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