Objective To study the clinical features and fibroblast growth factor receptor 3 (FGFR3) gene mutations of children with achondroplasia (ACH) through an analysis of 17 cases. Methods A retrospective analysis was performed on the clinical data and FGFR3 gene detection results of 17 children with ACH who were diagnosed from January 2009 to October 2021. Results Of the 17 children with ACH, common clinical manifestations included disproportionate short stature (100%, 17/17), macrocephaly (100%, 17/17), trident hand (82%, 14/17), and genu varum (88%, 15/17). The common imaging findings were rhizomelic shortening of the long bones (100%, 17/17) and narrowing of the lumbar intervertebral space (88%, 15/17). Major complications included skeletal dysplasia (100%, 17/17), middle ear dysfunction (82%, 14/17), motor/language developmental delay (88%, 15/17), chronic pain (59%, 10/17), sleep apnea (53%, 9/17), obesity (41%, 7/17), foramen magnum stenosis (35%, 6/17), and hydrocephalus (24%, 4/17). All 17 children (100%) had FGFR3 mutations, among whom 13 had c.1138G>A hotspot mutations of the FGFR3 gene, 2 had c.1138G>C mutations of the FGFR3 gene, and 2 had unreported mutations, with c.1252C>T mutations of the FGFR3 gene in one child and c.445+2_445+5delTAGG mutations of the FGFR3 gene in the other child. Conclusions This study identifies the unreported mutation sites of the FGFR3 gene, which extends the gene mutation spectrum of ACH. ACH is a progressive disease requiring lifelong management through multidisciplinary collaboration.
Key words
Achondroplasia /
Fibroblast growth factor receptor 3 gene /
Gene mutation /
Child
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
References
1 中国医师协会医学遗传医师分会, 中华医学会儿科学分会内分泌遗传代谢学组, 中华医学会儿科学分会罕见病学组, 等. 软骨发育不全诊断及治疗专家共识[J]. 中华儿科杂志, 2021, 59(7): 545-550. PMID: 34405635. DOI: 10.3760/cma.j.cn112140-20201229-01142.
2 Unger S, Bonafé L, Gouze E. Current care and investigational therapies in achondroplasia[J]. Curr Osteoporos Rep, 2017, 15(2): 53-60. PMID: 28224446. PMCID: PMC5435778. DOI: 10.1007/s11914-017-0347-2.
3 Pauli RM. Achondroplasia: a comprehensive clinical review[J]. Orphanet J Rare Dis, 2019, 14(1): 1. PMID: 30606190. PMCID: PMC6318916. DOI: 10.1186/s13023-018-0972-6.
4 Le Merrer M, Rousseau F, Legeai-Mallet L, et al. A gene for achondroplasia-hypochondroplasia maps to chromosome 4p[J]. Nat Genet, 1994, 6(3): 318-321. PMID: 8012398. DOI: 10.1038/ng0394-318.
5 代伟倩, 顾学范, 余永国. 中国210例软骨发育不全患儿临床遗传特征分析及生长发育曲线探索[J]. 中华儿科杂志, 2020, 58(6): 461-467. PMID: 32521957. DOI: 10.3760/cma.j.cn112140-20200217-00096.
6 Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. PMID: 25741868. PMCID: PMC4544753. DOI: 10.1038/gim.2015.30.
7 H?gler W, Ward LM. New developments in the management of achondroplasia[J]. Wien Med Wochenschr, 2020, 170(5-6): 104-111. PMID: 32144686. PMCID: PMC7098936. DOI: 10.1007/s10354-020-00741-6.
8 Wrobel W, Pach E, Ben-Skowronek I. Advantages and disadvantages of different treatment methods in achondroplasia: a review[J]. Int J Mol Sci, 2021, 22(11): 5573. PMID: 34070375. PMCID: PMC8197470. DOI: 10.3390/ijms22115573.
9 Cormier-Daire V, AlSayed M, Ben-Omran T, et al. The first European consensus on principles of management for achondroplasia[J]. Orphanet J Rare Dis, 2021, 16(1): 333. PMID: 34332609. PMCID: PMC8325831. DOI: 10.1186/s13023-021-01971-6.
10 Ornitz DM, Legeai-Mallet L. Achondroplasia: development, pathogenesis, and therapy[J]. Dev Dyn, 2017, 246(4): 291-309. PMID: 27987249. PMCID: PMC5354942. DOI: 10.1002/dvdy.24479.
11 Coi A, Santoro M, Garne E, et al. Epidemiology of achondroplasia: a population-based study in Europe[J]. Am J Med Genet A, 2019, 179(9): 1791-1798. PMID: 31294928. DOI: 10.1002/ajmg.a.61289.
12 Tenconi R, Khirani S, Amaddeo A, et al. Sleep-disordered breathing and its management in children with achondroplasia[J]. Am J Med Genet A, 2017, 173(4): 868-878. PMID: 28239978. DOI: 10.1002/ajmg.a.38130.
13 Kubota T, Adachi M, Kitaoka T, et al. Clinical practice guidelines for achondroplasia[J]. Clin Pediatr Endocrinol, 2020, 29(1): 25-42. PMID: 32029970. PMCID: PMC6958518. DOI: 10.1297/cpe.29.25.
14 Okenfuss E, Moghaddam B, Avins AL. Natural history of achondroplasia: a retrospective review of longitudinal clinical data[J]. Am J Med Genet A, 2020, 182(11): 2540-2551. PMID: 32864841. DOI: 10.1002/ajmg.a.61825.
15 Hoover-Fong J, Cheung MS, Fano V, et al. Lifetime impact of achondroplasia: current evidence and perspectives on the natural history[J]. Bone, 2021, 146(5): 115872. PMID: 33545406. DOI: 10.1016/j.bone.2021.115872.
16 Manikkam SA, Chetcuti K, Howell KB, et al. Temporal lobe malformations in achondroplasia: expanding the brain imaging phenotype associated with FGFR3-related skeletal dysplasias[J]. AJNR Am J Neuroradiol, 2018, 39(2): 380-384. PMID: 29170271. PMCID: PMC7410599. DOI: 10.3174/ajnr.A5468.
17 Ireland PJ, Pacey V, Zankl A, et al. Optimal management of complications associated with achondroplasia[J]. Appl Clin Genet, 2014, 7: 117-125. PMID: 25053890. PMCID: PMC4104450. DOI: 10.2147/TACG.S51485.
18 Bodensteiner JB. Neurological manifestations of achondroplasia[J]. Curr Neurol Neurosci Rep, 2019, 19(12): 105. PMID: 31782047. DOI: 10.1007/s11910-019-1008-x.
19 King JAJ, Vachhrajani S, Drake JM, et al. Neurosurgical implications of achondroplasia[J]. J Neurosurg Pediatr, 2009, 4(4): 297-306. PMID: 19795959. DOI: 10.3171/2009.3.PEDS08344.
20 Ireland PJ, Donaghey S, McGill J, et al. Development in children with achondroplasia: a prospective clinical cohort study[J]. Dev Med Child Neurol, 2012, 54(6): 532-537. PMID: 22409389. DOI: 10.1111/j.1469-8749.2012.04234.x.
21 Ceroni JRM, Soares DCDQ, Testai LDC, et al. Natural history of 39 patients with achondroplasia[J]. Clinics (Sao Paulo), 2018, 73: e324. PMID: 29972438. PMCID: PMC6005962. DOI: 10.6061/clinics/2018/e324.
22 Tunkel D, Alade Y, Kerbavaz R, et al. Hearing loss in skeletal dysplasia patients[J]. Am J Med Genet A, 2012, 158A(7): 1551-1555. PMID: 22628261. DOI: 10.1002/ajmg.a.35373.
23 Hoover-Fong J, Scott CI, Jones MC, et al. Health supervision for people with achondroplasia[J]. Pediatrics, 2020, 145(6): e20201010. PMID: 32457214. DOI: 10.1542/peds.2020-1010.
24 Fredwall SO, Steen U, de Vries O, et al. High prevalence of symptomatic spinal stenosis in Norwegian adults with achondroplasia: a population-based study[J]. Orphanet J Rare Dis, 2020, 15(1): 123. PMID: 32450891. PMCID: PMC7249360. DOI: 10.1186/s13023-020-01397-6.
25 Dhiman N, Albaghdadi A, Zogg CK, et al. Factors associated with health-related quality of life (HRQOL) in adults with short stature skeletal dysplasias[J]. Qual Life Res, 2017, 26(5): 1337-1348. PMID: 27866314. DOI: 10.1007/s11136-016-1455-7.
26 Hoover-Fong JE, Schulze KJ, McGready J, et al. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height[J]. Am J Clin Nutr, 2008, 88(2): 364-371. PMID: 18689372. DOI: 10.1093/ajcn/88.2.364.
27 Saint-Laurent C, Garcia S, Sarrazy V, et al. Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia[J]. PLoS One, 2018, 13(4): e0195876. PMID: 29652901. PMCID: PMC5898762. DOI: 10.1371/journal.pone.0195876.
28 Hoover-Fong J, McGready J, Schulze K, et al. A height-for-age growth reference for children with achondroplasia: expanded applications and comparison with original reference data[J]. Am J Med Genet A, 2017, 173(5): 1226-1230. PMID: 28374958. DOI: 10.1002/ajmg.a.38150.
29 Miccoli M, Bertelloni S, Massart F. Height outcome of recombinant human growth hormone treatment in achondroplasia children: a meta-analysis[J]. Horm Res Paediatr, 2016, 86(1): 27-34. PMID: 27355624. DOI: 10.1159/000446958.
PDF(631 KB)
