Multiple Self-Healing Squamous Epithelioma, Susceptibility To

A number sign (#) is used with this entry because susceptibility to multiple self-healing squamous epithelioma (MSSE) is conferred by heterozygous loss-of-function mutation in the TGFBR1 gene (190181) on chromosome 9q22.

Description

Individuals with multiple self-healing squamous epithelioma (MSSE) develop multiple invasive skin tumors that undergo spontaneous regression leaving pitted scars. Age at onset is highly variable, ranging from 8 to 62 years. The disorder shows autosomal dominant inheritance, and most affected families have originated from western Scotland (Bose et al., 2006). MSSE has been considered to be a variety of multiple keratoacanthoma (Biskind et al., 1957; Haydey et al., 1980).

Clinical Features

Ferguson Smith (1934) first described this disorder in a single case, that of a 23-year-old miner, who first developed spots on the legs at age 16 years. The lesions healed spontaneously, but were replaced by others at neighboring sites and later on the face and ears. A depressed scar remained after healing. The lesions resembled squamous carcinoma clinically and histologically. He continued to work except for a few months when lesions on the knees prevented him from kneeling. Ferguson Smith (1948) provided a follow-up of this patient. Treatment of large lesions on his right leg with radium was 'followed by necrosis of the tibia, and ultimately, at the patient's own request...amputation below the knee.' He was wearing a prosthesis to cover an extensive destruction of the nose. Ferguson-Smith (1974) reported that the patient died of 'suppurative meningitis' in December 1948. Autopsy findings were reported by Currie and Ferguson Smith (1952). In addition to the face, ears, arms and legs, the skin of the anus, scrotum and anterior abdominal wall were affected. All tumors were well-differentiated squamous epitheliomata with lymphatic infiltration of the anal and aural lesions. The anal tumor infiltrated the sphincter and muscle coats of the anal canal.

Sommerville and Milne (1950) reported 2 cases in each of 2 successive generations. Affected father and son were referred to by Biskind et al. (1957). Degos et al. (1964) described the condition in a woman and 2 daughters. Ereaux and Schopflocher (1965) observed affected brother and sister.

Ferguson-Smith et al. (1971), the geneticist son of the dermatologist who first described this condition, reviewed 62 cases in western Scotland. The lesions were found more frequently on exposed areas of the skin. Two girls had their first lesion during their thirteenth year; the oldest onset in a male was at age 56 and in a female at age 55. The mean age of onset in women was 25.5 and in men 26.9. Many examples of male-to-male transmission, equal involvement of the sexes, and precise agreement with the 50:50 segregation ratio proved autosomal dominant inheritance. A single instance of 'skipped generation' was found: the daughter of an affected male and mother of 2 affected daughters had unblemished skin when fully examined at age 57.

Mapping

In studies of 13 affected families, Goudie et al. (1991) demonstrated linkage between the MSSE locus and several markers on chromosome 9q31 (maximum lod score of 8.05 at marker D9S29). Goudie et al. (1993) found tight linkage of the locus, which they designated ESS1, to 9q31 (maximum lod score of 9.02 at D9S53). Multipoint linkage analysis demonstrated that the disease locus probably lies between D9S58 (9q22.3-q31) and ASSP3, a pseudogene of argininosuccinate synthetase (ASS; 603470), located at 9q11-q22. Comparison of markers associated with MESS in independently ascertained families suggested a common origin of the disease.

By direct sequencing and polymorphism analysis of affected individuals, Richards et al. (1997) excluded the XPA (611153) gene as the site of the mutation in MSSE. The Patched (PTCH; 601309) gene is mutated in Gorlin syndrome (109400); MSSE families were shown to share a common haplotype at 3 novel intragenic PTCH polymorphisms. Although no mutations were detected in MSSE families, PTCH was not excluded as the MSSE gene. Richards et al. (1997) concluded that the MSSE gene is on chromosome 9q22.3 between D9S197 and D9S287/D9S1809.

Blair et al. (1998) generated an integrated physical and genetic map of 9q22.1-q22.3. This region encompasses the MSSE critical interval, which the authors estimated at 2 Mb.

Bose et al. (2006) refined the MSSE critical region to a less than 1-cM interval between the ZNF169 (603404) and FANCC (227645) genes. The authors noted that there were some discrepancies between the physical assembly of the genome and the genetic map of this region. They found the order of markers to be D9S196-ZNF169-D9S280-FANCC-D9S1816-D9S287. Genetic mapping excluded the ZNF169, FANCC, PTCH, and TGFBR1 (190181) genes as involved in MSSE; further molecular analysis excluded the CDC14B (603505) gene. Molecular analysis of tissue from 5 of 12 tumors showed loss of heterozygosity of the MSSE region, with loss of the normal allele. The findings indicated that the MSSE gene is likely a tumor suppressor gene.

Molecular Genetics

In affected members of 18 different families with MSSE, Goudie et al. (2011) identified 11 different heterozygous mutations in the TGFBR1 gene (see, e.g., 190181.0009-190181.0012). The first mutations were found using high-throughput genomic sequencing and exon array capture of a 24.2-Mb region containing the MSSE locus; additional families were studied by sequencing. One mutation, G52R (190181.0010), was found in 6 Scottish families, including those reported by Ferguson-Smith et al. (1971). The mutations identified by Goudie et al. (2011) occurred in either the extracellular ligand-binding domain or in the serine/threonine kinase domain of the protein, and all were predicted or demonstrated to result in loss of receptor function. Several mutation carriers were unaffected, and tumor tissue from some patients showed loss of heterozygosity for the wildtype allele. Overall, the findings were consistent with wildtype TGFBR1 acting as a tumor suppressor, until somatic deletion by a classic second hit results in carcinogenesis.

Population Genetics

Ferguson-Smith et al. (1971) assembled reliable information on 62 cases in western Scotland, and suggested that all the Scottish cases derived from a single mutation which occurred before 1790. The Scottish cases were in 11 independently ascertained families but the genealogic connections of some could be demonstrated.

Nomenclature

The symbol for the self-healing squamous epithelioma locus on chromosome 9 was changed from ESS1 to MSSE when it was discovered that the symbol ESS1 was already used for a cell division gene in Saccharomyces cerevisiae (Richards et al., 1997).