Vohwinkel Syndrome (VS) is a rare autosomal dominant skin disorder with two main mutation types: the classic form caused by GJB2 gene mutations and loricrin keratoderma (LK) linked to LOR gene mutations. LK typically lacks hearing loss and often presents at birth as collodion baby syndrome. A 7-year-old male proband presenting with congenital thickening of the palms and soles was admitted to Başakşehir Çam and Sakura City Hospital. Whole-exome sequencing was performed from a whole blood sample using the MGI-400 platform, and common or benign mutations were excluded. Segregation analysis confirmed a pathogenic LOR mutation. Wild-type and mutant loricrin structures were modeled using I-TASSER and refined with ModRefiner. Protein interactions were analyzed via STRING, and docking with TGase 3 was performed using HDOCK. Structural visualization was completed using UCSF Chimera. A specific LOR mutation [NM_000427.3 c.684dup p.(Ser229ValfsTer107)] was identified, associated with palmoplantar keratoderma, ichthyosis-like plaques on the elbows and knees, anhidrosis, and absence of dental abnormalities, consistent with typical loricrin keratoderma (LK) cases. In silico analysis revealed that wild-type loricrin binds transglutaminase 3 (Tgase 3) with a lower score, and serine interactions present in normal loricrin were absent in the mutant form. Frameshift mutations also reduced glycine motifs critical for epidermal protein organization and skin flexibility. Genetic testing is essential for accurate diagnosis and differentiation of LK from other VS types. This case highlights the importance of genetic screening for early diagnosis and improved management, ultimately enhancing patient care in rare populations. Vohwinkel syndrome, also known as keratoderma hereditarian mutilans, is classified as a type of hereditary palmoplantar keratoderma (PPK). PPKs exist on a spectrum from inherited to acquired and can range in their presentation. A PPK may be an isolated finding or part of a syndrome with extracutaneous involvement. Rarely a PPK can be drug-induced or part of a paraneoplastic process. The classic Vohwinkel syndrome is a hereditary PPK associated with "starfish" keratoses on the knuckles, a PPK in a "honeycomb" pattern, hearing impairment, and mutilating digital constriction bands (pseudoainhum) that often lead to autoamputation of the affected digit(s). A variant of Vohwinkel syndrome, loricrin keratoderma, presents as a honeycomb PPK with pseudoainhum with the addition of ichthyosis; deafness is not a feature of this ichthyosiform variant.

Palmoplantar keratodermas (PPK) comprise a heterogeneous group of keratinization disorders that gradually progress during childhood, resulting in difficulties to establish a diagnosis and to identify a candidate gene for sequencing. Dermoscopic examination with staining of palmoplantar skin using a whiteboard marker, so-called "furrow ink test", could be a useful tool for differentiation between furrow and ridge in understanding the morphological characteristics of PPK. One of the striking features in autosomal dominant loricrin keratoderma (LK) is diffuse PPK with honeycomb pattern. In this study, we performed dermoscopic furrow ink test in a Japanese family of LK with the most frequent mutation c.684dup, p.Ser229Valfs*107 in the loricrin gene. The severe lesion revealed that irregular circular hyperkeratoses were aggregated and normal structures of furrows and ridges were disrupted. To accurately describe the nature of this dermoscopic patterned skin surface, we suggest that the condition could be termed as "irregular cobblestone appearance" rather than "honeycomb pattern". Regular cobblestone appearance to maintain parallel furrow structure was observed in early or mild hyperkeratotic lesions. Eccrine sweat glands that open on the surface of ridges nearly disappeared, resulting in hypohidrosis.

Revertant mosaicism refers to a condition in which a pathogenic germline mutation is spontaneously corrected in somatic cells, resulting in the presence of two or more cell populations with different genotypes in an organism arising from a single fertilized egg. If the revertant cells are clonally expanded due to a survival advantage over the surrounding mutant cells, patients benefit from this self-healing phenomenon which leads to the development of milder-than-expected clinical phenotypes; in genetic skin diseases, patients with revertant mosaicism present with small islands of healthy skin. To date, revertant mosaicism has been reported in ∼50 genetic diseases involving the skin, blood, liver, muscle, and brain. In this review, I briefly summarize current knowledge on revertant mosaicism in two particular skin diseases, ichthyosis with confetti (IWC) and loricrin keratoderma (LK), both of which develop numerous revertant skin patches. Notably, homologous recombination (HR) is the only mechanism underlying the reversion of pathogenic mutations in IWC and LK, and this was identified following the analysis of ∼50 revertant epidermis samples. All the samples showed long-tract loss of heterozygosity (LOH) that originated at regions centromeric to pathogenic mutations and extended to the telomere of the mutation-harboring chromosomes. Elucidating the molecular mechanisms underlying revertant mosaicism in IWC and LK-especially how mutant proteins induce long-tract LOH-would potentially expand the possibility of manipulating HR to induce the reversion of disease-causing mutations and help devising novel therapies not only for IWC and LK but also for other intractable genetic diseases.

Mutations in GJB2 encoding Connexin 26 (CX26) are associated with hearing loss and hyperproliferative skin disorders of differing severity including keratitis-ichthyosis-deafness (KID) and Vohwinkel syndrome. A 6-year-old Caucasian girl who presented with recurrent skin rashes and sensorineural hearing loss harboured a heterozygous point mutation in GJB2 (c.424T > C; p.F142L). To characterize the impact of CX26F142L on cellular events. Plasmids CX26WT, CX26F142L, CX26G12R (KID) or CX26D66H (Vohwinkel) were transfected into HeLa cells expressing Cx26 or Cx43 or into HaCaT cells, a model keratinocyte cell line. Confocal microscopy determined protein localization. MTT assays assessed cell viability in the presence or absence of carbenoxolone, a connexin-channel blocker. Co-immunoprecipitation/Western blot analysis determined Cx43:Cx26 interactions. Quantitative real-time polymerase chain reaction assessed changes in gene expression of ER stress markers. Dye uptake assays determined Connexin-channel functionality. F142L and G12R were restricted to perinuclear areas. Collapse of the microtubule network, rescued by co-treatment with paclitaxel, occurred. ER stress was not involved. Cell viability was reduced in cells expressing F142L and G12R but not D66H. Unlike G12R that forms "leaky" hemichannels, F142L had restricted permeability. Cell viability of F142L and G12R transfected cells was greater in HeLa cells expressing Cx43 than in native Cx-free HeLa cells. Co-immunoprecipitation suggested a possible interaction between Cx43 and the three mutations. Expression of CX26F142L and G12R results in microtubule collapse, rescued by interaction with Cx43. The GJB2 mutations interacted with Cx43 suggesting that unique Cx43:Cx26 channels are central to the diverse phenotype of CX26 skin-related channelopathies.