Table 1. Comparison of Diagnostic Criteria for Basal Cell Nevus Syndrome (BCNS) continued...
Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[63,67,71,89] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[90,91] Up to three times more males than females with BCNS are diagnosed with medulloblastoma. As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[63,76] Other reported malignancies include ovarian carcinoma, ovarian fibrosarcoma,[94,95] astrocytoma, melanoma, Hodgkin disease,[98,99] rhabdomyosarcoma, and undifferentiated sinonasal carcinoma.
Odontogenic keratocysts–or keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working group–are one of the major features of BCNS. Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH, supports the transition of terminology to reflect a neoplastic process. About half of KCOTs from individuals with BCNS show LOH of PTCH. The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[102,103] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS. KCOTs occur in 65% to 100% of individuals with BCNS,[67,104] with higher rates of occurrence in young females.
Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[106,107] fused, splayed or bifid ribs; and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria. Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.
A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children. All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.
Rombo syndrome, a very rare genetic disorder associated with BCC, has been outlined in three case series in the literature.[110,111,112] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet. Development of BCC occurs in the fourth decade. A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[110,112] Missing, irregularly distributed and/or misdirected eyelashes and eyebrows are another associated finding.[110,111]