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Background/Objectives: Epidermolysis bullosa is a group of diseases caused by mutations in skin structural proteins. Availability of genetic sequencing makes identification of causative mutations easier, and genotype‐phenotype description and correlation are important. We describe six patients with a keratin 5 mutation resulting in a glutamic acid to lysine substitution at position 477 (p.Glu477Lys) who have a distinctive, severe and sometimes fatal phenotype. We also perform in silico modeling to show protein structural changes resulting in instability. Methods: In this case series, we collected clinical data from six patients with this mutation identified from their national or local epidermolysis bullosa databases. We performed in silico modeling of the keratin 5‐keratin 14 coil 2B complex using CCBuilder and rendered with Pymol (Schrodinger, LLC, New York, NY). Results: Features include aplasia cutis congenita, generalized blistering, palmoplantar keratoderma, onychodystrophy, airway and developmental abnormalities, and a distinctive reticulated skin pattern. Our in silico model of the keratin 5 p.Glu477Lys mutation predicts conformational change and modification of the surface charge of the keratin heterodimer, severely impairing filament stability. Conclusions: Early recognition of the features of this genotype will improve care. In silico analysis of mutated keratin structures provides useful insights into structural instability.

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-alpha. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA: DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA: DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

Triple A or Allgrove Syndrome (OMIM#231550) is a rare, autosomal recessive genetic disorder in which patients typically suffer from chronic adrenal insufficiency due to resistance to ACTH (Addison's disease), esophageal achalasia, and defective tear formation (alacrima). The syndrome is caused by mutations in the AAAS gene on chromosome 12q13 encoding a 546 aminoacid protein named alacrimia-achalasia-adrenal insufficiency neurologic disorder (ALADIN), a constituent of eukaryotic nuclear pore complexes.We describe a case of Allgrove Syndrome presenting with anhidrosis and peculiar dental features resembling those of Ectodermal Dysplasia (ED).Given the clinical findings in this case we suggest the hypothesis that the pathogenetic mechanism in Allgrove syndrome is related to the ED.

Follicular mucinosis represents a term for a histopathologic reaction pattern in follicular epithelium. It is a characteristic of alopecia mucinosa. However, it may also occur in a variety of unrelated conditions. Epidermal nevi are considered to be hamartomatous disorders and they can show a predominant component of non-organoid (keratinocytes) and/or organoid nevi. All the cases of epidermal nevi described with mucin deposits until now are reported as mucinous nevus or mucinous eccrine nevus; in the first type of disorder, diffuse mucin deposition is only seen in the papillary dermis, and in the second type, the mucin is found around the proliferation of eccrine structures. We believe this is the first reported case of epidermal nevus along Blaschko's lines exhibiting typical microscopic findings of mucinosis exclusively distributed inside the follicular epithelia.