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Familial tylosis

Written2009-07Othman Saraj, Janusz A Jankowski
Digestive Disease Centre, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom (OS, JAJ); Gastrointestinal Cancer Presentation Group, Oxford University, Oxford, United Kingdom (JAJ); GI Centre, Queen Mary's Hospital, University of London, London, United Kingdom (JAJ)

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Other namesHowell-Evans syndromes
Tylosis oesophageal cancer
Focal non epidermolytic palmoplantar keratoderma (NEPPK) with carcinoma of the oesophagus
Atlas_Id 10100
Genes implicated inAAGAB   RHBDF2  
Note Synonyms include: (a) Tylosis oesophageal cancer or (b) Focal Non Epidermolytic Palmoplantar Keratoderma (NEPPK) with carcinoma of the oesophagus (Howel-Evans et al., 1958; Stevens et al., 1996).
Inheritance Is a rare autosomal dominant condition with full penetrance of skin phenotype by puberty. No race prevalence has been noted (Howel-Evans et al., 1958).


Phenotype and clinics Tylosis is divided into to types: Type A with late onset of NEPPK between age of 5 to 15 years and Type B with early onset around the first year of age (Maillefer and Greydanus, 1999; Nagai et al., 2000).
It usually involves the pressure areas mainly sole of feet and later mild involvement of palms (more obvious in manual workers). It can also affects frictional areas like elbows and knees. It regresses completely on bed rest (Howel-Evans et al., 1958; Stevens et al., 1996).
The affected skin has a thickened epidermis which sheds horny large flakes, usually in autumn, to leave a red tender surface which quickly get covered with another thick layer of epidermis (Howel-Evans et al., 1958).
Oral leukokeratosis (which are white "spongy" plaques) and follicular hyperkeratosis (which are pinkish-to-tan papules) on the body and flexure areas, are often seen in patients with tylosis and it could be a possible indication for developing oesophageal cancer (Tyldesly and Osborne-Hughes, 1973; Tyldesly, 1974).
See example of Tylosis on DermAtlas.
Neoplastic risk Malignancy Risk: Type A has a higher risk of developing squamous oesophageal carcinoma up to 95% by age of 65 years, while Type B runs a benign course (Howel-Evans et al., 1958; Ellis et al., 1994; Stevens et al., 1996).
These malignancies are predominantly in the distal esophagus whereas acquired squamous cell carcinomas are mostly mid-thoracic in location (Howel-Evans et al., 1958; Maillefer and Greydanus, 1999). Increase risk has been noted with history of smoking (Stevens et al., 1996).
Histological findings: Thickening of the all skin layers especially epidermis, hypertrophy of sweat glands and their ducts which often occluded by hyperplastic epithelium (Howel-Evans et al., 1958).
Treatment Monitoring: Annual endoscopic surveillance with biopsies taken should be offered to affected individuals in view of risk of oesophageal cancer (Robertson et al., 2008).
Prognosis Prognosis of squamous cell cancer of oesophagus: In general is poor with 5 year survival of 75% in Stage 0 (intraepithelial cancer) to <5% in stage IV (Distant metastasis). Overall survival is about 20-25% (Mayer, 2001).


Note The tylosis oesophageal cancer gene (RHBDF2) is localized to a small region on band 17q25, a region frequently deleted in persons with sporadic squamous cell oesophageal tumours (Kelsell et al., 1996; Risk et al., 2002).
So far studies has failed to identify RHBDF2 specific mutations in any of the 3 genes above (Langan et al., 2004).
However recent studies of the gene expression in the 42.5 kb RHBDF minimal region has shown down regulation of cytoglobin gene expression by 70% in tylotic patients which might contribute to RHBDF2 phenotype. This reduction exceeds the expected 50% effect from autosomal dominant conditions therefore rules out a simple haplo-insufficiency as a mechanism of the disease, instead a novel trans-allele interaction (ie the mutated allele causing suppression of the normal allele) has been suggested (McRonald et al., 2006).

Genes involved and Proteins

Location 17q25.1
Note RHBDF2 gene or tylosis with oesophageal cancer gene.
Description 42.5kb.
No mutations have been identified in the gene.


Tylosis associated with carcinoma of the oesophagus and oral leukoplakia in a large Liverpool family--a review of six generations.
Ellis A, Field JK, Field EA, Friedmann PS, Fryer A, Howard P, Leigh IM, Risk J, Shaw JM, Whittaker J.
Eur J Cancer B Oral Oncol. 1994;30B(2):102-12.
PMID 8032299
Molecular cloning, tissue expression, and chromosomal assignment of a novel gene encoding a subunit of the human signal-recognition particle.
Harada H, Nagai H, Mine N, Terada Y, Fujiwara H, Mikami I, Tsuneizumi M, Yabe A, Miyazaki K, Yokota T, Imoto I, Inazawa J, Emi M.
J Hum Genet. 2001;46(2):70-5.
PMID 11281415
Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis): a study of two families.
Howel-Evans W, McConnell RB, Clarke CA, Sheppard PM.
Q J Med. 1958 Jul;27(107):413-29.
PMID 13579162
Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with oesophageal cancer (TOC).
Kelsell DP, Risk JM, Leigh IM, Stevens HP, Ellis A, Hennies HC, Reis A, Weissenbach J, Bishop DT, Spurr NK, Field JK.
Hum Mol Genet. 1996 Jun;5(6):857-60.
PMID 8776604
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.
Langan JE, Cole CG, Huckle EJ, Byrne S, McRonald FE, Rowbottom L, Ellis A, Shaw JM, Leigh IM, Kelsell DP, Dunham I, Field JK, Risk JM.
Hum Genet. 2004 May;114(6):534-40. Epub 2004 Mar 9.
PMID 15007728
To B or not to B: is tylosis B truly benign? Two North American genealogies.
Maillefer RH, Greydanus MP.
Am J Gastroenterol. 1999 Mar;94(3):829-34.
PMID 10086674
Gastrointestinal tract cancer.
Mayer RJ.
Harrison's principles of internal medicine, 15th Edition , volume 1, Chapter 90, 2001, page 578-579.
Down-regulation of the cytoglobin gene, located on 17q25, in tylosis with oesophageal cancer (TOC): evidence for trans-allele repression.
McRonald FE, Liloglou T, Xinarianos G, Hill L, Rowbottom L, Langan JE, Ellis A, Shaw JM, Field JK, Risk JM.
Hum Mol Genet. 2006 Apr 15;15(8):1271-7. Epub 2006 Mar 1.
PMID 16510494
Palmoplantar keratosis.
Nagai H, Emi M.
Nippon Rinsho. 2000 Jul;58(7):1501-4. (REVIEW)
PMID 10921331
Characterization of a 500 kb region on 17q25 and the exclusion of candidate genes as the familial Tylosis Oesophageal Cancer (TOC) locus.
Risk JM, Evans KE, Jones J, Langan JE, Rowbottom L, McRonald FE, Mills HS, Ellis A, Shaw JM, Leigh IM, Kelsell DP, Field JK.
Oncogene. 2002 Sep 12;21(41):6395-402.
PMID 12214281
Genetics of gastroesophageal cancer: paradigms, paradoxes, and prognostic utility.
Robertson EV, Jankowski JA.
Am J Gastroenterol. 2008 Feb;103(2):443-9. Epub 2007 Oct 9. (REVIEW)
PMID 17925001
Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas.
Stevens HP, Kelsell DP, Bryant SP, Bishop DT, Spurr NK, Weissenbach J, Marger D, Marger RS, Leigh IM.
Arch Dermatol. 1996 Jun;132(6):640-51. (REVIEW)
PMID 8651714
Oral leukoplakia associated with tylosis and esophageal carcinoma.
Tyldesley WR.
J Oral Pathol. 1974;3(2):62-70.
PMID 4213563


This paper should be referenced as such :
Saraj, O ; Jankowski, JA
Familial tylosis
Atlas Genet Cytogenet Oncol Haematol. 2010;14(6):597-598.
Free journal version : [ pdf ]   [ DOI ]
On line version :

External links

Other databasepalmoplantar keratoderma /diseases/2826/epidermolytic-palmoplantar-keratoderma (GARD)
Genes implicated inAAGAB   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  
Genes implicated inRHBDF2   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

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