Tylosis With Esophageal Cancer

A number sign (#) is used with this entry because of evidence that tylosis with esophageal cancer is caused by heterozygous mutation in the RHBDF2 gene (614404) on chromosome 17q25.1.

Description

Palmoplantar keratoderma (PPK) is a complex group of hereditary syndromes that have been classified into diffuse, punctate, and focal forms according to the pattern of hyperkeratosis on the palms and soles (Lucker et al., 1994).

For a discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (144200).

Clinical Features

Palmoplantar keratoderma (tylosis) was associated with esophageal cancer in 2 kindreds (which perhaps were related) studied in Liverpool by Howel-Evans et al. (1958); the association was first reported by Clarke and McConnell (1954). The disorder is apparently distinct.

From Oxford, Shine and Allison (1966) described a 4-generation family cosegregating tylosis and esophageal stricture. The proband was a 61-year-old man who reported mild tylosis since adolescence and difficulty swallowing since infancy; he underwent surgery due to increasing severity of the dysphagia and hemorrhage, at which time he was found to have a squamous cell carcinoma at the site of an esophageal stricture as well as a sliding hiatal hernia, gastric-lined esophagus, and evidence of reflux esophagitis. The proband's 26-year-old son also had tylosis and dysphagia; resection of the esophageal stricture revealed hyperkeratosis of the stratified squamous epithelium with no evidence of malignancy and gastric mucous membrane lining the lower end of the esophagus. The proband's 23-year-old daughter had mild tylosis but no dysphagia, and a second son was under 1 year of age and did not manifest any abnormality. The proband's deceased mother was said to prefer to eat in solitude, in company ate very small amounts, and always wore gloves; her behavior was attributed to eccentricity by her family, but the authors suggested that she likely also had tylosis and dysphagia.

Harper et al. (1970) gave further information on the Liverpool families and added 2 families, each with 1 case of esophageal cancer with tylosis. Age of onset of the tylosis appears to be a feature distinguishing the cancer-prone from the nonprone form. Tylosis is late in onset in the form with esophageal cancer. Tyldesley (1974) pointed out that oral leukoplakia is also a feature of these cases. Ellis et al. (1994) reviewed the largest of the Liverpool families of tylosis with esophageal cancer. Tylosis had been diagnosed in 89 of 345 persons and 57 of the 89 were still alive. Of the 32 members of the family with tylosis who had died, 21 succumbed to cancer of the esophagus and 11 from other causes. In this family, tylosis had a late onset and was inherited as an autosomal dominant with complete penetrance by puberty, and involved other anatomic sites including oral leukoplakia and follicular changes. The epidermis from biopsies of the skin of the soles showed gross acanthosis, hyperkeratosis (without parakeratosis) and hypergranulosis, but there was no evidence of intracellular edema or lysis of any keratinocytes and no spongiosis. Field et al. (1997) reviewed the histologic features of the oral lesions in tylosis patients from the Liverpool family and proposed that the spectrum of diffuse oral lesions be referred to as 'leukokeratosis,' a descriptive clinical term that would encompass the 'leukoedemalike' lesions seen in the younger tylotic patients and the oral leukoplakia observed in the older members of the family. The authors noted that long-term follow-up indicated that the tylotic oral lesions are benign in nature.

Hennies et al. (1995) reported a 4-generation family from a formerly isolated Black Forest Valley in which 19 of 43 members were affected by palmoplantar keratoderma. Plantar hyperkeratosis became evident between ages 8 and 15 years, whereas manifestation of palmoplantar keratosis occurred later, between 14 and 25 years of age. Two members of the family had died from esophageal cancer, first diagnosed at 56 and 48 years of age, respectively. Further features of the disorder in this family were congenital oral and esophageal leukoplakia and a follicular keratosis, especially on the upper arms and thighs.

Stevens et al. (1996) restudied the extensively affected American pedigree originally reported by Marger and Marger (1993), identifying 125 affected individuals in 7 generations, with squamous cell carcinoma of the esophagus occurring in 8. The family was part of a larger pedigree with affected individuals still residing in Germany. The PPK was inherited as an autosomal dominant with full penetrance and usually developed between 6 and 12 years of age. Predominantly, the thickening involved the pressure areas of the soles, and calluses disappeared completely with prolonged bedrest or inactivity. The palms were not involved except for exaggerated calluses in manual workers. Frictional hyperkeratosis developed in areas other than the hands and feet at sites of recurrent physical trauma, such as the dorsal aspects of the proximal interphalangeal joints, elbows, knees, and outer aspect of the arm in an individual who repeatedly used the site to operate a machine. Stevens et al. (1996) stated that the clinical phenotype of the American family clearly identified it as a form of focal nonepidermolytic PPK. Review of the data on the Howell-Evans Liverpool pedigree supported the reassessment of the clinical phenotype as follows: the thickened skin is focal in nature, related to physical activity with sparing of the hands, and regresses completely on bedrest; the onset at 7 to 8 years of age is that of a focal not a diffuse PPK; and the presence of oral and follicular hyperkeratosis is typical. Stevens et al. (1996) referred to the Howell-Evans syndrome as palmoplantar ectodermal dysplasia type III. They provided an extensive classification of the palmoplantar keratodermas. It seemed quite clear in the family reported by Stevens et al. (1996) that the occurrence of esophageal cancer was related to the use of tobacco. In general, there was a low incidence of smoking on the part of affected and unaffected members, but of the 8 patients with esophageal cancer, 7 had either smoked heavily or chewed tobacco.

Saarinen et al. (2012) reported a 4-generation Finnish family in which 4 patients had plantar hyperkeratosis from early childhood, 1 of whom also had palmar keratosis and oral leukoplakia, and 2 of whom had thickening of the esophageal epithelium on endoscopy. Three family members had died of esophageal cancer, at ages 31, 48, and 82 years. In addition, 3 other deceased family members had a history of breast, colon, and gastric cancer but their skin status was not known.

Mapping

In mapping the genetic locus for keratosis palmaris et plantaris (without associated features) to chromosome 17 near the keratin type I genes, Rogaev et al. (1993) raised the possibility that the association with cancer may represent a contiguous gene syndrome. Blanchet-Bardon et al. (1987) observed hereditary epidermolytic palmoplantar keratoderma in association with breast and ovarian cancer in a large kindred. Rogaev et al. (1993) mapped the tylosis gene to the same region as that which carries the breast cancer locus (BRCA1; 113705).

In the largest of the original Liverpool families, Risk et al. (1994) excluded chromosome 12 as the site of the mutation but found linkage to markers on chromosome 17, indicating that the tylosis with esophageal cancer locus (TOC) lies within a 4-cM region between D17S785 and D17S937. It is located in the 17q23-qter region, telomeric to the type I keratin gene cluster.

In a 4-generation family from the Black Forest Valley with PPK and esophageal cancer, Hennies et al. (1995) mapped the TOC gene to 17q, distal to the type I keratin gene cluster.

Kelsell et al. (1996) used haplotype analysis for fine mapping of the TOC locus. Five representative samples from each of the 2 large pedigrees in Liverpool and in the US and from 1 smaller pedigree in Germany were used to investigate the possibility of a common ancestral mutation. Based on these studies, Kelsell et al. (1996) reduced the genetic interval containing the TOC locus to approximately 1 cM. The Liverpool and German families appeared to share a common haplotype in the disease gene region despite a difference in incidence of esophageal cancer between the pedigrees. The US and German pedigrees appeared to be genetically unrelated in the region of the disease locus.

In the 7-generation American family with focal NEPPK and squamous cell carcinoma of the esophagus originally reported by Marger and Marger (1993), Stevens et al. (1996) demonstrated linkage of the disorder to 17q24, obtaining a maximum 2-point lod score of 8.20 at zero recombination fraction for marker D17S1603.

In studies of 35 sporadic squamous cell carcinomas of the esophagus using 6 polymorphic microsatellite markers encompassing the region on 17q containing the TOC locus, von Brevern et al. (1998) found loss of heterozygosity at one or more loci in 24 cases (69%). Deletion was most frequently observed with the marker D17S801, which shows significant linkage to the TOC locus. The findings were consistent with the hypothesis that the tylosis esophageal cancer susceptibility gene is also involved in the pathogenesis of a proportion of sporadic squamous cell carcinomas of the esophagus.

Risk et al. (2002) indicated that the TOC locus maps to chromosome 17q25, a region frequently deleted in sporadic squamous cell esophageal tumors. By haplotype analysis, they reduced the TOC minimal region to a genetic interval of 2 cM between markers D17S785 and D17S751. By partial sequence data and complete physical maps, they estimated the actual size of this region to be only 0.5 Mb. Ten characterized genes in this region were assayed for mutations, but no disease-specific alterations were identified in the coding and promoter sequences.

Langan et al. (2004) identified additional microsatellite markers within the 500-kb critical region of TOC on chromosome 17q25. Fine mapping of the TOC disease locus by haplotype analysis of 7 polymorphic markers and 21 of 59 SNPs allowed reduction of the minimal region to 42.5 kb. One known gene, cytoglobin (CYGB; 608759), and 2 putative genes were found within this region, but none of them showed tylosis-specific mutations within their protein-coding regions. McRonald et al. (2006) found that cytoglobin gene expression was reduced by about 70% in esophageal biopsies from patients with TOC. Both alleles were equally repressed, excluding haploinsufficiency as a mechanism.

Molecular Genetics

Using targeted capture array and next-generation sequencing in an affected individual from the UK (Liverpool) family with tylosis and esophageal cancer originally reported by Clarke and McConnell (1954), Blaydon et al. (2012) identified a heterozygous missense mutation in the RHBDF2 gene (I186T; 614404.0001). Screening of other members of the UK family, as well as members of the US family with tylosis originally reported by Marger and Marger (1993), revealed that the I186T mutation segregated with disease in both families. Blaydon et al. (2012) stated that the segregation of 2 distinct disease haplotypes in these families had previously been shown, indicating that the mutation had likely arisen independently in the 2 families. Standard PCR and Sanger sequence analysis of RHBDF2 in the German family with tylosis originally reported by Hennies et al. (1995) revealed a different missense mutation (P189L; 614404.0002) that segregated with disease in that family. Functional data suggested that the altered RHBDF2 represents a gain-of-function allele that results in sustained EGFR (131550) signaling within cells, which in turn leads to a hyperproliferative phenotype. Blaydon et al. (2012) stated that their results supported the hypothesis that tylosis results from dysregulated wound repair that leads to precancerous lesions in the esophagus and other nonkeratinized epithelium of the upper gastrointestinal tract.

In a 4-generation Finnish family with tylosis and esophageal cancer, Saarinen et al. (2012) analyzed the RHBDF2 gene and identified heterozygosity for a missense mutation (D188N; 614404.0003) that segregated with disease in the family and was not found in 154 Finnish controls. The mutation was also detected in germline DNA from a family member who had died of breast cancer and whose skin status was unknown.

Pathogenesis

In addition to its role in the regulation of EGF (131530) processing, RHBDF2 regulates the multi-substrate ectodomain sheddase ADAM17 (603639). Brooke et al. (2014) found elevated levels of mature active ADAM17 relative to inactive pro-ADAM17 in immortalized keratinocytes from 2 British patients with TOC who had the I186T mutation in RHBDF2. Elevated active ADAM17 in TOC keratinocytes correlated with elevated plasma membrane ADAM17 localization and increased basal shedding of the ADAM17 substrates TNF-alpha (TNF; 191160), amphiregulin (AREG; 104640), and HBEGF (126150). Knockdown of ADAM17 via small interfering RNA inhibited excess shedding in TOC keratinocytes. Using transmission electron microscopy, Brooke et al. (2014) found that epidermis of 3 British patients with TOC showed immature desmosomes and increased desmosome turnover, concomitant with increased epidermal barrier function and resistance to infection. Many of these features were consistent with constitutive wound healing in TOC epidermis.

Nomenclature

Risk et al. (1994) used TOCG as a symbol for 'tylosis oesophageal cancer gene.' The gene was also symbolized TOC, dropping the 'G.' Although TEC would appear to be a more appropriate symbol in American English, which does not use the diphthong, the symbol TEC has already been used for a protein tyrosine kinase (600583).