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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

SyndromeMain clinical manifestations of the syndromeSkeletal manifestationsResponsible gene(s)Role of genes in bone and/or mineral metabolism
MEN1PHPT, hypophyseal adenomas, GEP-NETs, carcinoids, adrenal-cortical tumorsOsteoporosis and/or osteopeniaMEN1 (11q13)Regulation of osteogenesis, promotion of osteoblastic differentiation
MEN2MTC, PHEO, PHPT, CLA, HDMarfanoid 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
MEN4PHPT, hypophyseal adenomas, adrenal, renal and reproductive organs tumorsOsteoporosis and/or osteopeniaCDKN1B (12p13.1-P12)Regulation of longitudinal bone growth and endochondral ossification
VHLRetinal, cerebellar and medullary hemangioblastomas, RCC, PHEONo manifestation reported to dateVHL (3p25.3)Vascularization in endochondral and membranous ossification
PGL/PCC syndromesSecreting PGL e PHEO, HNPGLNo manifestation reported to dateSDHx (1q21; 1p36.1-p35; 11q23; 11q31.1)No role of the SDHx genes on bone metabolism reported to date
HPT-JTPHPT, ossifying fibromas of the maxilla and mandible, renal tumors and adenomatous polyps of the uterusOsteoporosis and / or osteopenia, ossifying fibromas of the maxilla and mandible, osteitis fibrosa cysticaHRPT2 / CDC73 (1q31.2)Transcriptional repression of osteoprogenitor cells necessary for cellular survival and regulation of cell differentiation and bone homeostasis
CSMultiple hamartomas, susceptibility to malignant tumors, skin and facial changes, CNS abnormalities and fibrocystic breast disease, thyroid carcinomaMacrocephaly, bone cysts, thoracic kyphosis, kyphoscoliosis, pectus excavatum, large hands and feet, syndactyly, maxillary and scapular hypoplasiaPTEN (10q23.3)Regulation of osteoblastic apoptosis/survival, osteoblastic differentiation regulation, indirect regulation of chondrocyte adaptation to hypoxic stress
CNCHeart, endocrine, cutaneous and neural myxomatous tumors, pigmented lesions of skin and mucous membranesOsteochondromyxomasPRKAR1A (17q22–24); or possible mutation in 2p16Osteoblastic differentiation and promotion of osteogenesis
TSCCNS, cardiac, renal, cutaneous, ocular and pulmonary hamartomas; pancreatic NETs, pituitary and parotid adenomasMetacarpal and metatarsal bone cysts, sclerotic bone lesionsTSC1 (9q34) and TSC2 (16p13)No studies are available to document a direct role of TSC1 and TSC2 in bone metabolism
NF1Café-au-lait spots, Lisch nodules, neurofibromas, neurofibrosarcomas, gliomas, PHEO, myeloid leukemia and GEP-NETsKyphoscoliosis, macrocephaly, sphenoid wing dysplasia, congenital curvature, and tibial pseudoarthrosisNF1 (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.