Howel-Evans syndrome
Tylosis with oesophageal cancer (TOC); palmoplantar keratoderma with oesophageal cancer; "Liverpool tylosis"; previously linked to "TOC1" locus on 17q25
Howel-Evans syndrome is a rare autosomal dominant cancer-predisposition syndrome originally described in two large kindreds from the Wirral / Liverpool region of England by Howel-Evans, McConnell and colleagues in the 1950s. The syndrome combines focal non-epidermolytic palmoplantar keratoderma (tylosis) — a thickening of the pressure-bearing surfaces of the palms and soles that develops in childhood — with a markedly elevated lifetime risk of oesophageal squamous cell carcinoma, approximately 90–95% by age 65. Causative germline missense mutations in RHBDF2 (encoding inactive rhomboid protease iRhom2) on chromosome 17q25.1 disrupt EGFR signalling and squamous epithelial homeostasis. The dermatologist is often the first to suspect the syndrome through the characteristic tylosis pattern, and prompt referral to clinical genetics for confirmation and to upper-GI surveillance endoscopy is critical because effective endoscopic surveillance can detect oesophageal SCC at curable stages.
Genetics
- Germline missense mutations of RHBDF2 on chromosome 17q25.1 — encoding inactive rhomboid protease iRhom2.
- iRhom2 regulates trafficking and shedding of EGFR ligands; mutated iRhom2 enhances EGFR signalling in the palmoplantar and oesophageal epithelium.
- Autosomal dominant; high penetrance — >95% develop tylosis by adolescence; oesophageal SCC risk approaches 90–95% by age 65.
- Confirm by germline RHBDF2 sequencing in suspected probands and cascade testing in family members.
Cutaneous features (tylosis)
- Focal non-epidermolytic palmoplantar keratoderma — thickening of the pressure-bearing surfaces of the palms (especially metacarpal pads) and soles (especially heels and forefoot).
- Onset typically in childhood (5–15 years).
- Painless or mildly tender; intermittent fissuring; hyperhidrosis common.
- Distinctive distribution — pressure-bearing rather than diffuse; spares fingertips, palms-finger junctions and the lateral hands.
- Oral leukoplakia in a substantial proportion — also pre-malignant for oral SCC.
- Skin findings precede oesophageal cancer by decades — providing the diagnostic and surveillance opportunity.
Cancer risk
- Oesophageal squamous cell carcinoma — lifetime risk ~90–95% by age 65; mean age at diagnosis 45–55.
- Synchronous and metachronous oesophageal SCCs common.
- Other risks — oral cavity SCC (in patients with oral leukoplakia), ?bladder SCC; smoking and alcohol multiply the oesophageal risk.
- Skin cancer risk is not significantly elevated above baseline despite the keratoderma — distinguishing it from other syndromes (Olmsted, dyskeratosis congenita) where keratoderma associates with cutaneous SCC.
Surveillance
- Refer to clinical genetics and a specialist upper-GI MDT.
- Upper GI endoscopy with chromoendoscopy / narrow-band imaging and quadrantic biopsies from age 30, repeated 1–3 yearly.
- Lifestyle counselling — strict avoidance of tobacco; limit alcohol; balanced diet rich in fruits and vegetables.
- Oral surveillance for any patient with oral leukoplakia.
- Genetic counselling and cascade testing of first-degree relatives.
- Surveillance is highly effective — endoscopically detected early-stage oesophageal SCC is curable with endoscopic mucosal resection / submucosal dissection or oesophagectomy.
Management
- Tylosis — symptomatic management:
- Daily emollients and keratolytics (urea 10–40%, salicylic acid 5–10%).
- Topical retinoids; oral acitretin for severe disease.
- Pressure-relieving footwear; podiatry input.
- Oral leukoplakia — biopsy any suspicious area; smoking cessation; surveillance every 6 months.
- Oesophageal SCC — managed per UK upper-GI cancer protocols (endoscopic resection for early lesions; oesophagectomy ± chemoradiotherapy for invasive disease); refer to upper-GI MDT.
References
- Howel-Evans W et al. Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis) — a study of two families. Q J Med; 1958.
- Blaydon DC et al. RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet; 2012.
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