Clinical characteristics.

Achondroplasia is the most common cause of disproportionate short stature. Affected individuals have rhizomelic shortening of the limbs, macrocephaly, and characteristic facial features with frontal bossing and midface retrusion. In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often both aberrant in pattern and delayed. Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy. Additional complications include obstructive sleep apnea, middle ear dysfunction, genu varum, kyphosis, and spinal stenosis.

Diagnosis/testing.

Achondroplasia can be diagnosed by characteristic clinical and radiographic findings in most affected individuals. In individuals in whom there is diagnostic uncertainty or who have atypical findings, identification of a heterozygous pathogenic variant in FGFR3 by molecular genetic testing can establish the diagnosis. Confirmatory molecular genetic testing may aid in obtaining targeted therapy.

Management.

Targeted therapies: Vosoritide, a C-type natriuretic peptide (CNP) analog, can increase height velocity in individuals with achondroplasia and is approved from birth until growth plates close. Vosoritide is administered daily. Navepegritide, a prodrug of CNP, is approved for increasing height velocity from age two years until growth plates close and is administered once weekly.

Treatment of manifestations: Additional treatment for short stature may include extended limb lengthening; suboccipital decompression as indicated for signs and symptoms of craniocervical junction compression; management of hydrocephalus per neurosurgeon; treatment of restrictive pulmonary disease per pediatric pulmonologist; routine immunizations to prevent respiratory disease; adenotonsillectomy, positive airway pressure, and, rarely, tracheostomy to correct obstructive sleep apnea; aggressive management of frequent otitis media including long-lasting pressure-equalizing tubes for middle ear dysfunction; speech therapy; evaluation and treatment by an orthopedist if progressive bowing of the legs arises; spinal surgery may be needed for severe, persistent kyphosis; surgery to correct spinal stenosis in symptomatic adults; standard treatments for obesity; modification in the school and work setting to optimize function; support in socialization and school adjustment.

Surveillance: Infants and children should be seen at a minimum of every six to 12 months. Monitor height, weight, and head circumference using growth curves standardized for achondroplasia; neurologic examinations monitoring for signs of cervical myelopathy; evaluation of developmental milestones throughout infancy and childhood using achondroplasia-specific standards; assess for manifestations of restrictive pulmonary disease throughout infancy; monitor for signs and symptoms of sleep apnea; follow-up hearing evaluation by age approximately one year and then annually through early childhood; assess for middle ear problems throughout childhood; clinical assessment for bowed legs and kyphosis, with radiographic evaluation and referral to an orthopedist if necessary. Adults should be seen every three to five years. In adults, clinical history and neurologic examination to screen for spinal stenosis; assessment of pain; monitor for hearing loss; assess for signs/symptoms of obstructive sleep apnea; monitor blood pressure; track weight and counsel regarding obesity; and discuss social adjustment at each visit.

Agents/circumstances to avoid: Rear-facing car seats should be used as long as possible to avoid injury from motor vehicle accident. Automatic baby swings should also be avoided because of head and neck movement in the swings. Avoid soft-back infant seats and front carriers without a firm back to prevent kyphosis. Avoid activities in which there is risk of injury to the craniocervical junction, such as collision sports; use of a trampoline; diving from diving boards; vaulting in gymnastics; and hanging upside down from the knees or feet on playground equipment.

Pregnancy management: Pregnant women with achondroplasia must undergo cesarean section delivery because of small pelvic size. A consultation with a pulmonologist is recommended in early pregnancy due to slightly increased risk of respiratory failure.

Genetic counseling.

Achondroplasia is inherited in an autosomal dominant manner. Approximately 80% of individuals with achondroplasia have parents of average stature and have achondroplasia as the result of a de novo pathogenic variant. Approximately 20% of individuals with achondroplasia have at least one parent with achondroplasia. If both parents are of average stature, the risk to sibs of a proband of having achondroplasia is very low but appears to exceed that of the general, comparable population because of the possibility of parental gonadal mosaicism. If an individual with achondroplasia has a reproductive partner of average stature, each child has a 50% chance of having achondroplasia. If an individual with achondroplasia has a reproductive partner with achondroplasia, each child has a 25% chance of having average stature, a 50% chance of having achondroplasia, and a 25% chance of having homozygous achondroplasia (a life-limiting condition). If an individual with achondroplasia has a reproductive partner with a different dominantly inherited skeletal dysplasia, each child has a 25% chance of having average stature, a 25% chance of having the same skeletal dysplasia as the father, a 25% chance of having the same skeletal dysplasia as the mother, and a 25% chance of inheriting a pathogenic variant from both parents and being at risk for a poor outcome. Once the FGFR3 pathogenic variant has been identified in a family member with achondroplasia, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

The diagnosis of achondroplasia should be suspected in a newborn with the following clinical features; characteristic radiographic features can confirm the diagnosis.

• Clinical features in a newborn
  • Proximal shortening of the arms
  • Large head
  • Narrow chest
  • Short fingers with a trident configuration
• Radiographic features in a newborn that can establish the diagnosis
  • Square ilia and horizontal acetabula
  • Narrow sacrosciatic notch
  • Proximal radiolucency of the femurs
  • Generalized metaphyseal abnormality including flaring
  • Decreasing interpedicular distance caudally

The diagnosis of achondroplasia should be suspected in an older individual with the following clinical and radiographic features that can be seen at any age and family history.

• Clinical features that may be seen at any age
  • Disproportionate short stature
  • Macrocephaly with frontal bossing
  • Midface retrusion and depressed nasal bridge with short nasal spine and anteverted nares
  • Rhizomelic (proximal) shortening of the arms with redundant skin folds on limbs
  • Limitation of elbow extension
  • Brachydactyly with trident configuration of the hands
  • Genu varum (bowlegs)
  • Thoracolumbar kyphosis (principally in infancy)
  • Exaggerated lumbar lordosis, which develops when walking begins
• Radiographic features that may be seen at any age
  • Short, robust tubular bones
  • Narrowing of the interpedicular distance of the caudal spine
  • Short pedicles on lateral spine radiograph
  • Square ilia and horizontal acetabula
  • Narrow sacrosciatic notch
  • Short femoral necks
  • Mild, generalized metaphyseal changes
• Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Approximately 80% of individuals with achondroplasia have achondroplasia as a result of a de novo FGFR3 pathogenic variant; therefore, absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of achondroplasia can be established in a proband solely on the basis of clinical and radiographic features described in Suggestive Findings.

Those with typical clinical and radiographic features generally do not need molecular confirmation of the diagnosis, although confirmation may aid in obtaining targeted therapy. In those in whom there is any uncertainty, identification of a heterozygous pathogenic (or likely pathogenic) variant in FGFR3 by molecular genetic testing can establish the diagnosis (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. (2) Identification of a heterozygous FGFR3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include targeted analysis and use of a multigene panel.

• Targeted analysis for the two common pathogenic variants should be pursued first given that an estimated 99% of individuals with achondroplasia have one of these two variants:
  • c.1138G>A (p.Gly380Arg)
  • c.1138G>C (p.Gly380Arg)
  Note: Since achondroplasia occurs through a gain-of-function mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant.
• A multigene panel that includes FGFR3 and other genes of interest (see Differential Diagnosis) may be performed next to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Individuals with achondroplasia have short stature with rhizomelic shortening of the limbs, macrocephaly, characteristic facies with frontal bossing and midface retrusion, exaggerated lumbar lordosis, limitation of elbow extension and rotation, genu varum, brachydactyly, and trident appearance of the hands. Excess mobility of the knees, hips, and most other joints is common [Pauli 2019].

Growth. Average adult height for men with achondroplasia is 129.9 ± 6.25 cm (51 inches) and for women, 122.4 ± 5.9 cm (48 inches). There are updated growth charts available for length, weight, head circumference, and height-to-weight ratio [Hoover-Fong et al 2021]. Vosoritide, a C-type natriuretic peptide (CNP) analog, is approved to increase height in individuals with achondroplasia starting at birth. Studies showed an average of 1.57 cm of additional height growth per year. Computer models have predicted total height gained of approximately 26 cm in males and 22 cm in females if medication is started at birth. Final adult height after treatment with vosoritide is still to be determined (see Management, Treatment of Manifestations). Treatment with vosoritide has also shown improved spinal sagittal balance, decreased leg bowing [Sawamura et al 2025], and improvement in physical aspects of health-related quality of life after three years [Savarirayan et al 2025b]. Navepegritide, a prodrug of CNP, is approved to increase growth velocity in children with achondroplasia from age two years until growth plates close. Annualized growth velocity increased by 1.78 cm per year in children age five years and older and 1.02 cm per year in children age two to five years. Placebo-controlled studies showed decreased leg bowing and increased spinal interpedicular growth [Ward et al 2025, Savarirayan et al 2026].

Obesity is a major problem in achondroplasia [Hecht et al 1988]. Excessive weight gain can manifest in early childhood. In adults, obesity can aggravate the morbidity associated with lumbar stenosis and contribute to nonspecific joint problems and possibly to early mortality from cardiovascular complications [Wynn et al 2007]. Using appropriate body mass index and weight for length curves for achondroplasia is paramount to obtain adequate health assessment.

Macrocephaly. Most children with achondroplasia are macrocephalic. Hydrocephalus requiring treatment occurs in less than 5% of individuals [Campbell et al 2023] and may be caused by increased intracranial venous pressure because of stenosis of the jugular foramina [Pauli 2019]. Literature now suggests that in some individuals foramen magnum stenosis may contribute to hydrocephalus, which is thus treatable by posterior fossa decompression or endoscopic third ventriculostomy (ETV) [Campbell et al 2023]. Anatomic differences of the skull and brain anatomy should be considered when considering ETV in individuals with achondroplasia [Shin et al 2024]. Sutural closure is markedly delayed (as evidenced by anterior fontanelle closure as late as age 5-6 years).

Narrow craniocervical junction. Some infants with achondroplasia die in the first year of life from complications related to the craniocervical junction; population-based studies suggest that this excess risk of death may be as high as 7.5% without assessment and intervention [Hecht et al 1987]. The risk appears to be secondary to central apnea associated with damage to respiratory control centers [Pauli et al 1995] and can be minimized by comprehensive evaluation of every infant with achondroplasia [Hoover-Fong et al 2020] and selective neurosurgical intervention [Bagley et al 2006]. With such evaluation and management this risk may be decreased to as little as 0.3% [Hashmi et al 2018]. With the advent of routine MRI, the hope is to detect compression prior to myelopathy. Quick brain MRI can be done without sedation. The best predictors of need for suboccipital decompression include lower-limb hyperreflexia or clonus, central hypopnea demonstrated by polysomnography, and reduced foramen magnum size, as determined by neuroimaging of the craniocervical junction. If CT is used, foraminal size can be compared with achondroplasia standards [Hecht et al 1989]. MRI examination provides direct visualization of the cord without radiation exposure, but there are no achondroplasia standards. T₂-weighted MRI may show evidence of spinal cord abnormalities, which may guide operative decision making [Shimony et al 2015]. Flexion and extension MRI can be done safely in the appropriate setting in instances where additional information is desired for surgical decision making [Masarwy et al 2025]. In one study, all children undergoing surgical decompression of the craniocervical junction showed marked improvement of neurologic function [Pauli et al 1995].

The Achondroplasia Foramen Magnum Score was published to help describe foramen magnum stenosis severity [Cheung et al 2021]. A large natural history study spanning 60 years demonstrated that 20.5% of individuals with achondroplasia underwent decompression and that 9% required a second decompression surgery [Legare et al 2021a]. In the last 35 years, that rate ranges from 23% to 24% at large skeletal dysplasia centers [Legare et al 2021a].

Development. In infancy, mild-to-moderate hypotonia is typical. Infants have difficulty in supporting their heads because of both hypotonia and large head size. Differences in body habitus cause motor delays and unusual patterns of motor development such as snowplowing (using the head and feet to leverage movement) [Ireland et al 2012]. Small joint hypermobility and short fingers can affect fine motor development and delay self-feeding [Ireland et al 2012]. Conductive hearing loss and oral motor hypotonia can contribute to delayed speech development [Ireland et al 2012].

Intelligence is in the average range unless hydrocephalus or other central nervous system complications occur. High-level executive function issues have been reported in some individuals including attention-deficit/hyperactivity disorder [Thompson et al 1999, Wigg et al 2016, Galasso et al 2019].

Seizures. There is a reported increased incidence of seizures [Legare et al 2021b]. Abnormal temporal lobes and rotation of hippocampus has also been described [Manikkam et al 2018].

Restrictive pulmonary disease. In infancy a small subset of individuals with achondroplasia have restrictive pulmonary issues. A small chest and increased compliance of the thoracic cage combine to result in smaller lung volumes and restrictive pulmonary disease [Pauli 2019]. Many infants show more rapid desaturations with minor respiratory events (e.g., physiologic periodic breathing or otherwise insignificant obstructive events), which translates into a higher hypopnea index on polysomnogram. A small number have, as a consequence of these features, chronic hypoxemia [Mogayzel et al 1998]. If a young infant has persistent tachypnea, poor weight gain, or evidence of respiratory failure, the polysomnogram obtained for other reasons in infants will show a low baseline oxygen saturation and/or desaturations associated with minimal respiratory irregularities. If such characteristics are recognized, referral to a pediatric pulmonologist is imperative. Treatment may include oxygen supplementation and, in a few, temporary tracheostomy. In virtually all instances, the need for a tracheostomy disappears as the child grows.

Sleep apnea. Obstructive sleep apnea is common in both older children and adults. It arises because of a combination of midface retrusion resulting in smaller airway size, hypertrophy of the lymphatic ring, airway malacia [Dessoffy et al 2014], and hypotonia of the airway.

Clinical signs and symptoms of obstructive sleep apnea may include the following:

• Difficult morning waking
• Excessive daytime somnolence
• Respiratory pauses during sleep
• Loud snoring
• Glottal stops or gasping
• Loud sighs while sleeping
• Poor daytime concentration
• Irritability, fatigue, depression
• Bedwetting
• Significant neck hyperextension

Clinical signs and symptoms of infantile sleep apnea include the following:

• Observed apnea or exaggerated periodic breathing
• Struggling to breathe
• Poor feeding
• Coughing
• Difficulty lying flat to sleep
• Frequent awakenings
• Significant neck hyperextension

Central sleep apnea as well as obstructive sleep apnea may be present in infants. Clinical history is a poor predictor of apnea, and polysomnography should be done [Carroll et al 1995, Hoover-Fong et al 2020]. Results should be interpreted in the context of age. It is important to note that there are many clinical factors other than apnea indices that need to be considered during the surgical decision-making process [Legare et al 2025]. A large natural history study demonstrated that approximately 45% of individuals with achondroplasia will undergo at least one pharyngeal surgery [Tunkel et al 2022].

Middle ear dysfunction is frequently a problem [Tunkel et al 2012], and if inadequately treated can result in conductive hearing loss of sufficient severity to interfere with language development. More than half of children will require pressure-equalizing tube placement [Berkowitz et al 1991, Tunkel et al 2022]. Overall, about 40% of individuals with achondroplasia have functionally relevant hearing loss.

Bowing of the lower legs is exceedingly common in those with achondroplasia. More than 90% of untreated adults have some degree of bowing [Kopits 1988a]. "Bowing" is actually a complex deformity arising from a combination of lateral bowing, differential growth between the tibia and fibula, internal tibial torsion, and dynamic instability of the knee [Inan et al 2006]. Based on a large natural history study, approximately 21% of individuals will require at least one lower extremity surgery [Nahm et al 2023].

Kyphosis at the thoracolumbar junction is present in 90%-95% of infants with achondroplasia [Pauli 2019]. Kyphosis improves significantly or resolves in the majority of children upon assuming an orthograde posture and beginning to walk [Margalit et al 2018]. In about 10%, it does not spontaneously resolve and can result in serious neurologic sequelae [Kopits 1988b]. Preventive strategies such as prevention of unsupported sitting, good back support as an infant, and thoracolumbar bracing if kyphosis is significant may reduce the need for surgical intervention [Pauli et al 1997, Xu et al 2018].

Spinal stenosis. The most common medical complaint in adulthood is symptomatic spinal stenosis involving L1-L4 [Hoover-Fong et al 2020]. A large natural history study showed that approximately 14% of individuals with achondroplasia have had a laminectomy by age 20 years, with the risk steadily increasing to more than 90% at age 80 years [Nahm et al 2023]. Symptoms range from intermittent, reversible, exercise-induced claudication to severe, irreversible abnormalities of leg function and of continence. Once bladder or bowel symptoms are seen, neurologic damage may be irreversible. Claudication and stenosis can both result in sensory (numbness, pain, feelings of heaviness) and motor symptoms (weakness, tripping, limited walking endurance). Vascular claudication results from engorged blood vessels after standing and walking and is fully reversible with rest. Spinal stenosis is actual impingement of the spinal cord or nerve root by the stenotic bone of the spinal canal, and symptoms are not reversible. Symptoms localized to a particular dermatome can result from stenosis of a particular nerve root foramina.

Other orthopedic issues

• Joint laxity. Most joints are hypermobile in childhood. This results in delayed acquisition of gross motor skills and dynamic knee varus in some children.
• Discoid lateral meniscus. This structural anomaly may result in chronic knee pain in some individuals [Akyol et al 2015, Hoernschemeyer et al 2016].
• Arthritis. Constitutive activation of fibroblast growth factor receptor 3 (FGFR3), as in achondroplasia, may protect against development of arthritis [Tang et al 2016].

Acanthosis nigricans may be seen in about 10% of individuals with achondroplasia [Smid et al 2018]. In this population it does not reflect hyperinsulinemia or malignancy.

Psychosocial implications. Health-related quality of life is decreased in both adults and children with achondroplasia. Depression and anxiety are also seen at higher levels than in the average-stature population. Screening at every encounter is recommended [Witt et al 2017, Llerena et al 2023].

Prognosis. Increased mortality in adults with achondroplasia has been reported [Wynn et al 2007]. Overall, life expectancy appeared to be decreased by about ten years. It is recommended that adults with achondroplasia continue with specialty care throughout the course of their life span [Fredwall et al 2024].

Homozygous achondroplasia, caused by biallelic pathogenic variants at nucleotide 1138 of FGFR3, is a severe disorder with radiologic changes qualitatively different from those of achondroplasia. Early death results from respiratory insufficiency because of the small thoracic cage and neurologic deficit from cervicomedullary stenosis [Hall 1988].

Genotype-Phenotype Correlations

Because nearly all instances of achondroplasia arise secondary to identical amino acid substitutions, genotype-phenotype correlation related to the primary pathogenic variant is not possible.

Penetrance

Penetrance is 100%; all individuals who have an FGFR3 heterozygous pathogenic variant associated with achondroplasia have the clinical manifestations of the disorder.

Nomenclature

Historically, the term "achondroplasia" was initially used to describe all individuals with short-limbed dwarfing disorders. Because achondroplasia is so common compared to other small stature processes, the term "dwarf" was previously used most often to refer to an individual with achondroplasia. Over the past 50 years diagnostic criteria have been available to distinguish true achondroplasia from other, superficially similar processes.

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], achondroplasia is referred to as FGFR3-related achondroplasia and is included in the FGFR3 chondrodysplasias group.

Prevalence

Achondroplasia is the most common form of inherited disproportionate short stature. Best estimates are that it occurs in 1:26,000-28,000 live births [Waller et al 2008].

Evaluations Following Initial Diagnosis

Clinical manifestations in achondroplasia vary modestly. In order to establish the extent of disease in an individual diagnosed with achondroplasia, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Recommendations for surveillance are incorporated into the American Academy of Pediatrics guidelines [Hoover-Fong et al 2020]. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

Children with achondroplasia should remain in rear-facing car seats as long as possible. Large heads with relatively lax neck ligaments place children at more risk in a motor vehicle accident.

Automatic baby swings should be avoided because of head and neck movement in the swings.

Protocols have been published regarding positioning that should be avoided in order to decrease the likelihood of development of a fixed, angular kyphosis [Pauli et al 1997]. These include prohibition of unsupported sitting in the first 12-14 months, emphasis on good back support, lots of prone-position activities, and limiting disadvantageous positioning (i.e., in a trunk-flexed position). Avoid soft-back infant seats, which increase the likelihood of developing kyphosis. Front carriers without a firm back should also be avoided.

Particularly in childhood, care must be taken to limit risk for injury to the spinal cord at the craniocervical junction. This should include prohibition of activities including collision sports (e.g., American football, ice hockey, rugby), use of a trampoline, diving from diving boards, vaulting in gymnastics, and hanging upside down from knees or feet on playground equipment due to the risk of falling onto the head or neck).

There is no increased risk for bone fragility or joint degeneration, and there are no related circumstances to avoid.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with achondroplasia must always be delivered by cesarean section because of the small size of the pelvis.

Pregnancy in a woman with achondroplasia is considered higher risk because of the slightly increased risk of respiratory failure. An initial consultation with a pulmonologist is recommended in early pregnancy.

Therapies Under Investigation

Administration of a prodrug C-type natriuretic peptide has been effective in clinical trials and application to the FDA is under way [Savarirayan et al 2023].

Other considerations include tyrosine kinase inhibition with infigratinib, which affects FGFR1, FGFR2, and FGFR3 [Savarirayan et al 2025a] and has shown promise in clinical trials. FGFR3-specific tyrosine kinase inhibitors are also just entering trials [Jonquoy et al 2012]. Meclizine may also show promise given its inhibition of one step of the RAS-MAPK pathway [Matsushita et al 2017].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Achondroplasia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 80% of individuals with achondroplasia have parents of average stature and have achondroplasia as a result of a de novo FGFR3 pathogenic variant. De novo pathogenic variants are associated with advanced paternal age, often defined as older than age 35 years [Stoll et al 1982]. The de novo pathogenic variants causing achondroplasia are exclusively inherited from the father [Wilkin et al 1998].
• Approximately 20% of individuals with achondroplasia have at least one parent with achondroplasia.
• If both parents are of average stature and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Presumed parental gonadal mosaicism has been reported [Dakouane Giudicelli et al 2008]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If both parents are of average stature, the risk to sibs of having achondroplasia is very low but appears to exceed that of the general, comparable population because of the possibility of parental gonadal mosaicism [Mettler & Fraser 2000, Natacci et al 2008].
• If one parent has achondroplasia, the risk to sibs is 50%.

Offspring of a proband

• If an individual with achondroplasia has a partner of average stature, each child has a 50% chance of having achondroplasia.
• If an individual with achondroplasia has a reproductive partner with achondroplasia, each child has a 25% chance of having average stature, a 50% chance of having achondroplasia, and a 25% chance of having homozygous achondroplasia (a life-limiting condition).
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with achondroplasia may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [Flynn & Pauli 2003]. If an individual with achondroplasia has a reproductive partner with a different dominantly inherited skeletal dysplasia, each child has a 25% chance of having average stature, a 25% chance of having the same skeletal dysplasia as the father, a 25% chance of having the same skeletal dysplasia as the mother, and a 25% chance of inheriting a pathogenic variant from both parents and being at risk for a poor outcome.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members are at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• Genetic counseling is recommended when both parents have a skeletal dysplasia.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancy. A high-risk pregnancy is one in which one or both parents have achondroplasia. Once the FGFR3 pathogenic variant has been identified in a family member with achondroplasia, prenatal and preimplantation genetic testing are possible. Noninvasive prenatal diagnosis using cell-free fetal DNA in maternal serum with high sensitivity and specificity has been reported [Chitty et al 2015, Vivanti et al 2019].

Low-risk pregnancy. Routine prenatal ultrasound examination may identify short fetal limbs and raise the possibility of achondroplasia in a fetus not known to be at increased risk. Shortening of the long bones (specifically the femurs), macrocephaly, increased metaphyseal-diaphyseal angle, tapering of the proximal femoral metaphysis, narrow thorax due to short ribs, short hands, platyspondyly, and polyhydramnios are all associated with a prenatal diagnosis of achondroplasia; molecular genetic testing can be used to confirm the diagnosis [Vallin et al 2025]. In rare instances, three-dimensional computed tomography scans may be done during pregnancy for further evaluation of the dysplasia [Waratani et al 2024].

When a pregnant woman is of average stature and the fetus has achondroplasia, fetal macrocephaly may cause cephalopelvic disproportion, potentially requiring delivery by cesarean section. Mode of delivery in women that are of average stature does not impact the likelihood that an infant with achondroplasia will require cervicomedullary decompression [Brar et al 2023].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

FGFR3 encodes fibroblast growth factor receptor 3 (FGFR3). The mature FGFR3 protein, like all of the FGFRs, is a membrane-spanning tyrosine kinase receptor with an extracellular ligand-binding domain consisting of three immunoglobulin (Ig) subdomains, a transmembrane domain, and a split intracellular tyrosine kinase domain [Laederich & Horton 2010]. Alternative splice sites in the FGFR genes result in tissue-specific isoforms [Chellaiah et al 1994].

FGFR3 is activated by various fibroblast growth factors (FGFs) [Ornitz 2005]. Binding appears to result in receptor dimerization, transactivation of tyrosine kinase, and transphosphorylation of tyrosine residues [Narayana & Horton 2015]. These modifications result in activation of a number of downstream signaling pathways, including signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK) [Deng et al 1996, Eswarakumar et al 2005], and a number of others [Narayana & Horton 2015, Ornitz & Itoh 2015, Brewer et al 2016]. Overall, these secondary pathways cause slowing of proliferation and differentiation of chondrocytes [Klag & Horton 2016].

The p.Gly380Arg pathogenic variant resulting in achondroplasia causes constitutive activation of FGFR3, which is, through its inhibition of chondrocyte proliferation and differentiation, a negative regulator of bone growth [Laederich & Horton 2010]. Indeed, the members of the family of bone dysplasias that includes hypochondroplasia, achondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia type I and II are each the result of allelic FGFR3 pathogenic variants that result in a graded series of FGFR3 activation [Naski et al 1996, Vajo et al 2000]. Although the precise consequences of the achondroplasia-causing variant in FGFR3 are still uncertain, the net result is excess inhibitory signaling in growth plate chondrocytes [Ornitz & Itoh 2015]. It remains uncertain what downstream pathways are principally involved in this effect. STAT1 appears to be important in suppression of chondrocyte proliferation, but in itself is not sufficient to fully explain the growth inhibition that results from FGFR3 pathogenic variants [Ornitz & Legeai-Mallet 2017]. A variety of therapeutic approaches are suggested by the current understanding of FGFs, FGFRs, STAT1, MAPK, and proteins interacting with these pathways [Klag & Horton 2016].

More than 99% of individuals with achondroplasia have one of two pathogenic variants in FGFR3. Two different substitutions at nucleotide 1138 both result in the amino acid change p.Gly380Arg (see Table 8). Several exceptions with pathogenic variants at other nucleotides have been reported. (For more information, see Table A, HGMD.)

Mechanism of disease causation. Gain of function resulting in constitutive activation of FGFR3

Author Notes

International Achondroplasia Forum

https://achondroplasiaforum.com/

Author History

Clair A Francomano, MD; National Institutes of Health (1998-2012)
Janet M Legare, MD (2018-present)
Peggy Modaff, MS (2025-present)
Richard M Pauli, MD, PhD; University of Wisconsin (2012-2020)
Douglas J Wilkin, PhD; Federal Bureau of Investigation (1998-2001)

Revision History

• 9 April 2026 (sw) Revision: navepegritide approved to increase height in children with achondroplasia
• 20 November 2025 (sw) Comprehensive update posted live
• 6 August 2020 (sw) Comprehensive update posted live
• 10 May 2018 (sw) Comprehensive update posted live
• 16 February 2012 (me) Comprehensive update posted live
• 9 January 2006 (me) Comprehensive update posted live
• 31 July 2003 (me) Comprehensive update posted live
• 8 March 2001 (me) Comprehensive update posted live
• 12 October 1998 (pb) Review posted live
• 26 June 1998 (cf) Original submission

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