RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.

Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

Defining the endoscopic appearances of tylosis using conventional and narrow-band imaging: a case series.

Tylosis is an autosomal dominant skin disorder strongly associated with esophageal squamous cell cancer. We present a single-operator experience of utilizing conventional endoscopy and narrow-band imaging with magnification to characterize esophageal appearances in tylosis. Nineteen consecutive patients with tylosis attending for surveillance endoscopy were studied. White-light imaging (WLI) and narrow-band imaging (NBI) were undertaken, with magnification being performed as necessary. On WLI, we classified 12 patients as having mild change, 5 moderate change, and 2 severe change. WLI can define changes to the esophageal mucosa of variable hyperkeratosis and identify more significant focal abnormalities. NBI enhances these mucosal changes, and NBI with magnification can demonstrate intrapapillary capillary loop changes compatible with dysplasia, prompting consideration of surgery. This report is the first to characterize the endoscopic appearances in tylosis.

Palmoplantar keratoderma as the initial sign in a peripheral T-cell lymphoma.

A 27-year-old male with an acquired severe, diffuse palmoplantar keratoderma as the initial sign of peripheral T-cell lymphoma is reported.

[Clinical and genetic characteristics of Buschke-Fischer-Brauer's disease in a Tunisian family]. / Etude clinique et génétique de la kératodermie palmoplantaire de Buschke-Fischer-Brauer dans une famille tunisienne.

BACKGROUND: Punctate palmoplantar keratoderma (PPPK), or Buschke-Fischer-Brauer's disease, is a rare form of genodermatosis with autosomal dominant transmission and with variable penetrance. Its molecular basis remains unknown. Two loci were found to be linked to this disease: one on 15q22 and the other on 8q24. We report the clinical and genetic characteristics of PPPK in a Tunisian family. PATIENTS AND METHODS: A Tunisian family with PPPK was identified through a proband. As far as possible, history taking, physical examination, histopathological tests and blood sampling for DNA extraction were carried out for each patient. RESULTS: Seventeen patients were included in this study. Age ranged from 15 to 81 years with a sex-ratio of 3.2 m/f. Lesions appeared between the ages of 10 and 65 years and at a mean of 28 years. Clinically, lesions ranged from few keratotic papules on the palms to coalescence of lesions in plaques over palmar and/or plantar surfaces. Hyperhydrosis, hypopigmented macules and nail dystrophy were frequently associated. In all patients, histopathological examination revealed thickening of the epidermis with compact orthohyperkeratosis overlying a small and sharply demarcated area of depressed epidermis. Mechanical measures and keratolytic ointments proved non-beneficial. Genotyping for chromosomes 8 and 15 as well as LOD scores confirmed genetic linkage with the suspected locus on chromosome 15q, with the interval of the locus in question reduced to 3.26 Mb. This region is flanked by markers D15S987 and D15S153. CONCLUSION: Our study of this family confirmed the classical characteristics of KPP-BFB as well as demonstrating several associated clinical signs of which the significance will be determined in subsequent studies. Further screening studies to identify mutated genes in the region of interest will help us to understand the molecular basis of this disease and hopefully to propose suitable treatment.

Acantholytic ectodermal dysplasia: clinicopathological study of a new desmosomal disorder.

We describe two boys with curly hair, palmoplantar keratoderma and skin fragility who presented clinical and histological features similar, but not identical, to those exhibited by patients with ectodermal dysplasia-skin fragility syndrome (McGrath syndrome) and other genetic desmosomal defects such as Carvajal syndrome and Naxos disease. Clinical features included trauma-induced blisters and erosions, palmoplantar keratoderma and hyperkeratotic, fissured plaques with perioral involvement. The patients had abundant curly scalp hair, and normal eyebrows and eyelashes. Sweating was normal. Nails were normal at birth but subsequently showed secondary dystrophy. Histopathological analysis of the skin demonstrated acantholysis and intercellular widening of the spinous and granular layers in involved regions. No involvement of scalp skin was seen. Desmosomes were markedly reduced in number and poorly developed with no clear insertions of the keratin filaments. The latter were clumped around the nuclei. Immunostaining of patient skin with antibodies raised against key desmosomal proteins demonstrated disrupted expression of desmoplakin, plakoglobin and desmoglein 1. Additional studies of the family history and of the desmoplakin, plakoglobin and desmoglein 1 genotype for both patients may help further elucidate the molecular cause of this variation on ectodermal dysplasia-skin fragility syndrome.

Mutation L437P in the 2B domain of keratin 1 causes diffuse palmoplantar keratoderma in a Chinese pedigree.

Diffuse palmoplantar keratoderma (DPPK) is an autosomal dominant genodermatosis characterized by uniform hyperkeratosis of the palm and sole epidermis. This disorder can be caused by mutations in the genes keratin 1, keratin 9, keratin 16, desmoglein 1 and plakoglobin. Here we present a DPPK Chinese pedigree and identify the aetiology as a novel missense mutation, L437P, located in a highly conserved helix motif in domain 2B of KRT1. Functional analysis shows that overexpression of the L437P mutant in cultured cells leads to abnormal intermediate filament networks and filament aggregation. This gain-of-function mutation highlights the role of domain 2B in mediating filament assembly.

Risk factors for esophageal cancer: emphasis on infectious agents.

Risk factors for esophageal cancer include genetic factors (such as tylosis) and infectious agents. A variety of organisms have been implicated in esophageal carcinogenesis, either directly or indirectly. In this review, we explore the normal esophageal flora and how it may be controlled, and also the variety of organisms that may affect esophageal carcinogenesis, either directly or indirectly. The organisms with potential direct effects in squamous cell carcinoma include human papillomavirus (HPV), Epstein-Barr virus, and polyoma viruses. Interestingly, HPV is now implicated in esophageal adenocarcinoma (EAC), not in its initiation but in the development of dysplasia, in which HPV33 in particular has been associated. Indirectly, Helicobacter pylori has been associated with EAC by, initially, causing increased acid secretion that increases acid reflux, and by reducing lower esophageal sphincter pressure, which increases gastroesophageal reflux; the latter increases the risk of Barrett's esophagus, and hence EAC. Conversely, subsequent atrophic gastritis may normalize that risk.

[Pathological features and gene mutation analysis in two pedigrees of diffuse palmoplantar keratoderma].

We report the clinical and pathological features of two pedigrees of palmoplantar keratoderma (PPK), the expression of keratin 9 (K9) in palm tissue and the mutation of the keratin 9 gene (KRT9). Histopathology and immunohistochemical assessment was performed to analyze the epidermis in the palm of the probands. Genomic DNA of 46 family individuals was used for amplification of exon 1 of KRT9. The mutations were determined by direct sequencing. Epidermal abnormalities in the palm of the two probands were characterized by vacuolar changes of suprabasal keratinocytes accompanied by thickening of the living epidermis and stratum corneum. K9 was also expressed in particular epithelial tissues. Direct sequencing of polymerase chain reaction products revealed heterozygous missense mutations in exon 1 of KRT9 (N160S and L167S) in the two families, respectively. N160S and L167S of KRT9 are disease-causing mutations in these two Chinese pedigrees with epidermolytic palmoplanter keratoderma (EPPK).

A novel mutation and large size polymorphism affecting the V2 domain of keratin 1 in an African-American family with severe, diffuse palmoplantar keratoderma of the ichthyosis hystrix Curth-Macklin type.

Keratin gene mutations affecting nonhelical head and tail domains are not usually associated with prominent skin blistering and keratin filament clumping. Instead, they have been associated with several distinct clinical phenotypes, such as epidermolysis bullosa simplex with mottled pigmentation (mutation P25L in the V1 domain of keratin 5), epidermolysis bullosa simplex with migratory circinate erythema (frameshift mutation c1649delG in the V2 domain of keratin 5), striate palmoplantar keratoderma (PPK), and ichthyosis hystrix Curth-Macklin (different frameshift mutations in the V2 domain of keratin 1 (K1)). We have studied a family with severe, diffuse, nonepidermolytic PPK and verrucous hyperkeratotic plaques over the joints and in flexures and identified a new KRT1 gene mutation that is predicted to completely alter the K1 tail domain. In addition, a new K1 size polymorphism has been detected, which is especially prevalent among the African-American population. These results further emphasize the functional importance of the nonhelical tail domain in keratin molecules despite the obvious variability in the number of glycine loop motifs and underscore the broad phenotypic spectrum of disorders due to dominant keratin tail mutations.

Multiple myeloma in a patient with systemic lupus erythematosus, myasthenia gravis and non-familial diffuse palmoplantar keratoderma.

The coexistence of autoimmune diseases and malignancies including lymphoproliferative diseases is often reported in the literature. Here we report an unusual case with two autoimmune diseases--myasthenia gravis (MG) and systemic lupus erythematosus (SLE) associated with unique palmoplantar keratoderma (PK) which preceded the development of multiple myeloma (MM) for twenty and seven years respectively. MG associated with non-malignant thymoma developed in 1981 and was successfully treated with thymectomy and physostigmine. Thirteen years later SLE was diagnosed and until now it is also accompanied by skin lesions corresponding to non-familial, diffuse palmoplantar keratoderma which is resistant to treatment. In 2001 the patient revealed inguinal and abdominal lymphadenopathy first diagnosed as extramedullary plasmacytoma and then as multiple myeloma on the basis of bone marrow infiltration and monoclonal gammopathy. Therapy with VAD regimen achieved complete remission of the MM and significant improvement of the skin changes lasting for six months. We failed to collect sufficient numbers of CD 34+ cells for peripheral blood stem cell transplantation. Now the malignancy is in partial remission after CHOP therapy and the skin lesions have returned to their initial status. To our knowledge, this is the first case to be reported with coexistence of these four diseases.

Oral tylosis: a re-appraisal.

The oral lesions in patients with tylosis (palmoplantar keratoderma) associated with oesophageal cancer, are evaluated, based on their clinical presentation, histological features and long term follow-up. The terminology of these lesions is discussed, together with a proposed reclassification of some forms of palmoplantar keratoderma.

Hereditary palmoplantar keratosis of the Gamborg Nielsen type. Clinical and ultrastructural characteristics of a new type of autosomal recessive palmoplantar keratosis.

A new kind of diffuse palmoplantar keratoderma with autosomal recessive inheritance and without associated symptoms was described in Norrbotten, Sweden by Gamborg Nielsen in 1985. Clinically, it ranges between the less severe dominant Unna-Thost type and the more severe recessive Meleda type, as it is milder than the latter. Skin biopsies of five patients from three different families with this new palmoplantar keratoderma, as well as five obligatory heterozygotes from one family, were investigated ultrastructurally in order to characterize this new entity and to differentiate it from the Meleda type. Several features are common to both autosomal recessive palmoplantar keratoses. They show a broadened granular layer, a transit region consisting of cells with a marginal envelope, and considerable hyperkeratosis. Morphologically, this transformation delay is less pronounced in the Gamborg Nielsen type than in the classical Meleda type. As is typical for ridged skin, both types of palmoplantar keratoses possess composite keratohyaline granules. In contrast to the normal appearance of keratohyaline granules in the Meleda type, the Gamborg Nielsen type also shows qualitative deviations of keratohyaline granules with different degrees of spongiosity and electron density and sometimes with a granular border. It seems that abnormal keratohyaline proteins are synthesized that behave differently. The sudden transformation of a granular into a horny cell is physiologically regulated by different enzymes. A delay in this process may be caused by a mutation that reduces or alters the enzymes concerned. We assume the palmoplantar keratoderma of the Gamborg Nielsen type to be a variant of the heterogeneous group of the Meleda type of palmoplantar keratoderma with autosomal recessive inheritance.