As pediatric anesthesiologists we routinely and regularly provide anesthesia and pain management to infants, children, adolescents, and adults with achondroplasia. Achondroplasia is the most common form of skeletal dysplasia and the clinical phenotype is well known and recognized by all of you: relative macrocephaly, frontal bossing, depressed nasal bridge, midface hypoplasia, disproportionate short limbs, stature, and hands, shortening of the long bones, and a long trunk. We treat many of the problems these patients develop over the natural history of the disorder: foramen magnum stenosis and resulting brain stem compression, upper airway obstruction with sleep disordered breathing problems, thoracolumbar kyphosis, scoliosis, lower limb surgery, spinal stenosis, PE tubes etc. In today’s PAAD, Savarirayan et al.1 review new targeted genetic treatments that cure/prevent many of the manifestations of this disorder. To my mind, this is nothing short of a medical miracle. I am also enclosing an International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia that may be invaluable to many of you.2 To be honest, after reading today’s PAAD, I am simply awe struck and almost speechless. Myron Yaster MD
Original article
Savarirayan R, Hoover-Fong J, Yap P, Fredwall SO. New treatments for children with achondroplasia. Lancet Child Adolesc Health. 2024 Apr;8(4):301-310. doi: 10.1016/S2352-4642(23)00310-3. PMID: 38485412.
Original article
Savarirayan R, Ireland P, Irving M, Thompson D, Alves I, Baratela WAR, Betts J, Bober MB, Boero S, Briddell J, Campbell J, Campeau PM, Carl-Innig P, Cheung MS, Cobourne M, Cormier-Daire V, Deladure-Molla M, Del Pino M, Elphick H, Fano V, Fauroux B, Gibbins J, Groves ML, Hagenäs L, Hannon T, Hoover-Fong J, Kaisermann M, Leiva-Gea A, Llerena J, Mackenzie W, Martin K, Mazzoleni F, McDonnell S, Meazzini MC, Milerad J, Mohnike K, Mortier GR, Offiah A, Ozono K, Phillips JA 3rd, Powell S, Prasad Y, Raggio C, Rosselli P, Rossiter J, Selicorni A, Sessa M, Theroux M, Thomas M, Trespedi L, Tunkel D, Wallis C, Wright M, Yasui N, Fredwall SO. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia. Nat Rev Endocrinol. 2022 Mar;18(3):173-189. doi: 10.1038/s41574-021-00595-x. Epub 2021 Nov 26. PMID: 34837063.
Over the course of their lifetimes, patients with achondroplasia have common complications and health issues that often require surgery (Table). We’ve decided to not discuss the perioperative management of these patients and refer you to the recent consensus statement 23 and an older review4 Rather, we are going to zero in on the molecular biology of achondroplasia and how this knowledge is providing targeted, curative therapies.
Achondroplasia is an inherited autosomal dominant musculoskeletal, dwarfing disorder caused by a “a gain-of-function mutation in the gene encoding fibroblast growth factor receptor 3, FGFR3 (4p16.3). This activation of FGFR3 and its inhibitory downstream signaling pathways results in slowing of endochondral ossification. Almost all individuals affected by achondroplasia have a 1138G→A (Gly380Arg) or 1138G→C (Gly380Arg) pathogenic variant within the transmembrane-encoding region of FGFR3.4 The delineation of the downstream pathways and understanding the consequences of these pathogenic variants over the past 20 years has laid the foundation for targeted therapies.”1
“Transmembrane FGFR3 pathogenic variant (yellow star in figure) in achondroplasia causes activation of downstream pathways, leading to the inhibition of chondrocyte proliferation and hypertrophy, and therefore impaired endochondral ossification. The therapies approved or in development for the treatment of achondroplasia target parts of this pathway to overcome this inhibition, including the blocking of RAF1 (C-type natriuretic peptide analogues, including vosoritide and navepegritide); the inactivation of the FGFR3 tyrosine kinase (infigratinib and SAR-442501); the inactivation of the MAPK pathway (meclizine); and the blocking of FGF2 binding to FGFR3 (RMB-007) (Figure).” 1
If you look closely at the right side of the figure, you can see that vasoritide, a modified analogue of C-type natriuretic peptide (CNP) plays a key role in the regulation of endochondral bone growth in humans (and laboratory animals). Under expression of CNP results in short stature5 and overexpression in skeletal overgrowth (Marfan syndrome).6 Administration of a modified CNP, vosoritide, results in the amelioration of the dwarfism phenotype in mice and humans, and in a double blind randomized controlled trial showed remarkable improvement in bone growth in patients with achondroplasia.7 Based on these results, vasoritide has been approved by the European Medicines Agency and the US Food and Drug administration for all children with achondroplasia with open growth plates (ie, from birth). WOW! Vosoritide is administered daily by subcutaneous injection. Again, looking at the right side of the figure you can see alternative therapeutic targets. Some of these alternative therapies are longer acting subcutaneous and oral modified CNPs. Some are still in development and others have already been approved.
One final thought from the authors of today’s PAAD “There are and will continue to be people with achondroplasia and their families who choose not to use these new medications, especially if the main goal is to increase linear growth, as reflected by clinical trials’ primary endpoints. To these individuals, short stature is a major contributor to their intrinsic personal identity and not a characteristic to be altered—these views must be respected. Long-term observational data are required to find out if these new pharmaceuticals will also alter baseline morbidity and mortality associated with achondroplasia. These new therapies will never replace the need for holistic care across the lifespan, advocacy, community education, and political support for individuals with achondroplasia and their families.”1
Send your thoughts and comments to Myron who will post in a Friday reader response.
References
1. Savarirayan R, Hoover-Fong J, Yap P, Fredwall SO. New treatments for children with achondroplasia. Lancet Child Adolesc Health 2024;8(4):301-310. (In eng). DOI: 10.1016/s2352-4642(23)00310-3.
2. Savarirayan R, Ireland P, Irving M, et al. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia. Nat Rev Endocrinol 2022;18(3):173-189. (In eng). DOI: 10.1038/s41574-021-00595-x.
3. White KK, Bompadre V, Goldberg MJ, et al. Best practices in peri-operative management of patients with skeletal dysplasias. Am J Med Genet A 2017;173(10):2584-2595. (In eng). DOI: 10.1002/ajmg.a.38357.
4. Ornitz DM, Legeai-Mallet L. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn 2017;246(4):291-309. (In eng). DOI: 10.1002/dvdy.24479.
5. Hisado-Oliva A, Ruzafa-Martin A, Sentchordi L, et al. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature. Genet Med 2018;20(1):91-97. (In eng). DOI: 10.1038/gim.2017.66.
6. Bocciardi R, Giorda R, Buttgereit J, et al. Overexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation. Hum Mutat 2007;28(7):724-31. (In eng). DOI: 10.1002/humu.20511.
7. Savarirayan R, Tofts L, Irving M, et al. Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study. Genet Med 2021;23(12):2443-2447. (In eng). DOI: 10.1038/s41436-021-01287-7.