Somatic IDH1 mutation in a pituitary adenoma of a patient with Maffucci syndrome

Abstract

Maffucci syndrome is a rare disease characterized by multiple enchondromas and soft-tissue hemangiomas. Additionally, neuroendocrine tumors including pituitary adenomas have been described in these patients. The underlying genetic etiology lies in somatic mosaicism of mutations in isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2). This report describes a patient with Maffucci syndrome who presented with intracranial tumors of the skull base and suprasellar region. The patient underwent resection of both intracranial tumors, revealing histopathological diagnoses of chondrosarcoma and pituitary adenoma. DNA sequencing of the tumors was performed to identify common IDH1/2 mutations. Clinical, radiological, and biochemical assessments were performed. Genotypic studies used standard Sanger sequencing in conjunction with a target-specific peptide nucleic acid to detect IDH1 mutations in tumor tissues. DNA sequencing demonstrated identical IDH1 mutations (c.394C > T) in both tumors. To the authors' knowledge, this report provides the first genetic evidence for the inclusion of pituitary adenomas among tumors characterizing Maffucci syndrome. In patients who are newly diagnosed with Maffucci syndrome, it is appropriate to monitor for development of pituitary pathology and neuroendocrine dysfunction.

Keywords: ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; GH = growth hormone; IDH1 = isocitrate dehydrogenase 1; IDH2 = isocitrate dehydrogenase 2; LH = luteinizing hormone; MEN1 = multiple endocrine neoplasia 1; Maffucci syndrome; PCR = polymerase chain reaction; PNA = peptide nucleic acid; PRL = prolactin; RET = rearranged during transfection; SDH = succinate dehydrogenase; TSH = thyroid-stimulating hormone; isocitrate dehydrogenase; oncology; pituitary adenoma; somatic mosaicism.

Fig. 1

Clinical presentation of index patient. A photograph of the index patient’s left hand is shown (a). Numerous palpable nodules were evident, which had been present since childhood. Multiple hemangiomas spread throughout his body were found, including his right buttock (inset). A radiograph of the left hand showed calcific nodules and lytic lesions of the phalanges, characteristic of enchondromas (b). 3D anterior (upper panel) and posterior (lower panel) reconstruction of a chest CT showed additional osseous lytic lesions (c). Whole-body bone scintigraphy revealed multiple areas of increased radiotracer uptake, suggestive of enchondromatosis (d). Figure is available in color online only.

Fig. 2

Radiographic and histological tumor characteristics. Axial (a) and sagittal (b) sections of a T1-weighted MRI study obtained after contrast administration demonstrated a heterogeneously enhancing lesion encasing the left jugular foramen of the skull base. Axial (c) and sagittal (d) T1-weighted MRI studies obtained after contrast administration showed a strongly enhancing suprasellar mass. A representative image of the H & E–stained sample (original magnification ×200), excised from the jugular foramen, exhibited increased cellular atypia amid a degenerative muco-myxoid chondroid matrix, suggestive of a Grade II chondrosarcoma (e). An H & E–stained photomicrograph (original magnification ×200) of tissue from the suprasellar mass showed monomorphic cellularity and disorganized reticulin meshwork (F). There was prominent positive staining for the neuroendocrine marker, synaptophysin, confirming neuroendocrine origin and diagnostic of pituitary adenoma (inset). Figure is available in color online only.

Fig. 3

DNA sequencing of tumor IDH1. Sanger sequencing of DNA extracted from the pituitary adenoma revealed a c.394C > T (R132C) mutation of IDH1 (center). Repeat sequencing was performed on DNA derived from remaining paraffin-embedded tissue, using PNA and nested PCR technique, which confirmed previous results (lower). Using the same methodology of PNA and nested PCR, the same c.394C > T mutation was found in DNA from the chondrosarcoma tissue (upper). Figure is available in color online only.