Poster presentationsSG11 KRT14 pathogenic or likely pathogenic variants beyond epidermolysis bullosa: dermatopathia pigmentosa reticularis
Authors: Schirwani Schaida , Kharbanda Mira 
Published: June 2024

Abstract
The KRT14 gene is 4615 base pairs long and has eight exons. It encodes the intermediate filament protein keratin 14, which is 472 amino acids long and has four helical domains flanked by a nonhelical head domain and tail domain. Keratin 14 partners with the keratin 5 protein, encoded by the KRT5 gene, to provide structural support in basal keratinocytes of the epidermis and to regulate the distribution of melanin. Variants in KRT14 are associated with distinct clinical phenotypes and interesting genotype–phenotype correlations. Dermatopathia pigmentosa reticularis (DPR), or Naegeli–Franceschetti–Jadassohn syndrome (NFJS), has been associated with frameshift and nonsense variants involving the nonhelical head domain of keratin 14. Frameshift and missense variants in other domains of the protein cause dominant and recessive forms of epidermolysis bullosa simplex. Five different KRT14 variants have been reported in seven families with NFJS/DPR, including the presented family. Until recently NFJS and DPR were considered separate disease entities, but recent research supports the view that they are a spectrum of the same condition. We present three generations of a family with DPR. The index case is a 20-year-old woman who, at the age of 8 years, was noted to have thickened skin on the soles of feet, brittle and thickened nails, and dental issues. On examination, she was found to have onycholysis of her fingernails, hypoplasia of her dermatoglyphs, onychogryphosis affecting all 10 toenails, and pitted palmoplantar keratoderma. Reticulate skin hyperpigmentation, which is a feature of this syndrome, was absent. She had extensive dental disease with multiple dental carries, and broken and missing teeth. She reported generalized hyperhidrosis, particularly severe axillary hyperhidrosis, and had noncicatricial alopecia. Her mother presented with features of the condition at a similar age. She had similar but milder features. She had onycholysis, a degree of onychogryphosis and some punctate plantar keratoderma. No hyperhidrosis or heat intolerance were reported. At the age of 43 years she had a full set of teeth with one dental extraction and one filling. The index patient’s maternal grandfather was reported to have similar nail and skin features. He was also reported to have lost most of his teeth at a young age. Genetic testing identified a heterozygous pathogenic variant 19C&gt;T, p.GIn7Ter, in KRT14, which confirmed the diagnosis of DPR in the index case. The mother was found to carry the same variant. DPR is an ultrarare autosomal dominant ectodermal dysplasia characterized by reticulate hyperpigmentation (which may fade), nail dystrophy, keratoderma, hypo- or hyperhidrosis, hair abnormalities, dental disease and hypoplastic dermatoglyphs. Management focuses on symptomatic relief. A confirmed molecular diagnosis is important so patients can be offered appropriate medical and dental management and prenatal options, if they wish to pursue preimplantation genetic diagnosis.