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.

White sponge nevus: A condition not always clinically suspected.

White sponge nevus (WSN) is an uncommon benign inherited disorder characterized by white and diffuse painless lesions in oral, esophageal, or genital mucosa. The lesions may develop at birth or later in childhood or adolescence, with careful clinical examination being sufficient for diagnosis in most cases. However, microscopic analysis may be necessary particularly in adults in which other whitish oral lesions may be clinically suspected. Dermatologists, dentists, and pathologists should consider WSN when evaluating multiple white oral lesions, thus preventing unnecessary treatments. Herein, we report four additional cases of WSN with emphasis on its clinical and histopathological features.

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.

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.

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.

[Current therapeutic approach of the white sponge naevus of the oral cavity]. / Approche thérapeutique actuelle du white sponge naevus de la cavité buccale.

We report a case of White Sponge Naevus of the tongue in a 50 years-old man. White Sponge Naevus of the oral cavity is a rare, benign and dominant autosomic inherited disorder, which presents in the form of a white, hyperplasic and verrucous or spongious lesion of the oral mucosa. Differential diagnosis is clinically difficult with more common white lesions of the oral cavity. Various therapeutic approaches have been proposed. Systemic antibiotics or local applications of retinoic acid provide limited benefits but are poorly effective. To our knowledge, CO2 Laser has never been tried to treat a White Sponge Naevus of the oral cavity. We performed a complete removal of the lesion with CO2 Laser, but complete recurrence occurred. Finally, a surgical resection was realized, which proved to be effective. Two years later, the patient is free of recurrence. This article proposes a review of the literature on what is known on White Sponge Naevus of the oral mucosa. We stress the importance of confrontation between anamnesis, clinical examination and pathologic findings to lead to the proper diagnosis of this rare disease.

White sponge nevus in a patient with EEC syndrome.

A 10-year-old boy, affected by cleft lip and palate and the Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome, presented with hypodontia, microdontia, enamel hypoplasia and caries, as well as white macules and plaques on the buccal mucosa bilaterally. Verrucous plaques were noted on the right side and a smooth diffuse white macule was present on the left side. Samples of each were taken by incisional biopsy. Microscopic analysis revealed oral mucosa comprised of hyperplastic stratified squamous epithelium with either hyperparakeratosis or lack of keratinization. There was extensive hydropic degeneration and sparse cells with perinuclear eosinophilic condensation were identified. The underlying fibrous connective tissue exhibited blood vessels with mild subepithelial mononuclear inflammatory infiltrate, bundles of skeletal striated muscle fibers, and areas of hemorrhage at deeper regions. White sponge nevus was diagnosed. To our knowledge, no other case of white sponge nevus has been reported in a patient with EEC syndrome. Considering the low prevalence of this disorder and also of the EEC syndrome, future studies on the etiology of the white sponge nevus might look at the common etiopathogenic aspects of both the white sponge nevus and the EEC syndrome.