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Table 1 Bone phenotypes in hereditary endocrine tumors, and possible molecular involvement of responsible genes in the regulation of bone and mineral metabolism

From: Bone tissue and mineral metabolism in hereditary endocrine tumors: clinical manifestations and genetic bases

Syndrome Main clinical manifestations of the syndrome Skeletal manifestations Responsible gene(s) Role of genes in bone and/or mineral metabolism
MEN1 PHPT, hypophyseal adenomas, GEP-NETs, carcinoids, adrenal-cortical tumors Osteoporosis and/or osteopenia MEN1 (11q13) Regulation of osteogenesis, promotion of osteoblastic differentiation
MEN2 MTC, PHEO, PHPT, CLA, HD Marfanoid habitus, pectus excavatum, pes cavus, equino-varus foot, femoral epiphysiolysis, kyphosis, scoliosis and increased joint laxity (MEN2B) RET (10q11.21) Possible up-regulation of chondromodulin-1, which promotes cartilage deposition and inhibits bone deposition
MEN4 PHPT, hypophyseal adenomas, adrenal, renal and reproductive organs tumors Osteoporosis and/or osteopenia CDKN1B (12p13.1-P12) Regulation of longitudinal bone growth and endochondral ossification
VHL Retinal, cerebellar and medullary hemangioblastomas, RCC, PHEO No manifestation reported to date VHL (3p25.3) Vascularization in endochondral and membranous ossification
PGL/PCC syndromes Secreting PGL e PHEO, HNPGL No manifestation reported to date SDHx (1q21; 1p36.1-p35; 11q23; 11q31.1) No role of the SDHx genes on bone metabolism reported to date
HPT-JT PHPT, ossifying fibromas of the maxilla and mandible, renal tumors and adenomatous polyps of the uterus Osteoporosis and / or osteopenia, ossifying fibromas of the maxilla and mandible, osteitis fibrosa cystica HRPT2 / CDC73 (1q31.2) Transcriptional repression of osteoprogenitor cells necessary for cellular survival and regulation of cell differentiation and bone homeostasis
CS Multiple hamartomas, susceptibility to malignant tumors, skin and facial changes, CNS abnormalities and fibrocystic breast disease, thyroid carcinoma Macrocephaly, bone cysts, thoracic kyphosis, kyphoscoliosis, pectus excavatum, large hands and feet, syndactyly, maxillary and scapular hypoplasia PTEN (10q23.3) Regulation of osteoblastic apoptosis/survival, osteoblastic differentiation regulation, indirect regulation of chondrocyte adaptation to hypoxic stress
CNC Heart, endocrine, cutaneous and neural myxomatous tumors, pigmented lesions of skin and mucous membranes Osteochondromyxomas PRKAR1A (17q22–24); or possible mutation in 2p16 Osteoblastic differentiation and promotion of osteogenesis
TSC CNS, cardiac, renal, cutaneous, ocular and pulmonary hamartomas; pancreatic NETs, pituitary and parotid adenomas Metacarpal and metatarsal bone cysts, sclerotic bone lesions TSC1 (9q34) and TSC2 (16p13) No studies are available to document a direct role of TSC1 and TSC2 in bone metabolism
NF1 Café-au-lait spots, Lisch nodules, neurofibromas, neurofibrosarcomas, gliomas, PHEO, myeloid leukemia and GEP-NETs Kyphoscoliosis, macrocephaly, sphenoid wing dysplasia, congenital curvature, and tibial pseudoarthrosis NF1 (17q11.2) Regulation of osteogenic proliferation and differentiation, reduction of expression of osteopontin (calcification inhibitor) in pre-osteoblastic MSC
  1. Footnotes: PHPT: Primary HyperParaThyroidism; GEP-NETs: GastroEnteroPancreatic NeuroEndocrine Tumors; MTC: Medullary Thyroid Carcinoma; PHEO: PHEOchromocytoma; CLA: Cutaneous Lichen Amyloidosis; HD: Hirschsprung Disease; RCC: Renal Cell Carcinoma; PGL: ParaGangLioma: HNPGL: Head and Neck ParaGangLioma.