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).