Punctate palmoplantar keratodermas (PPPKs) are characterized by circumscribed hyperkeratotic lesions on palms and soles. These genodermatoses exhibit both clinical and genetic heterogeneity. By applying whole exome sequencing to a Scottish kindred with autosomal dominant PPPK (OMIM #148600), we identified a heterozygous heterozygous nonsense mutation in AAGAB, encoding alpha-and gamma-adaptin binding protein p34. This gene is located within a previously reported PPPK locus on chromosome 15q22. Conventional sequencing identified a further 7 heterozygous loss-of-function mutations in 17 additional families with severe or mild forms of PPPK. The p34 polypeptide has a GTPase domain related to the Rab superfamily of vesicle transport proteins and was shown biochemically to bind both alpha-and gamma-adaptins, indicative of a role in vesicle biology. Ultrastuctural analysis of lesional epidermis confirmed abnormalities of intracellular vesicle populations. Immunohistochemistry showed hyperproliferative basal cells within the punctate lesions. RNAi knockdown of p34 in keratinocytes led to increased cell division and a marked increase in epidermal growth factor receptor (EGFR) protein, as well as alterations in the abundance and/or phosphorylation of a number of downstream signaling molecules. We hypothesize that p34 deficiency impairs endocytic recycling of EGFR, leading to a hyperproliferative form of hyperkeratosis due to increased EGFR signaling. Impaired epithelial differentiation of induced pluripotent stem cells from EEC ectodermal dysplasia patients is rescued by a small compound APR-246/PRIMA-1METR Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem cell deficiency. In this study, we designed a novel cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18+ progenitor cells but failed to further properly differentiate into K14+ cells (epidermis/limbus) or K3/K12+ cells (corneal epithelium). APR-246 (PRIMA-1MET), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate normal p63related signaling pathway. This study illustrates the relevance of iPSC for p63-related disorders. This unique model serves to characterize the abnormal molecular circuitry of this congenital disease and paves the way for future therapy of EEC. During development, multipotent progenitor cells establish tissue-specific programmes of gene expression that underlie a proces...

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The practice of reaching an audience through social media to promote non-surgical treatments of the face is in its infancy. Young adults, arguably the most health-literate generation to date, comprise both the majority of users targeted by social media and the fastest growing demographic seeking cosmetic consultation. We know that this age group is also at an increased risk of depression and body dysmorphia in an era where non-surgical cosmetic options are typically thought to be gateways to surgical treatments. In light of these facts, it seems the ethics of medicine might be lagging behind the amorphous, rapidly evolving nature of social media and, specifically, its use as a platform for business promotion and health information. As cosmetic treatments become a normalized facet of society's health care routine, in large part due to its ubiquity on social media platforms, its promotion by providers requires reexamination so that its pro-social potential can be realized. This is ensured by fostering a social media presence and in-office attitude that treatments should be an agreement between patient and provider on realistic expectations and how best to meet them.

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