Achondroplasia and other skeletal dysplasias are a group of rare genetic disorders characterized by abnormal development of bones, joints, or cartilage.
Achondroplasia is the most common form of skeletal dysplasia, involving impaired endochondral ossification. It is caused by pathogenic variants in the FGFR3 gene.
The mode of inheritance is autosomal dominant in 20% of cases (one copy of the abnormal gene is sufficient to cause the condition). However, in 80% of cases, there is no family history, as the FGFR3 mutation occurs spontaneously (de novo).
Newborns and infants with achondroplasia often present with hypotonia and delayed motor milestones. Physical traits of individuals with achondroplasia include short stature (maximum height 125–140 cm), accompanied by rhizomelia (disproportionate shortening of limbs, with the proximal segment shorter than the distal one), brachydactyly (short fingers), macrocephaly (enlarged head), frontal bossing (prominent forehead), midface hypoplasia (underdevelopment of the middle part of the face).
Diagnosis: Prenatal suspicion of achondroplasia can arise in the third trimester of pregnancy based on ultrasound findings of macrocephaly and disproportionate short stature. The diagnosis is confirmed through genetic testing of amniotic fluid.
Postnatal diagnosis is also genetic, involving the detection of pathogenic FGFR3 variants using molecular genetic testing.
Throughout childhood, height, weight, and head circumference should be monitored using standardized growth charts for achondroplasia. Patients require regular multidisciplinary evaluations to monitor, prevent, and manage complications that may arise over time.
Common Complications
- Spinal canal stenosis (narrowing of the spinal canal).
- Thoracolumbar kyphosis.
- Genu varum (bowed legs).
- Obstructive sleep apnea.
- Obesity.
- Frequent otitis media (ear infections).
- Medullary compression at the cranio-cervical junction.
Treatment and Management
Vosoritide, a modified C-type natriuretic peptide (CNP), is used to treat genetically confirmed achondroplasia in patients with open growth plates. This therapy enhances endochondral bone growth.
FGFR3 inhibits bone growth, while CNP accelerates it. In achondroplasia, the balance is tilted, leading to severely slowed bone growth. Vosoritide activates the CNP signaling pathway, complementing the natural CNP to counteract FGFR3 and restore a more balanced growth process.
- Fisher RS, Cross JH, French JA, et al. “Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology.” Epilepsia 2017;58(4):522–530. doi:10.1111/epi.13670
- Pack AM. “Epilepsy Overview and Revised Classification of Seizures and Epilepsies.” Continuum (Minneap Minn). 2019 Apr;25(2):306-321. doi: 10.1212/CON.0000000000000707. PMID: 30921011.
- Symonds JD, Zuberi SM, Stewart K, et al. “Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort.” Brain. 2019 Aug 1;142(8):2303-2318. doi: 10.1093/brain/awz195. PMID: 31302675; PMCID: PMC6658850.
Wang J, Lin ZJ, Liu L, et al. “Epilepsy-associated genes.” Seizure. 2017 Jan;44:11-20. doi: 10.1016/j.seizure.2016.11.030. Epub 2016 Dec 6. PMID: 28007376