Tylosis with Esophageal Cancer


Howel–Evans syndrome is a rare autosomal dominant inherited condition causing thickening of the skin in the palms of the hands and the soles of the feet (hyperkeratosis). It is a type of focal non-Epidermolytic Palmoplantar keratoderma (NEPPK). The syndrome is associated with an increased lifetime risk of Esophageal Cancer (UK spelling Oesophageal). It is sometimes known as Tylosis with Oesophageal Cancer (TOC). Mutations in the RHBDF2 gene have been linked to the condition.

Literature Analysis

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  • Missense Mutation
  • Molecular Sequence Data
  • Squamous Cell Carcinoma
  • Chromosomes, Artificial, Yeast
  • Membrane Proteins
  • Phenotype
  • Papilloma
  • Globins
  • Mutation
  • Base Sequence
  • Childhood Cancer
  • Skin
  • TRPV Cation Channels
  • Species Specificity
  • Immunoenzyme Techniques
  • Serine Proteases
  • Sequence Tagged Sites
  • cytoglobin
  • Esophageal Cancer
  • Exons
  • Loss of Heterozygosity
  • Protein Precursors
  • Keratin-16
  • Microsatellite Repeats
  • Chromosome 17
  • Allelic Imbalance
  • Single Nucleotide Polymorphism
  • Untranslated Regions
  • Chromosome Mapping
  • DNA Primers
  • Diffuse Palmoplantar Keratoderma (Tylosis)
  • Pachyonychia Congenita
  • RHBDF2
  • DNA Sequence Analysis
  • Haplotypes
  • Pedigree
  • Genes
  • RHBDL2
  • Genetic Linkage
  • Asian Continental Ancestry Group
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (1)

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RHBDF2 17q25.1 TEC, TOC, TOCG, RHBDL5, RHBDL6, iRhom2 Germline
-RHBDF2 mutations in Tylosis - a familial esophageal cancer syndrome

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

TOC Resources (3 links)

Latest Publications

Ellis A, Risk JM, Maruthappu T, Kelsell DP
Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms.
Orphanet J Rare Dis. 2015; 10:126 [PubMed] Free Access to Full Article Related Publications
Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet and is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95% at the age of 65 in one large family, however the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000. Oesophageal lesions appear as small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described. Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease, highlighting the importance of endoscopic surveillance in these patients. Oesophageal cancer associated with tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease. Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty. Mutations in RHBDF2 located on 17q25.1 have recently been found to be causative. A diagnosis of tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2. The key management goal is surveillance for early detection and treatment of oesophageal dysplasia. Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education. Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis. More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests. Genetic counselling can be offered to patients and family members once a family history has been established. The prognosis of tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals. In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later. This suggests that the presence of a screening program improves prognosis for these patients.

Saarinen S, Vahteristo P, Lehtonen R, et al.
Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.
Fam Cancer. 2012; 11(3):525-8 [PubMed] Related Publications
Tylosis with esophageal cancer (TOC) is a rare familial cancer syndrome inherited in an autosomal-dominant manner and characterized by esophageal cancer susceptibility and hyperkeratotic skin lesions. Two heterozygous missense mutations in the RHBDF2 gene were recently reported to be associated with TOC in three families: a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family. We aimed to validate these novel results in an independent material by screening RHBDF2 in a previously unreported Finnish TOC family. We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites. Thus, we confirmed RHBDF2 mutations as the underlying cause of the TOC syndrome and our results suggest that the TOC associated mutations might be specific for this particular site in the RHBDF2 gene. These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families.

Blaydon DC, Etheridge SL, Risk JM, et al.
RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
Am J Hum Genet. 2012; 90(2):340-6 [PubMed] Free Access to Full Article Related Publications
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.

Varela AB, Blanco Rodríguez MM, Boullosa PE, Silva JG
Tylosis A with squamous cell carcinoma of the oesophagus in a Spanish family.
Eur J Gastroenterol Hepatol. 2011; 23(3):286-8 [PubMed] Related Publications
Palmoplantar tylosis is a focal nonepidermolytic palmoplantar hyperkeratosis, which is inherited as an autosomal dominant condition. Two types have been described: an early onset type B tylosis, which occurs in the first year of life and is usually benign, and type A tylosis, which occurs between the ages of 5 and 15 years. Type A tylosis has been associated with a high incidence of oesophageal carcinoma in three families in England, Germany and the USA. This study describes an additional family from Spain with tylosis A, without any known relation to those described before.

Robertson EV, Jankowski JA
Genetics of gastroesophageal cancer: paradigms, paradoxes, and prognostic utility.
Am J Gastroenterol. 2008; 103(2):443-9 [PubMed] Related Publications
Hereditary diffuse gastric cancer and tylosis are autosomal dominant cancer susceptibility syndromes. Accumulating evidence also suggests a genetic contribution to Barrett's esophagus and adenocarcinoma, traditionally considered acquired disorders. In this article we review the current knowledge on the genetic mechanisms underlying hereditary diffuse gastric cancer, tylosis, and Barrett's esophagus. Hereditary diffuse gastric cancer is a paradigm for hereditary cancer susceptibility syndromes with E-cadherin implicated as the dominant oncogene in up to one-third of cases. Tylosis in contrast remains the paradox as whilst the putative abnormality has been localized to the long arm of chromosome 17, sequencing of this region has failed to reveal a disease causing mutation. In the case of Barrett's esophagus and adenocarcinoma, although a validated specific disease-associated gene is yet to be identified, the increasing body of evidence of a possible genetic link is paving the way for subsequent prognostic studies such as AspECT (Aspirin Esomeprazole Chemoprevention Trial). For the clinician these advances in understanding are already having implications for practice in terms of improved screening and the stratification of management strategies. As the mechanisms continue to be defined, there is the real possibility that these mechanisms could be exploited or subverted in the design of new therapies. In the meantime, however, clinicians should undertake rigorous biopsy programs to ensure early invasive lesions are detected.

McRonald FE, Liloglou T, Xinarianos G, et al.
Down-regulation of the cytoglobin gene, located on 17q25, in tylosis with oesophageal cancer (TOC): evidence for trans-allele repression.
Hum Mol Genet. 2006; 15(8):1271-7 [PubMed] Related Publications
Tylosis (focal non-epidermolytic palmoplantar keratoderma) is an autosomal dominant skin disorder that is associated with the early onset of squamous cell oesophageal cancer (SCOC) in three families. Our previous linkage and haplotype analyses have mapped the tylosis with oesophageal cancer (TOC) locus to a 42.5 kb region on chromosome 17q25 that has also been implicated in the aetiology of sporadically occurring SCOC from a number of different geographical populations. Oesophageal cancer is one of the 10 leading causes of cancer mortality worldwide. No inherited disease-causing mutations have been identified in the genes located in the 42.5 kb minimal region. We now show that cytoglobin gene expression in oesophageal biopsies from tylotic patients is dramatically reduced by approximately 70% compared with normal oesophagus. Furthermore, both alleles are equally repressed. Given the autosomal dominant nature of the disease, these results exclude haploinsufficiency as a mechanism of the disease and instead suggest a novel trans-allele interaction. We also show that the promoter is hypermethylated in sporadic oesophageal cancer samples: this may constitute the 'second hit' of a gene previously implicated in this disease by allelic imbalance studies.

Iwaya T, Maesawa C, Kimura T, et al.
Infrequent mutation of the human envoplakin gene is closely linked to the tylosis oesophageal cancer locus in sporadic oesophageal squamous cell carcinomas.
Oncol Rep. 2005; 13(4):703-7 [PubMed] Related Publications
Envoplakin (EVPL) is a member of the desmosomal plaque proteins attached to desmosomal cadherin and keratin filaments. The EVPL gene has been mapped to the tylosis oesophageal cancer (TOC) locus on chromosome 17q25, where it has been demonstrated to be frequently deleted in both familial and sporadic forms of oesophageal squamous cell carcinoma (OSC). In this study, we examined EVPL gene mutations in 10 OSC cell lines and 20 sporadic OSCs using reverse transcription-polymerase chain reaction single-strand conformational analysis (RT-PCR SSCP) followed by direct sequencing. We observed one somatic mutation (GCG to ACG at codon 1104, Ala to Thr: 1/20, 5%) in the central rod domain and 5 intragenic polymorphic sites, where frequent loss of heterozygosity (LOH) (63%) was detected. No mutations were detected in the OSC cell lines. The rate of EVPL gene mutation was quite low in contrast to the frequency of LOH on the TOC locus in sporadic OSCs, and the high incidence of oesophageal cancer development in tylosis families. Our results suggest that EVPL might not be the target gene responsible for OSC, despite its strong candidacy in terms of character and localization.

Shahabi M, Noori Daloii MR, Langan JE, et al.
An investigation of the tylosis with oesophageal cancer (TOC) locus in Iranian patients with oesophageal squamous cell carcinoma.
Int J Oncol. 2004; 25(2):389-95 [PubMed] Related Publications
Oesophageal cancer is one of the ten leading causes of cancer mortality worldwide. Earlier loss of heterozygosity (or allelic imbalance) studies have implicated regions on chromosomes 3p, 5q, 9p, 13q, 17p, 17q, and 18q in the development of sporadic oesophageal cancer and recent data have linked the familial tylosis with oesophageal cancer (TOC) gene-containing region on chromosome 17q25 with this cancer. We have studied allelic imbalance (AI) at microsatellite markers both closely linked to and distant from the TOC gene locus in 60 sporadic squamous cell oesophageal cancers from Iran and have investigated the most likely candidate gene by mutation analysis in these tumours. Forty-four out of these 60 samples (73%) show allelic imbalance at one or more loci within or adjacent to the TOC minimal region, while the highest incidence of AI was observed at the D17S2244 and D17S2246 loci (almost 70% AI in informative cases), correlating with the TOC minimal region. Analysis of the coding regions of a candidate gene in these tumours failed to show an equivalently high incidence of mutation, although two mutations and one polymorphism were observed. These data support and extend previous observations that the TOC region of chromosome 17q25 may be involved in the aetiology of the sporadic form of oesophageal cancer from a number of different geographical populations and suggest that the causative gene may be epigenetically silenced rather than mutated.

Langan JE, Cole CG, Huckle EJ, et al.
Novel microsatellite markers and single nucleotide polymorphisms refine the tylosis with oesophageal cancer (TOC) minimal region on 17q25 to 42.5 kb: sequencing does not identify the causative gene.
Hum Genet. 2004; 114(6):534-40 [PubMed] Related Publications
Tylosis (focal non-epidermolytic palmoplantar keratoderma) is associated with the early onset of squamous cell oesophageal cancer in three families. Linkage and haplotype analyses have previously mapped the tylosis with oesophageal cancer ( TOC) locus to a 500-kb region on chromosome 17q25 that has also been implicated in sporadically occurring squamous cell oesophageal cancer. In the current study, 17 additional putative microsatellite markers were identified within this 500-kb region by using sequence data and seven of these were shown to be polymorphic in the UK and US families. In addition, our complete sequence analysis of the non-repetitive parts of the TOC minimal region identified 53 novel and six known single nucleotide polymorphisms (SNPs) in one or both of these families. Further fine mapping of the TOC disease locus by haplotype analysis of the seven polymorphic markers and 21 of the 59 SNPs allowed the reduction of the minimal region to 42.5 kb. One known and two putative genes are located within this region but none of these genes shows tylosis-specific mutations within their protein-coding regions. Alternative mechanisms of disease gene action must therefore be considered.

Risk JM, Evans KE, Jones J, et al.
Characterization of a 500 kb region on 17q25 and the exclusion of candidate genes as the familial Tylosis Oesophageal Cancer (TOC) locus.
Oncogene. 2002; 21(41):6395-402 [PubMed] Related Publications
The locus for a syndrome of focal palmoplantar keratoderma (Tylosis) associated with squamous cell oesophageal cancer (TOC) has been mapped to chromosome 17q25, a region frequently deleted in sporadic squamous cell oesophageal tumours. Further haplotype analysis described here, based on revised maps of marker order, has reduced the TOC minimal region to a genetic interval of 2 cM limited by the microsatellite markers D17S785 and D17S751. Partial sequence data and complete physical maps estimate the actual size of this region to be only 0.5 Mb. This analysis allowed the exclusion of proposed candidate tumour suppressor genes including MLL septin-like fusion (MSF), survivin, and deleted in multiple human cancer (DMC1). Computer analysis of sequence data from the minimal region identified 13 candidate genes and the presence of 50-70 other 'gene fragments' as ESTs and/or predicted exons and genes. Ten of the characterized genes were assayed for mutations but no disease-specific alterations were identified in the coding and promoter sequences. This region of chromosome 17q25 is, therefore, relatively gene-rich, containing 13 known and possibly as many as 50 predicted genes. Further mutation analysis of these predicted genes, and others possibly residing in the region, is required in order to identify the elusive TOC locus.

Risk JM, Mills HS, Garde J, et al.
The tylosis esophageal cancer (TOC) locus: more than just a familial cancer gene.
Dis Esophagus. 1999; 12(3):173-6 [PubMed] Related Publications
Tylosis (focal non-epidermolytic palmoplantar keratoderma; NEPPK) is associated with esophageal cancer in three families, two of which contain six or seven generations. The causative locus, the tylosis esophageal cancer (TOC) gene, has been localized to a small region on chromosome 17q25. Recent loss of heterozygosity (LOH) studies have indicated a role for the TOC gene in sporadic squamous cell esophageal cancer and Barrett's adenocarcinoma. We have now integrated genetic and physical mapping data from the TOC region, based on microsatellite markers and radiation hybrid, yeast (YAC), bacterial (BAC) and P1 artificial chromosomal (PAC) clones, and formed a partial minimal contig of one non-chimeric YAC (330 kb) and one PAC. Twenty-three candidate genes, including envoplakin (EVPL), were mapped against this contig, but only one was shown to be located within the minimal region. This physical map will allow further characterization of the region and identification of a gene implicated in both familial and sporadic squamous cell esophageal carcinoma and Barrett's adenocarcinoma.

Risk JM, Ruhrberg C, Hennies H, et al.
Envoplakin, a possible candidate gene for focal NEPPK/esophageal cancer (TOC): the integration of genetic and physical maps of the TOC region on 17q25.
Genomics. 1999; 59(2):234-42 [PubMed] Related Publications
Focal nonepidermolytic palmoplantar keratoderma (NEPPK), or tylosis, is an autosomal, dominantly inherited disorder of the skin that manifests as focal thickening of the palmar and plantar surfaces. In three families studied, the skin disorder cosegregates with esophageal cancer and oral lesions. New haplotype analysis, presented here, places the tylosis esophageal cancer (TOC) locus between D17S1839 and D17S785. Envoplakin (EVPL) is a protein component of desmosomes and the cornified envelope that is expressed in epidermal and esophageal keratinocytes and has been localized to the TOC region. Mutation analysis of EVPL in the three affected families failed to show tylosis-specific mutations, and haplotype analysis of three intragenic sequence polymorphisms of the EVPL gene placed it proximal to D17S1839. Confirmation of the exclusion of EVPL as the TOC gene by location was obtained by integration of the genetic and physical mapping data using radiation hybrid, YAC, BAC, and PAC clones. This new physical map will allow further identification of candidate genes underlying NEPPK associated with esophageal cancer, which may also be implicated in the development of sporadic squamous cell esophageal carcinoma and Barrett's adenocarcinoma.

von Brevern M, Hollstein MC, Risk JM, et al.
Loss of heterozygosity in sporadic oesophageal tumors in the tylosis oesophageal cancer (TOC) gene region of chromosome 17q.
Oncogene. 1998; 17(16):2101-5 [PubMed] Related Publications
From the genotyping of UK and US tylotic families with a high risk of oesophageal cancer we have previously localized the tylosis-associated cancer susceptibility gene (TOC gene, tylosis oesophageal cancer gene) to a 1 cM region on the long arm of chromosome 17 (Kelsell et al., 1996). In the present study we investigated loss of heterozygosity (LOH) patterns of 35 sporadic squamous cell carcinomas of the oesophagus using six polymorphic microsatellite markers encompassing this locus. Twenty-four of the 35 cases (69%) revealed LOH at one or more loci. Deletion was most frequently observed with the marker D17S801 (64% LOH, informative cases), which shows significant linkage to the TOC locus. The LOH analysis in sporadic oesophageal cancer we report here is thus consistent with the hypothesis that the tylosis oesophageal cancer susceptibility gene is also involved in the pathogenesis of a proportion of sporadic squamous cell carcinomas of the oesophagus.

Iwaya T, Maesawa C, Ogasawara S, Tamura G
Tylosis esophageal cancer locus on chromosome 17q25.1 is commonly deleted in sporadic human esophageal cancer.
Gastroenterology. 1998; 114(6):1206-10 [PubMed] Related Publications
BACKGROUND & AIMS: Tumor-suppressor genes found in inherited cancer predisposition syndromes are also responsible for sporadic cancers of the same type. Recently, the tylosis oesophageal cancer (TOC) gene locus has been mapped to 17q25 by linkage analyses of pedigrees with focal nonepidermolytic palmoplantar keratoderma associated with a high risk of esophageal cancer development. The aim of this study was to clarify whether the TOC locus is affected in sporadic esophageal cancers.
METHODS: We investigated loss of heterozygosity (LOH) on 17q in 58 sporadic esophageal squamous cell carcinomas (ESCs) using 20 microsatellite markers focusing on the TOC locus.
RESULTS: LOH on 17q was observed in 37 of 52 (71%) informative cases at one or more loci, 80% (33/37) of which included the TOC locus. The smallest common deleted region was at D17S1839 within the TOC locus.
CONCLUSIONS: The constructed deletion map revealed that the TOC locus is commonly deleted in sporadic ESCs, suggesting that a tumor-suppressor gene responsible for ESC is contained within this locus.

Simon M, Hagedorn M
[The Clark-Howel-Evans-McConnell syndrome. Observations in one family over 5 generations].
Hautarzt. 1997; 48(11):800-5 [PubMed] Related Publications
The Clarke-Howel-Evans-McConnell syndrome is a rare hereditary disease characterized by palmoplantar keratoses, squamous cell carcinoma of the esophagus and oral leukoplakia. According to a new classification recently proposed by Stevens and colleagues, the syndrome can also be classified as palmoplantar ectodermal dysplasia type III. We report a family from the Black Forest region of Germany afflicted with the syndrome. The family was traced through five generation. 27 of 46 family members showed tylotic skin changes. In addition, 8 patients showed oral leukoplakia and 5 died from squamous cell carcinoma of the esophagus. Using screening examinations, early changes of the esophageal mucosa could be detected. The responsible gene has been mapped in the family. It is located at 17q23-qter, telomeric to the keratin II gene cluster. Therefore a defect in one of the well known keratin genes can be excluded as a cause of the syndrome.

Christiano AM
Frontiers in keratodermas: pushing the envelope.
Trends Genet. 1997; 13(6):227-33 [PubMed] Related Publications
A clinically and genetically heterogeneous group of disorders, known collectively as the palmoplantar keratodermas, are unified by the phenotypic characteristic of a thickening of the skin over the palms and soles. Although spectacular progress has been made in understanding the basis of many genodermatoses, the genetic defects causing many of the keratodermas are still largely unknown. These unusual phenotypes are beginning to capture the attention of investigators in epidermal biology, and several compelling lines of evidence point to the cornified cell envelope and structural components of the desmosome as potential underlying targets of disease. It is anticipated that understanding the molecular basis of the keratodermas will underscore the importance of the integrity of the cell envelope and the desmosome, and provide new insights into the mechanisms of epidermal differentiation and related disorders.

Ruhrberg C, Williamson JA, Sheer D, Watt FM
Chromosomal localisation of the human envoplakin gene (EVPL) to the region of the tylosis oesophageal cancer gene (TOCG) on 17q25.
Genomics. 1996; 37(3):381-5 [PubMed] Related Publications
Envoplakin is a membrane-associated precursor of the epidermal cornified envelope. Envoplakin is homologous to desmoplakin I and desmoplakin II (DPI/II), bullous pemphigoid antigen 1 (BPAG1), and plectin and is proposed to link desmosomes and keratin filaments to the cornified envelope. We describe the isolation of cosmids and yeast artificial chromosomes containing the complete human envoplakin gene (EVPL) and show, by analysis of somatic cell hybrids and chromosomal in situ hybridisation, that the envoplakin gene, unlike the genes encoding BPAG1 and DPI/II, maps to 17q25 and is physically linked to D17S1603. This sequence-tagged site segregates with the autosomal dominant human disease focal nonepidermolytic palmoplantar keratosis (NEPKK; "tylosis"), which is associated with an increased risk of oesophageal cancer. The chromosomal localisation of the envoplakin gene, the homology of the encoded protein to keratin-binding proteins, and its expression in epidermal and oesophageal keratinocytes all raise the possibility that loss of envoplakin function could be responsible for this form of palmoplantar keratoderma.

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Cite this page: Cotterill SJ. Tylosis with Esophageal Cancer, Cancer Genetics Web: http://www.cancer-genetics.org/Tylosis.htm Accessed:

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