Pilomatrixoma

A number sign (#) is used with this entry because at least some cases of pilomatrixoma are caused by somatic mutation in the beta-catenin gene (CTNNB1; 116806) on chromosome 3p22.

Clinical Features

Pilomatrixoma is the term used by Jones and Campbell (1969) for this tumor. The lesions are firm, circumscribed tumors, usually in the head and neck area, which feel like buttons and are attached to the subcutaneous tissue and overlying skin. Kawamura and Sekimura (1939) observed affected brother and sister. Duperrat and Albert (1948) described 5 affected persons in 2 generations of a family. Geiser (1960) reported affected father and daughter.

Hills and Ive (1992) described a mother and daughter with multiple pilomatrixomas. Neither patient showed any stigmata of myotonic dystrophy (160900), and there were no osteomas on skull x-ray. Colonic polyposis was also excluded.

Associations with Other Disorders

Cantwell and Reed (1965) reported multiple calcifying epithelioma in association with myotonic dystrophy, and Harper (1971) reported sibs with this combination and has seen at least 6 other confirmed instances of the association.

Masuno et al. (1998) pointed to the occurrence of pilomatrixomas in Rubinstein-Taybi syndrome (180849).

A combination of pilomatricomas and adenomatous polyposis coli (608456) as an autosomal recessive trait has been reported with mutation in the MYH gene (604933) (Baglioni et al., 2005).

Mapping

As mutations in the CTNNB1 gene on 3p22-p21.3 can cause pilomatrixomas, this disorder maps to that location.

Molecular Genetics

In patients with pilomatrixoma, Chan et al. (1999) identified mutations in the beta-catenin gene (e.g., 116806.0002). Moreno-Bueno et al. (2001) analyzed the expression pattern of beta-catenin in normal anagen hair follicles and in 40 human pilomatrixomas by immunohistochemistry. In 11 of these tumors they also studied exon 3 beta-catenin gene mutations by PCR and direct sequencing. As these mutations have been related to a replication error (RER) phenotype in other tumor types, Moreno-Bueno et al. (2001) explored whether or not this association also occurs in pilomatrixomas. Beta-catenin was expressed in the cell membranes of the outer and inner root sheaths and in matrix cells located at the base and periphery of the hair follicle bulb. However, central matrix cells that differentiate into cortical cells, cortical, and cuticular cells expressed beta-catenin in the nucleus, suggesting a role in signal transduction. In addition, some fibroblasts of the dermal papilla also showed nuclear expression of beta-catenin. All 40 analyzed pilomatrixomas showed intense nuclear and cytoplasmic beta-catenin expression in proliferating matrix (basaloid) cells. In areas of maturation, transitional cells mainly showed cytoplasmic and membranous expression of beta-catenin, while only a few cells retained nuclear expression. Shadow or ghost cells did not show beta-catenin expression. Three of 11 tumors (26%) had beta-catenin mutations. All 3 had the same heterozygous missense mutation: a G-to-T change affecting the first nucleotide at codon 32 (116806.0016). None of the 11 tumors studied had a positive RER phenotype. Moreno-Bueno et al. (2001) concluded that the Wnt/beta-catenin/Tcf-Lef pathway is activated in normal matrix cells of the hair follicle to induce differentiation to the hair shaft. Additionally, the beta-catenin mutation in matrix cells of the hair follicle stabilizes beta-catenin protein, which translocates into the nucleus, where it activates gene transcription together with lymphoid enhancer factor-1 (153245)-producing pilomatrixoma. These mutations occur without an underlying defect in DNA mismatch repair.