Years published: 1986, 1990, 1992, 1993, 1994, 1995, 1997, 2001, 2004, 2007, 2018, 2023
NORD gratefully acknowledges Janet Legare MD, Clinical Professor of Pediatrics, Divisions of Genetics and Development, Director Neuromotor Clinic, Director Midwest Regional Bone Dysplasia Clinic, University of Wisconsin School of Medicine and Public Health, Sarah Zhou, MD Candidate, McGill University School of Medicine, and Richard M. Pauli, MD, PhD, School of Medicine and Public Health, University of Wisconsin, for assistance in the preparation of this report.
Achondroplasia is the most commonly occurring abnormality of bone growth (skeletal dysplasia), occurring in approximately 1 in 20,000-30,000 live births. This genetic disorder is characterized by an unusually large head (macrocephaly), short upper arms (rhizomelic dwarfism), elbow flexion contractures, trident hands, leg bowing and short stature (adult height of approximately 4 feet). Achondroplasia does not typically cause impairment or deficiencies in mental abilities. If the bones that join the head and neck do not compress the brainstem or upper spinal cord (craniocervical junction compression), life expectancy is near normal.
Achondroplasia is caused by a change (pathogenic variant) in the fibroblast growth factor receptor 3 (FGFR3) gene which is a regulator of bone growth at cartilage growth plates. Clinical features result from decreased growth of bones that grow through cartilage. Achondroplasia occurs because of a spontaneous change in the FGFR3 gene in approximately 80 percent of patients; in the remaining 20 percent it is inherited from a parent.
This rare genetic disorder is characterized by distinctive features: short stature (usually under 4 feet 6 inches); an unusually large head (macrocephaly) with a prominent forehead (frontal bossing) and flat (depressed) nasal bridge; short arms and legs; prominent abdomen and buttocks (due to inward curve of the spine) and short hands with fingers that assume a “trident” or three-pronged position during extension.
Newborns have a relatively large cranium with a broad forehead, midface hypoplasia (flatter midface), mildly narrower chest and short extremities. About 5% of infants may develop an excessive accumulation of fluid around the brain under pressure (hydrocephalus). Due to hypotonia and joint laxity, motor milestones are usually delayed. Expressive speech may also be delayed.
Achondroplasia is caused by a specific change (pathogenic variant) in the FGFR3 gene. About 98% of cases result from the exact same change in the DNA in this gene.
For most patients (about 80%), there is no apparent family history of the condition. Increased age of the father (advanced paternal age) is thought to be a contributing factor in cases of sporadic achondroplasia.
Less commonly, achondroplasia is inherited from a parent and follows an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Achondroplasia appears to affect males and females in equal numbers. This disorder begins in the developing fetus and is the most common form of skeletal dysplasia that causes dwarfism. The estimated frequency of achondroplasia has ranged from about one in 20,000 to one in 30,000 live births.
Clinical and radiologic features of achondroplasia are well-characterized. Patients with typical findings generally do not need molecular genetic testing to confirm the diagnosis. However, since medications to treat growth in children with achondroplasia are now available, molecular confirmation of diagnosis is frequently desired. When clinical features raise suspicion of achondroplasia in a newborn, X-rays can be used to help confirm the diagnosis. If there is uncertainty, identification of the genetic variant of the FGFR3 gene by molecular genetic testing can be used to establish the diagnosis. Below is a list adapted from Legare (2023) that provides clinical signs that may be used in the diagnosis of achondroplasia:
• Disproportionate short stature
• Macrocephaly with frontal bossing
• Backward displacement of the midface and depressed nasal bridge
• Shortening of the arms with redundant skin folds on limbs
• Limitation of elbow extension
• Shortened fingers and toes (brachydactyly)
• Trident configuration of the hands
• Bowed legs
• Exaggerated inward curve of the spine (lumbar lordosis)
• Joint laxity
Treatment is generally supportive for symptoms. However, new drugs that modify endochondral bone growth are in development and one has been approved by the U.S. Food and Drug Administration (FDA). Increased bone growth may help to treat the medical problems associated with achondroplasia.
Vosoritide, a C-type natriuretic peptide (CNP) analog, was FDA approved in 2021 to increase height in children with achondroplasia and open epiphyses from age five years until growth plates close. Studies in younger age groups are ongoing, as are studies looking at possible medical benefits of the drug.
Other therapies under development include weekly CNP injections attached to a prodrug, tyrosine kinase inhibitors for FGFR1-3, FGFR3 antibodies and tyrosine kinase inhibitors specific for FGFR3.
Recommendations for managing children with achondroplasia are outlined by the American Academy of Pediatrics Committee on Genetics, which are designed to supplement guidelines for children with average stature.
As outlined in Legare (2023), recommendations for the manifestations of achondroplasia include:
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Hoover-Fong J, Scott CI, Jones MC; COMMITTEE ON GENETICS. Health Supervision for People With Achondroplasia.Pediatrics. 2020 Jun;145(6):e20201010. doi: 10.1542/peds.2020-1010. PMID: 32457214 Review.
Savarirayan R, Tofts L, Irving M, et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial [published correction appears in Lancet. 2020 Oct 10;396(10257):1070]. Lancet. 2020;396(10252):684-692. doi:10.1016/S0140-6736(20)31541-5
Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis. 2019 Jan 3;14(1):1. doi: 10.1186/s13023-018-0972-6. PMID: 30606190 ree PMC article. Review.
Legare JM. Achondroplasia. 1998 Oct 12 [Updated 2023 May 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1152/ Accessed Nov 13, 2023.
Bober MB, Bellus GA, Nikkel SM, et al. Hypochondroplasia. 1999 Jul 15 [Updated 2020 May 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1477/ Accessed Nov 13, 2023.
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