No abstract

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients.

A mutant of Drosophila melanogaster carrying the lethal(l) myospheroid mutation [l(1)mys] has a defective musculature and a phenotype that suggests a defect of basement membranes. The genomic region that is interrupted by an insertion in a mutant carrying l(l)mys was used to isolate cDNA clones, and their sequences are presented here. The cDNA sequence predicts a cysteine-rich integral membrane protein that displays 45% sequence identity to chicken integrin and the human fibronectin receptor (3 subunit and much greater similarity over localized segments. These similarities extend to other vertebrate integrin (3 subunits, and we conclude that the myospheroid protein is an integrin (3 subunit of Drosophila. This implies evolutionary conservation of a group of transmembrane proteins that are receptors for extracellular matrix and, coupled with the myospheroid phenotype, indicates an important role for the interaction of cells with extraceliular matrix during development.

Pregnant women tend to find the prospect of a Down syndrome-affected birth more burdensome than a procedure-related miscarriage, calling into question the equal risk threshold for prenatal diagnosis. Individual preferences for those outcomes varied profoundly. Current guidelines do not appropriately consider individual preferences in lower-risk women, and the process for developing prenatal testing guidelines should be reconsidered to better reflect individual values.

The longitudinal integrated clerkship is a model of clinical education driven by tenets of social cognitive theory, situated learning, and workplace learning theories, and built on a foundation of continuity between students, patients, clinicians, and a system of care. Principles and goals of this type of clerkship are aligned with primary care principles, including patient-centered care and systems-based practice. Academic medical centers can partner with community health systems around a longitudinal integrated clerkship to provide mutual benefits for both organizations, creating a sustainable model of clinical training that addresses medical education and community health needs. A successful one-year longitudinal integrated clerkship was created in partnership between an academic medical center and an integrated community health system. Compared with traditional clerkship students, students in this clerkship had better scores on Clinical Performance Examinations, internal medicine examinations, and high perceptions of direct observation of clinical skills.Advantages for the academic medical center include mitigating the resources required to run a longitudinal integrated clerkship while providing primary care training and addressing core competencies such as systems-based practice, practice-based learning, and interprofessional care. Advantages for the community health system include faculty development, academic appointments, professional satisfaction, and recruitment.Success factors include continued support and investment from both organizations' leadership, high-quality faculty development, incentives for community-based physician educators, and emphasis on the mutually beneficial relationship for both organizations. Development of a longitudinal integrated clerkship in a community health system can serve as a model for developing and expanding these clerkship options for academic medical centers.