Achondroplasia

Disease Overview

Summary

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.

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Synonyms

• ACH
• achondroplastic dwarfism
• dwarf, achondroplastic

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Signs & Symptoms

General
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.

Infancy
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.

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Causes

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.

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Affected populations

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.

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Disorders with Similar Symptoms

Symptoms of the following disorders may be similar to those of Achondroplasia. Comparisons may be useful for a differential diagnosis:

Hypochrondroplasia is a genetic disorder characterized by small stature and disproportionately short arms, legs, hands and feet (i.e., short-limbed dwarfism). Short stature often is not recognized until early to mid-childhood or, in some people, as late as adulthood. Affected individuals may also develop bowing of the legs during early childhood that often improves with age. Additional abnormalities may be present, such as an unusually large head (macrocephaly), a relatively prominent forehead, limited extension and rotation of the elbows and/or other physical features. In about 10 percent of patients, mild cognitive delays may be present. Hypochondroplasia can occur sporadically with no apparent family history. In other cases, the condition is follows autosomal dominant inheritance. Hypochondroplasia and achondroplasia may result from different variants of the FGFR3 gene. (For more information on this disorder, choose “Hypochondroplasia” as your search term in the Rare Disease Database.)

Additional disorders may be characterized by small stature and disproportionately short arms and legs (short-limbed dwarfism), abnormal enlargement of the head (macrocephaly), additional malformations of the skull and facial (craniofacial) region and/or other symptoms and findings similar to those associated with achondroplasia. Achondroplasia may be distinguished from other forms of short-limbed dwarfism through thorough clinical examination, x-ray studies or molecular testing. (For more information on these disorders, choose “dwarfism” or the exact disease name in question as your search term in the Rare Disease Database.)

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Diagnosis

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

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Standard Therapies

Treatment
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:

• Hydrocephalus: If signs/symptoms of increased intracranial pressure arise (accelerated head growth, bulging fontanelle, vision changes, headache), referral to a neurosurgeon is required. Computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain in infancy may be done to determine the presence of hydrocephalus.
• Craniocervical junction constriction: Predictors of the need for suboccipital decompression require evaluation by a medical professional. Indication of symptomatic compression requires urgent referral to a neurosurgeon.
• Obstructive sleep apnea: Can be treated with weight reduction, surgery to remove tonsils and adenoids (adenotonsillectomy), positive airway pressure and, rarely, surgery to create an opening in the neck (tracheostomy).
• Middle ear dysfunction: Ear tubes may be needed until the age of seven or eight to manage frequent middle ear infections and prevent potential hearing loss.
• Short stature: Studies on the use of growth hormone have shown initial acceleration of growth, but with lessening effect over time and little lasting benefit.
• Obesity: Measures to avoid obesity should begin in early childhood. Standard weight-by-height grids specific for achondroplasia should be used to monitor progress.
• Varus deformity: Symptomatic bowing of the legs (varus deformity) requires referral to an orthopedist. However, asymptomatic bowing does not usually warrant surgical correction.
• Spinal deformities: Preventive measures including prohibition of unsupported sitting in the first 12-18 months of life decrease risk of developing a fixed backwards curve in the mid-spine (kyphosis). Bracing or surgery may be necessary, depending on the degree of severity of such a deformity if preventive measures are unsuccessful.
• Spinal stenosis: If signs/symptoms of spinal stenosis arise, urgent surgical referral is appropriate.
• Immunization: All routine immunizations are necessary.
• Adaptive needs: Environmental modifications of the home and school may be necessary to accommodate for short stature.
• Socialization: Patients with achondroplasia may encounter difficulties in socialization and school adjustment. Support groups (such as Little People of America) can help assist families with these issues through peer support, personal example and social awareness programs.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
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.

INTERNET
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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Programs & Resources

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Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

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