Howel–Evans syndrome

Overview

Howel–Evans syndrome, also known as tylosis with esophageal cancer, is a rare hereditary condition characterized by thickening of the skin on the palms and soles (palmoplantar keratoderma) and a markedly increased risk of developing squamous cell carcinoma of the esophagus. It is inherited in an autosomal dominant pattern and is considered one of the few syndromes where a dermatological condition is strongly linked to internal malignancy.

Causes

The syndrome is caused by mutations in the RHBDF2 gene located on chromosome 17q25. This gene plays a role in epidermal growth factor receptor (EGFR) signaling, which is important in cell growth and differentiation. Mutations in RHBDF2 lead to abnormal keratinocyte proliferation and are believed to predispose affected individuals to esophageal cancer through dysregulation of epithelial homeostasis.

Symptoms

Clinical manifestations of Howel–Evans syndrome typically appear in childhood or adolescence and may include:

• Diffuse palmoplantar keratoderma (thickened skin on palms and soles)

• Hyperhidrosis (excessive sweating of hands and feet)

• Fissures or painful cracks in the skin of palms and soles

• Family history of esophageal cancer, usually in middle age

While the skin changes are often the first sign, the most serious aspect of the syndrome is the significantly elevated lifetime risk of esophageal squamous cell carcinoma, often developing between ages 45 and 65.

Diagnosis

Diagnosis is typically based on a combination of clinical features, family history, and genetic testing. Key diagnostic steps include:

• Clinical examination revealing characteristic palmoplantar keratoderma

• Detailed family history of esophageal cancer and skin findings

• Genetic testing to confirm RHBDF2 gene mutation

• Upper gastrointestinal endoscopy and biopsies for early detection of esophageal dysplasia or carcinoma

Early diagnosis allows for enhanced surveillance and preventive strategies for esophageal cancer.

Treatment

Management of Howel–Evans syndrome is twofold: treating skin symptoms and implementing cancer surveillance. Treatment options include:

• Topical keratolytic agents (e.g., salicylic acid, urea) to manage thickened skin

• Emollients and moisturizers to reduce skin cracking and discomfort

• Oral retinoids in severe keratoderma cases

• Regular endoscopic screening of the esophagus starting in early adulthood

• Endoscopic removal or ablation of dysplastic lesions if found

Family members may also be advised to undergo genetic counseling and testing.

Prognosis

While the skin symptoms of Howel–Evans syndrome are chronic and manageable, the prognosis largely depends on the early detection and management of esophageal cancer. With regular surveillance, early-stage esophageal lesions can be detected and treated, significantly improving outcomes. Without screening, there is a high risk of developing advanced esophageal carcinoma, which carries a poor prognosis. Therefore, lifelong monitoring is essential for affected individuals.