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A MUTATION OF THE FGFR3 GENE

Achondroplasia occurs in 1 out of 25,000 live births and affects around 250,000 people worldwide1,2

Achondroplasia is the most common type of skeletal dysplasia and accounts for nearly 90% of disproportionate short stature or dwarfism. Characterised by impaired endochondral bone growth, it is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene and has distinct physical characteristics:1,3-8

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Touch to reveal the impacted systems

Macrocephaly, frontal bossing, and midface hypoplasia

Disproportionately shorter proximal limb bones

Narrow trunk

Disproportionate short stature

(longer upper body compared with lower body)

Genu varum

Silhouette of a child with achondroplasia highlighting five key physical characteristics

Physical characteristics, such as height, are indicators of bone growth throughout the body

FGFR3 affects endochondral bone growth throughout the entire body9

Endochondral ossification, the replacement of cartilage by bone, occurs throughout the body and is involved in the development of roughly 90% of all bones. This process begins in utero and continues into early adulthood.10-12

Understand endochondral bone growth at every level

In endochondral ossification, the precursor to prospective bone is cartilage

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Cartilage growth plate (without mutation)9,13,14

  • Cartilage is composed of chondrocytes and an extracellular matrix
  • Chondrocytes play a key role in endochondral ossification, directly contributing to the elongation of bones throughout development
  • Chondrocytes result from the differentiation of embyronic mesenchymal cells
  • Chondrocytes undergo proliferation
  • Cartilage matrix is secreted
  • Chondrocytes enlarge and expand, establishing a new extracellular matrix through this process of hypertrophy

Cartilage Growth Plate

Bone
Image of cartilage growth plate without achondroplasia

Chondrocyte (without mutation)15,16

  • Two signalling pathways play an important role in regulating the function of chondrocytes
  • FGFR3 activation signals to slow bone growth
Chondrocyte Cell

Dig deep enough to get to the underlying cause

The gain-of-function mutation causes FGFR3 to excessively generate signals to slow down bone growth, overwhelming the counteracting signalling from the NPRB/CNP pathway, and resulting in impaired bone growth.4,16

CNP pathway (without mutation)

Chondrocyte (without mutation)

Image of chondrocyte without achondroplasia Image of chondrocyte without achondroplasia

Chondrocyte without FGFR3 mutation

CNP pathway (with mutation)

Chondrocyte (with mutation)

Image of chondrocyte with achondroplasia

Chondrocyte with FGFR3 mutation

CNP pathway (without mutation)15,16

  • Natriuretic peptide receptor B (NPRB) activation by CNP blocks the FGFR3 signal to restore bone growth

CNP pathway (without mutation)15,16

  • Natriuretic peptide receptor B (NPRB) activation by CNP blocks the FGFR3 signal to restore bone growth
Chondrocyte Cell

Dig deep enough to get to the underlying cause

Chondrocyte Cell

Chondrocyte without FGFR3 mutation

Chondrocyte Cell

Chondrocyte with FGFR3 mutation

The gain-of-function mutation causes FGFR3 to excessively generate signals to slow down bone growth, overwhelming the counteracting signalling from the NPRB/CNP pathway, and resulting in impaired bone growth.4,16

CNP pathway (without mutation)

Chondrocyte Cell

CNP pathway (with mutation)

Chondrocyte Cell

Chondrocyte (without mutation)

Chondrocyte Cell

Chondrocyte (with mutation)

Chondrocyte Cell

Cartilage growth plates

Without mutation

Bone
Growth Plate

With mutation

Growth Plate
Bone

This leads to a multisystemic impact that parents may not be prepared for

Most parents are of average stature, which means they need your expertise to prepare them for the multisystemic complications caused by impaired bone growth.4,17

References: 1. Ireland PJ, Pacey V, Zankl A, Edwards P, Johnston LM, Savarirayan R. Optimal management of complications associated with achondroplasia. Appl Clin Genet. 2014;7:117-125. Published online Jun 24, 2014. 2. Wynn J, King TM, Gambello MJ, Waller DK, Hecht JT. Mortality in achondroplasia study: a 42-year follow-up. Am J Med Genet A. 2007;143A:2502–2511. 3. Waller DK, Correa A, Vo TM, et al. The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US. Am J Med Genet A. 2008;146A(18):2385-2389. 4. Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis. 2019;14(1):1. 5. Laederich MB, Horton WA. Achondroplasia: pathogenesis and implications for future treatment. Curr Opin Pediatr. 2010;22(4):516-523. 6. Hoover-Fong J, Scott CI, Jones MC; Committee on Genetics. Health supervision for people with achondroplasia. Pediatrics. 2020;145(6):e20201010. 7. Chilbule SK, Dutt V, Madjhuri V. Limb lengthening in achondroplasia. Indian J Orthop. 2016;50(4):397-405. 8. Hoover-Fong J, Schulze KJ, McGready J, Barnes H, Scott CI. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr. 2008;88:364 -71. 9. Matsushita T, Wilcox WR, Chan YY, et al. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet. 2009;18(2):227-240. 10. Berendsen AD, Olsen BR. Bone development. Bone. 2015;80:14-18. 11. Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3(Suppl 3):S131-S139. 12. Hill MA. Musculoskeletal system - bone development timeline. Embryology. June 19, 2020. Accessed September 4, 2020. https://embryology.med.unsw.edu.au/embryology/index.php/Musculoskeletal_System_-_Bone_Development_Timeline. 13. Xie Y, Zhou S, Chen H, Du X, Chen L. Recent research on the growth plate: advances in fibroblast growth factor signaling in growth plate development and disorders. J Mol Endocrinol. 2014;53(1):T11-T34. 14. Mackie EJ, Tatarczuch L, Mirams M. The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. J Endocrinol. 2011;211(2):109-121. 15. Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007;370(9582):162-172. 16. Vasques GA, Arnhold IJ, Jorge AA. Role of the natriuretic peptide system in normal growth and growth disorders. Horm Res Paediatr. 2014;82(4):222-229. 17. Hecht JT, Bodensteiner JB, Butler IJ. Neurologic manifestations of achondroplasia. Handb Clin Neurol. 2014;119:551-563.