Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Role of thyroid hormones in craniofacial development

Abstract

The development of the craniofacial skeleton relies on complex temporospatial organization of diverse cell types by key signalling molecules. Even minor disruptions to these processes can result in deleterious consequences for the structure and function of the skull. Thyroid hormone deficiency causes delayed craniofacial and tooth development, dysplastic facial features and delayed development of the ossicles in the middle ear. Thyroid hormone excess, by contrast, accelerates development of the skull and, in severe cases, might lead to craniosynostosis with neurological sequelae and facial hypoplasia. The pathogenesis of these important abnormalities remains poorly understood and underinvestigated. The orchestration of craniofacial development and regulation of suture and synchondrosis growth is dependent on several critical signalling pathways. The underlying mechanisms by which these key pathways regulate craniofacial growth and maturation are largely unclear, but studies of single-gene disorders resulting in craniofacial malformations have identified a number of critical signalling molecules and receptors. The craniofacial consequences resulting from gain-of-function and loss-of-function mutations affecting insulin-like growth factor 1, fibroblast growth factor receptor and WNT signalling are similar to the effects of altered thyroid status and mutations affecting thyroid hormone action, suggesting that these critical pathways interact in the regulation of craniofacial development.

Key points

  • Thyroid hormone deficiency during development results in delayed intramembranous and endochondral ossification in the skull, which manifests as patent or persistent fontanelles, patent sutures, delayed dentition, wormian bones and deafness.

  • Thyroid hormone excess during development results in advanced intramembranous and endochondral ossification in the skull, which manifests as premature fusion of the calvarial sutures and cranial base synchondroses.

  • These characteristic craniofacial malformations indicate that thyroid hormones have a pivotal role in development and growth of the craniofacial skeleton and demonstrate that the skull is exquisitely sensitive to changes in thyroid status.

  • Thyroid hormone-induced changes in fibroblast growth factor receptor, insulin-like growth factor 1 and WNT signalling in osteoblasts and chondrocytes indicate that these pathways are intricately involved in the regulation of craniofacial development by T3.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Craniofacial development.
Fig. 2: Key signalling pathways in craniofacial development.
Fig. 3: Thyroid hormone action in chondrocytes and osteoblasts.
Fig. 4: Mechanism of thyroid hormone action in the skull.

Similar content being viewed by others

References

  1. Bassett, J. H. D. & Williams, G. R. Role of thyroid hormones in skeletal development and bone maintenance. Endocr. Rev. 37, 135–187 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Jin, S. W., Sim, K. B. & Kim, S. D. Development and growth of the normal cranial vault: an embryological review. J. Korean Neurosurg. Soc. 59, 192–196 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sperber, G. H. & Sperber, S. M. Craniofacial Embyrogenetics and Development (PMPHUSA, 2018).

  4. Moreira, C. A., Dempster, D. W. & Baron, R. Anatomy and Ultrastructure of Bone – Histogenesis, Growth and Remodeling (MDText.com, 2019).

  5. Mishina, Y. & Snider, T. N. Neural crest cell signaling pathways critical to cranial bone development and pathology. Exp. Cell Res. 325, 138–147 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hall, B. K. & Miyake, T. All for one and one for all: condensations and the initiation of skeletal development. Bioessays 22, 138–147 (2000).

    CAS  PubMed  Google Scholar 

  7. DeLise, A. M., Fischer, L. & Tuan, R. S. Cellular interactions and signaling in cartilage development. Osteoarthritis Cartilage 8, 309–334 (2000).

    CAS  PubMed  Google Scholar 

  8. Long, F. & Ornitz, D. M. Development of the endochondral skeleton. Cold Spring Harb. Perspect. Biol. 5, a008334 (2013).

    PubMed  PubMed Central  Google Scholar 

  9. Garg, P. et al. Prospective review of mesenchymal stem cells differentiation into osteoblasts. Orthop. Surg. 9, 13–19 (2017).

    PubMed  PubMed Central  Google Scholar 

  10. Hata, K., Takahata, Y., Murakami, T. & Nishimura, R. Transcriptional network controlling endochondral ossification. J. Bone Metab. 24, 75–82 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Mackie, E. J., Ahmed, Y. A., Tatarczuch, L., Chen, K. S. & Mirams, M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int. J. Biochem. Cell Biol. 40, 46–62 (2008).

    CAS  PubMed  Google Scholar 

  12. Mackie, E. J., Tatarczuch, L. & Mirams, M. The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. J. Endocrinol. 211, 109–121 (2011).

    CAS  PubMed  Google Scholar 

  13. Park, R. W. et al. Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage. Biol. Open 4, 608–621 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Houben, A. et al. β-catenin activity in late hypertrophic chondrocytes locally orchestrates osteoblastogenesis and osteoclastogenesis. Development 143, 3826–3838 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Aghajanian, P., Xing, W., Cheng, S. & Mohan, S. Epiphyseal bone formation occurs via thyroid hormone regulation of chondrocyte to osteoblast transdifferentiation. Sci. Rep. 7, 10432 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. Morriss-Kay, G. M. & Wilkie, A. O. Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. J. Anat. 207, 637–653 (2005).

    PubMed  PubMed Central  Google Scholar 

  17. Yoshida, T., Vivatbutsiri, P., Morriss-Kay, G. M., Saga, Y. & Iseki, S. Cell lineage in mammalian craniofacial mesenchyme. Mech. Dev. 125, 797–808 (2008).

    CAS  PubMed  Google Scholar 

  18. Jiang, X., Iseki, S., Maxson, R. E., Sucov, H. M. & Morriss-Kay, G. M. Tissue origins and interactions in the mammalian skull vault. Dev. Biol. 241, 106–116 (2002).

    CAS  PubMed  Google Scholar 

  19. Han, J. et al. Concerted action of Msx1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone development. Mech. Dev. 124, 729–745 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Ishii, M., Sun, J., Ting, M. C. & Maxson, R. E. in Craniofacial Development 1st edn Vol. 115 (ed. Chai, Y.) 131–156 (Elsevier, 2015).

  21. Pal, G. P., Tamankar, B. P., Routal, R. V. & Bhagwat, S. S. The ossification of the membranous part of the squamous occipital bone in man. J. Anat. 138, 259–266 (1984).

    PubMed  PubMed Central  Google Scholar 

  22. Bellary, S. S. et al. Wormian bones: a review. Clin. Anat. 26, 922–927 (2013).

    PubMed  Google Scholar 

  23. Bradley, J. P., Levine, J. P., Roth, D. A., McCarthy, J. G. & Longaker, M. T. Studies in cranial suture biology: IV. Temporal sequence of posterior frontal cranial suture fusion in the mouse. Plast. Reconstr. Surg. 98, 1039–1045 (1996).

    CAS  PubMed  Google Scholar 

  24. McBratney-Owen, B., Iseki, S., Bamforth, S. D., Olsen, B. R. & Morriss-Kay, G. M. Developmental and tissue origins of the mammalian cranial base. Dev. Biol. 322, 121–132 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cheng, A., Hardingham, T. E. & Kimber, S. J. Generating cartilage repair from pluripotent stem cells. Tissue Eng. Part B Rev. 20, 257–266 (2014).

    PubMed  Google Scholar 

  26. Foster, N. C., Henstock, J. R., Reinwald, Y. & El Haj, A. J. Dynamic 3D culture: Models of chondrogenesis and endochondral ossification. Birth Defects Res. C Embryo Today 105, 19–33 (2015).

    CAS  PubMed  Google Scholar 

  27. Thorogood, P. The developmental specification of the vertebrate skull. Development 103, 141–153 (1988).

    PubMed  Google Scholar 

  28. Wei, X., Hu, M., Mishina, Y. & Liu, F. Developmental regulation of the growth plate and cranial synchondrosis. J. Dent. Res. 95, 1221–1229 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mallo, M. Formation of the middle ear: recent progress on the development and molecular mechanisms. Dev. Biol. 231, 410–419 (2001).

    CAS  PubMed  Google Scholar 

  30. Stocum, D. L. & Roberts, W. E. Part I: Development and physiology of the temporomadibular joint. Curr. Osteoporos. Rep. 16, 360–368 (2018).

    PubMed  Google Scholar 

  31. Krishnan, K. & Kanchan, T. Evaluation of spheno-occipital synchondrosis: a review of literature and considerations from forensic anthropologic point of view. J. Forensic Dent. Sci. 5, 72–76 (2013).

    Google Scholar 

  32. Coll, G. et al. Human foramen magum area and posterior cranial fossa volume growth in relation to cranial base synchondrosis closure in the course of child development. Neurosurgery 79, 722–735 (2016).

    PubMed  Google Scholar 

  33. Vora, S. R., Camci, E. D. & Cox, T. C. Postnatal ontogeny of the cranial base and craniofacial skeleton in male C57BL/6J mice: a reference standard for quantitative analysis. Front. Physiol. 6, 417 (2016).

    PubMed  PubMed Central  Google Scholar 

  34. Kiesler, J. & Ricer, R. The abnormal fontanel. Am. Fam. Physician 67, 2547–2552 (2003).

    PubMed  Google Scholar 

  35. Cendekiawan, T., Wong, R. W. K. & Rabie, A. B. M. Relationships between cranial base synchondroses and craniofacial development: a review. Open Anat. J. 2, 67–75 (2010).

    Google Scholar 

  36. Goldstein, J. A. et al. Earlier evidence of shpeno-occipital synchondrosis fusion correlates with severity of midface hypoplasia in patients with syndromic craniosynostosis. Plast. Reconstr. Surg. 134, 504–510 (2014).

    CAS  PubMed  Google Scholar 

  37. Mazzaferro, D. M. et al. Incidence of cranial base suture fusion in infants with craniosynostosis. Plast. Reconstr. Surg. 141, 559e–570e (2018).

    CAS  PubMed  Google Scholar 

  38. Tubbs, R. S. & Oakes, W. J. The Chiari Malformations (Springer, 2013).

  39. Neben, C. L. & Merrill, A. E. in Craniofacial Development 1st edn Vol. 115 (ed. Chai, Y.) 493–542 (Elsevier, 2015).

  40. Farrell, B. & Breeze, A. L. Structure, activation and dysregulation of fibroblast growth factor receptor kinases: perspectives for clinical targeting. Biochem. Soc. Trans. 46, 1753–1770 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ornitz, D. M. & Marie, P. J. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 16, 1446–1465 (2002).

    CAS  PubMed  Google Scholar 

  42. Su, N., Jin, M. & Chen, L. Role of FGF/FGFR signaling in skeletal development and homeostasis learning from mouse models. Bone Res. 2, 14003 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. Prochazkova, K., Prochazka, J., Marangoni, P. & Klein, O. D. Bones, glands, ears and more: the multiple roles of FGF10 in craniofacial development. Front. Genet. 9, 542 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Helsten, T., Schwaederle, M. & Kurzrock, R. Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biological and clinical implications. Cancer Metastasis Rev. 34, 479–496 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhou, Y. X. et al. A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. Hum. Mol. Genet. 9, 2001–2008 (2000).

    CAS  PubMed  Google Scholar 

  46. Merrill, A. E. et al. Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am. J. Med. Genet. 90, 550–557 (2012).

    CAS  Google Scholar 

  47. Jarzabek, K., Wolczynski, S., Lesniewicz, R., Plessis, G. & Kottler, M. L. Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome. Adv. Med. Sci. 57, 314–321 (2012).

    CAS  PubMed  Google Scholar 

  48. Wang, Y. et al. Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse. Development 132, 3537–3548 (2005).

    CAS  PubMed  Google Scholar 

  49. Pierre-Kahn, A., Hirsch, J. F., Renier, D., Metzger, J. & Maroteaux, P. Hydrocephalus and achondroplasia. A study of 25 observations. Childs Brain 7, 205–219 (1980).

    CAS  PubMed  Google Scholar 

  50. Arnaud-López, L., Fragoso, R., Mantilla-Capacho, J. & Barros-Núñez, P. Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clin. Genet. 72, 405–410 (2007).

    PubMed  Google Scholar 

  51. Abdel-Salam, G. M. H. et al. Muenke syndrome with pigmentary disorder and probable hemimegalencephaly: an expansion of the phenotype. Am. J. Med. Genet. A 155A, 207–214 (2011).

    PubMed  Google Scholar 

  52. Lee, Y. C., Song, I. W., Pai, Y. J., Chen, S. D. & Chen, Y. T. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia. Sci. Rep. 7, 43220 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ornitz, D. M. & Itoh, N. The fibroblast growth factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 4, 215–266 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Adamek, A. & Kasprzak, A. Insulin-like growth factor (IGF) system in liver disease. Int. J. Mol. Sci. 19, E1308 (2018).

    PubMed  Google Scholar 

  55. Roth, D. A. et al. Immunolocalization of transforming growth factor β1, β2, and β3 and insulin-like growth factor I in premature cranial suture fusion. Plast. Reconstr. Surg. 99, 300–309 (1997).

    CAS  PubMed  Google Scholar 

  56. Thaller, S. R., Hoyt, J., Tesluk, H. & Holmes, R. The effect of insulin growth factor-1 on calvarial sutures in a Sprague-Dawley rat. J. Craniofac. Surg. 4, 35–39 (1993).

    CAS  PubMed  Google Scholar 

  57. Bradley, J. P. et al. Increased IGF-I and IGF-II mRNA and IGF-I peptide in fusing rat cranial sutures suggest evidence for a paracrine role of insulin like growth factors in suture fusion. Plast. Reconstr. Surg. 104, 129–138 (1999).

    CAS  PubMed  Google Scholar 

  58. Woods, K. A., Camacho-Hubner, C., Savage, M. O. & Clark, A. J. L. Intrauterine growth retardation and postnatal growth failure associated with deletion of the Insulin-like growth factor i gene. N. Engl. J. Med. 335, 1363–1367 (1996).

    CAS  PubMed  Google Scholar 

  59. Begemann, M. et al. Paternally inherited IGF2 mutation and growth restriction. N. Engl. J. Med. 373, 349–356 (2015).

    CAS  PubMed  Google Scholar 

  60. Qiao, M., Shapiro, P., Kumar, R. & Passaniti, A. Insulin-like growth factor-1 regulates endogenous RUNX2 activity in endothelial cells through a phosphatidylinositol 3-kinase/ERK-dependent and Akt-independent signaling pathway. J. Biol. Chem. 279, 42709–42718 (2004).

    CAS  PubMed  Google Scholar 

  61. Fujita, T. et al. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. J. Cell Biol. 166, 85–95 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Longobardi, L. et al. Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. J. Bone Miner. Res. 21, 626–636 (2006).

    CAS  PubMed  Google Scholar 

  63. Zhou, Q. et al. IGF-I induces adipose derived mesenchymal cell chondrogenic differentiation in vitro and enhances chondrogenesis in vivo. In Vitro Cell Dev. Biol. Anim. 52, 356–364 (2016).

    CAS  PubMed  Google Scholar 

  64. Wang, J., Zhou, J. & Bondy, C. A. Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J. 13, 1985–1990 (1999).

    CAS  PubMed  Google Scholar 

  65. Hardouin, S. N., Guo, R., Romeo, P.-H., Nagy, A. & Aubin, J. E. Impaired mesenchymal stem cell differentiation and osteoclastogenesis in mice deficient for Igf2-P2 transcripts. Development 138, 203–213 (2011).

    CAS  PubMed  Google Scholar 

  66. Abuzzahab, M. J. et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N. Engl. J. Med. 349, 2211–2222 (2003).

    CAS  PubMed  Google Scholar 

  67. Raile, K. et al. Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor I receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R. J. Clin. Endocrinol. Metab. 91, 2264–2271 (2006).

    CAS  PubMed  Google Scholar 

  68. Fang, P. et al. Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R). J. Clin. Endocrinol. Metab. 97, E243–E247 (2012).

    CAS  PubMed  Google Scholar 

  69. Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. & Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993).

    CAS  PubMed  Google Scholar 

  70. Woitge, H. W. & Kream, B. E. Calvariae from fetal mice with a disrupted Igf1 gene have reuced rates of collagen synthesis but maintain responsiveness to glucocorticoids. J. Bone Miner. Res. 15, 1956–1964 (2000).

    CAS  PubMed  Google Scholar 

  71. Huang, R. L., Yuan, Y., Tu, J., Zou, G. M. & Li, Q. Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation. Cell Death Dis. 5, e1187 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Phimphilai, M., Zhao, Z., Boules, H., Roca, H. & Franceschi, R. T. BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype. J. Bone Miner. Res. 21, 637–646 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L. & Karsenty, G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89, 747–754 (1997).

    CAS  PubMed  Google Scholar 

  74. Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764 (1997).

    CAS  PubMed  Google Scholar 

  75. Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765–771 (1997).

    CAS  PubMed  Google Scholar 

  76. Enomoto, H. et al. Cbfa1 is a positive regulatory factor in chondrocyte maturation. J. Biol. Chem. 275, 8695–8702 (2000).

    CAS  PubMed  Google Scholar 

  77. Chen, H. et al. Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation. J. Bone Miner. Res. 29, 2653–2665 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kawane, T. et al. Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation by regulating Fgfr2 and Fgfr3. Sci. Rep. 8, 13551 (2018).

    PubMed  PubMed Central  Google Scholar 

  79. Zheng, Q. et al. Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J. Cell Biol. 162, 833–842 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Yan, J. et al. Smad4 deficiency impairs chondrocyte hypertrophy via the Runx2 transcription factor in mouse skeletal development. J. Biol. Chem. 293, 9162–9175 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Bialek, P. et al. A Twist code determines the onset of osteoblast differentiation. Dev. Cell 6, 423–435 (2004).

    CAS  PubMed  Google Scholar 

  82. Shirakabe, K., Terasawa, K., Miyama, K., Shibuya, H. & Nishida, E. Regulation of the activity of the transcription factor Runx2 by two homeobox, Msx2 and Dlx5. Genes Cells 6, 851–856 (2001).

    CAS  PubMed  Google Scholar 

  83. Widelitz, R. Wnt signaling through canonical and non-canonical pathways: recent progress. Growth Factors 23, 111–116 (2005).

    CAS  PubMed  Google Scholar 

  84. Nusse, R. & Clevers, H. Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017).

    CAS  PubMed  Google Scholar 

  85. Parr, B. A., Shea, M. J., Vassileva, G. & McMahon, A. P. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. Development 119, 247–261 (1993).

    CAS  PubMed  Google Scholar 

  86. Kato, M. et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J. Cell Biol. 157, 303–314 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Day, T. F., Guo, X., Garrett-Beal, L. & Yang, Y. Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739–750 (2005).

    CAS  PubMed  Google Scholar 

  88. Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).

    CAS  PubMed  Google Scholar 

  89. Song, L. et al. Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion. Development 136, 3161–3171 (2009).

    CAS  PubMed  Google Scholar 

  90. Roetzer, K. M. et al. Novel familial mutation of LRP5 causing high bone mass: genetic analysis, clinical presentation, and characterization of bone matrix mineralization. Bone 107, 154–160 (2018).

    CAS  PubMed  Google Scholar 

  91. Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521 (2002).

    CAS  PubMed  Google Scholar 

  92. Rawadi, G., Vayssière, B., Dunn, F., Baron, R. & Roman-Roman, S. BMP-2 controls alkaline phosphatase expression and osteoblast mineralisation by a Wnt autocrine loop. J. Bone Miner. Res. 18, 1842–1853 (2003).

    CAS  PubMed  Google Scholar 

  93. Gaur, T. et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J. Biol. Chem. 280, 33132–33140 (2005).

    CAS  PubMed  Google Scholar 

  94. Nagayama, M. et al. Wnt/beta-catenin signaling regulates cranial base development and growth. J. Dent. Res. 87, 244–249 (2008).

    CAS  PubMed  Google Scholar 

  95. Brownstein, M. J., Eskay, R. L. & Palkovits, M. Thryotropin releasing hormone in the median eminence is in processes of paraventricular nucleus neurons. Neuropeptides 2, 197–201 (1982).

    CAS  Google Scholar 

  96. Segerson, T. P. et al. Localization of thyrotropin-releasing hormone prohormone messenger ribonucleic acid in rat brain by in situ hybridization. Endocrinology 121, 98–107 (1987).

    CAS  PubMed  Google Scholar 

  97. Szarek, E., Cheah, P. S., Schwartz, J. & Thomas, P. Molecular genetics of the developing neuroendocrine hypothalamus. Mol. Cell Endocrinol. 323, 115–123 (2010).

    CAS  PubMed  Google Scholar 

  98. Harris, A. R. et al. The physiological role of thyrotropin-releasing hormone in the regulation of thyroid-stimulating hormone and prolactin secretion in the rat. J. Clin. Invest. 61, 441–448 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Steinfelder, H. J. et al. Thyrotropin-releasing hormone regulation of human TSHB expression: role of the pituitary-specific transcription factor (Pit-1/GHF-1) and potential interaction with a thyroid hormone-inhibitory element. Proc. Natl Acad. Sci. USA 88, 3130–3134 (1991).

    CAS  PubMed  Google Scholar 

  100. Sun, Y., Lu, X. & Gershengorn, M. C. Thyrotropin-releasing hormone receptors – similarities and differences. J. Mol. Endocrinol. 30, 87–97 (2003).

    CAS  PubMed  Google Scholar 

  101. Negi, C. S. Introduction to Endocrinology (PHI Learning, 2009).

  102. Kopp, P. The TSH receptor and its role in thyroid disease. Cell Mol. Life Sci. 58, 1301–1322 (2001).

    CAS  PubMed  Google Scholar 

  103. Abel, E. D., Ahima, R. S., Boers, M. E., Elmquist, J. K. & Wondisford, F. E. Critical role for thyroid hormone receptor β2 in the regulation of paraventricular thyrotropin-releasing hormone neurons. J. Clin. Invest. 107, 1017-1023 (2001).

  104. O’Shea, P. J. et al. Advanced bone formation in mice with a dominant-negative mutation in the thyroid hormone receptor β gene due to activation of Wnt/β-catenin protein signaling. J. Biol. Chem. 287, 17812–17822 (2012).

    PubMed  PubMed Central  Google Scholar 

  105. Taylor, P. N. et al. Whole-genome sequence-based analysis of thyroid function. Nat. Commun. 6, 5681–5690 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Teumer, A. et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat. Commun. 9, 4455 (2018).

    Google Scholar 

  107. Friesema, E. C. et al. Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol. Endocrinol. 22, 1357–1369 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Visser, W. E., Friesema, E. C. & Visser, T. J. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol. Endocrinol. 25, 1–14 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Wirth, E. K., Schweizer, U. & Köhrle, J. Transport of thyroid hormone in the brain. Front. Endocrinol. 5, 98 (2014).

    Google Scholar 

  110. Capelo, L. P., Beber, E. H., Fonseca, T. L. & Gouveia, C. H. A. The monocarboxylate transporter 8 and L-type amino acid transporters 1 and 2 are expressed in mouse skeletons and osteoblastic MC3T3-E1 cells. Thyroid 19, 171–180 (2009).

    CAS  PubMed  Google Scholar 

  111. Abe, S. et al. Monocarboxylate transporter 10 functions as a thyroid hormone transporter in chondrocytes. Endocrinology 153, 4049–4058 (2012).

    CAS  PubMed  Google Scholar 

  112. Leitch, V. D. et al. An essential physiological role for MCT8 in bone in male mice. Endocrinology 158, 3055–3066 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Braverman, L. E., Ingbar, S. H. & Sterling, K. Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic subjects. J. Clin. Invest. 49, 855–864 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Gereben, B. et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr. Rev. 29, 898–938 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Arrojo e Drigo, R. & Bianco, A. C. Type 2 deiodinase at the crossroads of thyroid hormone action. Int. J. Biochem. Cell Biol. 43, 1432–1441 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. St. Germain, D. L., Galton, V. A. & Hernandez, A. Minireview: defining the roles of the iodothyronine deiodinases: current concepts and challenges. Endocrinology 150, 1097–1107 (2009).

    Google Scholar 

  117. Kanatani, M. et al. Thyroid hormone stimulates osteoclast differentiation by a mechanism independent of RANKL-RANK interaction. J. Cell. Physiol. 201, 17–25 (2004).

    CAS  PubMed  Google Scholar 

  118. Williams, A. J. et al. Iodothyronine deiodinase enzyme activities in bone. Bone 43, 126–134 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Hönes, G. S. et al. Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. Proc. Natl Acad. Sci. USA 114, E11323–E11332 (2017).

    PubMed  Google Scholar 

  120. Flamant, F. et al. Thyroid hormone signaling pathways: time for a more precise nomenclature. Endocrinology 158, 2052–2057 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Astapova, I. et al. The nuclear receptor corepressor (NCoR) controls thyroid hormone sensitivity and the set point of the hypothalamic-pituitary-thyroid axis. Mol. Endocrinol. 25, 212–224 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Leng, X., Tsai, S. Y., O’Malley, B. W. & Tsai, M. J. Ligand-dependent conformational changes in thyroid hormone and retinoic acid receptors are potentially enhanced by heterodimerization with retinoic X receptor. J. Steroid Biochem. Mol. Biol. 46, 643–661 (1993).

    CAS  PubMed  Google Scholar 

  123. Wagner, R. L. et al. A structural role for hormone in the thyroid hormone receptor. Nature 378, 690–697 (1995).

    CAS  PubMed  Google Scholar 

  124. Fondell, J. D., Ge, H. & Roeder, R. G. Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc. Natl Acad. Sci. USA 93, 8329–8333 (1996).

    CAS  PubMed  Google Scholar 

  125. Hiroi, Y. et al. Rapid nongenomic actions of thyroid hormone. Proc. Natl Acad. Sci. USA 103, 14104–14109 (2006).

    CAS  PubMed  Google Scholar 

  126. Martin, N. P. et al. A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology 155, 3713–3724 (2014).

    PubMed  PubMed Central  Google Scholar 

  127. Forrest, D., Sjoberg, M. & Vennstrom, B. Contrasting developmental and tissue-specific expression of alpha and beta thyroid hormone receptor genes. EMBO J. 9, 1519–1528 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Cray, J. J. Jr, Khaksarfard, K., Weinberg, S. M., Elsalanty, M. & Yu, J. C. Effects of thyroxine exposure on osteogenesis in mouse calvarial pre-osteoblasts. PLoS One 8, e69067 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Park, S.-H. et al. Potential of L-thyroxine to differentiate osteoblast-like cells via angiopoietin1. Biochem. Biophys. Res. Commun. 478, 1409–1415 (2016).

    CAS  PubMed  Google Scholar 

  130. Kassem, M., Mosekilde, L. & Ericksen, E. F. Effects of triiodothyronine on DNA synthesis and differentiation markers of normal human osteoblast-like cells in vitro. Biochem. Mol. Biol. Int. 30, 779–788 (1993).

    CAS  PubMed  Google Scholar 

  131. Ishisaki, A. et al. Activation of p38 mitogen-activated protein kinase mediates thyroid hormone-stimulated osteocalcin synthesis in osteoblasts. Mol. Cell. Endocrinol. 214, 189–195 (2004).

    CAS  PubMed  Google Scholar 

  132. Stevens, D. A. et al. Thyroid hormone activates fibroblast growth factor receptor-1 in bone. Mol. Endocrinol. 17, 1751–1766 (2003).

    CAS  PubMed  Google Scholar 

  133. Xing, W. et al. Genetic evidence that thyroid hormone is indispensable for prepubertal insulin-like growth factor-I expression and bone acquisition in mice. J. Bone Miner. Res. 27, 1067–1079 (2012).

    CAS  PubMed  Google Scholar 

  134. Tsourdi, E., Rijntjes, E., Kohrle, J., Hofbauer, L. C. & Rauner, M. Hyperthyroidism and hypothyroidism in male mice and their effects on bone mass, bone turnover, and the Wnt inhibitors sclerostin and dickkopf-1. Endocrinology 156, 3517–3527 (2015).

    CAS  PubMed  Google Scholar 

  135. Hu, Z. et al. Energy metabolism in the bone is associated with histomorphometric changes in rats with hyperthyroidism. Cell. Physiol. Biochem. 46, 1471–1482 (2018).

    CAS  PubMed  Google Scholar 

  136. Cheng, S., Xing, W., Pourteymoor, S. & Mohan, S. Effects of thyroxine (T4), 3,5,3’-triiodo-L-thyronine (T3) and their metabolites on osteoblast differentiation. Calcif. Tissue Int. 99, 435–442 (2016).

    CAS  PubMed  Google Scholar 

  137. O’Shea, P. J., Guigon, C. J., Williams, G. R. & Cheng, S. Y. Regulation of fibroblast growth factor receptor-1 (FGFR1) by thyroid hormone: identification of a thyroid hormone response element in the murine Fgfr1 promoter. Endocrinology 148, 5966–5976 (2007).

    CAS  PubMed  Google Scholar 

  138. Robson, H., Siebler, T., Stevens, D. A., Shalet, S. M. & Williams, G. R. Thyroid hormone acts directly on growth plate chondrocytes to promote hypertrophic differentiation and inhibit clonal expansion and cell proliferation. Endocrinology 141, 3887–3897 (2000).

    CAS  PubMed  Google Scholar 

  139. Miura, M. et al. Thyroid hormones promote chondrocyte differentiation in mouse ATDC5 cells and stimulate endochondral ossification in fetal mouse tibias through iodothyronine deiodinases in the growth plate. J. Bone Miner. Res. 17, 443–454 (2002).

    CAS  PubMed  Google Scholar 

  140. Okubo, Y. & Reddi, A. H. Thyroxine downregulates Sox9 and promotes chondrocyte hypertrophy. Biochem. Biophys. Res. Commun. 306, 186–190 (2003).

    CAS  PubMed  Google Scholar 

  141. Barnard, J. C. et al. Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis. Endocrinology 146, 5568–5580 (2005).

    CAS  PubMed  Google Scholar 

  142. Britto, J. M., Fenton, A. J., Holloway, W. R. & Nicholson, G. C. Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption. Endocrinology 134, 169–176 (1994).

    CAS  PubMed  Google Scholar 

  143. Gouveia, C. H. A., Miranda-Rodrigues, M., Martins, G. M. & Neofiti-Papi, B. Thyroid hormone and skeletal development. Vitam. Horm. 106, 383–472 (2018).

    PubMed  Google Scholar 

  144. Lindsey, R. C., Aghajanian, P. & Mohan, S. Thyroid hormone signaling in the development of the endochondral skeleton. Vitam. Horm. 106, 351–381 (2018).

    PubMed  Google Scholar 

  145. Wassner, A. J. & Brown, R. S. Congenital hypothyroidism: recent advances. Curr. Opin. Endocrinol. Diabetes Obes. 22, 407–412 (2015).

    CAS  PubMed  Google Scholar 

  146. Bakker, B. et al. Two decades of screening for congenital hypothyroidism in the Netherlands: TPO gene mutations in total iodide organification defects (an update). J. Endocrinol. Metab. 85, 3708–3712 (2000).

    CAS  Google Scholar 

  147. Moreno, J. C. et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N. Engl. J. Med. 347, 95–102 (2002).

    CAS  PubMed  Google Scholar 

  148. Macchia, P. E. et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat. Genet. 19, 83–86 (1998).

    CAS  PubMed  Google Scholar 

  149. Tao, Y. X. Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic implications. Phamacol. Ther. 111, 949–973 (2006).

    CAS  Google Scholar 

  150. Dumitrescu, A. M. et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat. Genet. 37, 1247–1252 (2005).

    CAS  PubMed  Google Scholar 

  151. Bubenik, J. L., Miniard, A. & Driscoll, D. Characterization of the UGA-recoding and SECIS-binding activities of SECIS-binding protein 2. RNA Biol. 11, 1402–1413 (2014).

    PubMed  Google Scholar 

  152. Smith, D. W. & Popich, G. Large fontanels in congenital hypothyroidism: a potental clue toward earlier recognition. J. Pediatr. 80, 753–756 (1972).

    CAS  PubMed  Google Scholar 

  153. Loevy, H. T., Aduss, H. & Rosenthal, I. M. Tooth eruption and craniofacial development in congenital hypothyroidism: report of case. J. Am. Dent. Assoc. 115, 429–431 (1987).

    CAS  PubMed  Google Scholar 

  154. Kaplan, S. B., Kemp, S. S. & Oh, K. S. Radiographic manifestations of congenital anomalies of the skull. Radiol. Clin. North Am. 29, 195–218 (1991).

    CAS  PubMed  Google Scholar 

  155. Pezzuti, I. L., Lima, P. P. & Dias, V. M. Congenital hypothyroidism: the clinical profile of affected newborns identified by the Newborn Screening Program of the State of Minas Gerais, Brazil. J. Pediatr. (Rio J) 85, 72–79 (2009).

    Google Scholar 

  156. Bretones, P. et al. A familial case of congenital hypothyroidism caused by a homozygous mutation of the thyrotropin receptor gene. Thyroid 11, 977–980 (2001).

    CAS  PubMed  Google Scholar 

  157. Gagné, N., Parma, J., Deal, C., Vassart, G. & Van Vliet, G. Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities? J. Clin. Endocrinol. Metab. 83, 1771–1775 (1998).

    PubMed  Google Scholar 

  158. Azevedo, M. F. et al. Selenoprotein-related disease in a young girl caused by nonsense mutations in the SBP2 gene. J. Clin. Endocrinol. Metab. 95, 4066–4071 (2010).

    CAS  PubMed  Google Scholar 

  159. Huffmeier, U., Tietze, H. U. & Rauch, A. Severe skeletal dysplasia caused by undiagnosed hypothyroidism. Eur. J. Med. Genet. 50, 209–215 (2007).

    PubMed  Google Scholar 

  160. Vakili, R. & Mazlouman, S. J. Dyshormonogenic hypothyroidism with normal neurological development, unexplained short stature and facial anomalies in three siblings. Clin. Dysmorphology 12, 21–27 (2003).

    Google Scholar 

  161. Di Cosmo, C. et al. Clinical and molecular characterization of a novel selenocysteine insertion sequence-binding protein 2 (SBP2) gene mutation (R128X). J. Clin. Endocrinol. Metab. 94, 4003–4009 (2009).

    PubMed  PubMed Central  Google Scholar 

  162. Meyerhoff, W. L. Hypothyroidism and the ear: electrophysiological, morphological and chemical considerations. Laryngoscope 89, 1–25 (1979).

    CAS  PubMed  Google Scholar 

  163. Gecgelen Cesur, M., Cesur, G., Ogrenim, M. & Alkan, A. Do prenatal and postnatal hypothyroidism affect the craniofacial structure?: an experimental study. Angle Orthod. 86, 983–990 (2016).

    Google Scholar 

  164. Nanto-Salonen, K., Glasscock, G. F. & Rosenfeld, R. G. The effects of thyroid hormone on insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) expression in the neonatal rat: prolonged high expression of IGFBP-2 in methimazole-induced congenital hypothyroidism. Endocrinology 129, 2563–2570 (1991).

    CAS  PubMed  Google Scholar 

  165. Abe, E. et al. TSH is a negative regulator of skeletal remodelling. Cell 115, 151–162 (2003).

    CAS  PubMed  Google Scholar 

  166. Cordas, E. A. et al. Thyroid hormone receptors control developmental maturation of the middle ear and the size of the ossicular bones. Endocrinology 153, 1548–1560 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Seeher, S. et al. Secisbp2 is essential for embryonic development and enhances selenoprotein expression. Antioxid. Redox Signal. 21, 835–849 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Bassett, J. H. D. et al. A lack of thyroid hormones rather than excess thyrotropin causes abnormal skeletal development in hypothyroidism. Mol. Endocrinol. 22, 501–512 (2008).

    CAS  PubMed  Google Scholar 

  169. Endo, T. & Kobayashi, T. Excess TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate. Am. J. Physiol. Endocrinol. Metab. 305, E660–E666 (2013).

    CAS  PubMed  Google Scholar 

  170. Takeuchi, H., Nakagawa, Y. & Igarashi, Y. Studies on gene expression in calvaria and serum levels of insulin-like growth factor-I and bone Gla protein in the methimazole-induced congenital hypothyroid rat. Endocr. J. 40, 351–362 (1993).

    CAS  PubMed  Google Scholar 

  171. Keer, S. et al. Anatomical assessment of the adult skeleton of zebrafish reared under different thyroid hormone profiles. Anat. Rec. 302, 1754–1769 (2019).

    CAS  Google Scholar 

  172. Campinho, M. A. et al. A thyroid hormone regulated asymmetric responsive centre is correlated with eye migration during flatfish metamorphosis. Sci. Rep. 8, 12267 (2018).

    PubMed  PubMed Central  Google Scholar 

  173. Hunter, I., Greene, S. A., MacDonald, T. M. & Morris, A. D. Prevalence and aetiology of hypothyroidism in the young. Arch. Dis. Child. 83, 207–210 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Gutch, M. et al. Skeletal manifestations of juvenile hypothyroidism and the impact of treatment on skeletal system. Indian. J. Endocrinol. Metab. 17, S181–S183 (2013).

    PubMed  PubMed Central  Google Scholar 

  175. Marzuillo, P. et al. Very early onset of autoimmune thyroiditis in a toddler with severe hypothyroidism presentation: a case report. Ital. J. Pediatr. 42, 61 (2016).

    PubMed  PubMed Central  Google Scholar 

  176. Rivkees, S. A., Bode, H. H. & Crawford, J. D. Long-term growth in juvenile acquired hypothyroidism: the failure to achieve normal adult stature. N. Engl. J. Med. 318, 599–602 (1988).

    CAS  PubMed  Google Scholar 

  177. Boersma, B., Otten, B. J., Stoelinga, G. B. & Wit, J. M. Catch-up growth after prolonged hypothyroidism. Eur. J. Pediatr. 155, 362–367 (1996).

    CAS  PubMed  Google Scholar 

  178. Liddell, H. S. The growth of the head in thyroidectomized sheep. Anat. Rec. 30, 327–332 (1925).

    Google Scholar 

  179. Todd, T. W. & Wharton, R. E. The effect of thyroid deficiency upon skull growth in the sheep. Am. J. Anat. 55, 97–116 (1934).

    Google Scholar 

  180. Hunter, M. W. & Sawin, P. B. The effects of thyroidectomy on the skull of the domestic rabbit. Am. J. Anat. 71, 417–449 (1942).

    Google Scholar 

  181. Horn, G. & Ford, E. H. R. The effects of thyroid deficiency on the growth of the rat skull. J. Anat. 95, 131–136 (1961).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Dawson, A., McNaughton, F. J., Goldsmith, A. R. & Degen, A. A. Ratite-like neoteny induced by neonatal thyroidectomy of European starlings, Sturnus vulgaris. J. Zool. 232, 633–639 (1994).

    Google Scholar 

  183. Dye, J. A. & Kinder, F. S. A prepotent factor in the determination of skull shape. Am. J. Anat. 54, 333–346 (1934).

    Google Scholar 

  184. Sun, H. et al. New case of thyroid hormone resistance α caused by a mutation of THRA/TRα1. J. Endocr. Soc. 3, 665–669 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Bochukova, E. et al. A mutation in the thyroid hormone receptor alpha gene. N. Engl. J. Med. 366, 243–249 (2012).

    CAS  PubMed  Google Scholar 

  186. Fozzatti, L. et al. Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α. Proc. Natl Acad. Sci. USA 110, 7850–7855 (2013).

    CAS  PubMed  Google Scholar 

  187. Markossian, S. et al. CRISPR/Cas9 editing of the mouse Thra gene produces models with variable resistance to thyroid hormone. Thyroid 28, 139–150 (2018).

    CAS  PubMed  Google Scholar 

  188. Demir, K. et al. Diverse genotypes and phenotypes of three novel thyroid hormone receptor-α mutants. J. Clin. Endocrinol. Metab. 101, 2945–2954 (2016).

    CAS  PubMed  Google Scholar 

  189. van Mullem, A. et al. Clinical phenotype and mutant TRα1. N. Engl. J. Med. 366, 1451–1453 (2012).

    PubMed  Google Scholar 

  190. Moran, C. et al. Contrasting phenotypes in resistance to thyroid hormone alpha correlate with divergent properties of thyroid hormone receptor α1 mutant proteins. Thyroid 27, 973–982 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. van Gucht, A. L. et al. Resistance to thyroid hormone alpha in an 18-month old girl: clinical, therapeutic, and molecular characteristics. Thyroid 26, 338–346 (2016).

    PubMed  Google Scholar 

  192. Espiard, S. et al. A novel mutation in THRA gene associated with an atypical phenotype of resistance to thyroid hormone. J. Clin. Endocrinol. Metab. 100, 2841–2848 (2015).

    CAS  PubMed  Google Scholar 

  193. Van Mullem, A. et al. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor: consequences of LT4 treatment. J. Clin. Endocrinol. Metab. 98, 3029–3038 (2013).

    PubMed  Google Scholar 

  194. Moran, C. et al. Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol. 2, 619–626 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Moran, C. et al. An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor α. J. Clin. Endocrinol. Metab. 98, 4254–4261 (2013).

    CAS  PubMed  Google Scholar 

  196. O’Shea, P. J. et al. Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor α1 or β. Mol. Endocrinol. 19, 3045–3059 (2005).

    PubMed  Google Scholar 

  197. Bassett, J. H. D. et al. Thyroid hormone receptor α mutation causes a severe and thyroxine-resistant skeletal dysplasia in female mice. Endocrinology 155, 3699–3712 (2014).

    PubMed  PubMed Central  Google Scholar 

  198. Tinnikov, A. et al. Retardation of post-natal development caused by a negatively acting thyroid hormone receptor α1. EMBO J. 21, 5079–5087 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Bassett, J. H. D. et al. Thyroid status during skeletal development determines adult bone structure and mineralization. Mol. Endocrinol. 21, 1893–1904 (2007).

    CAS  PubMed  Google Scholar 

  200. Desjardin, C. et al. Chondrocytes play a major role in the stimulation of bone growth by thyroid hormone. Endocrinology 155, 3123–3135 (2014).

    PubMed  Google Scholar 

  201. Leger, J. & Carel, J. C. Hyperthyroidism in childood: causes, when and how to treat. J. Clin. Res. Pediatr. Endocrinol. 5, 50–56 (2013).

    PubMed  PubMed Central  Google Scholar 

  202. Havgaard Kjær, R., Smedegård Andersen, M. & Hansen, D. Increasing incidence of juvenile thyrotoxicosis in Denmark: a nationwide study, 1998-2012. Horm. Res. Paediatr. 84, 102–107 (2015).

    PubMed  Google Scholar 

  203. Kopp, P. et al. Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N. Engl. J. Med. 322, 150–154 (1995).

    Google Scholar 

  204. Johnsonbaugh, R. E., Bryan, R. N., Hierlwimmer, U. R. & Georges, L. P. Premature craniosynostosis: a common complication of juvenile thyrotoxicosis. J. Pediatr. 93, 188–199 (1978).

    CAS  PubMed  Google Scholar 

  205. Hirano, A., Akita, S. & Fujii, T. Craniofacial deformities associated with juvenile hyperthyroidism. Cleft Palate Craniofac. J. 32, 328–333 (1995).

    CAS  PubMed  Google Scholar 

  206. Higashino, T. & Hirabayashi, S. A secondary craniosynostosis associated with juvenile hypothyroidism. J. Plast. Reconstr. Aesthet. Surg. 66, e284–e286 (2013).

    PubMed  Google Scholar 

  207. Riggs, W. Jr, Wilroy, R. S. Jr & Etteldorf, J. N. Neonatal hyperthyroidism with accelerated skeletal maturation, craniosynostosis, and brachydactyly. Radiology 105, 621–625 (1972).

    PubMed  Google Scholar 

  208. Vucic, S. et al. Thyroid function during early life and dental development. J. Dent. Res. 96, 1020–1026 (2017).

    CAS  PubMed  Google Scholar 

  209. Fuhrer, D., Wonerow, P., Willgerodt, H. & Paschke, R. Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J. Clin. Endocrinol. Metab. 82, 4234–4238 (1997).

    CAS  PubMed  Google Scholar 

  210. Kopp, P., Jameson, J. L. & Roe, T. F. Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene. Thyroid 7, 765–770 (1997).

    CAS  PubMed  Google Scholar 

  211. Wilroy, R. S. J. & Etteldorf, J. N. Familial hyperthyroidism including two siblings with neonatal Graves’ disease. J. Pediatr. 78, 625–632 (1971).

    PubMed  Google Scholar 

  212. Menking, M. et al. Premature craniosynostosis associated with hyperthyroidism in 4 children with reference to 5 further cases in the literature. Monatsschr. Kinderheilkd. 120, 106–110 (1972).

    CAS  PubMed  Google Scholar 

  213. Karnofsky, D. & Cronkite, E. P. Effect of thyroxine on eruption of teeth in newborn rats. Exp. Biol. Med. 40, 568–570 (1939).

    CAS  Google Scholar 

  214. Hoath, S. B. & Pickens, W. L. Effect of thyroid hormone and epidermal growth factor on tactile hair development and craniofacial morphogenesis in the postnatal rat. J. Craniofac. Genet. Dev. Biol. 7, 161–167 (1987).

    CAS  PubMed  Google Scholar 

  215. Akita, S., Nakamura, T., Hirano, A., Fujii, T. & Yamashita, S. Thyroid hormone action on rat calvarial sutures. Thyroid 4, 99–106 (1994).

    CAS  PubMed  Google Scholar 

  216. Durham, E. L. et al. Thyroxine exposure effects on the cranial base. Calcif. Tissue Int. 101, 300–311 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Jaeschke, H. et al. Hyperthyroidism and papillary thyroid carcinoma in thyrotropin receptor D633H mutant mice. Thyroid 28, 1372–1386 (2018).

    CAS  PubMed  Google Scholar 

  218. Neumann, S., Krohn, K., Chey, S. & Paschke, R. Mutations in the mouse TSH receptor equivalent to human constitutively activating TSH receptor mutations also cause constitutive activity. Horm. Metab. Res. 33, 263–269 (2001).

    CAS  PubMed  Google Scholar 

  219. Vela, A. et al. Thyroid hormone resistance from newborns to adults: a Spanish experience. J. Endocrinol. Invest. 42, 941–949 (2019).

    CAS  PubMed  Google Scholar 

  220. Phillips, S. A. et al. Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant. J. Clin. Endocrinol. Metab. 86, 5142–5147 (2001).

    CAS  PubMed  Google Scholar 

  221. Yoh, S. M., Chatterjee, V. K. & Privalsky, M. L. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. Mol. Endocrinol. 11, 470–480 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Refetoff, S. & Dumitrescu, A. M. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract. Res. Clin. Endocrinol. Metab. 21, 277–305 (2007).

    CAS  PubMed  Google Scholar 

  223. Weiss, R. E. & Refetoff, S. Resistance to thyroid hormone. Rev. Endocr. Metab. Disord. 1, 97–108 (2000).

    CAS  PubMed  Google Scholar 

  224. Dumitrescu, A. M. & Refetoff, S. The syndromes of reduced sensitivity to thyroid hormone. Biochim. Biophys. Acta 1830, 3987–4003 (2013).

    CAS  PubMed  Google Scholar 

  225. Bassett, J. H. D. et al. Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism. Mol. Endocrinol. 21, 1095–1107 (2007).

    CAS  PubMed  Google Scholar 

  226. O’Shea, P. J. et al. A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone. Mol. Endocrinol. 17, 1410–1424 (2003).

    CAS  PubMed  Google Scholar 

  227. Pepene, C. E. et al. Effects of triiodothyronine on the insulin-like growth factor system in primary human osteoblastic cells in vitro. Bone 29, 540–546 (2001).

    CAS  PubMed  Google Scholar 

  228. Zhang, W. et al. Effects of insulin and insulin-like growth factor 1 on osteoblast proliferation and differentiation: differential signalling via Akt and ERK. Cell Biochem. Funct. 30, 297–302 (2012).

    CAS  PubMed  Google Scholar 

  229. Rodriguez-Carballo, E., Gámez, B. & Ventura, F. p38 MAPK signaling in osteoblast differentiation. Front. Cell Dev. Biol. 4, 40 (2016).

    PubMed  PubMed Central  Google Scholar 

  230. Bassett, J. H. D., Swinhoe, R., Chassande, O., Samarut, J. & Williams, G. R. Thyroid hormone regulates heparan sulfate proteoglycan expression in the growth plate. Endocrinology 147, 295–305 (2006).

    CAS  PubMed  Google Scholar 

  231. Wang, L., Shao, Y. Y. & Ballock, R. T. Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of beta-catenin signaling. J. Bone Miner. Res. 25, 1138–1146 (2010).

    CAS  PubMed  Google Scholar 

  232. Tsourdi, E. et al. The role of dickkopf-1 in thyroid hormone-induced changes of bone remodeling in male mice. Endocrinology 160, 664–674 (2019).

    PubMed  Google Scholar 

  233. Wang, L., Shao, Y. Y. & Ballock, R. T. Thyroid hormone interacts with the Wnt/beta-catenin signaling pathway in the terminal differentiation of growth plate chondrocytes. J. Bone Miner. Res. 22, 1988–1995 (2007).

    CAS  PubMed  Google Scholar 

  234. Fryns, J. P. & Moerman, P. Unknown syndrome: abnormal facies, hypothyroidism, and severe retardation: a second patient. J. Med. Genet. 25, 498–499 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Ma, D. et al. A de novo 10.79 Mb interstitial deletion at 2q13q14.2 involving PAX8 causing hypothyroidism and mullerian agenesis: a novel case report and literature review. Mol. Cytogenet. 7, 85 (2014).

    PubMed  PubMed Central  Google Scholar 

  236. Robinson, D. C., Hall, R. & Munro, D. S. Graves’s disease, an unusual complication: raised intracranial pressure due to premature fusion of skull sutures. Arch. Dis. Child. 44, 252–257 (1969).

    CAS  Google Scholar 

  237. Penfold, J. L. & Simpson, D. A. Premature craniosynostosis - a complication of thyroid replacement therapy. J. Pediatr. 86, 360–363 (1975).

    CAS  PubMed  Google Scholar 

  238. Howie, R. N. et al. Effects of in utero thyroxine exposure on murine cranial suture growth. PLoS One 11, e0167805 (2016).

    PubMed  PubMed Central  Google Scholar 

  239. Supornsilchai, V. et al. Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene. Clin. Endocrinol. 70, 623–628 (2009).

    CAS  Google Scholar 

  240. Gruters, A. et al. Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. J. Clin. Endocrinol. Metab. 83, 1431–1436 (1998).

    CAS  PubMed  Google Scholar 

  241. Chawla, R. et al. Squamosal suture craniosynostosis due to hyperthyroidism caused by an activating TSH receptor mutation (T632I). Thyroid 25, 1167–1172 (2015).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

J.H.D.B. and G.R.W. are funded by a Wellcome Trust Joint Investigator Award (110141/Z/15/Z and 110140/Z/15/Z).

Author information

Authors and Affiliations

Authors

Contributions

V.D.L., J.H.D.B. and G.R.W. researched data for the article, made substantial contributions to discussion of content of the article, wrote the article and reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to J. H. Duncan Bassett or Graham R. Williams.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Glossary

Craniosynostosis

Premature fusion of the fibrous calvarial sutures.

Facial hypoplasia

Reduced growth of features in the midface, which results in an abnormal facial appearance.

Calvaria

The upper part of the skull that surrounds the brain.

Wormian bones

Additional bones that form between sutures in the skull.

Mineral apposition

The deposition of mineral-containing bone matrix during new bone formation.

Thyroid gland dysgenesis

Abnormal or underdevelopment of the thyroid gland.

Iodine organification

The incorporation of iodine into the thyroglobulin protein during the synthesis of thyroid hormones by thyroid follicular cells.

Dyshormonogenesis

The inability to concentrate iodine or synthesize thyroid hormones in thyroid follicular cells.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leitch, V.D., Bassett, J.H.D. & Williams, G.R. Role of thyroid hormones in craniofacial development. Nat Rev Endocrinol 16, 147–164 (2020). https://doi.org/10.1038/s41574-019-0304-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-019-0304-5

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing