American Journal of Medical Genetics 134A:212–214 (2005) Clinical Report A Kindred With MYH-Associated Polyposis and Pilomatricomas Silvana Baglioni, 1 German Melean, 1 Francesca Gensini, 1 Marco Santucci, 2 Marco Scatizzi, 3 Laura Papi, 1 and Maurizio Genuardi 1 * 1 Department of Clinical Pathophysiology, Section of Medical Genetics, University of Florence, Florence, Italy 2 Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy 3 Unit of Surgery, Careggi Hospital, Florence, Italy MYH-associated polyposis (MAP) is a recently described autosomal recessive form of familial adenomatous polyposis (FAP) associated with susceptibility to colorectal carcinoma (CRC). MAP is caused by biallelic inactivating mutations of the MYH gene, a component of the base excision repair (BER) machinery, whose dysfunction leads to an increase in the rate of G > T transversions following DNA oxidative damage. MAP patients can present with either classic or attenuated polyposis. However, the MAP colonic and extra- colonic phenotype has yet to be defined. We report on two siblings, born from consanguineous par- ents, who were found to be homozygotes for an MYH frameshift mutation. The propositus pre- sented with a low number of colonic lesions and an early-onset CRC. Both siblings had a history of pilomatricomas, benign tumors derived from hair follicles, in childhood. The findings presented provide further evidence of phenotypic variabil- ity in MAP, and suggest that multiple pilomatri- comas may be a useful cutaneous marker of MAP. ß 2005 Wiley-Liss, Inc. KEY WORDS: colorectal adenoma; colorectal cancer; b-catenin; APC; polyposis; MYH INTRODUCTION MYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to multiple colorectal adenomas and cancer [Al-Tassan et al., 2002]. The MYH gene encodes a glycosylase, which is involved in the base excision repair (BER) pathway. BER plays an important role in the repair of DNA mutations caused by reactive oxygen species generated during aerobic metabolism [Lindahl, 1993]. Oxidative damage con- verts guanine into 8-oxo-7,8-dihydro-2 0 deoxyguanosine (8-oxo- G) which mispairs with adenine, resulting in G:C ! T:A transversion mutations particularly at GAA sequences [Nghiem et al., 1988]. The high level of oxidative damage affecting colonic epithelium may explain the specific predis- position to colonic tumors in patients with MYH defects. Colorectal tumorigenesis in MAP patients is characterized by the presence of a distinct pattern of somatic Adenomatous Polyposis Coli (APC) gene mutations, namely GAA ! TAA transversions [Al-Tassan et al., 2002]. Pilomatricomas are benign, calcifying cutaneous tumors of hair matrix cells which are usually solitary and asymptomatic. Familial multiple pilomatricomas are rare, and usually show an autosomal dominant pattern of inheritance [Grabczynska et al., 2002]. A single multiple pilomatricoma family, with three affected siblings, suggesting autosomal recessive inheri- tance, has been described [Karpuzoglu et al., 2003]. Multiple pilomatricomas have been observed in the context of myotonic dystrophy [Kopeloff et al., 1992; Geh and Moss, 1999], Rubinstein–Taybi syndrome [Cambiagni et al., 1994], and Gardner syndrome, a variant of familial adenomatous poly- posis (FAP) [Pujol et al., 1995]. b-Catenin, involved in WNT signalling, plays a role in normal hair development, and is degraded upon interaction with the APC protein [Smits et al., 1987; Rubinfeld et al., 1993]. Transgenic mice expressing stable b-catenin develop skin follicle tumors resembling human pilomatricomas [Gat et al., 1998]. Activating mutations of the b-catenin gene (CTNNB1) have been found in 30%–100% of sporadic pilomatricomas [Kajino et al., 2001; Moreno-Bueno et al., 2001]. Mutations are almost exclusively located in the NH 2 -terminus of the gene within the 3rd exon (codons 33, 44, and 45), and they determine b-catenin activation either through modification of the phos- phorylation sites or alteration of a domain responsible for APC binding [Morin et al., 1997; Iwao et al., 1998; Sparks et al., 1998]. Herein, we report a family that provides evidence for a link between MYH mutations, colorectal tumors and pilomatricomas. CLINICAL REPORT The pedigree of the family is shown in Figure 1. III-14 e III-15 were born from consanguineous parents. Subject III-14 was diagnosed with low-grade rectal adenocarcinoma and two polyps of the ascending colon at the age of 32 years. He under- went anterior resection of the rectum following pre-operative radio- and chemotherapy. Polyps were removed by endoscopic resection. At the age of 10 years, a pilomatricoma located on the left arm and a facial sweat gland adenoma had been removed. His sister (III-15) underwent colonoscopic examination at the age of 29 years, following cancer diagnosis in the brother. Four polyps were detected: two tubular adenomas in the caecum, one tubulovillous adenoma in the transverse colon and a rectal polyp. The latter one was endoscopically resected, and right hemicolectomy was performed to remove the other lesions. She had a history of pilomatricomas initially diagnosed at 4 years of age. Overall, eight lesions, located on the face, arms and shoulder were surgically removed. Following the findings of colorectal tumors in III-14 and III- 15, several family members, including the parents (II-6, II-7), all living maternal uncles (II-9, II-10), and the youngest *Correspondence to: Maurizio Genuardi, M.D., Department of Clinical Pathophysiology, Section of Medical Genetics, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy. E-mail: mailto:m.genuardi@dfc.unifi.it Received 15 July 2004; Accepted 10 November 2004 DOI 10.1002/ajmg.a.30585 ß 2005 Wiley-Liss, Inc.