Bannayan–Riley–Ruvalcaba syndrome (BRRS, MIM 153480), a rare autosomal dominant congenital disorder, is characterized by macrocephaly, lipomatosis, hemangiomatosis, and speckled penis (Gorlin et al. 1992). Other features include Hashimoto thyroiditis, gastrointestinal (GI) hamartomatous polyposis most likely not associated with GI malignancy, hypotonia, and variable mental retardation and psychomotor delay. While a lipid storage myopathy is still considered a component to BRRS, its original etiology, long-chain acyl-coA dehydrogenase (LCHAD) deficiency, has been questioned.
Germline PTEN mutations were originally found in two classic BRRS families (Marsh et al. 1997), and thus, a subset of BRRS is allelic to Cowden syndrome (Marsh et al. 1999). Subsequently, 60 % of a series of BRRS probands were found to have germline PTEN mutations (Marsh et al. 1999). Of those that were mutation negative after PCR-based mutational analysis of exons 1–9 and flanking intronic regions, 10 % have been found to carry large deletions including or encompassing PTEN (Zhou et al. 2003a, b). Genotype-phenotype association analysis reveals that BRRS carrying germline PTEN mutations were at increased risk of neoplasia, especially malignant breast disease, and lipomatosis compared to those without PTEN mutations (Marsh et al. 1999).
Traditionally, medical management of BRRS has been symptomatic. However, given the genotype-phenotype association and that a subset of BRRS is allelic to Cowden syndrome, individuals with BRRS, especially those found to have germline PTEN mutations, should undergo similar surveillance and management to individuals with Cowden syndrome. Because thyroid cancers can occur even in the teens in BRRS, it would be prudent to begin annual comprehensive physical examinations, paying particular attention to the neck, in the early teens.