White Sponge Nevus Research Articles

Cannon's Disease: Clinical and Diagnostic Implications: A Case Report

Cannon's disease or white sponge naevus is a relatively rare genetically determined skin disorder. It is inherited as an autosomal dominant trait that displays a high degree of penetrance and expressivity. This article describes cases of Cannon's disease in a mother and her son.

The keratins and their disorders.

Diseases caused by mutations in gene encoding keratin intermediate filaments (IF) are characterized by a loss of structural integrity in the cells expressing those keratins in vivo. This is manifested as cell fragility, compensatory epidermal hyperkeratosis, and keratin filament aggregation in some affected tissues. Keratin disorders are a novel molecular category including quite different phenotypes such as epidermolysis bullosa simplex (EBS), bullous congenital ichthyosiform erthroderma (BCIE), pachyonychia congenital (PC), steatocystoma multiplex, ichthyosis bullosa of Siemens (IBS), and white sponge nevus (WSN) of the orogenital mucosa.

Orthodontic therapy in a patient with white sponge nevus

An undesirable effect of fixed orthodontic appliances is irritation of the oral mucosa. Lesions are common, but they usually heal quickly because of the fast metabolism of oral mucosa cells. Alterations accompanying some injuries are temporary, but some are irreversible because of attrition. White sponge nevus constitutes a special situation, and little information about it is available in the orthodontic literature. This report presents a patient with white sponge nevus who received orthodontic treatment over a 40-month period. The condition was also noted in a sibling. Because of the similarity between white sponge nevus and other diseases, including some that are malignant, a thorough clinical history and differential diagnosis are essential.

The molecular genetics of keratin disorders.

Keratins are the type I and II intermediate filament proteins which form a cytoskeletal network within all epithelial cells. They are expressed in pairs in a tissue- and differentiation-specific fashion. Epidermolysis bullosa simplex (EBS) was the first human disorder to be associated with keratin mutations. The abnormal keratin filament aggregates observed in basal cell keratinocytes of some EBS patients are composed of keratins K5 and K14. Dominant mutations in the genes encoding these proteins were shown to disrupt the keratin filament cytoskeleton resulting in cells that are less resilient and blister with mild physical trauma. Identification of mutations in other keratin genes soon followed with attention focussed on disorders showing abnormal clumping of keratin filaments in specific cells. For example, in bullous congenital ichthyosiform erythroderma, clumping of filaments in the suprabasal cells led to the identification of mutations in the suprabasal keratins, K1 and K10. Mutations have now been identified in 18 keratins, all of which produce a fragile cell phenotype. These include ichthyosis bullosa of Siemens (K2e), epidermolytic palmoplantar keratoderma (K1, K9), pachyonychia congenita (K6a, K6b, K16, K17), white sponge nevus (K4, K13), Meesmann's corneal dystrophy (K3, K12), cryptogenic cirrhosis (K8, K18) and monilethrix (hHb6, hHb1).In general, these disorders are inherited as autosomal dominant traits and the mutations act in a dominant-negative manner. Therefore, treatment in the form of gene therapy is difficult, as the mutant gene needs to be inactivated. Ways of achieving this are actively being studied. Reliable mutation detection methods from genomic DNA are now available. This enables rapid screening of patients for keratin mutations. For some of the more severe phenotypes, prenatal diagnosis may be requested and this can now be performed from chorionic villus samples at an early stage of the pregnancy. This review article describes the discovery of, to date, mutations in 18 keratin genes associated with inherited human diseases.

Hereditary benign intraepithelial dyskeratosis: Report of two cases with prominent oral lesions

Hereditary benign intraepithelial dyskeratosis is a rare autosomal dominant disorder of the oral and ocular mucosa initially described in the Haliwa-Saponi Native American tribe of North Carolina. We describe 2 sisters with the characteristic oral and ocular findings. This entity should be distinguished from several other diseases that cause white lesions in the mouth including white sponge nevus. (J Am Acad Dermatol 2001;45:634-6.)

Pagetoid dyskeratosis of the lips.

Pagetoid dyskeratosis is an incidental finding in a variety of lesions of the skin and squamous mucosa. The lesion is considered a selective keratinocytic response in which a small part of the normal population of keratinocytes is induced to proliferate in response to friction. As far as we know, pagetoid dyskeratosis has not been reported in the lips. In this article, we describe the location of the lesion in the lips and its incidence in a group of 90 unselected patients who underwent biopsy or were surgically treated for diverse labial lesions. Histochemical staining and immunohistochemical studies were performed in selected cases. Pagetoid dyskeratosis was found in 38 cases (42.2%) but only in 6 cases (6.7%) the lesion was conspicuous. There was no significant difference between the upper and the lower lip in terms of incidence of the lesion. Labial pagetoid dyskeratosis was more frequent in younger patients (46.7 +/- 25.0 versus 58.5 +/- 20.5; p < 0.05) and in women (chi(2) = 3.89; p < 0.05). Pagetoid cells were more common in suprabasal location and in the labial mucosa. These cells showed positivity for high-molecular weight cytokeratin and negative reaction for low-molecular weight cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and human papilloma virus. The immunohistochemical profile is different from the surrounding keratinocytes, indicating premature keratinization. The main differential diagnoses include white sponge nevus, leukoedema, oral koilocytoses, hairy leukoplakia, pagetoid squamous cell carcinoma in situ, and extramammary Paget's disease of the oral mucosa. The morphologic features of dyskeratotic pagetoid cells are distinctive and easily recognized as an incidental finding, thus preventing confusion with other important entities including an intraepidermal tumor.

A novel mutation in the keratin 13 gene causing oral white sponge nevus.

White sponge nevus (WSN) is an autosomal-dominantly inherited form of mucosal leukokeratosis. Defects in keratins, proteins that form the stress-bearing cytoskeleton in epithelia, have been shown to cause several epithelial fragility disorders. Recently, mutations in the genes encoding mucosal-specific keratins K4 and K13 were shown to be the underlying cause of WSN. We have studied a large Scottish family with 19 persons affected by WSN in four generations. The K4 locus was excluded by genetic linkage analysis; however, genetic linkage consistent with a K13 defect was obtained. Subsequently, a heterozygous missense mutation 335A>G was detected in exon 1 of the KRT13 gene, predicting the amino acid change N112S in the 1A domain of the K13 polypeptide. The mutation was confirmed in affected family members and was excluded from 50 unaffected people by restriction enzyme analysis. These results confirm that mucosal keratin defects are the cause of WSN.

A Glutamine Insertion in the 1A Alpha Helical Domain of the Keratin 4 Gene in a Familial Case of White Sponge Nevus

White Sponge Nevus (WSN) is a rare, autosomal dominant disorder that predominantly affects noncornified stratified squamous epithelia. Clinically, it is characterized by the presence of soft, white, and "spongy" plaques in the oral mucosa. The characteristic histopathologic features are epithelial thickening, parakeratosis, and vacuolization of the suprabasal layer of oral epithelial keratinocytes. Mutations in keratin 4 (K4) and keratin 13 (K13) genes have already been demonstrated to be responsible for WSN; the identification of new keratin mutations in a stratified squamous epithelia closely related to epidermis is of relevance for the understanding of the biochemistry of intermediate filaments, and for genotype phenotype correlations. In this study we investigated a 27-y-old, female Italian patient, affected by white asymptomatic oral plaques. Sequence analysis revealed a 3 bp (ACA) heterozygous insertion localized in the helix initiation motif of the 1A alpha helical domain of K4. We report this new K4 gene mutation and describe an amino acid insertion, in the 1A domain, responsible for a keratin disease.

Perianal White Sponge Nevus In A Hispanic Female: A Case Study

This article presents a case history of white sponge nevus (WSN) in the perianal area of a 23-year-old Hispanic female. WSN is a rare, autosomal dominant disorder that affects the noncornified stratified squamous epithelia. Clinically, the lesions are characterized by the presence of white, spongy plaques in the oral cavity. Extraoral lesions are found in other mucosal sites but are relatively uncommon in the absence of oral manifestations. Because WSN is rare, the differential diagnosis of this lesion may be difficult and the diagnosis is best made by a tissue biopsy performed in the context of a detailed patient and family history. The problems associated with differential diagnosis are addressed.

Identification of two novel mutations in keratin 13 as the cause of white sponge naevus.

White sponge naevus (WSN) is a rare autosomal dominant condition which is characterised by benign, white spongy plaques (oral leukokeratoses) affecting non-cornifying, wet mucosa. WSN shares several ultrastructural characteristics (eg, epithelial thickening, acanthosis, keratin filament aggregation) with a number of epithelial disorders caused by mutations in keratin genes and to-date two mutations, one in each of the mucosal specific keratins, K4 and K13, have been identified as the molecular basis of the disorder. To identify the molecular basis of WSN in two families with a history of the disease. Two novel mutations were identified in helix initiation motif of K13. A T-to-C transition was found in the affected members of one family which is predicted to change leucine115 to proline. In the second family, a similar T-to-C transition was found in codon 108 which is predicted to change methionine to threonine in the protein sequence. These changes were not found in 50 unrelated, unaffected individuals. The mutations in the helix initiation motif of K13 are the cause of WSN in these families. These cases confirm mutations in the mucosal specific keratins as a significant cause of the disorder.

Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation.

Keratins are obligate heterodimer proteins that form the intermediate filament cytoskeleton of all epithelial cells. Keratins are tissue and differentiation specific and are expressed in pairs of types I and II proteins. The spectrum of inherited human keratin diseases has steadily increased since the causative role of mutations in the basal keratinocyte keratins 5 and 14 in epidermolysis bullosa simplex (EBS) was first reported in 1991. At the time of writing, mutations in 15 epithelial keratins and two trichocyte keratins have been associated with human diseases which include EBS, bullous congenital ichthyosiform erythroderma, epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, diffuse and focal non-epidermolytic palmoplantar keratoderma, pachyonychia congenita and monilethrix. Mutations in extracutaneous keratins have been reported in oral white sponge naevus and Meesmann's corneal dystrophy. New subtleties of phenotype-genotype correlation are emerging within the keratin diseases with widely varying clinical presentations attributable to similar mutations within the same keratin. Mutations in keratin-associated proteins have recently been reported for the first time. This article reviews clinical, ultrastructural and molecular aspects of all the keratin diseases described to date and delineates potential future areas of research in this field.

Orofacial disease: update for the dental clinical team: 3. White lesions.

White lesions usually contain an increased amount of keratin. Some are rare congenital conditions, such as white sponge naevus and dyskeratosis congenita, unlikely to be seen in general dental practice. Inflammatory causes include candidosis and hairy leukoplakia, both now common in HIV disease. Non-infective causes include the common lesion of lichen planus, and the less common condition lupus erythematosus. Neoplastic and possibly preneoplastic causes include carcinoma, keratoses and leukoplakia. This article discusses the more common causes of oral white lesions. The first article in this series presented several general observations on diagnosis and treatment which should be borne in mind in relation to this article.

Arginine in the beginning of the 1A rod domain of the keratin 10 gene is the hot spot for the mutation in epidermolytic hyperkeratosis

Keratin intermediate filaments are expressed in specific type I/type II pairs in the stage of differentiation of keratinocytes. The mutations in the keratin genes expressed in the epidermis are etiologically responsible for several epidermal genetic skin diseases, such as epidermolysis bullosa simplex, epidermolytic hyperkeratosis (EHK), ichthyosis bullosa of Siemens, palmoplantar keratoderma, pachyonchia congenita and white sponge nevus. The mutations of keratins 1/10 which are expressed in spinous and granular layers are confirmed to cause EHK. There are several trials to correlate between the clinical phenotypes and sites of mutations of the keratin genes. One of these is that EHK is divided into two groups: the palms and soles involvement (PS) group and the non-palms and soles (NPS) group. So far the PS group had the mutations in the keratin 1 and the NPS group in keratin 10. Most of the mutations of the NPS group were reported in the beginning of the 1A rod domain and over 2/3 of the mutations in the 1A rod domain were the base pair substitution of arginine. Here we find two different mutations in two unrelated Korean kindreds classified as NPS group—R156C and R156H—in the 1A rod domain of keratin 10. Our results are compatible with the above classification and suggest that the arginine in the beginning of the 1A rod domain is the hot spot for the mutation of the keratin 10 gene.

Mouse Keratin 4 Is Necessary for Internal Epithelial Integrity

Keratins are intermediate filaments of epithelial cells. Mutations in keratin genes expressed in skin lead to human disorders, including epidermolysis bullosa simplex and epidermolytic hyperkeratosis. We examined the role of keratin 4 (K4) in maintaining the integrity of internal epithelial linings by using gene targeting to generate mice containing a null mutation in the epithelial K4 gene. Homozygous mice that do not express K4 develop a spectrum of phenotypes that affect several organs which express K4 including the esophagus, tongue, and cornea. The cellular phenotypes include basal hyperplasia, lack of maturation, hyperkeratosis, atypical nuclei, perinuclear clearing, and cell degeneration. These results are consistent with the notion that K4 is required for internal epithelial cell integrity. As mutations in K4 in humans lead to a disorder called white sponge nevus, the K4-deficient mice may serve as models for white sponge nevus and for understanding the role of K4 in cellular proliferation and differentiation.

白色海綿状母斑の一例

The white sponge nevus was first described by Canonn in 1935. This lesion affected the oral mucous membrane, vagina, and rectal mucosa. In Japanese literature, only 6 cases were reported.It is said that this disease is caused by an autosomal dominant gene trait?Histological appearance demonstrated vacuolation in the epithelial layer and epithelial hyperplasia. There was no evidence of dysplasia or malignancy of epithelium. The 7th case in Japan was reported herein.

Human keratin diseases: hereditary fragility of specific epithelial tissues.

Keratins are heteropolymeric proteins which form the intermediate filament cytoskeleton in epithelial cells. Since 1991, mutations in several keratin genes have been found to cause a variety of human diseases affecting the epidermis and other epithelial structures. Epidermolysis bullosa simplex (EBS) was the first mechanobullous disease for which the underlying genetic lesion was found, with mutations in both the K5 and K14 genes rendering basal epidermal keratinocytes less resilient to trauma, resulting in skin fragility. The site of mutation in the keratin protein correlates with phenotypic severity in this disorder. Since mutations were identified in the basal cell keratins, the total number of keratin genes associated with diseases has risen to eleven. The rod domains of suprabasal keratins K1 and K10 are mutated in bullous congenital ichthyosiform erythroderma (BCIE; also called epidermolytic hyperkeratosis, EH) and mosaicism for K1/K10 mutations results in a nevoid distribution of EH. An unusual mutation in the VI domain of K1 has also been found to cause diffuse non-epidermolytic palmoplantar keratoderma (DNEPPK). Mutations in palmoplantar specific keratin K9 cause epidermolytic palmoplantar keratoderma (EPPK) and mutations in the late differentiation suprabasal keratin K2e cause ichthyosis bullosa of Siemens (IBS). In the last year or so, mutations were discovered in differentiation specific keratins K6a and K16 causing pachyonychia congenita type 1 and K17 mutations occur in pachyonychia congenita type 2. K16 and K17 mutations have also been reported to produce phenotypes with little or no nail changes: K16 mutations can present as focal non-epidermolytic palmoplantar keratoderma (NEPPK) and K17 mutations can result in a phenotype resembling steatocystoma multiplex. Recently, mutation of mucosal keratin pair K4 and K13 has been shown to underlie white sponge nevus (WSN). This year, the first mutations in a keratin-associated protein, plectin, were shown to cause a variant of epidermolysis bullosa associated with late-onset muscular dystrophy (MD-EBS). An unusual mutation has been identified in K5 which is responsible for EBS with mottled pigmentation and genetic linkage analysis suggests that the hair disorder monilethrix is likely to be due to a mutation in a hair keratin. The study of keratin diseases has led to a better understanding of the importance of the intermediate filament cytoskeleton and associated connector molecules in maintaining the structural integrity of the epidermis and other high stress epithelial tissues, as well as allowing diagnosis at the molecular level thus facilitating prenatal testing for this heterogeneous group of genodermatoses.

口腔内白色海綿状母斑の１例

A case of a white sponge nevus involving the oral mucosa in a 20-year-old woman is presented. Physical examination revealed that the lesion was located only in the oral cavity. A biopsy showed hyperkeratosis and acanthosis with some vacuolation in the squamous epithelium. Based on these features, a white sponge nevus was diagnosed. Investigation of the patient's pedigree suggested that this case was sporadic, although the disease shows autosomal dominant inheritance.

Keratin 13 point mutation underlies the hereditary mucosal epithelial disorder white sponge nevus.

Although pathogenic keratin mutations have been well characterized in inherited epidermal disorders, analogous defects in keratins expressed in non-epidermal epithelia have yet to be described. White sponge nevus (WSN) is a rare autosomal dominant disorder of non-cornifying squamous epithelial differentiation that presents clinically as bilateral white, soft, thick plaques of the oral mucosa. Less frequently the mucous membranes of the nose, esophagus, genitalia and rectum are involved. Histopathological features, including epithelial thickening, parakeratosis, extensive vacuolization of the suprabasal keratinocytes and compact aggregates of keratin intermediate filaments (KIF) in the upper spinous layers, resemble those found in epidermal disorders due to keratin defects. We analysed a multigenerational family with WSN and found cosegregation of the disease with the keratin gene cluster on chromosome 17. We identified a missense mutation in one allele of keratin 13 that leads to proline substitution for a conserved leucine. The mutation occurred within the conserved 1A region of the helical rod domain, which is critical for KIF stability and is the site of most pathogenic keratin mutations. This mutation enlarges the spectrum of keratins with disease-causing defects to include mucosally expressed keratin 13, and extends the known keratin diseases to disorders of non-cornifying stratified squamous epithelia.

A mutation in the mucosal keratin K4 is associated with oral white sponge nevus.

White sponge nevus (WSN) is a benign autosomal dominant disorder which affects non-cornifying stratified squamous epithelia (MIM 193900) (ref. 1). Phenotypically it presents as white 'spongy' plaques (oral leukokeratoses), most commonly in the mouth but also reported in the esophagus and anogenital mucosa. Histologically, the plaques show evidence of hyperproliferation, acanthosis and tonofilament aggregation. These types of pathogenic changes are characteristic of many of the epidermal keratin disorders. Keratins are expressed in pairs by epithelial cells in a tissue and cell specific manner. The major differentiation specific keratins of the buccal mucosa, nasal, esophageal and anogenital epithelia are K4 and K13 (ref. 7). The tissue distribution and nature of the lesions in patients affected by WSN suggested that mutations in K4 and/or K13 might be responsible for this disorder. We have now confirmed this hypothesis and report here a three base-pair (bp) deletion in the helix initiation peptide of K4 in affected members from two families with this condition.

White sponge nevus. Seven cases in the same family

AbstractSeven cases of white sponge nevus in seven women of the same family are reported. At birth the patients had lesions consisting of asymptomatic white spongy plaques located on the oral mucosa; in two patients the lesions also involved the vaginal mucosa. The lesions improved after antibiotic treatment. Histology was performed in four cases and an ultrastructural study in one. The findings were consistent with the diagnosis of white sponge nevus in all cases. Differential diagnosis was made with other conditions presenting as white lesions of the oral mucosa.