Advertisement

Hormones

, Volume 14, Issue 1, pp 19–31 | Cite as

Bone status in genetic syndromes: A review

  • Stefano Stagi
  • Chiara Iurato
  • Elisabetta Lapi
  • Loredana Cavalli
  • Maria Luisa Brandi
  • Maurizio de Martino
Review

Abstract

More and more data seem to indicate the presence of an increasing number of syndromes and genetic diseases characterized by impaired bone mass and quality. Meanwhile, the improvement of etiopathogenetic knowledge and the employment of more adequate treatments have generated a significant increase in survival related to these syndromes and diseases. It is thus important to identify and treat bone impairment in these patients in order to assure a better quality of life. This review provides an updated overview of bone pathophysiology and characteristics in patients with Down, Turner, Klinefelter, Marfan, Williams, Prader-Willi, Noonan, and 22q11 deletions syndrome. In addition, some options for the treatment of the bone status impairment in these patients will be briefly discussed.

Key words

Bone mineral density Fragility fractures Genetic syndrome Osteoporosis Syndromes 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ma NS, Gordon CM, 2012 Pediatric osteoporosis: where are we now? J Pediatr 161: 983–990.CrossRefPubMedGoogle Scholar
  2. 2.
    Stagi S, Cavalli L, Iurato C, Seminara S, Brandi ML, de Martino M, 2013 Bone metabolism in children and adolescents: main characteristics of the determinants of peak bone mass. Clin Cases Miner Bone Metab 10: 172–179.PubMedGoogle Scholar
  3. 3.
    Stagi S, Cavalli L, Seminara S, de Martino M, Brandi ML, 2014 The ever-expanding conundrum of primary osteoporosis: aetiopathogenesis, diagnosis, and treatment. Ital J Pediatr 40: 55.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ott SM, 1990 Attainment of peak bone mass. J Clin Endocrinol Metab 71: 1082A–1082C.CrossRefPubMedGoogle Scholar
  5. 5.
    Kelly PJ, Twomey L, Sambrook PN, Eisman JA, 1990 Sex differences in peak adult bone mineral density. J Bone Miner Res 5: 1169–1175.CrossRefPubMedGoogle Scholar
  6. 6.
    von Scheven E, Corbin KJ, Stagi S, Cimaz R, 2014 Glucocorticoid-associated osteoporosis in chronic inflammatory diseases: epidemiology, mechanisms, diagnosis, and treatment. Curr Osteoporos Rep 12: 289–299.CrossRefGoogle Scholar
  7. 7.
    Stagi S, Cavalli L, Iurato C, Seminara S, Brandi ML, de Martino M, 2013 Bone health in children and adolescents: the available imaging techniques. Clin Cases Miner Bone Metab 10: 166–171.PubMedGoogle Scholar
  8. 8.
    Bogunovic L, Doyle SM, Vogiatzi MG, 2009 Measurement of bone density in the pediatric population. Curr Opin Pediatr 21: 77–82.CrossRefPubMedGoogle Scholar
  9. 9.
    Weijerman ME, van Furth AM, Vonk Noordegraaf A, van Wouwe JP, Broers CJ, Gemke RJ, 2008 Prevalence, neonatal characteristics, and first-year mortality of Down syndrome: a national study. J Pediatr 152: 15–19.CrossRefPubMedGoogle Scholar
  10. 10.
    González-Agüero A, Vicente-Rodríguez G, Moreno LA, Casajüs JA, 2011 Bone mass in male and female children and adolescents with Down syndrome. Osteoporos Int 22: 2151–2157.CrossRefPubMedGoogle Scholar
  11. 11.
    González-Agüero A, Vicente-Rodríguez G, Gömez-Cabello A, Ara I, Moreno LA, Casajús JA, 2012 A 21-week bone deposition promoting exercise programme increases bone mass in young people with Down syndrome. Dev Med Child Neurol 54: 552–556.CrossRefPubMedGoogle Scholar
  12. 12.
    Fowler TW, McKelvey KD, Akel NS, et al, 2012 Low bone turnover and low BMD in Down syndrome: effect of intermittent PTH treatment. PLoS One 7: e42967.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    McKelvey KD, Fowler TW, Akel NS, et al, 2013 Low bone turnover and low bone density in a cohort of adults with Down syndrome. Osteoporos Int 24: 1333–1338.CrossRefPubMedGoogle Scholar
  14. 14.
    Wu J, 2013 Bone mass and density in preadolescent boys with and without Down syndrome. Osteoporos Int 24: 2847–2854.CrossRefPubMedGoogle Scholar
  15. 15.
    González-Agüero A, Vicente-Rodráguez G, Gómez-Cabello A, Casajús JA, 2013 Cortical and trabecular bone at the radius and tibia in male and female adolescents with Down syndrome: a peripheral quantitative computed tomography (pQCT) study. Osteoporos Int 24: 1035–1044.CrossRefPubMedGoogle Scholar
  16. 16.
    Hawli Y, Nasrallah M, El-Hajj Fuleihan G, 2009 Endocrine and musculoskeletal abnormalities in patients with Down syndrome. Nat Rev Endocrinol 5: 327–334.CrossRefPubMedGoogle Scholar
  17. 17.
    Matute-Llorente A, González-Agüero A, Gómez-Cabello A, Vicente-Rodríguez G, Casajús JA, 2013 Decreased levels of physical activity in adolescents with Down syndrome are related with low bone mineral density: a cross-sectional study. BMC Endocr Disord 13: 22.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Reza SM, Rasool H, Mansour S, Abdollah H, 2013 Effects of calcium and training on the development of bone density in children with Down syndrome. Res Dev Disabil 34: 4304–4309.CrossRefPubMedGoogle Scholar
  19. 19.
    Stagi S, Lapi E, Romano S, et al, 2015 Determinants of vitamin D levels in children and adolescents with Down syndrome. Int J Endocrinol [Ahead of print]Google Scholar
  20. 20.
    Ferry B, Gavris M, Tifrea C, et al, 2014 The bone tissue of children and adolescents with Down syndrome is sensitive to mechanical stress in certain skeletal locations: A 1-year physical training program study. Res Dev Disabil 35: 2077–2084.CrossRefPubMedGoogle Scholar
  21. 21.
    Gravholt CH, 2004 Epidemiological, endocrine and metabolic features in Turner syndrome. Eur J Endocrinol 151: 657–687.CrossRefPubMedGoogle Scholar
  22. 22.
    Hjerrild BE, Mortensen KH, Gravholt CH, 2008 Turner syndrome and clinical treatment. Br Med Bull 86: 77–93.CrossRefPubMedGoogle Scholar
  23. 23.
    Lisá L, Neradilová M, Tomásová H, Kouba M, Preucil P, 1996 Changes in bone metabolism in girls with Turner’s syndrome. Cas Lek Cesk 135: 178–180.PubMedGoogle Scholar
  24. 24.
    Benetti-Pinto CL, Bedone A, Magna LA, Marques-Neto JF, 2002 Factors associated with the reduction of bone density in patients with gonadal dysgenesis. Fertil Steril 77: 571–575.CrossRefPubMedGoogle Scholar
  25. 25.
    Nadeem M, Roche EF, 2012 Bone health in children and adolescent with Turner syndrome. J Pediatr Endocrinol Metab 25: 823–833.CrossRefPubMedGoogle Scholar
  26. 26.
    Hansen S, Brixen K, Gravholt CH, 2012 Compromised trabecular microarchitecture and lower finite element estimates of radius and tibia bone strength in adults with turner syndrome: a cross-sectional study using high-resolution-pQCT. J Bone Miner Res 27: 1794–1803.CrossRefPubMedGoogle Scholar
  27. 27.
    Shaw NJ, Rehan VK, Husain S, Marshall T, Smith CS, 1997 Bone mineral density in Turner’s syndrome-a longitudinal study. Clin Endocrinol (Oxf) 47: 367–370.CrossRefGoogle Scholar
  28. 28.
    Bertelloni S, Cinquanta L, Baroncelli GI, Simi P, Rossi S, Saggese G, 2000 Volumetric bone mineral density in young women with Turner’s syndrome treated with estrogens or estrogens plus growth hormone. Horm Res 53: 72–76.PubMedGoogle Scholar
  29. 29.
    Neely EK, Marcus R, Rosenfeld RG, Bachrach LK, 1993 Turner syndrome adolescents receiving growth hormone are not osteopenic. J Clin Endocrinol Metab 76: 861–866.PubMedGoogle Scholar
  30. 30.
    Sas Tc, de Muinck Keizer-Schrama SM, Stijnen T, et al, 2001 Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner’s syndrome participating in a randomized dose-response study. Pediatr Res 50: 417–422.CrossRefPubMedGoogle Scholar
  31. 31.
    Lleo A, Moroni L, Caliari L, Invernizzi P, 2012 Autoimmunity and Turner’s syndrome. Autoimmun Rev 11: A538–A543.CrossRefPubMedGoogle Scholar
  32. 32.
    Peralta López M, Miras M, Silvano L, et al, 2011 Vitamin D receptor genotypes are associated with bone mass in patients with Turner syndrome. J Pediatr Endocrinol Metab 24: 307–312.PubMedGoogle Scholar
  33. 33.
    Visootsak J, Graham JM Jr, 2006 Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis 1: 42.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ferlin A, Schipilliti M, Vinanzi C, et al, 2011 Bone mass in subjects with Klinefelter syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism. J Clin Endocrinol Metab 96: E739–E745.CrossRefPubMedGoogle Scholar
  35. 35.
    Bojesen A, Gravholt CH, 2007 Klinefelter syndrome in clinical practice. Nat Clin Pract Urol 4: 192–204.CrossRefPubMedGoogle Scholar
  36. 36.
    Marcus R, Leary D, Schneider DL, Shane E, Favus M, Quigley CA, 2000 The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome. J Clin Endocrinol Metab 85: 1032–1037.CrossRefPubMedGoogle Scholar
  37. 37.
    Ferlin A, Schipilliti M, Foresta C, 2011 Bone density and risk of osteoporosis in Klinefelter syndrome. Acta Paediatr 100: 878–884.CrossRefPubMedGoogle Scholar
  38. 38.
    Jo DG, Lee HS, Joo YM, Seo JT, 2013 Effect of testosterone replacement therapy on bone mineral density in patients with Klinefelter syndrome. Yonsei Med J 54: 1331–1335.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E, 2004 X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab 89: 6208–6217.CrossRefPubMedGoogle Scholar
  40. 40.
    Bojesen A, Hertz JM, Gravholt CH, 2011 Genotype and phenotype in Klinefelter syndrome — impact of androgen receptor polymorphism and skewed X inactivation. Int J Androl 34: e642–e648.CrossRefPubMedGoogle Scholar
  41. 41.
    Francis RM, Peacock M, Aaron JE, et al, 1986 Osteoporosis in hypogonadal men: role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption, and low bone formation. Bone 7: 261–268.CrossRefPubMedGoogle Scholar
  42. 42.
    Stepan JJ, Burckhardt P, Hána V, 2003 The effects of three-month intravenous ibandronate on bone mineral density and bone remodeling in Klinefelter’s syndrome: the influence of vitamin D deficiency and hormonal status. Bone 33: 589–596.CrossRefPubMedGoogle Scholar
  43. 43.
    Aksglaede L, Molgaard C, Skakkebaek NE, Juul A, 2008 Normal bone mineral content but unfavourable muscle/fat ratio in Klinefelter syndrome. Arch Dis Child 93: 30–34.CrossRefPubMedGoogle Scholar
  44. 44.
    Buiting K, 2010 Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C Semin Med Genet 154C: 365–376.CrossRefPubMedGoogle Scholar
  45. 45.
    Colmenares A, Pinto G, Taupin P, et al, 2011 Effects on growth and metabolism of growth hormone treatment for 3 years in 36 children with Prader-Willi syndrome. Horm Res Paediatr 75: 123–130.CrossRefPubMedGoogle Scholar
  46. 46.
    Reus L, Zwarts M, van Vlimmeren LA, et al, 2011 Motor problems in Prader-Willi syndrome: a systematic review on body composition and neuromuscular functioning. Neurosci Biobehav Rev 35: 956–969.CrossRefPubMedGoogle Scholar
  47. 47.
    Frost HM, 2003 Bone’s mechanostat: a 2003 update. Anat Rec A Discov Mol Cell Evol Biol 275: 1081–1101.CrossRefPubMedGoogle Scholar
  48. 48.
    Höybye C, Hilding A, Jacobsson H, Thorén M, 2002 Metabolic profile and body composition in adults with Prader-Willi syndrome and severe obesity. J Clin Endocrinol Metab 87: 3590–3597.CrossRefPubMedGoogle Scholar
  49. 49.
    Butler MG, Haber L, Mernaugh R, Carlson MG, Price R, Feurer ID, 2001 Decreased bone mineral density in Prader-Willi syndrome: comparison with obese subjects. Am J Med Genet 103: 216–222.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Vestergaard P, Kristensen K, Bruun JM, et al, 2004 Reduced bone mineral density and increased bone turnover in Prader-Willi syndrome compared with controls matched for sex and body mass index—a cross-sectional study. J Pediatr 144: 614–619.CrossRefPubMedGoogle Scholar
  51. 51.
    Edouard T, Deal C, Van Vliet G, et al, 2012 Muscle-bone characteristics in children with Prader-Willi syndrome. J Clin Endocrinol Metab 97: E275–E281.CrossRefPubMedGoogle Scholar
  52. 52.
    Carrel AL, Myers SE, Whitman BY, Eickhoff J, Allen DB, 2010 Long-term growth hormone therapy changes the natural history of body composition and motor function in children with prader-willi syndrome. J Clin Endocrinol Metab 95: 1131–1136.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    de Lind van Wijngaarden RF, Festen DA, Otten BJ, et al, 2009 Bone mineral density and effects of growth hormone treatment in prepubertal children with Prader-Willi syndrome: a randomized controlled trial. J Clin Endocrinol Metab 94: 3763–3771.CrossRefPubMedGoogle Scholar
  54. 54.
    Khare M, Gold JA, Wencel M, et al, 2014 Effect of genetic subtypes and growth hormone treatment on bone mineral density in Prader-Willi syndrome. J Pediatr Endocrinol Metab 27: 511–518.CrossRefPubMedGoogle Scholar
  55. 55.
    Gelb BD, Tartaglia M, 2006 Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. Hum Mol Genet 15 Spec No 2: R220–R226.CrossRefPubMedGoogle Scholar
  56. 56.
    Romano AA, Allanson JE, Dahlgren J, et al, 2010 Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 126: 746–759.CrossRefPubMedGoogle Scholar
  57. 57.
    Tartaglia M, Martinelli S, Cazzaniga G, et al, 2004 Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 104: 307–313.CrossRefPubMedGoogle Scholar
  58. 58.
    Stevenson DA, Schwarz EL, Carey JC, et al, 2011 Bone resorption in syndromes of the Ras/MAPK pathway. Clin Genet 80: 566–573.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Takagi M, Miyashita Y, Koga M, Ebara S, Arita N, Kasayama S, 2000 Estrogen deficiency is a potential cause for osteopenia in adult male patients with Noonan’s syndrome. Calcif Tissue Int 66: 200–203.CrossRefPubMedGoogle Scholar
  60. 60.
    Noordam C, Span J, van Rijn RR, Gomes-Jardin E, van Kuijk C, Otten BJ, 2002 Bone mineral density and body composition in Noonan’s syndrome: effects of growth hormone treatment. J Pediatr Endocrinol Metab 15: 81–87.PubMedGoogle Scholar
  61. 61.
    Reinker KA, Stevenson DA, Tsung A, 2011 Orthopaedic conditions in Ras/MAPK related disorders. J Pediatr Orthop 31: 599–605.CrossRefPubMedGoogle Scholar
  62. 62.
    Choudhry KS, Grover M, Tran AA, O’Brian Smith E, Ellis KJ, Lee BH, 2012 Decreased bone mineralization in children with Noonan syndrome: another consequence of dysregulated RAS MAPKinase pathway? Mol Genet Metab 106: 237–240.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    McCormick F, 1995 Ras signaling and NF 1. Curr Opin Genet Dev 5: 51–55.CrossRefPubMedGoogle Scholar
  64. 64.
    Yu X, Chen S, Potter OL, et al, 2005 Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning. Bone 36: 793–802.CrossRefPubMedGoogle Scholar
  65. 65.
    Gray JR, Bridges AB, Faed MJ, et al, 1994 Ascertainment and severity of Marfan syndrome in a Scottish population. J Med Genet 31: 51–54.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Tang Y, Wu X, Lei W, et al, 2009 TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 15: 757–765.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Mohammad KS, Chen CG, Balooch G, et al, 2009 Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS One 4: e5275.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Nistala H, Lee-Arteaga S, Carta L, et al, 2010 Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome. Hum Mol Genet 19: 4790–4798.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Kohlmeier L, Gasner C, Bachrach LK, Marcus R, 1995 The bone mineral status of patients with Marfan syndrome. J Bone Miner Res 10: 1550–1555.CrossRefPubMedGoogle Scholar
  70. 70.
    Kohlmeier L, Gasner C, Marcus R, 1993 Bone mineral status of women with Marfan syndrome. Am J Med 95: 568–572.CrossRefPubMedGoogle Scholar
  71. 71.
    Tobias JH, Dalzell N, Child AH, 1995 Assessment of bone mineral density in women with Marfan syndrome. Br J Rheumatol 34: 516–519.CrossRefPubMedGoogle Scholar
  72. 72.
    Carter N, Duncan E, Wordsworth P, 2000 Bone mineral density in adults with Marfan syndrome. Rheumatology (Oxford) 39: 307–309.CrossRefGoogle Scholar
  73. 73.
    Le Parc JM, Plantin P, Jondeau G, Goldschild M, Albert M, Boileau C, 1999 Bone mineral density in sixty adult patients with Marfan syndrome. Osteoporos Int 10: 475–479.CrossRefPubMedGoogle Scholar
  74. 74.
    Moura B, Tubach F, Sulpice M, et al, 2006 Bone mineral density in Marfan syndrome. A large case-control study. Joint Bone Spine 73: 733–735.CrossRefPubMedGoogle Scholar
  75. 75.
    Nickerson E, Greenberg F, Keating MT, McCaskill C, Shaffer LG, 1995 Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome. Am J Hum Genet 56: 1156–1161.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Giampietro PF, Peterson M, Schneider R, et al, 2003 Assessment of bone mineral density in adults and children with Marfan syndrome. Osteoporos Int 14: 559–563.CrossRefPubMedGoogle Scholar
  77. 77.
    Giampietro PF, Peterson MG, Schneider R, et al, 2007 Bone mineral density determinations by dual-energy x-ray absorptiometry in the management of patients with Marfan syndrome-some factors which affect the measurement. HSS J 3: 89–92.CrossRefPubMedGoogle Scholar
  78. 78.
    Gray JR, Bridges AB, Mole PA, Pringle T, Boxer M, Paterson CR, 1993 Osteoporosis and the Marfan syndrome. Postgrad Med J 69: 373–375.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Grover M, Brunetti-Pierri N, Belmont J, et al, 2012 Assessment of bone mineral status in children with Marfan syndrome. Am J Med Genet A 158A: 2221–2224.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Grimm T, Wesselhoeft H, 1980 The genetic aspects of Williams-Beuren syndrome and the isolated form of the supravalvular aortic stenosis. Investigation of 128 families. Z Kardiol 69: 168–172.PubMedGoogle Scholar
  81. 81.
    Cherniske EM, Carpenter TO, Klaiman C, et al, 2004 Multisystem study of 20 older adults with Williams syndrome. Am J Med Genet A 131: 255–264.CrossRefPubMedGoogle Scholar
  82. 82.
    Pober BR, 2010 Williams-Beuren syndrome. N Engl J Med 362: 239–252.CrossRefPubMedGoogle Scholar
  83. 83.
    Knudtzon J, Aksnes L, Akslen LA, Aarskog D, 1987 Elevated 1,25-dihydroxyvitamin D and normocalcaemia in presumed familial Williams syndrome. Clin Genet 32: 369–374.CrossRefPubMedGoogle Scholar
  84. 84.
    Maggadottir SM, Sullivan KE, 2013 The Diverse Clinical Features of Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome). J Allergy Clin Immunol Pract 1: 589–594.CrossRefPubMedGoogle Scholar
  85. 85.
    Gao S, Li X, Amendt BA, 2013 Understanding the role of Tbx1 as a candidate gene for 22q11.2 deletion syndrome. Curr Allergy Asthma Rep 13: 613–621.CrossRefPubMedGoogle Scholar
  86. 86.
    Stagi S, Lapi E, Gambineri E, et al, 2010 Bone density and metabolism in subjects with microdeletion of chromosome 22q11 (del22q11). Eur J Endocrinol 163: 329–337.CrossRefPubMedGoogle Scholar
  87. 87.
    Kaufman JM, Ostertag A, Saint-Pierre A, et al, 2008 Genome-wide linkage screen of bone mineral density (BMD) in European pedigrees ascertained through a male relative with low BMD values: evidence for quantitative trait loci on 17q21-23, 11q12-13, 13q12-14, and 22q11. J Clin Endocrinol Metab 93: 3755–3762.CrossRefPubMedGoogle Scholar
  88. 88.
    Lee SK, Lee MJ, Lee HJ, Kim BK, Sohn YB, Chung YS, 2013 A Case of CATCH22 Syndrome Diagnosed in Postmenopausal Woman. J Bone Metab 20: 57–60.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Díaz-Soto G, Mora-Porta M, Nicolau J, Perea V, Halperin I, Puig-Domingo M, 2012 Efficacy and safety of long term treatment of unresponsive hypoparathyroidism using multipulse subcutaneous infusion of teriparatide. Horm Metab Res 44: 708–710.CrossRefPubMedGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2015

Authors and Affiliations

  • Stefano Stagi
    • 1
  • Chiara Iurato
    • 1
  • Elisabetta Lapi
    • 2
  • Loredana Cavalli
    • 3
  • Maria Luisa Brandi
    • 3
  • Maurizio de Martino
    • 1
  1. 1.Department of Health SciencesUniversity of Florence, Anna Meyer Children’s University HospitalFlorenceItaly
  2. 2.Genetics and Molecular Medicine UnitAnna Meyer Children’s University HospitalFlorenceItaly
  3. 3.Department of Internal Medicine, Endocrinology UnitUniversity of FlorenceFlorenceItaly

Personalised recommendations