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Clin Neuropathol. 2017 Sep/Oct;36(5):213-221. doi: 10.5414/NP301022.

Familial melanoma-astrocytoma syndrome: synchronous diffuse astrocytoma and pleomorphic xanthoastrocytoma in a patient with germline CDKN2A/B deletion and a significant family history.


Familial melanoma-astrocytoma syndrome is a tumor predisposition syndrome caused by inactivating germline alteration of the <italic>CDKN2A</italic> tumor suppressor gene on chromosome 9p21. While some families with germline <italic>CDKN2A</italic> mutations are prone to development of just melanomas, other families develop both melanomas, astrocytomas, and occasionally other nervous-system neoplasms including peripheral nerve sheath tumors and meningiomas. The histologic spectrum of the astrocytomas that arise as part of this syndrome is not well described, nor are the additional genetic alterations that drive these astrocytomas apart from the germline <italic>CDKN2A</italic> inactivation. Herein, we report the case of a young man with synchronous development of a pleomorphic xanthoastrocytoma, diffuse astrocytoma, and paraspinal mass radiographically consistent with a peripheral nerve sheath tumor. His paternal family history is significant for melanoma, glioblastoma, and oral squamous cell carcinoma. Genomic profiling revealed that he harbors a heterozygous deletion in the germline of chromosome 9p21.3 encompassing the <italic>CDKN2A</italic> and <italic>CDKN2B</italic> tumor suppressor genes. Both the pleomorphic xanthoastrocytoma and diffuse astrocytoma were found to have homozygous deletion of <italic>CDKN2A/B</italic> due to somatic loss of the other copy of chromosome 9p containing the remaining intact alleles. Additional somatic alterations included <italic>BRAF</italic> p.V600E mutation in the pleomorphic xanthoastrocytoma and <italic>PTPN11</italic>, <italic>ATRX</italic>, and <italic>NF1</italic> mutations in the diffuse astrocytoma. The presence of germline <italic>CDKN2A/B</italic> inactivation together with the presence of multiple anatomically, histologically, and genetically distinct astrocytic neoplasms, both with accompanying somatic loss of heterozygosity for the <italic>CDKN2A/B</italic> deletion, led to a diagnosis of familial melanoma-astrocytoma syndrome. This remarkable case illustrates the histologic and genetic diversity that astrocytomas arising as part of this rare glioma predisposition syndrome can demonstrate.

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