) was correlated with patient age and histologic findings (specifically, whether the pathologic changes were infiltrating or noninfiltrating in nature). The prevalence of malignant conditions increased directly with age. The presence of grouped microcalcifications as the sole indicator of malignancy was seen in 100% (seven of seven) of the patients in the 30-39-year age group, 64% (18 of 28) in the 40-49-year age group, 37% (11 of 30) in the 50-59-year age group, 30% (seven of 23) in the 60-69-year age group, and 23% (six of 26) in the 70-85-year age group. Of the 49 tumors that were manifested solely as microcalcifications, 34 (69%) were noninfiltrating. The finding of grouped microcalcifications should be aggressively investigated, since it may indicate noninfiltrating carcinoma in an early stage, when the potential for cure is greatest.     

Does Physical Activity in Adolescence Have Site‐Specific and Sex‐Specific Benefits on Young Adult Bone Size,Content, and Estimated Strength?

The long‐term benefits of habitual physical activity during adolescence on adult bone structure and strength are poorly understood. We investigated whether physically active adolescents had greater bone size, density, content, and estimated bone strength in young adulthood when compared to their peers who were inactive during adolescence. Peripheral quantitative computed tomography (pQCT) was used to measure the tibia and radius of 122 (73 females) participants (age mean ± SD, 29.3 ± 2.3 years) of the Saskatchewan Pediatric Bone Mineral Accrual Study (PBMAS). Total bone area (ToA), cortical density (CoD), cortical area (CoA), cortical content (CoC), and estimated bone strength in torsion (SSI_p) and muscle area (MuA) were measured at the diaphyses (66% tibia and 65% radius). Total density (ToD), trabecular density (TrD), trabecular content (TrC), and estimated bone strength in compression (BSI_c) were measured at the distal ends (4%). Participants were grouped by their adolescent physical activity (PA) levels (inactive, average, and active) based on mean PA Z‐scores obtained from serial questionnaire assessments completed during adolescence. We compared adult bone outcomes across adolescent PA groups in each sex using analysis of covariance followed by post hoc pairwise comparisons with Bonferroni adjustments. When adjusted for adult height, MuA, and PA, adult males who were more physically active than their peers in adolescence had 13% greater adjusted torsional bone strength (SSI_p, p < 0.05) and 10% greater adjusted ToA (p < 0.05) at the tibia diaphysis. Females who were more active in adolescence had 10% larger adjusted CoA (p < 0.05), 12% greater adjusted CoC (p < 0.05) at the tibia diaphysis, and 3% greater adjusted TrC (p < 0.05) at the distal tibia when compared to their inactive peers. Benefits to tibia bone size, content, and strength in those who were more active during adolescence seemed to persist into young adulthood, with greater ToA and SSI_p in males, and greater CoA, CoC, and TrC in females. © 2014 American Society for Bone and Mineral Research.     

Linkage of a familial platelet disorder with a propensity to develop myeloid malignancies to human chromosome 21q22.1-22.2

Linkage analysis was performed on a large pedigree with an autosomal dominant platelet disorder and a striking propensity in affected family members to develop hematologic malignancy, predominantly acute myelogenous leukemia. We report the linkage of the autosomal dominant platelet disorder to markers on chromosome 21q22. Four genetic markers completely cosegregate with the trait and yield maximum logarithm of difference scores ranging from 4.9 to 10.5 (theta = .001). Two flanking markers, D21S1265 and D21S167, define a critical region for the disease locus of 15.2 centimorgan. Further analysis of this locus may identify a gene product that affects platelet production and function and contributes to the molecular evolution of hematologic malignancy.