Multiple Self-Healing Squamous Epithelioma

Multiple self-healing squamous epithelioma (also known as Ferguson-Smith disease (FSD)) is a rare inherited skin cancer syndrome characterized by the development of multiple locally invasive skin tumors resembling keratoacanthomas of the face and limbs which usually heal spontaneously after several months leaving pitted scars.

Epidemiology

The prevalence is unknown but to date over 100 cases have been reported with several large affected families originating in western Scotland.

Clinical description

Tumors typically start as a reddish macule which becomes papular, enlarged and ulcerated. As the tumor involutes, a horny plug forms that falls out leaving a deep pit with irregular, over-hanging edges. Tumors have a predilection for sun-exposed areas, especially nose, ears and circumoral regions. Lesions on the limbs are often larger and leave flat scars. The trunk is seldom affected. Lifetime tumor numbers range from a few to over a hundred. The age of onset of a first tumor is very variable ranging from 8 to over 70 years (median 28 years). Histological assessment of these tumors reveals well differentiated squamous carcinomas. Treatment with radiotherapy must be avoided because more numerous, more invasive tumors arise in previously irradiated skin.

Etiology

FSD may be due to loss of function mutations in the gene TGFBR1 (9q22) which encodes a transmembrane serine/threonine kinase receptor involved in TGF-β signaling. Mutations in the gene TGFBR1 are also found in Loeys-Dietz syndrome (LDS; see this term) but the spectrum of TGFBR1 mutations differs and the mutations found in most FSD families have not been associated with a predisposition to aortic aneurysm or other developmental defects that occur in LDS. It has been suggested that FSD is an oligogenic trait. Inherited permissive variants at TGFBR1 and a second, as yet unidentified, linked locus on the long arm of chromosome 9 appear to be required for tumor development. 90% of TGFBR1 mutation carriers in affected families developed the condition by age 60. Palmar and plantar skin are not affected suggesting that the tumors arise from hair follicles.

Genetic counseling

Although FSD is likely to be an oligogenic trait, the condition is inherited in an autosomal dominant manner because the TGFBR1 mutations and predisposing variants at the second linked locus are usually inherited together in affected families.