Malignant transformation of white sponge nevus: a case report of a novel keratin 4 mutation.

BACKGROUND: White Sponge Nevus (WSN) is traditionally considered a benign genetic disorder affecting the oral mucosa, primarily caused by pathogenic mutations in keratin 4 (KRT4) or keratin 13 (KRT13). Despite its benign nature, recent evidence has begun to question the malignant potential of WSN. CASE PRESENTATION: We report a case involving a 70-year-old man who presented with a white lesion on the right floor of his mouth. Initial diagnostic evaluations confirmed the lesion as WSN. Over a one-year follow-up, the lesion underwent malignant transformation, evolving into local epithelial moderate-to-severe dysplasia. Exome sequencing identified a novel insertion mutation in exon 1 of the KRT4 gene, resulting in a deletion-insertion amino acid mutation involving glycine. Single-cell RNA sequencing further revealed altered epithelial proliferation and differentiation dynamics within the lesion. CONCLUSIONS: This case not only expands the known genetic spectrum of KRT4 mutations associated with WSN but also provides preliminary evidence suggesting the malignant potential of WSN. The novel pathogenic mutation in KRT4 is postulated to alter epithelial proliferation and differentiation, thereby raising concerns about the malignant transformation of WSN. Further studies are warranted to confirm these findings.

[A boy with white sponge naevus of the buccal mucosa]. / Een jongen met witte afwijkingen op het mondslijmvlies.

White sponge naevus (WSN) is a rare, autosomal dominant disorder that causes various complaints WSN is most commonly found on the buccal mucosa. Clinically, the white, slightly elevated lesions of WSN may be confused with other disorders on oral mucosa. We report a case of WSN in a 14-year-old boy who had complaints for a considerable period of time. WSN is caused by mutations in KRT4 and KRT13.

Keratin 13 deficiency causes white sponge nevus in mice.

White sponge nevus (WSN) is a benign autosomal dominant disorder characterized by the formation of white spongy plaques in the oral mucosa. Keratin (KRT) 13 is highly expressed in the mucosa, and mutations in this gene have been commonly associated with WSN patients. However, it remains unknown whether there is a causal relationship between KRT13 mutations and WSN and what the underlying mechanisms might be. Here, we use mouse genetic models to demonstrate that Krt13 is crucial for the maintenance of epithelial integrity. Krt13 knockout mice show a WSN-like phenotype in several tissues, including the tongue, buccal mucosa, and esophagus. Transcriptome analyses uncover that Krt13 regulates a cohort of gene networks in tongue epithelial cells, including epithelial differentiation, immune responses, stress-activated kinase signaling, and metabolic processes. We also provide evidence that epithelial cells without Krt13 are susceptible to mechanical stresses experienced during postnatal life, resulting in unbalanced cell proliferation and differentiation. These data demonstrate that Krt13 is essential for maintaining epithelial homeostasis and loss of Krt13 causes the WSN-like phenotype in mice.

The molecular-based differentiation of Heck's disease from its mimics including oral condyloma and white sponge nevus.

Heck's disease (focal or multifocal epithelial hyperplasia) is a benign, rare condition of the skin and mucous membranes induced by human papillomavirus (HPV) infection. Other entities that can induce large papillomatous lesions that involve the mucous membranes and skin include condyloma acuminatum, which is sexually transmitted, and white sponge nevus, often due to a mutation of cytokeratin 4 or 13. Six cases diagnosed as either Heck's disease (n = 2) or white sponge nevus (n = 4) and 6 oral condyloma were compared on histologic grounds and analyzed in situ for HPV DNA, including HPVs 6,11, and 13, as well as cytokeratins 4 and 13. Each case showed marked acanthosis, and para/hyperkeratosis. More variable histologic findings included rete ridge elongation, keratinocyte degeneration, and perinuclear halos. High copy HPV 13 DNA was evident in the squamous cells towards the surface in the two cases diagnosed as Heck's disease and in two cases diagnosed as white sponge nevus on clinical grounds. HPV 6/11 was found in each of the six condyloma. Marked decrease in either cytokeratin 4 or 13 was evident in the two cases diagnosed as white sponge nevus that were HPV DNA negative. It is concluded that in situ hybridization analyses including HPVs 6, 11, and 13 as well as immunohistochemistry for cytokeratins 4 and 13 can differentiate Heck's disease from condyloma and white sponge nevus, which can be difficult to differentiate on clinical and histologic grounds.

Keratin 4 regulates the development of human white sponge nevus.

BACKGROUND: The aim of this study was to investigate the roles of keratin 4 (KRT4) gene in the development of human white sponge nevus (WSN). METHODS: Transgenic mice were created using the microinjection method with pcDNA3.1 vectors expressing KRT4 wild-type (WT) gene and E520K mutation. Polymerase chain reaction (PCR) and Western blotting were used to identify the genotype of transgenic founders and their filial generations. Expression of KRT4 in mouse oral mucosa was characterized by immunohistochemistry (IHC), and the whole epithelium layer of transgenic mice was observed using transmission electron microscope (TEM). RESULTS: The positive rate of KRT4 transgenic mice in F1 generation was 45.5%. Expression level of KRT4 protein was significantly higher in 2-month-old transgenic mice than WT mice. Furthermore, all the epithelial lamina of 3-month-old transgenic mice showed reduced staining of KRT4. The surface and spinous layers were full of hyalocytes and bubble cells, which are similar to the clinical symptoms of WSN. For the ultrastructure, both tonofilaments and Odland bodies increased. CONCLUSIONS: Our study indicated the mutated KRT4 gene may play important roles in the pathogenesis of WSN.

Clinical features and molecular genetic analysis in a Turkish family with oral white sponge nevus.

BACKGROUND: Oral white sponge nevus (WSN) is a rare autosomal dominant benign condition, characterized by asymptomatic spongy white plaques. Mutations in Keratin 4 (KRT4) and 13 (KRT13) have been shown to cause WSN. Familial cases are uncommon due to irregular penetrance. Thus, the aim of the study was: a) to demonstrate the clinical and histopathological features of a three-generation Turkish family with oral WSN b) to determine whether KRT4 or KRT13 gene mutation was the molecular basis of WSN. MATERIAL AND METHODS: Out of twenty members of the family ten were available for assessment. Venous blood samples from six affected and five unaffected members and 48 healthy controls were obtained for genetic mutational analysis. Polymerase chain reaction was used to amplify all exons within KRT4 and KRT13 genes. These products were sequenced and the data was examined for mutations and polymorphisms. RESULTS: Varying presentation and severity of clinical features were observed. Analysis of the KRT13 gene revealed the sequence variant Y118D as the disease-causing mutation. One patient revealed several previously unreported polymorphisms including a novel mutation in exon 1 of the KRT13 gene and a heterozygous deletion in exon 1 of KRT4. This deletion in the KRT4 gene was found to be a common polymorphism reflecting a high allele frequency of 31.25% in the Turkish population. CONCLUSIONS: Oral WSN may manifest variable clinical features. The novel mutation found in the KRT13 gene is believed to add evidence for a mutational hotspot in the mucosal keratins. Molecular genetic analysis is required to establish correct diagnosis and appropriate genetic consultation.

Mutations in the genes for keratin-4 and keratin-13 in Swedish patients with white sponge nevus.

BACKGROUND: White sponge nevus is a rare autosomal dominant disorder that affects the non-keratinised stratified squamous epithelium. Mutations in the genes that encode mucosa-specific keratin-4 and keratin-13 are strongly linked to the manifestation of white sponge nevus. This study involved mutational analysis of the genes encoding keratin-4 and keratin-13 in two Swedish families with white sponge nevus. METHODS: The diagnosis of white sponge nevus was based on disease history, clinical characteristics of the lesions and, in the majority of the cases, histopathological examination. Samples were collected from the affected buccal mucosa using buccal swabs. DNA was subsequently extracted and amplified using touchdown-PCR. The keratin-4 and keratin-13 genes were sequenced, and a genetic analysis was performed. RESULTS: A novel heterozygous missense mutation was identified in exon 1A of the keratin-4 gene in Family 2. In addition, previously reported heterozygous missense mutations were identified in the keratin-4 (E449K, A72V, Q156R, R208H) and keratin-13 (L115P) genes in both families. CONCLUSION: We describe a novel heterozygous missense mutation in the keratin-4 gene of a Swedish family with white sponge nevus. Our results support the notion that mutations in keratin-4 and keratin-13 are the underlying cause of white sponge nevus.

Expression profiling of white sponge nevus by RNA sequencing revealed pathological pathways.

BACKGROUND: White sponge nevus (WSN) is a rare periodontal hereditary disease. To date, almost all WSN studies have focused on case reports or mutation reports. Thus, the mechanism behind WSN is still unclear. We investigated the pathogenesis of WSN using expression profiling. METHODS: Sequence analysis of samples from a WSN Chinese family revealed a mutation (332 T > C) in the KRT13 gene that resulted in the amino acid change Leu111Pro. The pathological pathway behind the WSN expression profile was investigated by RNA sequencing (RNA-seq). RESULTS: Construction of a heatmap revealed 24 activated genes and 57 reduced genes in the WSN patients. The ribosome structure was damaged in the WSN patients. Moreover, the translation rate was limited in the WSN patients, whereas ubiquitin-mediated proteolysis was enhanced. CONCLUSIONS: Our results suggest that the abnormal degradation of the KRT13 protein in WSN patients may be associated with keratin 7 (KRT7) and an abnormal ubiquitination process.

Current approaches to the diagnosis and treatment of white sponge nevus.

White sponge nevus (WSN) in the oral mucosa is a rare autosomal dominant genetic disease. The involved mucosa is white or greyish, thickened, folded and spongy. The genes associated with WSN include mutant cytokeratin keratin 4 (KRT4) and keratin 13 (KRT13). In recent years, new cases of WSN and associated mutations have been reported. Here, we summarise the recent progress in our understanding of WSN, including clinical reports, genetics, animal models, treatment, pathogenic mechanisms and future directions. Gene-based diagnosis and gene therapy for WSN may become available in the near future and could provide a reference and instruction for treating other KRT-associated diseases.

Mutation of keratin 4 gene causing white sponge nevus in a Japanese family.

White sponge nevus (WSN) is a rare autosomal dominant disorder characterized by white plaques of oral mucosa; it is benign condition with no effective treatment. The disorder usually manifests during early childhood or adolescence. Mutations of keratin 4 or 13 gene have been identified as causing WSN. The aim of this study is to determine whether keratin 4 or 13 gene mutation was the molecular basis of WSN in a Japanese family. The proband in this family was an 11-year-old boy, with three other people affected by WSN. Genomic DNA was extracted from two affected members and an unaffected member. Segments of keratin 4 and 13 genes were amplified by PCR, and direct DNA sequencing was carried out. Sequence analysis revealed a heterozygous 3bp deletion (N160Del) localized in the helix-initiation motif at the beginning of alpha-helical domain 1A of keratin 4 gene from affected members. One member lacking the phenotype was genetically tested normal. The authors identified a mutation of the keratin 4 gene recurrent in a family affected by WSN. Further investigation of the multifunctional role of keratin genes is warranted in the group of inherited epithelial disorders that may result in identification of effective treatment for this genetic disease.

Familial white sponge nevus of the oral mucosa: report of occurrence in three generations.

White sponge nevus is a rare, inherited disorder that usually presents as nonpainful white plaque primarily involving the buccal mucosa, gingiva, and palate. Extraoral lesions most often occur in the esophagus or anogenital area, but almost invariably follow the development of typical buccal lesions. This article presents a familial case of white sponge nevus in which oral lesions were found in patients in three generations of the same family. Histologic findings include hyperkeratosis, acanthosis, and perinuclear eosinophilic condensation of epithelial cell cytoplasm, which serve to confirm white sponge nevus as the diagnosis. Clinical presentation and histopathology of white sponge nevus are discussed in relation to the differential diagnosis of other oral leukokeratoses.

Familial case of oral white sponge nevus--a rare hereditary condition.

White sponge nevus (WSN) is an autosomal dominant skin disorder characterized by white, corrugated and diffuse plaques mainly affecting the oral mucosa. The condition has a high penetrance and variable expressivity, but familial reports are uncommon. This report presents a familial case of WSN in which two sisters are affected by the disorder.

Caso familiar de nevo branco esponjoso oral: uma rara condição hereditária / Familial case of oral white sponge nevus: a rare hereditary condition

O nevo branco esponjoso é uma desordem autossômica dominante, caracterizada por placas brancas difusas, rugosas, que afetam principalmente a mucosa bucal. A condição tem um alto grau de penetrância e expressividade variada, embora os relatos familiais sejam incomuns. Este artigo relata um caso familiar de nevo branco esponjoso em que duas irmãs são afetadas por esta condição.

White sponge nevus (WSN) is an autosomal dominant skin disorder characterized by white, corrugated and diffuse plaques mainly affecting the oral mucosa. The condition has a high penetrance and variable expressivity, but familial reports are uncommon. This report presents a familial case of WSN in which two sisters are affected by the disorder.

White sponge nevus: presentation of a new family.

We present an occurrence of white sponge disease affecting four members of the same family: a father and three children. The lesions consisted of white asymptomatic patches in the oral mucosa.

White sponge nevus. A case report.

White sponge nevus is a rare autosomal dominant hereditary disorder manifesting upon physical examination as white symmetric, diffuse, thickened, corrugated or velvety plaques on the oral, esophageal or genital mucosa. They are also found to be bilateral and asymptomatic. The tissue changes can be present at birth or manifest during childhood or adolescence, and this disorder occurs in females more than in males. It is a benign condition since cases of malignancy have not been reported, and it does not require treatment. Therefore, it is important to establish a differential diagnosis to rule out other white lesions that occur on the oral mucosa, mainly those in which there is a risk of malignancy. A case of white sponge nevus is reported along with a discussion on the differential diagnosis and clinical management.

White sponge nevus: report of a three-generation family.

OBJECTIVE: White sponge nevus (WSN) is a rare autosomal dominant disorder that results in soft, white, and spongy plaques in the oral mucosa. The aim of this study was to describe the clinical, histopathologic, and genetic features of a family, spanning 3 generations, affected by WSN. STUDY DESIGN: This study was performed using a cross-sectional layout analyzing a family with WSN. RESULTS: Clinical examination of family members revealed that of 23 descendants, 8 (34.78%) had WSN features. Unaffected and affected members transmitted the disease to their offspring. The offspring recurrence risk was 0.34, and an incomplete level of penetrance was observed. The lesions showed many clinical and histopathologic similarities to cases previously reported. The most affected sites were buccal and labial mucosa, with a rare appearance in the palate. No extraoral lesion was found. Histological examination showed intense acanthosis and hyperparakeratosis-induced epithelial hyperplasia. Within the spinous layer, cells showing perinuclear eosinophilic condensation of the cytokeratin (CK) filaments were frequent. CONCLUSION: The disease was transmitted by an autosomal dominant mode of inheritance, appearing mainly in the buccal and labial mucosa.