Case report
The patient was a 19-year-old man with a familial medical history of liver cancer through his paternal grandfather. He had no known family history of GGS, although family members could not be tested. In addition, he had no physical features characteristic of GGS such as palmar or plantar pits or lamellar calcification of the falx cerebri or rib anomalies or macrocephaly. At the age of 1 year, he developed medulloblastoma in the cerebellar vermis with hydrocephalus (Fig. 1A). After he underwent ventriculoperitoneal shunt placement and gross total tumor excision, he was administered combination chemotherapy. Owing to the early age of onset, high-dose chemotherapy with autologous peripheral blood stem cell transplantation was administered to avoid radiation. Remission was maintained thereafter. The total doses of chemotherapy with cyclophosphamide, cisplatin, etoposide, vincristine, thiotepa, and melphalan were 12 g/m2, 360 mg/m2, 2 g/m2, 15 mg/m2, 26 mg/kg, and 6 mg/kg, respectively. At the age of 8 years, he developed osteosarcoma of the right tibia (Fig. 1B). He received chemotherapy and underwent gross total resection of the osteosarcoma. The total doses of chemotherapy, which included cisplatin, doxorubicin, methotrexate, ifosfamide, and pirarubicine during that period, were 500 mg/m2, 180 mg/m2, 216 g/m2, 36 g/m2, and 585 mg/m2, respectively. He maintained remission of both cancers and had subclinical cardiac dysfunction and cisplatin-induced hearing loss as a late effect. At the age of 11, during a follow-up, a blood test revealed pancytopenia. A bone marrow examination confirmed the diagnosis of myelodysplastic syndrome (MDS) refractory anemia with an excess of blasts 2 (Fig. 1C). Fluorescent in situ hybridization revealed monosomy 7 and trisomy 8, and reverse transcription polymerase chain reaction revealed AML1/EVI1 gene translocation, which indicated treatment-related MDS. Owing to the cardiotoxicity of anthracyclines and hypoplastic marrow, Acute myeloblastic leukemia-type induction chemotherapy was predicted to be poorly tolerated. Therefore, he started chemotherapy with low-dose cytarabine and azacitidine but failed to achieve remission. He underwent allogeneic peripheral blood stem cell transplantation from a human leukocyte antigen-matched sibling. After transplantation, azacitidine therapy was continued to achieve a molecular complete remission. The patient has been in remission ever since. The total doses of chemotherapy with cytarabine, azacitidine, busulfan, fludarabine, and melphalan were 50 mg/m2,182 mg/m2, 6.4 mg/kg, 120 mg/m2, and 140 mg/m2, respectively.
On account that the patient had developed medulloblastoma, osteosarcoma, and MDS, we suspected Li-Fraumeni syndrome and searched for TP53mutations. In the somatic cell line (i.e., peripheral blood in the pretransplant nonremission phase), mutations were detected in exon 5, which has been reported in tumor cells, but no mutations were detected in the germ cell line (e.g., nails) in exons 2 through 11.
At the age of 19 years, a growing black nevus was found on the scalp. A biopsy confirmed the diagnosis of basal cell carcinoma (Fig. 1D). A total tumor resection was performed. Also at the age of 19, a benign odontogenic keratocyst was found in the jaw for which a total excision was performed (Fig. 1E).
Cancer predisposition syndrome was suspected, based on the clinical course at that point. We conducted whole exome sequencing, while focusing especially on potential pathogenic variants in cancer predisposing genes in nail and oral mucosa samples referring to the recent paper5). Owing to the low frequency of frameshift mutations in the PTCH1 gene (exon10: c.1350delC: p.L450fs) in the oral mucosa, samples of basal cell carcinoma and normal skin were re-examined by using the Sanger method. The sequence ofPTCH1 is shown in Fig. 2. The frameshift of PTCH1 was confirmed in the basal cell carcinoma sample (Fig. 2D), and the same mutation was confirmed in the normal skin sample (Fig. 2C). To obtain the precise frequency of mutation alleles, we conducted droplet digital polymerase chain reaction procedures using the QX-200 droplet generator (Bio-Rad, Hercules, CA, USA). The mutation allele frequency was 11.6% in the oral mucosa sample, 9.8% in the nail sample, 13.8% in the normal skin sample, and 32.7% in the basal cell carcinoma sample (Fig. 2E).