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Achondroplasia

Author
Carlos A Bacino, MD, FACMG
Section Editor
Sihoun Hahn, MD, PhD
Deputy Editor
Elizabeth TePas, MD, MS

INTRODUCTION

Achondroplasia is the most common bone dysplasia in humans, with a prevalence of approximately 1 in 20,000 livebirths. It is an autosomal dominant condition caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. The most salient clinical features include disproportionate short stature (adult height is approximately 4 feet), long bone shortening that predominantly affects the proximal aspects of the upper and lower extremities (rhizomelic shortening), and macrocephaly. Patients with achondroplasia may have delayed motor development early on, but cognition is normal. There are a number of medical issues associated with this disorder.

The clinical findings, diagnosis, treatment options, and anticipatory guidance are discussed in this topic review. An overview of the diagnostic approach to skeletal dysplasias is presented in detail separately. (See "Skeletal dysplasias: Approach to evaluation".)

GENETICS

Patients with achondroplasia have gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene [1]. Two specific mutations in the FGFR3 gene account for almost all cases of achondroplasia. These mutations occur at the same nucleotide in the FGFR3 gene, 1138G>A (98 percent) and 1138G>C (1 percent), in both cases resulting in a glycine-to-arginine substitution in amino acid 380 (p.Gly380Arg) in the transmembrane domain of the FGFR3 gene. This mutation permanently activates the FGFR3 receptor, inhibiting chondrocyte proliferation, which ultimately leads to impaired endochondral bone formation, growth restriction, bone shortening, and other skeletal anomalies [2].

INHERITANCE

Achondroplasia is inherited in an autosomal dominant manner. Approximately 80 percent of cases are the result of new (de novo) mutations, while the remaining are inherited. When both parents have achondroplasia, the risk to their children of having homozygous achondroplasia (a lethal condition) is 25 percent and of having achondroplasia is 50 percent.

CLINICAL MANIFESTATIONS

Achondroplasia is characterized by distinctive craniofacial features, disproportionate short stature with rhizomelic shortening of the arms and the legs (picture 1), brachydactyly (shortening of the fingers and toes) (picture 2), kyphoscoliosis (figure 1), and accentuated lumbar lordosis. The craniofacial features and bone shortening are clearly present at birth. The craniofacial features include macrocephaly, frontal bossing, and midface retrusion. The nose is flattened out, often referred to as saddle nose deformity. The kyphoscoliosis can be seen from birth through infancy and typically decreases once the child starts to bear weight and ambulate. The lumbar lordosis is typically seen after ambulation starts at approximately 1.5 years of age.

            

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Literature review current through: Nov 2016. | This topic last updated: Fri Oct 28 00:00:00 GMT 2016.
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References
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  1. Shiang R, Thompson LM, Zhu YZ, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994; 78:335.
  2. Sahni M, Ambrosetti DC, Mansukhani A, et al. FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 1999; 13:1361.
  3. Todorov AB, Scott CI Jr, Warren AE, Leeper JD. Developmental screening tests in achondroplastic children. Am J Med Genet 1981; 9:19.
  4. Fowler ES, Glinski LP, Reiser CA, et al. Biophysical bases for delayed and aberrant motor development in young children with achondroplasia. J Dev Behav Pediatr 1997; 18:143.
  5. Spranger JW, Brill P, Superti-Furga A, et al. Bone displasias. In: An Atlas of Genetic Disorders of Skeletal Development, 3rd ed., Oxford University Press, 2012.
  6. Kao SC, Waziri MH, Smith WL, et al. MR imaging of the craniovertebral junction, cranium, and brain in children with achondroplasia. AJR Am J Roentgenol 1989; 153:565.
  7. Hecht JT, Horton WA, Reid CS, et al. Growth of the foramen magnum in achondroplasia. Am J Med Genet 1989; 32:528.
  8. Bober MB, Bellus GA, Nikkel SM, Tiller GE. Hypochondroplasia. In: GeneReviews [Internet], Eds. Pagon RA, Adam MP, Ardinger HH, et al. University of Washington, Seattle, 2004.
  9. Karczeski B, Cutting GR. Thanatophoric Dysplasia. In: GeneReviews [Internet], Eds. Pagon RA, Adam MP, Ardinger HH, et al. University of Washington, Seattle, 2004.
  10. Pauli RM, Conroy MM, Langer LO Jr, et al. Homozygous achondroplasia with survival beyond infancy. Am J Med Genet 1983; 16:459.
  11. Hoover-Fong JE, McGready J, Schulze KJ, et al. Weight for age charts for children with achondroplasia. Am J Med Genet A 2007; 143A:2227.
  12. Rimoin DL. Cervicomedullary junction compression in infants with achondroplasia: when to perform neurosurgical decompression. Am J Hum Genet 1995; 56:824.
  13. Pauli RM, Horton VK, Glinski LP, Reiser CA. Prospective assessment of risks for cervicomedullary-junction compression in infants with achondroplasia. Am J Hum Genet 1995; 56:732.
  14. Hecht JT, Francomano CA, Horton WA, Annegers JF. Mortality in achondroplasia. Am J Hum Genet 1987; 41:454.
  15. Danielpour M, Wilcox WR, Alanay Y, et al. Dynamic cervicomedullary cord compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia. Report of four cases. J Neurosurg 2007; 107:504.
  16. Horton WA, Rotter JI, Kaitila I, et al. Growth curves in achondroplasia. Birth Defects Orig Artic Ser 1977; 13:101.
  17. Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr 1978; 93:435.
  18. Yasui N, Kawabata H, Kojimoto H, et al. Lengthening of the lower limbs in patients with achondroplasia and hypochondroplasia. Clin Orthop Relat Res 1997; :298.
  19. Baumgart R, Betz A, Schweiberer L. A fully implantable motorized intramedullary nail for limb lengthening and bone transport. Clin Orthop Relat Res 1997; :135.
  20. Ain MC, Shirley ED, Pirouzmanesh A, et al. Genu varum in achondroplasia. J Pediatr Orthop 2006; 26:375.
  21. Yasoda A, Ogawa Y, Suda M, et al. Natriuretic peptide regulation of endochondral ossification. Evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. J Biol Chem 1998; 273:11695.
  22. Yasoda A, Komatsu Y, Chusho H, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 2004; 10:80.