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Growth plate gene involment and isolated short stature

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Abstract

Purpose

Short stature is a common clinical presentation, thus it is widely accepted that it is a polygenic trait. However, genome wide association and next generation sequencing studies have recently challenged this view, suggesting that many of the children classified as idiopathic short stature could instead have monogenic defects. Linear growth is determined primarily by chondrogenesis at the growth plate. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is perfectly coordinated by complex networks of local paracrine and endocrine factors. Alterations in genes which control growth plate development can explain a large number of cases of isolated short stature, allowing an etiological diagnosis.

Methods/Results

We reviewed recent data on the genetic alterations in fundamental cellular processes, paracrine signaling, and cartilage matrix formation associated with impaired growth plate chondrogenesis. In particular we focused on growth plate gene involvement in nonsyndromic short stature.

Conclusions

The identification of genetic basis of growth failure will have a significant impact on the care of children affected with short stature.

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References

  1. A.R. Wood, T. Esko, J. Yang, S. Vedantam, T.H. Pers, S. Gustafsson et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. E. Marouli, M. Graff, C. Medina-Gomez, K.S. Lo, A.R. Wood, T.R. Kjaer et al. Rare and low-frequency coding variants alter human adult height. Nature 542, 186–190 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. J. Baron, L. Sävendahl, F. De Luca, A. Dauber, M. Phillip, J.M. Wit et al. Short and tall stature: a new paradigm emerges. Nat. Rev. Endocrinol. 11, 735–746 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. A. Dauber, M.T. Muñoz-Calvo, V. Barrios, H.M. Domené, S. Kloverpris, C. Serra-Juhé et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol. Med. 8, 363–374 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. M.R. Jepsen, S. Kløverpris, J.H. Mikkelsen, J.H. Pedersen, E.M. Füchtbauer, L.S. Laursen et al. Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis. J. Biol. Chem. 290, 3430–3439 (2015)

    CAS  PubMed  Google Scholar 

  6. P. Kruszka, A.R. Porras, Y.A. Addissie, A. Moresco, S. Medrano, G.T.K. Mok et al. Noonan syndrome in diverse populations. Am. J. Med. Genet. A 173, 2323–2334 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. M.F. Faienza, L. Giordani, M. Ferraris, G. Bona, L. Cavallo, PTPN11 gene mutation and severe neonatal hypertrophic cardiomyopathy: what is the link? Pediatr. Cardiol. 30, 1012–1015 (2009)

    PubMed  Google Scholar 

  8. G.A. Vasques, N.L.M. Andrade, A.A.L. Jorge, Genetic causes of isolated short stature. Arch. Endocrinol. Metab. 63, 70–78 (2019)

    PubMed  Google Scholar 

  9. Y.H. Jee, J. Baron, O. Nilsson, New developments in the genetic diagnosis of short stature. Curr. Opin. Pediatr. 30, 541–547 (2018)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. O. Nilsson, R. Marino, F. De Luca, M. Phillip, J. Baron, Endocrine regulation of the growth plate. Horm. Res. 64, 157–165 (2005)

    CAS  PubMed  Google Scholar 

  11. H.M. Kronenberg, Developmental regulation of the growth plate. Nature 423, 332–336 (2003)

    CAS  PubMed  Google Scholar 

  12. G. Brunetti, G. D’Amato, M. Chiarito, A. Tullo, G. Colaianni, S. Colucci et al. An update on the role of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways in pediatric diseases. World J. Pediatr. 15, 4–11 (2019)

    CAS  PubMed  Google Scholar 

  13. M.F. Faienza, A. Ventura, M. Delvecchio, A. Fusillo, L. Piacente, G. Aceto et al. High sclerostin and Dickkopf-1 (DKK-1) serum levels in children and adolescents with type 1 diabetes mellitus. J. Clin. Endocrinol. Metab. 102, 1174–1181 (2017)

    PubMed  Google Scholar 

  14. G. Brunetti, F. Papadia, A. Tummolo, R. Fischetto, F. Nicastro, L. Piacente et al. Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α. Osteoporos. Int. 27, 2355–2365 (2016)

    CAS  PubMed  Google Scholar 

  15. Y. Rellmann, R. Dreier, Different forms of ER stress in chondrocytes result in short stature disorders and degenerative cartilage diseases: new insights by cartilage-specific ERp57 knockout mice. Oxid. Med. Cell. Longev. 17, 8421394 (2018)

    Google Scholar 

  16. M. Guo, Z. Liu, J. Willen, C.P. Shaw, D. Richard, E. Jagoda et al. Epigenetic profiling of growth plate chondrocytes sheds insight into regulatory genetic variation influencing height. Elife 6, pii: e29329 (2017)

    Google Scholar 

  17. A. Marchini, T. Marttila, A. Winter, S. Caldeira, I. Malanchi, R.J. Blaschke et al. The short stature homeodomain protein SHOX induces cellular growth arrest and apoptosis and is expressed in human growth plate chondrocytes. J. Biol. Chem. 279, 37103–37114 (2004)

    CAS  PubMed  Google Scholar 

  18. G. Binder, Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Horm. Res. Paediatr. 75, 81–89 (2011)

    CAS  PubMed  Google Scholar 

  19. A. Marchini, T. Ogata, G.A. Rappold, A track record on SHOX: from basic research to complex models and therapy. Endocr. Rev. 37, 417–448 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. V. Belin, V. Cusin, G. Viot, D. Girlich, A. Toutain, A. Moncla et al. SHOX mutations in dys-chondrosteosis (Leri-Weill syndrome). Nat. Genet. 19, 67–69 (1998)

    CAS  PubMed  Google Scholar 

  21. M.J. Kang, Novel genetic cause of idiopathic short stature. Ann. Pediatr. Endocrinol. Metab. 22, 153–157 (2017)

    PubMed  PubMed Central  Google Scholar 

  22. E. Rao, B. Weiss, M. Fukami, A. Rump, B. Niesler, A. Mertz et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat. Genet. 16, 54–63 (1997)

    CAS  PubMed  Google Scholar 

  23. A.C. Malaquias, R.C. Scalco, E.G. Fontenele, E.F. Costalonga, A.D. Baldin, A.F. Braz et al. The sitting height/height ratio for age in healthy and short individuals and its potential role in selecting short children for SHOX analysis. Horm. Res. Paediatr. 80, 449–456 (2013)

    CAS  PubMed  Google Scholar 

  24. G. Binder, G.A. Rappold, in SHOX Deficiency Disorders, ed. by M.P. Adam, H.H. Ardinger, R.A. Pagon, S.E. Wallace, L.J.H. Bean, K. Stephens, A. Amemiya, GeneReviews® [Internet] (University of Washington: Seattle, WA, 1993–2020) 2005 Dec 12 [updated 2018 Jun 28].

  25. J.C. Lui, O. Nilsson, Y. Chan, C.D. Palmer, A.C. Andrade et al. Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height. Hum. Mol. Genet. 21, 5193–5201 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. L.R. Potter, S. Abbey-Hosch, D.M. Dickey, Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr. Rev. 27, 47–72 (2006)

    CAS  PubMed  Google Scholar 

  27. K. Pejchalova, P. Krejci, W.R. Wilcox, C-natriuretic peptide: an important regulator of cartilage. Mol. Genet. Metab. 92, 210–215 (2007)

    CAS  PubMed  Google Scholar 

  28. A. Ozasa, Y. Komatsu, A. Yasoda, M. Miura, Y. Sakuma, Y. Nakatsuru et al. Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone 36, 1056–1064 (2005)

    CAS  PubMed  Google Scholar 

  29. P. Krejci, B. Masri, V. Fontaine, P.B. Mekikian, M. Weis, H. Prats et al. Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. J. Cell Sci. 118(Pt 21), 5089–50100 (2005)

    CAS  PubMed  Google Scholar 

  30. C.F. Bartels, H. Bukulmez, P. Padayatti, D.K. Rhee, C. van Ravenswaaij-Arts, R.M. Pauli et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am. J. Hum. Genet. 75, 27–34 (2004)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. R.C. Olney, H. Bukulmez, C.F. Bartels, T.C. Prickett, E.A. Espiner, L.R. Potter et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J. Clin. Endocrinol. Metab. 91, 1229–1232 (2006)

    CAS  PubMed  Google Scholar 

  32. G.A. Vasques, N. Amano, A.J. Docko, M.F. Funari, E.P. Quedas, M.Y. Nishi et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. J. Clin. Endocrinol. Metab. 98, E1636–E1644 (2013)

    CAS  PubMed  Google Scholar 

  33. S.R. Wang, C.M. Jacobsen, H. Carmichael, A.B. Edmund, J.W. Robinson, R.C. Olney et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Hum. Mutat. 36, 474–481 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. A. Hisado-Oliva, A. Ruzafa-Martin, L. Sentchordi, M.F.A. Funari, C. Bezanilla-Lopez, M. Alonso-Bernaldez et al. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature. Genet. Med. 20, 91–97 (2018)

    CAS  PubMed  Google Scholar 

  35. Z. Liu, K.J. Lavine, I.H. Hung, D.M. Ornitz, FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev. Biol. 302, 80–91 (2007)

    CAS  PubMed  Google Scholar 

  36. I.H. Hung, K. Yu, K.J. Lavine, D.M. Ornitz, FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev. Biol. 307, 300–313 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. D.M. Ornitz, P.J. Marie, Fibroblast growth factors in skeletal development. Curr. Top. Dev. Biol. 133, 195–234 (2019)

    CAS  PubMed  Google Scholar 

  38. A. Yasoda, Y. Komatsu, H. Chusho, T. Miyazawa, A. Ozasa, M. Miura et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat. Med. 10, 80–86 (2004)

    CAS  PubMed  Google Scholar 

  39. S.G. Kant, I. Cervenkova, L. Balek, L. Trantirek, G.W. Santen, M.C. de Vries et al. A novel variant of FGFR3 causes proportionate short stature. Eur. J. Endocrinol. 172, 763–770 (2015)

    CAS  PubMed  Google Scholar 

  40. L. Plachy, V. Strakova, L. Elblova, B. Obermannova, S. Kolouskova, M. Snajderova, High prevalence of growth plate gene variants in children with familial short stature treated with GH. J. Clin. Endocrinol. Metab. 104, 4273–4281 (2019)

    PubMed  Google Scholar 

  41. B. Lanske, A.C. Karaplis, K. Lee, A. Luz, A. Vortkamp, A. Pirro et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663–666 (1996)

    CAS  PubMed  Google Scholar 

  42. A. Vortkamp, K. Lee, B. Lanske, G.V. Segre, H.M. Kronenberg, C.J. Tabin, Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273, 613–622 (1996)

    CAS  PubMed  Google Scholar 

  43. J.M. Kindblom, O. Nilsson, T. Hurme, C. Ohlsson, L. Savendahl, Expression and localization of Indian hedgehog (Ihh) and parathyroid hormone related protein (PTHrP) in the human growth plate during pubertal development. J. Endocrinol. 174, R1–R6 (2002)

    CAS  PubMed  Google Scholar 

  44. A.J. Will, G. Cova, M. Osterwalder, W.L. Chan, L. Wittler, N. Brieske et al. Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog). Nat. Genet. 49, 1539–1545 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  45. G.A. Vasques, M.F.A. Funari, F.M. Ferreira, M. Aza-Carmona, L. Sentchordi-Montané, J. Barraza-García et al. IHH gene mutations causing short stature with nonspecific skeletal abnormalities and response to growth hormone therapy. J. Clin. Endocrinol. Metab. 103, 604–614 (2018)

    PubMed  Google Scholar 

  46. K.L. Lauing, M. Cortes, M.S. Domowicz, J.G. Henry, A.T. Baria, N.B. Schwartz, Aggrecan is required for growth plate cytoarchitecture and differentiation. Dev. Biol. 396, 224–236 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  47. M. Cortes, A.T. Baria, N.B. Schwartz, Sulfation of chondroitin sulfate proteoglycans is necessary for proper indian hedgehog signaling in the developing growth plate. Development 136, 1697–1706 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  48. N.B. Schwartz, M. Domowicz, Chondrodysplasias due to proteoglycan defects. Glycobiology 12, 57R–68R (2002)

    CAS  PubMed  Google Scholar 

  49. L. Gleghorn, R. Ramesar, P. Beighton, G. Wallis, A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis. Am. J. Hum. Genet. 77, 484–490 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. O. Nilsson, M.H. Guo, N. Dunbar, J. Popovic, D. Flynn, C. Jacobsen et al. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J. Clin. Endocrinol. Metab. 99, E1510–E1518 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  51. M. Aza-Carmona, V. Barca-Tierno, A. Hisado-Oliva, A. Belinchón, D. Gorbenko-del Blanco, J.I. Rodriguez et al. NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development. PLoS One 8(9), e83104 (2014)

    Google Scholar 

  52. J.B. Quintos, M.H. Guo, A. Dauber, Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene. J. Pediatr. Endocrinol. Metab. 28, 927–932 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  53. A. Gkourogianni, M. Andrew, L. Tyzinski, M. Crocker, J. Douglas, N. Dunbar et al. Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations. J. Clin. Endocrinol. Metab. 102, 460–469 (2017)

    PubMed  Google Scholar 

  54. S. Dateki, A. Nakatomi, S. Watanabe, H. Shimizu, Y. Inoue, H. Baba et al. Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation. J. Hum. Genet. 62, 717–721 (2017)

    CAS  PubMed  Google Scholar 

  55. N.N. Hauer, H. Sticht, S. Boppudi, C. Büttner, C. Kraus, U. Trautmann et al. Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature. Sci. Rep. 7, 12225 (2017)

    PubMed  PubMed Central  Google Scholar 

  56. M. van der Steen, R. Pfundt, S.J.W.H. Maas, W.M. Bakker-van Waarde, R.J. Odink, A.C.S. Hokken-Koelega, ACAN gene mutations in short children born SGA and response to growth hormone treatment. J. Clin. Endocrinol. Metab. 5, 1458–1467 (2017)

    Google Scholar 

  57. C. Tatsi, A. Gkourogianni, K. Mohnike, D. DeArment, S. Witchel, A.C. Andrade et al. Aggrecan mutations in nonfamilial short stature and short stature without accelerated skeletal maturation. J. Endocr. Soc. 1, 1006–1011 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Paediatric Unit, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari, Italy

    Maria Felicia Faienza & Mariangela Chiarito

  2. Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University of Bari “A. Moro”, Bari, Italy

    Giacomina Brunetti

  3. Neonatal Intensive Care Unit, Di Venere Hospital, Bari, Italy

    Gabriele D’Amato

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  1. Maria Felicia Faienza
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  2. Mariangela Chiarito
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  3. Giacomina Brunetti
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  4. Gabriele D’Amato
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Contributions

M.F.F. designed the study and prepared the first draft of the paper. She is guarantor. M.C. and G.B. design the figures and revised critically the paper; G.D. search the literature data and revised the final draft. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

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Correspondence to Maria Felicia Faienza.

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Faienza, M.F., Chiarito, M., Brunetti, G. et al. Growth plate gene involment and isolated short stature. Endocrine 71, 28–34 (2021). https://doi.org/10.1007/s12020-020-02362-w

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