C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia
The New England Journal of Medicine Downloaded from nejm.org on September 25, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved
C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia
To the Editor: Savarirayan et al. (July 4 issue)1 report increased skeletal growth in patients with achondroplasia (a common type of dwarfism caused by activating mutations in the tyrosine kinase fibroblast growth factor receptor 3 gene FGFR3) who received vosoritide, a stable analogue of C-type natriuretic peptide. Their study is a breakthrough in treatment for achondroplasia, and it offers an intriguing possibility of broader clinical applications. FGFR3 is a negative regulator of growth, as evidenced by skeletal overgrowth in mice with deleted fgfr3 and tall stature in humans with loss-of-function mutations in FGFR3. 2 In contrast, C-type natriuretic peptide increases growth and functions mainly through mechanistic inhibition of the FGFR3 pathway.3 Because FGFR3 and C-type natriuretic peptide are both physiologic regulators, therapeutic manipulation of the interaction between FGFR3 and C-type natriuretic peptide may be associated with increased skeletal growth in conditions involving short stature, such as idiopathic short stature. These conditions constitute approximately 60% of all forms of dwarfism in developed countries and have unknown genetic causes, and patients with these conditions have a limited response to growth hormone therapy.4,5 Pavel Krejci, Ph.D. Masaryk University Brno, Czech Republic This email address is being protected from spambots. You need JavaScript enabled to view it. No potential conflict of interest relevant to this letter was reported. 1. Savarirayan R, Irving M, Bacino CA, et al. C-type natriuretic peptide analogue therapy in children with achondroplasia. N Engl J Med 2019;381:25-35. 2. Toydemir RM, Brassington AE, Bayrak-Toydemir P, et al. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet 2006;79: 935-41. 3. Yasoda A, Komatsu Y, Chusho H, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPKdependent pathway. Nat Med 2004;10:80-6. 4. Baron J, Sävendahl L, De Luca F, et al. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol 2015;11:735-46. 5. Finkelstein BS, Imperiale TF, Speroff T, Marrero U, Radcliffe DJ, Cuttler L. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med 2002;156:230-40. DOI: 10.1056/NEJMc1910394 The authors reply: We agree with Krejci that our study results are relevant for the potentially wider therapeutic use of C-type natriuretic peptide analogues such as vosoritide for other related growth disorders. C-type natriuretic peptide treatment might be most effective in persons with conditions such as achondroplasia that involve skeletal dysplasia due to imbalance of the FGFR3–C-type natriuretic peptide axis affecting the endochondral growth plate. These disorders include those caused by increased FGFR3 activity, such as hypochondroplasia, thanatophoric dysplasia (types 1 and 2), and severe achondroplasia with developmental delay and acanthosis nigricans,1 as well as those caused by decreased activity of C-type natriuretic peptide. Other such conditions may include acromesomelic dysplasia, Maroteaux type,2 which is caused by homozygous inactivating mutations in NPR2 encoding the natriuretic peptide receptor B gene; idiopathic short stature due to heterozygous inactivating mutations in NPR23 ; and heterozygous inactivating mutations in NPCC (encoding C-type natriuretic The New England Journal of Medicine Downloaded from nejm.org on September 25, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. The new england journal o f medicine 1292 n engl j med 381;13 nejm.org September 26, 2019 peptide itself), which result in short stature with short hands.4 A recent study showed increased growth in a murine model of Braf-related cardiofaciocutaneous syndrome treated with C-type natriuretic peptide.5 These findings suggest that such therapy might have a beneficial effect on growth in humans with cardiofaciocutaneous syndrome and in those with other related disorders involving abnormal RAS–mitogen-activated protein kinase signaling. Ravi Savarirayan, M.B., B.S., M.D. Murdoch Children’s Research Institute Parkville, VIC, Australia This email address is being protected from spambots. You need JavaScript enabled to view it. Melita Irving, M.B., B.S., M.D. Guy’s and St. Thomas’ NHS Foundation Trust London, United Kingdom Jonathan Day, M.B., B.S., Ph.D. BioMarin London, United Kingdom Since publication of their article, the authors report no further potential conflict of interest. 1. Bonafe L, Cormier-Daire V, Hall C, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A 2015;167A:2869-92. 2. Bartels CF, Bükülmez H, Padayatti P, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 2004;75:27-34. 3. Vasques GA, Amano N, Docko AJ, 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 2013;98(10):E1636- E1644. 4. 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;20:91-7. 5. Inoue SI, Morozumi N, Yoshikiyo K, Maeda H, Aoki Y. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome. Hum Mol Genet 2019; 28:74-83.
C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia
To the Editor: Savarirayan et al. (July 4 issue)1 report increased skeletal growth in patients with achondroplasia (a common type of dwarfism caused by activating mutations in the tyrosine kinase fibroblast growth factor receptor 3 gene FGFR3) who received vosoritide, a stable analogue of C-type natriuretic peptide. Their study is a breakthrough in treatment for achondroplasia, and it offers an intriguing possibility of broader clinical applications. FGFR3 is a negative regulator of growth, as evidenced by skeletal overgrowth in mice with deleted fgfr3 and tall stature in humans with loss-of-function mutations in FGFR3. 2 In contrast, C-type natriuretic peptide increases growth and functions mainly through mechanistic inhibition of the FGFR3 pathway.3 Because FGFR3 and C-type natriuretic peptide are both physiologic regulators, therapeutic manipulation of the interaction between FGFR3 and C-type natriuretic peptide may be associated with increased skeletal growth in conditions involving short stature, such as idiopathic short stature. These conditions constitute approximately 60% of all forms of dwarfism in developed countries and have unknown genetic causes, and patients with these conditions have a limited response to growth hormone therapy.4,5 Pavel Krejci, Ph.D. Masaryk University Brno, Czech Republic This email address is being protected from spambots. You need JavaScript enabled to view it. No potential conflict of interest relevant to this letter was reported. 1. Savarirayan R, Irving M, Bacino CA, et al. C-type natriuretic peptide analogue therapy in children with achondroplasia. N Engl J Med 2019;381:25-35. 2. Toydemir RM, Brassington AE, Bayrak-Toydemir P, et al. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet 2006;79: 935-41. 3. Yasoda A, Komatsu Y, Chusho H, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPKdependent pathway. Nat Med 2004;10:80-6. 4. Baron J, Sävendahl L, De Luca F, et al. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol 2015;11:735-46. 5. Finkelstein BS, Imperiale TF, Speroff T, Marrero U, Radcliffe DJ, Cuttler L. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med 2002;156:230-40. DOI: 10.1056/NEJMc1910394 The authors reply: We agree with Krejci that our study results are relevant for the potentially wider therapeutic use of C-type natriuretic peptide analogues such as vosoritide for other related growth disorders. C-type natriuretic peptide treatment might be most effective in persons with conditions such as achondroplasia that involve skeletal dysplasia due to imbalance of the FGFR3–C-type natriuretic peptide axis affecting the endochondral growth plate. These disorders include those caused by increased FGFR3 activity, such as hypochondroplasia, thanatophoric dysplasia (types 1 and 2), and severe achondroplasia with developmental delay and acanthosis nigricans,1 as well as those caused by decreased activity of C-type natriuretic peptide. Other such conditions may include acromesomelic dysplasia, Maroteaux type,2 which is caused by homozygous inactivating mutations in NPR2 encoding the natriuretic peptide receptor B gene; idiopathic short stature due to heterozygous inactivating mutations in NPR23 ; and heterozygous inactivating mutations in NPCC (encoding C-type natriuretic The New England Journal of Medicine Downloaded from nejm.org on September 25, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. The new england journal o f medicine 1292 n engl j med 381;13 nejm.org September 26, 2019 peptide itself), which result in short stature with short hands.4 A recent study showed increased growth in a murine model of Braf-related cardiofaciocutaneous syndrome treated with C-type natriuretic peptide.5 These findings suggest that such therapy might have a beneficial effect on growth in humans with cardiofaciocutaneous syndrome and in those with other related disorders involving abnormal RAS–mitogen-activated protein kinase signaling. Ravi Savarirayan, M.B., B.S., M.D. Murdoch Children’s Research Institute Parkville, VIC, Australia This email address is being protected from spambots. You need JavaScript enabled to view it. Melita Irving, M.B., B.S., M.D. Guy’s and St. Thomas’ NHS Foundation Trust London, United Kingdom Jonathan Day, M.B., B.S., Ph.D. BioMarin London, United Kingdom Since publication of their article, the authors report no further potential conflict of interest. 1. Bonafe L, Cormier-Daire V, Hall C, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A 2015;167A:2869-92. 2. Bartels CF, Bükülmez H, Padayatti P, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 2004;75:27-34. 3. Vasques GA, Amano N, Docko AJ, 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 2013;98(10):E1636- E1644. 4. 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;20:91-7. 5. Inoue SI, Morozumi N, Yoshikiyo K, Maeda H, Aoki Y. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome. Hum Mol Genet 2019; 28:74-83.
