Two Novel TMPRSS6 Variants in a Compound Heterozygous Child With Iron Refractory Iron Deficiency Anemia.

We describe a Caucasian family with asymptomatic, nonconsanguineous parents, and a daughter with unexplained microcytic anemia diagnosed on routine hemoglobin screening at her 12-month well child check. After failed response to oral and parental iron supplementation, iron refractory iron deficiency anemia was suspected. The family underwent genetic testing and the proband was found to be a compound heterozygote for 2 previously unreported TMPRSS6 variants.

Fifty Years of Chronic Rhinosinusitis in Children: The Accepted, the Unknown, and Thoughts for the Future.

Chronic sinusitis is an often-used term in both lay and medical circumstances. In children, it has significant but largely undefined healthcare costs. Chronic rhinosinusitis (CRS) in children has well demarcated time periods and symptoms, although the actual pathway from normal sinus to CRS is not well understood. There is reasonable consensus as to the standards for diagnosis, the selection of a first-round antibiotic, and length of treatment. However, no recent prospective studies of antibiotics are available. Areas of continued speculation include the following: the microbiome of pediatric CRS, the best use of standard imaging, alternative antibiotic selection, ancillary therapy, and treatment of refractory CRS. In addition, older adolescents can present with a more adult-oriented CRS with or without polyps, suggesting a broader spectrum of disease than is commonly recognized. An accounting of the accepted elements of pediatric rhinosinusitis, as well as areas for future research, is emphasized in this review and, where appropriate, suggestions for potential investigations are offered.

Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer.

Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal ligand binding and internalization. M6P/IGF2R is a tumor suppressor gene that exhibits loss of heterozygosity and is mutated in several cancers. We tested the potential dominant-negative effects of two cancer-associated mutations that truncate M6P/IGF2R in ectodomain repeats 9 and 14. Our hypothesis was that co-expression of the truncated receptors with the wild-type/endogenous full-length M6P/IGF2R would interfere with M6P/IGF2R function by heterodimer interference. Immunoprecipitation confirmed formation of heterodimeric complexes between full-length M6P/IGF2Rs and the truncated receptors, termed Rep9F and Rep14F. Remarkably, increasing expression of either Rep9F or Rep14F provoked decreased levels of full-length M6P/IGF2Rs in both cell lysates and plasma membranes, indicating a dominant-negative effect on receptor availability. Loss of full-length M6P/IGF2R was not due to increased proteasomal or lysosomal degradation, but instead arose from increased proteolytic cleavage of cell-surface M6P/IGF2Rs, resulting in ectodomain release, by a mechanism that was inhibited by metal ion chelators. These data suggest that M6P/IGF2R truncation mutants may contribute to the cancer phenotype by decreasing the availability of full-length M6P/IGF2Rs to perform tumor-suppressive functions such as binding/internalization of receptor ligands such as insulin-like growth factor II.