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.