SUMMARY This report identifies human skeletal diseases associated with mutations in WNT1. In ten family members with dominantly inherited early-onset osteoporosis, a heterozygous missense variation c.652T>G (p.Cys218Gly) in WNT1 segregated with the disease, and a homozygous nonsense mutation (c.884C>A, p.Ser295*) was identified in two siblings with recessive osteogenesis imperfecta. In vitro, aberrant forms of WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. Wnt1 was clearly expressed in bone marrow, especially in B cell lineage and hematopoietic progenitors; lineage tracing identified expression in a subset of osteocytes, suggesting altered cross-talk of WNT signaling between hematopoietic and osteoblastic lineage cells in these diseases.

In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.

Pediatric hematology oncology nurses face a variety of stressors while working in this specialty field. Through hematology oncology staff group discussions, nurses identified a myriad physical and emotional stressors they experienced, and expressed concern regarding possible burnout. They described facing stressors related to experiencing loss, grief, moral and ethical dilemmas, and administering complex treatment regimens. To address these concerns, a hematology oncology nursing supportive care committee envisioned and implemented 3 off-site self-care retreats. The committee's primary purpose was to create a therapeutic and supportive environment for all participants, while allowing time for relaxation, reflection, and serenity. The primary goals for the retreats were to heal nurses from their reported past trauma and stress and to provide them effective coping strategies for the ongoing stressors they will inevitably face. In a collaborative effort, the committee members developed an agenda including presentations, group discussions, and relaxation activities. Written evaluations were completed by each participant to assess the benefit of the retreat. Overall feedback was extremely positive, with the majority of the participants finding great value in this experience.

Introduction Osteogenesis imperfecta (OI), Ehlers-Danlos syndrome (EDS), and osteopetrosis (OPT)are collectively common inherited skeletal diseases. Evaluation of subjects with these conditions often includes molecular testing which has important counseling, therapeutic and sometimes legal implications. Since several different genes have been implicated in these conditions, Sanger sequencing of each gene can be a prohibitively expensive and time consuming way to reach a molecular diagnosis. Methods In order to circumvent these problems, we have designed and tested a NGS platform that would allow simultaneous sequencing on a single diagnostic platform of different genes implicated in OI, OPT, EDS, and other inherited conditions leading to low or high bone mineral density. We used a liquid-phase probe library that captures 602 exons (~100 kb) of 34 selected genes and have applied it to test clinical samples from patients with bone disorders. Results NGS of the captured exons by Illumina HiSeq2000 resulted in an average coverage of over 900X. The platform was successfully validated by identifying mutations in 6 patients with known mutations. Moreover, in 4 patients with OI or OPT without a prior molecular diagnosis, the assay was able to detect the causative mutations. Conclusions In conclusion, our NGS panel provides a fast and accurate method to arrive at a molecular diagnosis in most patients with inherited high or low bone mineral density disorders.

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