Familial tylosis

2009-07-01   Othman 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 Marys Hospital, University of London, London, United Kingdom (JAJ)



Familial tylosis


Howell-Evans syndromes , Tylosis oesophageal cancer , Focal non epidermolytic palmoplantar keratoderma (NEPPK) with carcinoma of the oesophagus


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).


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).




148500 , 148600


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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).


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 of squamous cell cancer of oesophagus: In general is poor with 5 year survival of 75% in Stage 0 (intraepithelial cancer) to



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).
This region contains 5end of uncharacterized (FM8) gene, which is likely non coding RNA, a promoter of another gene and the whole cytoglobin gene (Langan et al., 2004).
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




RHBDF2 gene or tylosis with oesophageal cancer gene.


No mutations have been identified in the gene.


Pubmed IDLast YearTitleAuthors
80322991994Tylosis associated with carcinoma of the oesophagus and oral leukoplakia in a large Liverpool family--a review of six generations.Ellis A et al
112814152001Molecular cloning, tissue expression, and chromosomal assignment of a novel gene encoding a subunit of the human signal-recognition particle.Harada H et al
135791621958Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis): a study of two families.HOWEL-EVANS W et al
87766041996Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with oesophageal cancer (TOC).Kelsell DP et al
150077282004Novel 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 et al
100866741999To B or not to B: is tylosis B truly benign? Two North American genealogies.Maillefer RH et al
165104942006Down-regulation of the cytoglobin gene, located on 17q25, in tylosis with oesophageal cancer (TOC): evidence for trans-allele repression.McRonald FE et al
109213312000[Palmoplantar keratosis].Nagai H et al
122142812002Characterization of a 500 kb region on 17q25 and the exclusion of candidate genes as the familial Tylosis Oesophageal Cancer (TOC) locus.Risk JM et al
179250012008Genetics of gastroesophageal cancer: paradigms, paradoxes, and prognostic utility.Robertson EV et al
86517141996Linkage 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 et al
42135631974Oral leukoplakia associated with tylosis and esophageal carcinoma.Tyldesley WR et al