Somatic Mutations of theMEN1Gene and Microsatellite Instability in a Case of Tertiary Hyperparathyroidism Occurring during High Phosphate Therapy for Acquired, Hypophosphatemic Osteomalacia

Abstract

Somatic mutations of the MEN type 1 (MEN1) gene were recently shown to be responsible for tumorigenesis in 13-26% of sporadic, nonfamilial primary hyperparathyroidism. However, it is unknown whether these mutations are also involved in tumorigenesis of parathyroid glands occurring during high phosphate therapy for hypophosphatemic rickets or osteomalacia. A male patient with adult-onset, hypophosphatemic osteomalacia had been treated with 1alpha-OHD3 and oral phosphate for 13 yr when tertiary hyperparathyroidism developed. After total resection of four enlarged parathyroid glands and autotransplantation of a hyperplastic gland, the patient has continued to do well for the last 2 yr. Sequence analysis of the coding exons of MEN1 gene revealed a 36-bp deletion with a 2-bp insertion (exon 2) in the right upper parathyroid gland accompanied with loss of heterozygosity at 11q13 locus and a heterozygous mutation of 2-bp deletion (AG) in exon 10 in the right lower gland, in which microsatellite instability was also found. No MEN1 gene mutation was detected in the other two hyperplastic parathyroid glands or in the peripheral blood. These findings indicate that MEN1 gene mutations contributed to tumorigenesis of the right upper parathyroid gland in this case of phosphate-induced tertiary hyperparathyroidism. Very recently a bone tumor was found in the right femoral neck, and the tumor (chondroblastoma) was resected.

TIO Associated with Hyperparathyroidism: A Rarity, a Rule, or a Novel HPT-PMT Syndrome—A Case Study with Literature Review

“…e multiple endocrine neoplasia type 1 (MEN1) gene encodes menin, a transcription factor expressed in many tissues and involved in the development of endocrine and nonendocrine tumors [12]. Since the cloning of the MEN1 gene, more than 1,500 germline and somatic mutations have been reported, including those found in 35-50% of parathyroid adenomas [12], parathyroid hyperplasia [13], and some mesenchymal tumors [14]. Of relevance, MEN1 mutation has been found in a patient with HPT and TIO due to benign chondroblastoma [13].…”

“…Since the cloning of the MEN1 gene, more than 1,500 germline and somatic mutations have been reported, including those found in 35-50% of parathyroid adenomas [12], parathyroid hyperplasia [13], and some mesenchymal tumors [14]. Of relevance, MEN1 mutation has been found in a patient with HPT and TIO due to benign chondroblastoma [13]. e patient has presented with generalized bone pain, difficulties walking, hypophosphatemia, osteomalacia, and high Case Reports in Endocrinology PTH and diagnosed as HPT.…”

“…e patient has presented with generalized bone pain, difficulties walking, hypophosphatemia, osteomalacia, and high Case Reports in Endocrinology PTH and diagnosed as HPT. He has been treated with a subtotal (three and a half glands) parathyroidectomy and pathology-confirmed hyperplastic lesions in all parathyroid glands [13]. Due to persistent hypophosphatemia, further investigations have been performed and have shown high circulating FGF23 prompting the diagnosis of TIO, while genetic testing has shown somatic mutation of the MEN1 gene in hyperplastic parathyroid lesions.…”

“…Due to persistent hypophosphatemia, further investigations have been performed and have shown high circulating FGF23 prompting the diagnosis of TIO, while genetic testing has shown somatic mutation of the MEN1 gene in hyperplastic parathyroid lesions. On follow-up, a benign chondroblastoma of the femur has been found and presumed to be the cause of TIO [13]. e EEF2K gene encoding for eukaryotic elongation factor 2 kinase (eEF2K) is suggested to be involved in tumorigenesis [15].…”

Management of X-linked hypophosphatemia in adults

“…Secondary and tertiary hyperparathyroidism have been repeatedly reported in XLH patients [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The precise prevalence and pathophysiology of secondary hyperparathyroidism, which is defined by low to normal calcemia and increased PTH concentrations, in adult XLH patients is not known.…”