Discussion
GGS is a cancer predisposition syndrome characterized by a PTCH1mutation2,3). The mutation sites of PTCH1 in GGS vary widely and are distributed nearly evenly from exon 2 to 21 with no obvious hot spots. In addition, no clear correlation between genotype and phenotype existed. The most common mutations are frameshift mutations with small base insertions or deletions, followed by nonsense mutations.
GGS, also called “nevoid basal cell carcinoma syndrome,” is characterized by congenital malformations, particularly high carcinogenicity, and skeletal abnormalities. Diagnostic criteria for GGS have been proposed6). The major criteria are multiple basal cell carcinomas, odontogenic keratocysts in the jaw, palmar or plantar pits, calcifications of the falx cerebri, rib abnormalities, and first-degree relatives with GGS. The minor features are other skeletal abnormalities, ovarian fibromas, medulloblastomas, macrocephaly, and other congenital anomalies. A positive diagnosis is established by the presence of two major criteria or by one major and two minor criteria.
The patient had basal cell carcinoma, odontogenic keratocysts, and medulloblastoma, and met the diagnostic criteria for GGS. Congenital malformations and skeletal anomalies were not observed in this patient, but the PTCH1 mutation was a mosaic at a very low rate. Therefore, it may not appear as a phenotype.
However, osteosarcoma and MDS have rarely been reported in children with GGS, unlike basal cell carcinoma, odontogenic keratocyst, and medulloblastoma, which are frequently reported. Some cases of childhood medulloblastoma are successfully treated with chemotherapy and radiation therapy; however, osteosarcoma and MDS develop later7,8). The incidence of second cancers after chemotherapy with alkylating agents in GGS is unknown. In this patient, osteosarcoma and MDS were likely treatment-related second cancers.
Based on literature reports, 5 (3.9%) of 129 patients with medulloblastoma have germline mutations, including in the TP 53 ,PTCH1 , and SUFU genes, and all of these patients had SHH medulloblastoma9). Two patients diagnosed with GGS had germline PTCH1 and SUFU mutations. Radiation therapy for hereditary diseases such as GGS in medulloblastoma causes basal cell carcinoma and intracranial and sinus tumors10). Therefore, radiation therapy should be avoided whenever possible. Furthermore, de-escalation therapeutic protocol in medulloblastoma patients with APC germline mutation was proposed because of an excellent prognosis and high risk of second cancers11). Thus, all patients with SHH medulloblastoma should routinely undergo genetic testing, especially young patients.
Early genetic testing may be recommended for people with a type of tumor such as medulloblastoma that is typical of cancer predisposition syndrome. For children with cancer predisposition, planning treatment strategies, based on the risk of developing a second cancer, is important. Further advances in comprehensive multigenetic analysis are needed. In addition, further studies are needed to determine whether the intensity of therapy can be reduced in patients with cancer predisposition syndrome.