Novel Germline PTEN Mutation Associated with Cowden Syndrome and Osteosarcoma

Abstract

Background: Cowden syndrome (CS) is a rare autosomal-dominant inherited disorder characterized by multiple hamartomas. While the hamartomas are benign, patients with CS have increased risk of osteosarcoma and of breast, thyroid, endometrial, soft-tissue and colonic neoplasms. Germline mutations of phosphatase and tensin homolog (PTEN) are implicated in CS and in the development of osteosarcoma. We report a patient with CS who presented with osteosarcoma, ganglioneuromatosis and a benign breast mass. Osteosarcoma, as presentation of CS, is rare (only one report in the English literature). Genomic DNA from the patient's peripheral blood was quantified by spectrophotometry, then underwent sequence enrichment, polymerase chain reaction and next-generation sequencing. Molecular analysis revealed a non-synonymous c.17_18delAA frameshift mutation in exon 1 of PTEN and a c.116G>T (p.R39L) missense mutation of serine/threonine kinase 11 (STK11) of unknown significance.

Conclusion: We report a patient with CS presenting with ganglioneuromatosis, benign breast mass and osteosarcoma, harboring a novel molecular alteration in PTEN which to our knowledge has not been previously reported.

Keywords: Cowden syndrome; PTEN; ganglioneuroma; hamartoma; osteosarcoma.

Figure 1. Lateral radiograph showing the osteosarcoma of distal left femur as a radiodense lesion. A Codman’s triangle of reactive bone can be seen in the lateral cortex.

Figure 2. A: Low-power view of the osteosarcoma and its interphase with the adjacent soft tissue. B: At high power, neoplastic cells with nuclear atypia can be seen, surrounded by lace-like deposition of osteoid.

Figure 3. A: Endoscopy showing multiple mucosal polypoid lesions with broad base. B and C: Microscopically, each polyp was composed of a colonic mucosa expanded by a proliferation of spindle cells and ganglion cells, isolated or in clusters, displacing and distorting the crypts. D: Mutations found in the phosphatase and tensin homolog (PTEN) and serine/threonine kinase 11 (STK11) genes.