Howel–Evans syndrome is an extremely rare condition involving thickening of the skin in the palms of the hands and the soles of the feet (hyperkeratosis).

[2] This condition is inherited as an autosomal dominant syndrome and characterized by palmoplantar keratoderma, oral precursor lesions particularly on the gums (leukoplakia) and a high lifetime risk of esophageal cancer (95% develop esophageal cancer by the age of 65).

[5] Cytoglobin gene expression in oesophageal biopsies is significantly reduced (70% reduction) in this condition.

The gene responsible is RHBDF2 (Rhomboid family member 2), which is located on the long arm of chromosome 17 (at 17q25).

It is thought to play an important role in the epithelial response to injury in the esophagus and skin.

[23] A second related gene – rhomboid family 1 (RHBDF1) – appears to be important in head and neck cancer.