NLM Citation: 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; 1993-2024.
Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/

Achondroplasia
Synonym: FGFR3-Related Achondroplasia
Janet M Legare, MD1
Created: October 12, 1998; Revised: May 11, 2023.

Summary
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, 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 can establish the diagnosis.

Management
Treatment of manifestations: Vosoritide, a C-type natriuretic peptide (CNP) analog, was recently approved to
enhance height in individuals with achondroplasia from age five years until growth plates close.
Ventriculoperitoneal shunt may be required for increased intracranial pressure; suboccipital decompression as
indicated for signs and symptoms of craniocervical junction compression; adenotonsillectomy, positive airway
pressure, and, rarely, tracheostomy to correct obstructive sleep apnea; pressure-equalizing tubes for middle ear
dysfunction; monitor and treat obesity; 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; modification in the school and work setting to optimize function; educational support in
socialization and school adjustment.
Surveillance: Monitor height, weight, and head circumference in childhood using growth curves standardized for
achondroplasia; evaluation of developmental milestones throughout infancy and childhood using

Author Affiliation: 1 School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; Email:
[email protected].

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Washington, Seattle. All rights reserved.
2 GeneReviews®

achondroplasia-specific standards; baseline neuroimaging of craniocervical junction and brain in infancy;

neurologic examinations monitoring for signs of cervical myelopathy; monitor for signs and symptoms of sleep
apnea; hearing evaluation as a newborn and tympanometric and behavioral audiometric evaluation by age
approximately one year; monitor for middle ear problems or evidence of hearing loss in childhood; clinical
assessment for kyphosis and bowed legs, with radiographic evaluation and referral to an orthopedist if
necessary; in adults, clinical history and neurologic examination to screen for spinal stenosis with development
of any new signs or symptoms or at least every three to five years; discuss social adjustment at each visit with
primary care provider.
Agents/circumstances to avoid: Rear-facing car seats should be used as long as possible to avoid injury from
motor vehicle accident. Avoid soft-back infant seats and front carriers without a firm back. 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 (due to risk of falling onto the head or neck).
Pregnancy management: Pregnant women with achondroplasia must undergo cesarean section delivery because
of small pelvic size.

Genetic counseling
Achondroplasia is inherited in an autosomal dominant manner. Around 80% of individuals with achondroplasia
have parents with average stature and have achondroplasia as the result of a de novo pathogenic variant. Such
parents have a very low risk of having another child with achondroplasia. An individual with achondroplasia
who has a reproductive partner with average stature is at 50% risk in each pregnancy of having a child with
achondroplasia. When both parents have achondroplasia, the risk to their offspring of having average stature is
25%; of having achondroplasia, 50%; and of having homozygous achondroplasia (a lethal condition), 25%. If the
proband and the proband's reproductive partner are affected with different dominantly inherited skeletal
dysplasias, genetic counseling becomes more complicated because of the risk of inheriting two dominant skeletal
dysplasias. If the FGFR3 pathogenic variant has been identified in the affected parent or parents, prenatal testing
for a pregnancy at increased risk for achondroplasia is possible.

Diagnosis
Both the clinical and radiologic features of achondroplasia have been well defined [Langer et al 1967], although
no formal diagnostic algorithms have been published.

Suggestive Findings
The diagnosis of achondroplasia should be suspected in the newborn with proximal shortening of the arms,
large head, narrow chest, and short fingers. When there is clinical suspicion, radiographic features can confirm
the diagnosis; neonatal radiographs will show square ilia and horizontal acetabula, narrow sacrosciatic notch,
proximal radiolucency of the femurs, generalized metaphyseal abnormality, and decreasing interpedicular
distance caudally.
Features that may be seen at any age
• Disproportionate short stature
• Macrocephaly with frontal bossing
• Midface retrusion and depressed nasal bridge
• Rhizomelic (proximal) shortening of the arms with redundant skin folds on limbs
• Limitation of elbow extension
• Brachydactyly
Achondroplasia 3

• Trident configuration of the hands

• Genu varum (bowlegs)
• Thoracolumbar kyphosis (principally in infancy)
• Exaggerated lumbar lordosis, which develops when walking begins
Radiographic findings
• Short, robust tubular bones
• Narrowing of the interpedicular distance of the caudal spine
• Square ilia and horizontal acetabula
• Narrow sacrosciatic notch
• Proximal femoral radiolucency
• Mild, generalized metaphyseal changes

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 findings generally do not need molecular confirmation of the diagnosis, although
confirmation may aid in receiving new treatments. 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 ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely
pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both
can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section
is understood to include any likely pathogenic variants. (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:
• c.1138G>A (p.Gly380Arg)
• c.1138G>C (p.Gly380Arg)
Note: Since achondroplasia occurs through a gain-of-function mechanism and large intragenic deletion or
duplication has 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. 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; thus, clinicians need to determine which
multigene panel is most likely to identify the genetic cause of the condition while limiting identification of
variants of uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. (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.
4 GeneReviews®

Table 1. Molecular Genetic Testing Used in Achondroplasia

Proportion of Probands with a Pathogenic
Gene 1 Method
Variant 2 Detectable by Method
Targeted analysis for pathogenic variants ~99% 3
FGFR3
Sequence analysis 4 >99% 5, 6
1. See Table A. Genes and Databases for chromosome locus and protein.
2. See Molecular Genetics for information on variants detected in this gene.
3. Pathogenic variant c.1138G>A (p.Gly380Arg) is identified in approximately 98% of individuals with achondroplasia; pathogenic
variant c.1138G>C (p.Gly380Arg) is identified in approximately 1% of individuals with achondroplasia.
4. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants
may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene
deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5. Includes the two pathogenic variants detected by targeted analysis
6. Shiang et al [1994], Bellus et al [1995]

Clinical Characteristics
Clinical Description
Individuals with achondroplasia have short stature caused by 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 131±5.6 cm; for women, 124±5.9 cm. Vosoritide, a
C-type natriuretic peptide (CNP) analog, was recently approved to increase height in individuals older than age
five years with achondroplasia. Studies showed an average of 1.6 cm of additional height growth per year. Final
adult height after treatment with vosoritide is still to be determined (see Management, Treatment of
Manifestations).
Obesity is a major problem in achondroplasia [Hecht et al 1988]. Excessive weight gain is 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].
Development. In infancy, mild-to-moderate hypotonia is typical. Infants have difficulty in supporting their
heads because of both hypotonia and large head size. That and differences in body habitus cause motor delays
and unusual patterns of motor development such as snowplowing (using the head and feet to leverage
movement) [Fowler et al 1997, Ireland et al 2010, 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 can
contribute to delayed speech development [Ireland et al 2012].
Intelligence is normal unless hydrocephalus or other central nervous system complications occur. High-level
executive function issues have been reported in some individuals [Wigg et al 2016].
Macrocephaly. Most children with achondroplasia are macrocephalic [Horton et al 1978]. Hydrocephalus
requiring treatment, which probably occurs in 5% or fewer [Pauli & Botto 2020], may be caused by increased
intracranial venous pressure because of stenosis of the jugular foramina [Pierre-Kahn et al 1980, Steinbok et al
1989]. More recent literature suggests that in some individuals foramen magnum stenosis may contribute to
hydrocephalus, which is thus treatable by posterior fossa decompression or endoscopic third ventriculostomy
[Etus & Ceylan 2005, Swift et al 2012].
Achondroplasia 5

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 [Trotter et al 2005] 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]. 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 computerized
tomography (CT) is used, foraminal size can be compared with achondroplasia standards [Hecht et al 1989].
Magnetic resonance (MR) 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]. In one study, all children undergoing surgical
decompression of the craniocervical junction showed marked improvement of neurologic function [Pauli et al
1995]. Quality-of-life indices determined up to 20 years after such surgery were comparable to quality-of-life
indices in those for whom surgery was not indicated in childhood [Ho et al 2004]. A similar mechanism of
injury can result in high cervical myelopathy (asymmetric or increased reflexes, weakness, persisting hypotonia,
and poor balance) [Hecht et al 1984].
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 [Hunter et al 1996b; S Balasubramaniam 2020, unpublished]. Many
infants show more rapid desaturations with minor respiratory events (e.g., physiologic periodic breathing or
otherwise insignificant obstructive events). A small number have, as a consequence of these features, chronic
hypoxemia [Mogayzel et al 1998]. If a young infant has persistent tachypnea, failure to thrive, 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 [Waters et al 1995], hypertrophy of the
lymphatic ring, airway malacia [Dessoffy et al 2014], and, perhaps, abnormal innervation of the airway
musculature [Tasker et al 1998].
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
Clinical signs and symptoms of infantile sleep apnea include the following:
• Observed apnea or exaggerated periodic breathing
6 GeneReviews®

• Struggling to breathe
• Poor feeding
• Coughing
• Difficulty lying flat to sleep
• Frequent awakenings
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].
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]. Overall, about 40% of individuals with
achondroplasia have functionally relevant hearing loss. Expressive language development is also frequently
delayed [Ireland et al 2012], although the strength of the relationship between hearing loss and expressive
language issues is uncertain.
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, internal tibial torsion, and dynamic instability of the knee [Inan et al 2006].
Kyphosis at the thoracolumbar junction is present in 90%-95% of infants with achondroplasia [Pauli et al 1997].
In about 10% it does not spontaneously resolve and can result in serious neurologic sequelae [Kopits 1988b].
Preventive strategies [Pauli et al 1997, Xu et al 2018] may reduce the need for surgical intervention.
Spinal stenosis. The most common medical complaint in adulthood is symptomatic spinal stenosis involving
L1-L4 [Kahanovitz et al 1982, Hoover-Fong et al 2020]. Symptoms range from intermittent, reversible, exercise-
induced claudication to severe, irreversible abnormalities of leg function and of continence [Pyeritz et al 1987].
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 nonreversible. 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. In general, this has minor consequences except for
knee instability in a subset of individuals.
• Discoid lateral meniscus. This recently recognized structural anomaly may result in chronic knee pain in
some individuals [Akyol et al 2015, Hoernschemeyer et al 2016].
• Arthritis. Constitutive activation of FGFR-3, 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.
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.
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].
Achondroplasia 7

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 1:26,000-1:28,000 live births [Waller et al 2008].

Genetically Related (Allelic) Disorders

Other phenotypes associated with pathogenic variants in FGFR3 include the following:
• Hypochondroplasia
• SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia (OMIM
616482). Note that acanthosis nigricans may also be seen in persons with other FGFR3-caused disorders
[Smid et al 2018].
• Thanatophoric dysplasia (types I and II)
• FGFR-related craniosynostosis, including Muenke syndrome and Crouzon syndrome with acanthosis
nigricans
• Isolated familial acanthosis nigricans [Fukuchi et al 2018]
• CATSHL syndrome (camptodactyly, tall stature, hearing loss) (OMIM 610474), an overgrowth disorder
caused by pathogenic loss-of-function variants in FGFR3
For other phenotypes associated with pathogenic variants in FGFR3, see OMIM 134934.

Differential Diagnosis
While more than 450 skeletal dysplasias that cause short stature are recognized [Mortier et al 2019], many are
extremely rare; and virtually all have clinical and radiographic features that readily distinguish them from
achondroplasia. Conditions that may be confused with achondroplasia include the following:
• Hypochondroplasia (also usually caused by pathogenic variants in FGFR3). This distinction is sometimes
the most difficult to make. In fact, there appears to be some overlap between the radiologic and clinical
phenotypes of these two conditions [Almeida et al 2009].
• Thanatophoric dysplasia
• SADDAN syndrome (OMIM 616482)
8 GeneReviews®

• Cartilage-hair hypoplasia (metaphyseal chondrodysplasia, McKusick type)

• Other metaphyseal dysplasias
• Pseudoachondroplasia (a clinically and genetically distinct skeletal dysplasia; but the similar nomenclature
may cause confusion)

Management
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 following evaluations are recommended if they have not already
been completed:
• Clinical genetics consultation including neurologic exam and, if feasible, consultation with a clinician
experienced in caring for children with bone dysplasias
• Documentation of length, weight, and head circumference compared with achondroplasia-specific growth
standards
• Assessment of the craniocervical junction including neurologic history and examination, neuroimaging of
the craniocervical junction using either CT or MR, and polysomnography as soon after birth as possible.
If CT is obtained, compare it to published standards for achondroplasia. When both sagittal and
transverse dimensions are greater than 1 SD below the mean for achondroplasia, and clinical features are
also present, the individual is at increased risk of requiring decompression surgery [Pauli et al 1995]. If
MRI is done, findings including obliteration of the subarachnoid fluid layer, deformation of the cord, or
T2 signal abnormality are helpful in determining whether decompression may be needed in combination
with clinical features [Pauli 2019, Hoover-Fong et al 2020].
• Baseline neuroimaging of the brain as soon after diagnosis as possible to assess ventricular size
• Audiologic evaluation as a newborn and repeated at age one year. In those in whom diagnosis is delayed,
audiologic screen should be completed at diagnosis and if concerns arise [Pauli 2019, Hoover-Fong et al
2020].

Treatment of Manifestations
Vosoritide, a C-type natriuretic peptide (CNP) analog, has recently been approved to increase height in children
with achondroplasia from age five years until growth plates close. Phase III studies showed an increase in
annualized growth velocity of 1.57 cm/year when given at doses of 15 µg/kg subcutaneously daily. The most
common side effects were injection site reactions and transient hypotension. Injections should be given after a
meal and drinking 8-12 oz of fluids to minimize hypotension. Studies in younger age groups are ongoing, as are
studies looking at possible medical benefits of the drug [Savarirayan et al 2021, Chan et al 2022].
Recommendations for health supervision of children with achondroplasia were outlined by the American
Academy of Pediatrics Committee on Genetics [Hoover-Fong et al 2020]. These recommendations serve as
guidelines and do not replace individual decision making. A recent review [Pauli & Botto 2020] also provides
management recommendations. Specialized skeletal dysplasia clinics exist; their recommendations may vary
slightly from these general guidelines.
The recommendations include (but are not limited to) the following.
Hydrocephalus. If signs or symptoms of increased intracranial pressure arise (e.g., accelerating head growth,
persistently bulging fontanelle, marked increase in superficial venous prominence over the face, irritability,
vomiting, vision changes, headache), referral to a neurosurgeon is needed.
Achondroplasia 9

The presumed etiology of hydrocephalus in achondroplasia is increased intracranial venous pressure secondary
to stenosis of the jugular foramina. Therefore, ventriculoperitoneal shunting has been the standard treatment.
However, endoscopic third ventriculostomy may be beneficial in some individuals [Swift et al 2012], implying
that other mechanisms, such as obstruction of fourth ventricular exit foramina from the craniocervical stenosis,
may be relevant [Etus & Ceylan 2005].
Craniocervical junction constriction. The best predictors of need for suboccipital decompression:
• Lower-limb hyperreflexia or clonus
• Central hypopnea demonstrated by polysomnography
• Reduced foramen magnum size, determined by CT examination of the craniocervical junction and by
comparison with the norms for children with achondroplasia [Pauli et al 1995]
• Evidence of spinal cord compression and/or T2-weighted signal abnormality; more recently proposed as
another factor to be considered in a decision to operate [Shimony et al 2015, Hoover-Fong et al 2020]
If there is clear indication of symptomatic compression, urgent referral to a pediatric neurosurgeon for
decompression surgery should be initiated [Bagley et al 2006].
Obstructive sleep apnea. Treatment may include the following:
• Adenotonsillectomy
• Positive airway pressure
• Tracheostomy for extreme cases
• Weight reduction
Improvement in disturbed sleep and some improvement in neurologic function can result from these
interventions [Tenconi et al 2017].
In rare instances in which the obstruction is severe enough to require tracheostomy, surgical intervention to
advance the midface has been used to alleviate upper airway obstruction [Elwood et al 2003].
Middle ear dysfunction. Aggressive management of frequent middle ear infections, persistent middle ear fluid,
and consequent hearing loss should be undertaken as needed. Long-lasting tubes are recommended because
they are frequently needed until age seven or eight years [Pauli 2019].
Implementation of appropriate therapies is warranted at any age if concerns arise [Hoover-Fong et al 2020].
Short stature. A number of studies have assessed growth hormone (GH) therapy as a possible treatment for the
short stature of achondroplasia [Miccoli et al 2016, Harada et al 2017].
• In general, these and other series show initial acceleration of growth, but with lessening effect over time.
• On average, only about 3 cm of additional adult height can be expected [Harada et al 2017].
Extended limb lengthening using various techniques remains an option for some. Increases in height of up to
30-35 cm may be obtained [Schiedel & Rodl 2012]. Complications are frequent and may be serious [Chilbule et
al 2016].
• Although some have advocated performing these procedures as early as ages six to eight years, many
pediatricians, clinical geneticists, and ethicists have advocated postponing such surgery until the young
person is able to participate in making an informed decision.
• At least in North America, only a tiny proportion of affected individuals elect to undergo extended limb
lengthening. The Medical Advisory Board of Little People of America has published a statement regarding
use of extended limb lengthening.
10 GeneReviews®

Obesity. Measures to avoid obesity should start in early childhood. Standard treatments for obesity should be
effective in people with achondroplasia, although caloric needs are less [Takken et al 2007].
• Standard weight and weight-by-height grids specific for achondroplasia [Hunter et al 1996a, Hoover-Fong
et al 2007] should be used to monitor progress. It is important to note that these curves are not ideal
weight-for-height curves; they were generated from thousands of data points from individuals with
achondroplasia.
• Body mass index (BMI) standards have been generated for children age 16 and under [Hoover-Fong et al
2008, Tofts et al 2017]. BMI has not been standardized for adults with achondroplasia; comparison to
average-stature BMI curves will yield misleading results [Schulze et al 2013].
Varus deformity. Annual orthopedic surveillance either by a provider familiar with achondroplasia or an
orthopedic surgeon is indicated [Hoover-Fong et al 2020]. Criteria for surgical intervention have been published
[Kopits 1980, Pauli & Botto 2020].
Presence of progressive, symptomatic bowing should prompt referral to an orthopedist. Varus deformity alone,
without symptoms, does not usually warrant surgical correction. Various interventions may be elected (e.g.,
guided growth using eight-Plates, valgus-producing and derotational osteotomies). No controlled studies
comparing outcomes of treatment options have been completed.
Kyphosis. Infants with achondroplasia frequently develop a flexible kyphosis. A protocol to help prevent the
development of a fixed, angular kyphosis is available and includes avoidance of flexible-backed strollers, swings,
and carriers. Counsel against unsupported sitting; always apply counter pressure to the back when holding the
infant [Pauli et al 1997].
• Kyphosis improves significantly or resolves in the majority of children upon assuming an orthograde
posture and beginning to walk [Margalit et al 2018].
• In children in whom spontaneous remission does not arise after trunk strength increases and the child
begins to walk, bracing is usually sufficient to prevent persistence of the thoracolumbar kyphosis [Xu et al
2018].
• If a severe kyphosis persists, spinal surgery may be necessary to prevent neurologic complications [Ain &
Browne 2004].
Spinal stenosis. If severe signs and/or symptoms of spinal stenosis arise, urgent surgical referral is appropriate.
Extended and wide laminectomies [Pyeritz et al 1987, Lonstein 1988] are usually recommended. Urgency
depends on level (e.g., thoracic vs lumbar) and degree of stenosis. Individuals had better outcomes and function
the sooner they underwent surgery after developing symptoms [Carlisle et al 2011].
Immunization. Nothing about achondroplasia precludes all routine immunizations. Given increased respiratory
risks, DTaP, pneumococcal, and influenza vaccines are especially important.
Adaptive needs. Due to short stature, environmental modifications are necessary. In school these may include
step stools, lowered light switches, appropriate-height toilets or other means to make them accessible, lower
desks, and foot support in front of chairs. All children need to be able to independently escape the building
should an emergency arise. Small hands and ligamentous laxity can make fine motor activities difficult.
Appropriate adaptations include the use of smaller keyboards, weighted pens, and smoother writing surfaces.
Most children should have an IEP or 504 plan.
Pedal extenders for driving are almost always needed. Also needed may be workplace modification such as lower
desks, smaller keyboards, step stools, and toileting access.
Socialization. Because of the highly visible nature of the short stature associated with achondroplasia, affected
persons and their families may encounter difficulties in socialization and school adjustment.
Achondroplasia 11

Support groups (see Resources) such as the Little People of America, Inc (LPA) can assist families with these
issues through peer support, personal example, and social awareness programs.
Information on employment, education, disability rights, adoption of children with short stature, medical issues,
suitable clothing, adaptive devices, and parenting is available through a national newsletter, seminars, and
workshops.

Surveillance
Recommendations for surveillance are incorporated into the American Academy of Pediatrics guidelines
[Hoover-Fong et al 2020].
Growth. Monitor height and weight at each physician contact using growth curves standardized for
achondroplasia [Hoover-Fong et al 2007].
Development. Screening of developmental milestones throughout infancy and early childhood should be
performed and compared with those specific for achondroplasia [Ireland et al 2012]. Special attention should be
paid to motor and expressive language development. Speech evaluation as part of developmental assessment is
recommended at every well-child and clinical genetics visit.
Head growth and risk for hydrocephalus. Perform complete baseline neuroimaging of the brain in infancy.
Head circumference should be measured at every physician contact until around age six years given that sutural
closure is markedly delayed (as evidenced by anterior fontanelle closure as late as age 5-6 years). Occipitofrontal
circumference should continue to be measured throughout childhood at well checks and genetics visits, plotting
it on growth curves standardized for achondroplasia [Horton et al 1978].
Craniocervical junction. Every infant should undergo neuroimaging of the craniocervical junction as soon as
possible after diagnosis.
Overnight polysomnography should also be completed as soon as possible after initial diagnosis in infancy, and
interpreted with consideration of features important in assessing the craniocervical junction. Increased central
apnea is indicative of cord compression at the craniocervical junction.
Neurologic examination including monitoring for signs of cervical myelopathy such as persistent hypotonia,
hyperreflexia, clonus, and asymmetries should be incorporated into each physical examination in infancy and
childhood.
Obstructive sleep apnea. Inquiry should be made regarding the following signs and symptoms of disordered
breathing in sleep:
• 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
If worrisome nighttime or daytime features arise, polysomnography should be repeated.
Ears and hearing. In addition to newborn screening, each infant should have audiometric evaluation by age
approximately one year.
12 GeneReviews®

Evidence for middle ear problems or hearing loss should be sought throughout childhood. Audiologic
evaluations should be completed yearly throughout childhood.
Kyphosis. The spine of the infant and child should be clinically assessed every six months. If severe kyphosis
appears to be developing, radiologic assessment is needed (lateral in sitting or standing, depending on age, and
lateral cross-table prone or cross-table supine over a bolster). When the child begins to walk and if the kyphosis
is resolving, assessment can be less frequent.
Legs. Clinical assessment for development of bowing and/or internal tibial torsion should be part of each
physical assessment. If progressive pain or substantial deformity arises, referral to orthopedics is appropriate.
Spinal stenosis. Because adults with achondroplasia are at increased risk for spinal stenosis, a clinical history
and neurologic examination is warranted any time new signs or symptoms develop, or at least every three to five
years.
Adaptation to difference. Inquiry regarding social adjustment should be part of each primary physician contact.
Encourage independence.
Specialty assessment. Parallel care with a geneticist or other provider experienced in the care of individuals with
bone dysplasias is often helpful. In general, infants and toddlers should be evaluated every six months, children
yearly, and adolescents every one to two years.

Agents/Circumstances to Avoid
Children with achondroplasia should remain rear-facing in car seats as long as possible. Large heads with
relatively lax neck ligaments place children at more risk in a motor vehicle accident.
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.
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).
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
When the pregnant woman is of average stature and the fetus has achondroplasia, fetal macrocephaly may cause
cephalopelvic disproportion, potentially requiring delivery by cesarean section.
Pregnant women with achondroplasia must always be delivered by cesarean section because of the small size of
the pelvis.
Achondroplasia 13

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 C-type natriuretic peptide analog attached to a depot protein is in clinical trial
(NCT04085523) [Breinholt et al 2019]. Other considerations include tyrosine kinase inhibition [Komla-Ebri et al
2016], a soluble recombinant human FGFR3 decoy [Gonçalves et al 2020], and meclizine [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.

Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of
inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The
following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to
substitute for consultation with a genetics professional. —ED.

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].
• The remaining 20% of individuals with achondroplasia have at least one affected parent.
• Presumed parental germline mosaicism [Natacci et al 2008] (and/or advantageous survival of sperm
precursors harboring the FGFR3 pathogenic variant) has been reported in rare cases in which parents with
average stature have more than one affected child.
Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:
• If the parents are of average stature, the risk to sibs of having achondroplasia is very low but appears to
exceed that in the general, comparable population because of the possibility of parental germline
mosaicism [Mettler & Fraser 2000, Natacci et al 2008].
• If one parent has achondroplasia, the risk to sibs is 50%.
Offspring of a proband
• The risk to offspring of an individual with achondroplasia of inheriting the FGFR3 pathogenic variant is
50%.
• An individual with achondroplasia who has a partner of average stature is at 50% risk of having a child
with achondroplasia.
14 GeneReviews®

• When both parents have achondroplasia, their offspring have a 25% chance of having average stature, a
50% chance of having achondroplasia, and a 25% chance of having homozygous achondroplasia (a lethal
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].
• When the proband and the proband's reproductive partner are affected with different dominantly
inherited skeletal dysplasias, each child is at 25% risk of having average stature, 25% risk of having the
same skeletal dysplasia as the father, 25% risk of having the same skeletal dysplasia as the mother, and 25%
risk 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

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband
with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence
of the disorder, the pathogenic variant is likely de novo. However, nonmedical explanations including alternate
paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.
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 the affected parent or parents, prenatal and preimplantation
genetic testing are possible [Gooding et al 2002]. 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. Ultrasound findings of achondroplasia
generally are not apparent until 24 weeks' gestation, although widening of the femoral diaphysis-metaphysis
angle may allow earlier detection [Khalil et al 2016].
Guidelines for prenatal diagnosis of skeletal dysplasias are available [Krakow et al 2009]. Chitty et al [2011]
published the frequency of various ultrasonographic features in fetuses with achondroplasia, and Hatzaki et al
[2011] used a combination of 3D ultrasonography and molecular analysis to enhance diagnostic accuracy of
FGFR3-related dysplasias.
Achondroplasia 15

Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries
for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the
information provided by other organizations. For information on selection criteria, click here.
• MedlinePlus
Achondroplasia
• NCBI Genes and Disease
Achondroplasia
• Child Growth Foundation
United Kingdom
Phone: 0208 995 0257
Email: [email protected]
www.childgrowthfoundation.org
• Human Growth Foundation
www.hgfound.org
• Little People of America
Phone: 888-LPA-2001; 714-368-3689
Fax: 707-721-1896
Email: [email protected]
www.lpaonline.org
• MAGIC Foundation
Phone: 800-362-4423
Email: [email protected]
www.magicfoundation.org
• Medline Plus
Dwarfism
• UCLA International Skeletal Dysplasia Registry (ISDR)
Phone: 310-825-8998
International Skeletal Dysplasia Registry

Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables
may contain more recent information. —ED.
Table A. Achondroplasia: Genes and Databases
Gene Chromosome Locus Protein Locus-Specific HGMD ClinVar
Databases
FGFR3 4p16.3 Fibroblast growth FGFR3 @ LOVD FGFR3 FGFR3
factor receptor 3
Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.
16 GeneReviews®

Table B. OMIM Entries for Achondroplasia (View All in OMIM)

100800 ACHONDROPLASIA; ACH
134934 FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3

Gene structure. The 4.3-kb cDNA has 19 exons and encodes an 806-residue protein (isoform 1).
Pathogenic variants. 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 (Table
2). Several exceptions with pathogenic variants at other nucleotides have been reported. (For more information,
see Table A, HGMD.)
Table 2. FGFR3 Pathogenic Variants Discussed in This GeneReview
DNA Nucleotide Change Predicted Protein Change Reference Sequences
c.1138G>A p.Gly380Arg NM_000142.4
c.1138G>C p.Gly380Arg NP_000133.1

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of
variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick
Reference for an explanation of nomenclature.

Normal gene product. Fibroblast growth factor receptor 3 (FGFR-3). The mature FGFR-3 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].
FGFR-3 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].
Abnormal gene product. The p.Gly380Arg pathogenic variant resulting in achondroplasia causes constitutive
activation of FGFR-3, 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, SADDAN dysplasia, and thanatophoric dysplasia type I and II are
each the result of allelic FGFR3 pathogenic variants that result in a graded series of FGFR-3 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 current understanding of FGFs, FGFRs, STAT1, MAPK, and proteins interacting
with these pathways [Klag & Horton 2016].
Achondroplasia 17

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

Revision History
• 11 May 2023 (sw) Revision: "FGFR3-Related Achondroplasia" added as a synonym; Nosology of Genetic
Skeletal Disorders: 2023 Revision [Unger et al 2023] added to Nomenclature
• 6 January 2022 (aa) Revision: new treatments approved (vosoritide); in clinical trials [Gonçalves et al
2020]
• 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

References
Literature Cited
Ain MC, Browne JA. Spinal arthrodesis with instrumentation for thoracolumbar kyphosis in pediatric
achondroplasia. Spine. 2004;29:2075–80. PubMed PMID: 15371713.
Akyol Y, Aaverill LW, Atanda A, Kecskemethy HH, Bober MB, Mackenzie WG. Magnetic resonance evaluation
of the knee in children and adolescents with achondroplasia. Pediatr Radiol. 2015;45:888–95. PubMed
PMID: 25432442.
Almeida MR, Campos-Xavier AB, Medeira A, Corderiro I, Sousa AB, Lima M, Soares G, Rocha M, Saraiva J,
Ramos L, Sousa S, Marcelino JP, Correia A, Santos HG. Clinical and molecular diagnosis of the skeletal
dysplasias associated with mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) in
Portugal. Clin Genet. 2009;75:150–6. PubMed PMID: 19215249.
Bagley CA, Pindrik JA, Bookland MJ, Camara-Quintana JQ, Carson BS. Cervicomedullary decompression for
foramen magnum stenosis in achondroplasia. J Neurosurg. 2006;104:166–72. PubMed PMID: 16572633.
Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, Kaitila I, McIntosh I,
Francomano CA. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet.
1995;56:368–73. PubMed PMID: 7847369.
Berkowitz RG, Grundfast KM, Scott C, Saal H, Stern H, Rosenbaum K. Middle ear disease in childhood
achondroplasia. Ear Nose Throat J. 1991;70:305–8. PubMed PMID: 1914954.
Breinholt VM, Rasmussen CE, Mygind PH, Kjelgaard-Hansen M, Faltinger F, Bernhard A, Zettler J, Hersel U.
TransCon CNP, a sustained-release c-type natriuretic peptide prodrug, a potentially safe and efficacious new
therapeutic modality for the treatment of comorbidities associated with fibroblast growth factor receptor 3-
related skeletal dysplasias. J Pharmacol Exp Ther. 2019;370:459–71. PubMed PMID: 31235532.
18 GeneReviews®

Brewer JR, Mazot P, Soriano P. Genetic insights into the mechanisms of Fgf signaling. Genes Devel.
2016;30:751–71. PubMed PMID: 27036966.
Carlisle ES, Ting BL, Abdullah MA, Skolasky RL, Schkrohowsky JG, Yost MT, Rigamonti D, Ain MC.
Laminectomy in patients with achondroplasia: the impact of time to surgery on long-term function. Spine
(Phila Pa 1976). 2011;36:886–92. PubMed PMID: 20739914.
Carroll JL, McColley SA, Marcus CL, Curtis S, Loughlin GM. Inability of clinical history to distinguish primary
snoring from obstructive sleep apnea syndrome in children. Chest. 1995;108:610–8. PubMed PMID:
7656605.
Chan ML, Qi Y, Larimore K, Cherukuri A, Seid L, Jayaram K, Jeha G, Fisheleva E, Day J, Hunsman-Labed A,
Savarirayan R, Irving M, Bacino CA, Hoover-Fong J, Ozono K, Mohnike K, Wilcox WR, Horton WA,
Henshaw J. Pharmacokinetics and exposure-response of vosoritide in children with achondroplasia. Clin
Pharmacokinet. 2022;61:263–80. PubMed PMID: 34431071.
Chellaiah AT, McEwen DG, Werner S, Xu J, Ornitz DM. Fibroblast growth factor receptor (FGFR) 3. Alternative
splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1. J Biol
Chem. 1994;269:11620–7. PubMed PMID: 7512569.
Chilbule SK, Dutt V, Madhuri V. Limb lengthening in achondroplasia. Indian J Orthop. 2016;50:397–405.
PubMed PMID: 27512222.
Chitty LS, Griffin DR, Meaney C, Barrett A, Khalil A, Pajkrt E, Cole TJ. New aids for the non-invasive prenatal
diagnosis of achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-
free DNA in maternal plasma. Ultrasound Obstet Gynecol. 2011;37:283–9. PubMed PMID: 21105021.
Chitty LS, Mason S, Barrett AN, McKay F, Lench N, Daley R, Jenkins LA. Non-invasive prenatal diagnosis of
achondroplasia and thanatophoric dysplasia: next-generation sequencing allows for a safer, more accurate,
and comprehensive approach. Prenat Diagn. 2015;35:656–62. PubMed PMID: 25728633.
Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P. Fibroblast growth factor receptor 3 is a negative regulator
of bone growth. Cell. 1996;84:911–21. PubMed PMID: 8601314.
Dessoffy KE, Modaff P, Pauli RM. Airway malacia in children with achondroplasia. Am J Med Genet A.
2014;164A:407–14. PubMed PMID: 24311312.
Elwood ET, Burstein FD, Graham L, Williams JK, Paschal M. Midface distraction to alleviate upper airway
obstruction in achondroplastic dwarfs. Cleft Palate Craniofac J. 2003;40:100–3. PubMed PMID: 12498613.
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine
Growth Factor Rev. 2005;16:139–49. PubMed PMID: 15863030.
Etus V, Ceylan S. The role of endoscopic third ventriculostomy in the treatment of triventricular hydrocephalus
seen in children with achondroplasia. J Neurosurg. 2005;103:260–5. PubMed PMID: 16238080.
Flynn MA, Pauli RM. Double heterozygosity in bone growth disorders: four new observations and review. Am J
Med Genet A. 2003;121A:193–208. PubMed PMID: 12923858.
Fowler ES, Glinski LP, Reiser CA, Horton VK, Pauli RM. Biophysical bases for delayed and aberrant motor
development in young children with achondroplasia. J Dev Behav Pediatr. 1997;18:143–50. PubMed PMID:
9213228.
Fukuchi K, Tatsuno K, Matsushita K, Kubo A, Ito T, Tokura Y. Familial acanthosis nigricans with p.K650T
FGFR3 mutation. J Dermatol. 2018;45:207–10. PubMed PMID: 29068064.
Gonçalves D, Rignol G, Dellugat P, Hartmann G, Sarrazy Garcia S, Stavenhagen J, Santarelli L, Gouze E, Czech
C. In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as
treatment for achondroplasia. PLoS One. 2020;15:e0244368. PubMed PMID: 33370388.
Gooding HC, Boehm K, Thompson RE, Hadley D, Francomano CA, Biesecker BB. Issues surrounding prenatal
genetic testing for achondroplasia. Prenat Diagn. 2002;22:933–40. PubMed PMID: 12378581.
Achondroplasia 19

Hall JG. The natural history of achondroplasia. Basic Life Sci. 1988;48:3–9. PubMed PMID: 3071358.
Harada D, Namba N, Hanioka Y, Ueyama K, Sakamoto N, Nakano Y, Izui M, Nagamatsu Y, Kashiwagi H,
Yamamuro M, Ishiura Y, Ogitani A, Seino Y. Final adult height in long-term growth hormone-treated
achondroplasia patients. Eur J Pediatr. 2017;176:873–9. PubMed PMID: 28501952.
Hashmi SS, Gamble C, Hoover-Fong H, Alade AY, Pauli RM, Modaff P, Carney M, Brown C, Bober MB, Hecht
JT. Multicenter study of mortality in achondroplasia. Am J Med Genet A. 2018;176:2359–64. PubMed PMID:
30276962.
Hatzaki A, Sifakis S, Apostolopoulou D, Bouzarelou D, Konstantinidou A, Kappou D, Sideris A, Tzortzis E,
Athanassiadis A, Forentin L, Theodoropoulos P, Makatsoris C, Karadimas C, Velissariou V. FGFR3 related
skeletal dysplasias diagnosed prenatally by ultrasonography and molecular analysis: presentation of 17 cases.
Am J Med Genet A. 2011;155A:2426–35. PubMed PMID: 21910223.
Hecht JT, Butler KJ, Cott Cl Jr. Long-term neurological sequelae in achondroplasia. Eur J Pediatr. 1984;143:58–
60. PubMed PMID: 6510432.
Hecht JT, Francomano CA, Horton WA, Annegers JF. Mortality in achondroplasia. Am J Hum Genet.
1987;41:454–64. PubMed PMID: 3631079.
Hecht JT, Hood OJ, Schwartz RJ, Hennessey JC, Bernhardt BA, Horton WA. Obesity in achondroplasia. Am J
Med Genet. 1988;31:597–602. PubMed PMID: 3228140.
Hecht JT, Horton WA, Reid CS, Pyeritz RE, Chakraborty R. Growth of the foramen magnum in achondroplasia.
Am J Med Genet. 1989;32:528–35. PubMed PMID: 2773998.
Ho NC, Guarnieri M, Brant LJ, Park SS, Sun B, North M, Francomano CA, Carson BS. Living with
achondroplasia: quality of life evaluation following cervicomedullary decompression. Am J Med Genet A.
2004;131:163–7. PubMed PMID: 15487008.
Hoernschemeyer DG, Atanda A Jr, Dean-Davis E, Gupta SK. Discoid meniscus associated with achondroplasia.
Orthopedics. 2016;39:e498–503. PubMed PMID: 27135452.
Hoover-Fong JE, McGready J, Schulze KJ, Barnes H, Scott CI. Weight for age charts for children with
achondroplasia. Am J Med Genet A. 2007;143A:2227–35. PubMed PMID: 17764078.
Hoover-Fong JE, Schulze KJ, McGready J, Barnes H, Scott CI. Age-appropriate body mass index in children with
achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr. 2008;88:364–71. PubMed
PMID: 18689372.
Hoover-Fong J, Scott CI, Jones MC, et al. Health supervision for people with achondroplasia. Pediatrics.
2020;145:e20201010. PubMed PMID: 32457214.
Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall JG. Standard growth curves for achondroplasia. J Pediatr.
1978;93:435–8. PubMed PMID: 690757.
Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to
bank on. J Community Genet. 2022;13:389–97. PubMed PMID: 35834113.
Hunter AG, Hecht JT, Scott CI. Standard weight for height curves in achondroplasia. Am J Med Genet.
1996a;62:255–61. PubMed PMID: 8882783.
Hunter AG, Reid CS, Pauli RM, Scott CI. Standard curves of chest circumference in achondroplasia and the
relationship of chest circumference to respiratory problems. Am J Med Genet. 1996b;62:91–7. PubMed
PMID: 8779333.
Inan M, Thacker M, Church C, Miller F, Mackenzie WG, Conklin D. Dynamic lower extremity alignment in
children with achondroplasia. J Pediatr Orthop. 2006;26:526–9. PubMed PMID: 16791073.
20 GeneReviews®

Ireland PJ, Donaghey S, McGill J, Zankl A, Ware RS, Pacey V, Ault J, Savarirayan R, Sillence D, Thompson E,
Townshend S, Johnston LM. Development in children with achondroplasia: a prospective clinical cohort
study. Dev Med Child Neurol. 2012;54:532–7. PubMed PMID: 22409389.
Ireland PJ, Johnson S, Donaghey S, Johnston L, McGill J, Zankl A, Ware RS, Pacey V, Ault J, Savarirayan R,
Sillence D, Thompson E, Townshend S. Developmental milestones in infants and young Australasian
children with achondroplasia. J Dev Behav Pediatr. 2010;31:41–7. PubMed PMID: 20081435.
Kahanovitz N, Rimoin DL, Sillence DO. The clinical spectrum of lumbar spine disease in achondroplasia. Spine.
1982;7:137–40. PubMed PMID: 7089690.
Khalil A, Chaoui R, Lebek H, Esser T, Entezami M, Toms J, Thilaganathan B. Widening of the femoral
diaphysis-metaphysis angle at 20-24 weeks: a marker for the detection of achondroplasia prior to the onset of
skeletal shortening. Am J Obstet Gynecol. 2016;214:291–2. PubMed PMID: 26450406.
Klag KA, Horton WA. Advances in treatment of achondroplasia and osteoarthritis. Hum Mol Genet.
2016;25:R2–R8. PubMed PMID: 26443596.
Komla-Ebri D, Dambroise E, Kramer I, Benoist-Lasselin C, Kaci N, Le Gall C, Martin L, Busca P, Barbault F,
Graus-Porta D, Munnich A, Kneissel M, Di Rocco F, Biosse-Duplan M, Legeai-Mallet L. Tyrosine kinase
inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest.
2016;126:1871–84. PubMed PMID: 27064282.
Kopits SE. Correction of bowleg deformity in achondroplasia. Johns Hopkins Med J. 1980;146:206–9. PubMed
PMID: 7382244.
Kopits SE. Orthopedic aspect of achondroplasia in children. Basic Life Sci. 1988a;48:189–97. PubMed PMID:
3240253.
Kopits SE. Thoracolumbar kyphosis and lumbosacral hyperlordosis in achondroplastic children. Basic Life Sci.
1988b;48:241–55. PubMed PMID: 3240259.
Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet
Med. 2009;11:127–33. PubMed PMID: 19265753.
Laederich MB, Horton WA. Achondroplasia: pathogenesis and implications for future treatment. Curr Opin
Pediatr. 2010;22:516–23. PubMed PMID: 20601886.
Langer LO, Baumann PA, Gorlin RJ. Achondroplasia. Am J Roentgenol Radium Ther Nucl Med. 1967;100:12–
26.
Lonstein JE. Treatment of kyphosis and lumbar stenosis in achondroplasia. Basic Life Sci. 1988;48:283–92.
PubMed PMID: 3240263.
Margalit A, McKean G, Lawing C, Galey S, Ain MC. Walking out of the curve: thoracolumbar kyphosis in
achondroplasia. J Pediatr Orthop. 2018;38:491–7. PubMed PMID: 27636912.
Matsushita M, Mishima K, Esaki R, Ishiguro N, Ohno K, Kitoh H. Maternal administration of meclizine for the
treatment of foramen magnum stenosis in transgenic mice with achondroplasia. J Neurosurg Pediatr.
2017;19:91–5. PubMed PMID: 27767902.
Mettler G, Fraser FC. Recurrence risk for sibs of children with "sporadic" achondroplasia. Am J Med Genet.
2000;90:250–1. PubMed PMID: 10678665.
Miccoli M, Bertelloni S, Massart F. Height outcome of recombinant human growth hormone treatment in
achondroplasia children: a meta-analysis. Horm Res Paediatr. 2016;86:27–34. PubMed PMID: 27355624.
Mogayzel PJ Jr, Carroll JL, Loughlin GM, Hurko O, Francomano CA, Marcus CL. Sleep-disordered breathing in
children with achondroplasia. J Pediatr. 1998;132:667–71. PubMed PMID: 9580768.
Achondroplasia 21

Mortier GR, Cohn DH, Cormier-Daire V, Hall C, Krakow D, Mundlos S, Nishimura G, Robertson S, Sangiorgi
L, Savarirayan R, Sillence D, Superti-Farga A, Unger S, Warman ML. Nosology and classification of genetic
skeletal disorders: 2019 revision. Am J Med Genet A. 2019;179:2393–419. PubMed PMID: 31633310.
Narayana J, Horton WA. FGFR3 biology and skeletal disease. Connect Tissue Res. 2015;56:427–33. PubMed
PMID: 26075305.
Naski MC, Wang Q, Xu J, Ornitz DM. Graded activation of fibroblast growth factor receptor 3 by mutation
causing achondroplasia and thanatophoric dysplasia. Nat Genet. 1996;13:233–7. PubMed PMID: 8640234.
Natacci F, Baffico M, Cavallari U, Bedeschi MF, Mura I, Paffoni A, Setti PL, Baldi M, Lalatta F. Germline
mosaicism in achondroplasia detected in sperm DNA of the father of three affected sibs. Am J Med Genet A.
2008;146A:784–6. PubMed PMID: 18266238.
Ornitz DM. FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev. 2005;16:205–
13. PubMed PMID: 15863035.
Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015;4:215–
66. PubMed PMID: 25772309.
Ornitz DM, Legeai-Mallet L. Achondroplasia: development, pathogenesis and therapy. Dev Dyn. 2017;246:291–
309. PubMed PMID: 27987249.
Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis. 2019;14:1. PubMed PMID:
30606190.
Pauli RM, Botto LD. Achondroplasia. In: Carey JC, Cassidy SB, Battaglia A, Viskochil D, eds. Cassidy and
Allanson's Management of Genetic Syndromes. 4 ed. New York, NY: John Wiley & Sons; 2020.
Pauli RM, Breed A, Horton VK, Glinski LP, Reiser CA. Prevention of fixed, angular kyphosis in achondroplasia.
J Pediatr Orthop. 1997;17:726–33. PubMed PMID: 9591973.
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;56:732–44. PubMed PMID: 7887429.
Pierre-Kahn A, Hirsch JF, Renier D, Metzger J, Maroteaux P. Hydrocephalus and achondroplasia. A study of 25
observations. Childs Brain. 1980;7:205–19. PubMed PMID: 7438842.
Pyeritz RE, Sack GH, Udvarhelyi GB. Thoracolumbar laminectomy in achondroplasia: long-term results in 22
patients. Am J Med Genet. 1987;28:433–44. PubMed PMID: 3425618.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E,
Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint
consensus recommendation of the American College of Medical Genetics and Genomics and the Association
for Molecular Pathology. Genet Med. 2015;17:405–24. PubMed PMID: 25741868.
Savarirayan R, Tofts L, Irving M, Wilcox WR, Bacino CA, Hoover-Fong J, Ullot Font R, Harmatz P, Rutsch F,
Bober MB, Polgreen LE, Ginebreda I, Mohnike K, Charrow J, Hoernschemeyer D, Ozono K, Alanay Y,
Arundel P, Kotani Y, Yasui N, White KK, Saal HM, Leiva-Gea A, Luna-González F, Mochizuki H, Basel D,
Porco DM, Jayaram K, Fisheleva E, Huntsman-Labed A, Day JRS. Safe and persistent growth-promoting
effects of vosoritide in children with achondroplasia: 2-year results from an open-label, Phase 3 extension
study. Genet Med. 2021;23:2443–7. PubMed PMID: 34341520.
Schiedel F, Rodl R. Lower limb lengthening in patients with disproportionate short stature with achondroplasia:
a systematic review of the last 20 years. Disabil Rehabil. 2012;34:982–7. PubMed PMID: 22112021.
Schulze KJ, Alade YA, McGready J, Hoover-Fong JE. Body mass index (BMI); the case for condition-specific cut-
offs for overweight and obesity in skeletal dysplasias. Am J Med Genet A. 2013;161A:2110–2. PubMed
PMID: 23798488.
22 GeneReviews®

Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ. Mutations in
the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia.
Cell. 1994;78:335–42. PubMed PMID: 7913883.
Shimony N, Ben-Sira L, Sivan Y, Constantini S, Roth J. Surgical treatment for cervicomedullary compression
among infants with achondroplasia. Childs Nerv syst. 2015;31:743–50. PubMed PMID: 25686888.
Smid CJ, Modaff P, Alade A, Legare JM, Pauli RM. Acanthosis nigricans in achondroplasia. Am J Med Genet A.
2018;176:2630–6. PubMed PMID: 30380187.
Steinbok P, Hall J, Flodmark O. Hydrocephalus in achondroplasia: the possible role of intracranial venous
hypertension. J Neurosurg. 1989;71:42–8. PubMed PMID: 2786928.
Stoll C, Roth MP, Bigel P. A reexamination on parental age effect on the occurrence of new mutations for
achondroplasia. Prog Clin Biol Res. 1982;104:419–26. PubMed PMID: 6891789.
Swift D, Nagy L, Robertson B. Endoscopic third ventriculostomy in hydrocephalus associated with
achondroplasia. J Neurosurg Pediatr. 2012;9:73–81. PubMed PMID: 22208325.
Takken T, van Bergen MW, Sakkers RJ, Helders PJ, Engelbert RH. Cardiopulmonary exercise capacity, muscle
strength, and physical activity in children and adolescents with achondroplasia. J Pediatr. 2007;150:26–30.
PubMed PMID: 17188608.
Tang J, Su N, Zhou S, Xie Y, Huang J, Wen X, Wang Z, Wang Q, Xu W, Du X, Chen H, Chen L. Fibroblast growth
factor receptor 3 inhibits osteoarthritis progression in the knee joints of adult mice. Arthritis Rheumatol.
2016;68:2432–43. PubMed PMID: 27159076.
Tasker RC, Dundas I, Laverty A, Fletcher M, Lane R, Stocks J. Distinct patterns of respiratory difficulty in young
children with achondroplasia: a clinical, sleep, and lung functions study. Arch Dis Child. 1998;79:99–108.
PubMed PMID: 9797588.
Tenconi R, Khirani S, Amaddeo A, Michot C, Baujat G, Couloigner V, De Sanctis L, James S, Zerah M, Cormier-
Daire V, Fauroux B. Sleep-disordered breathing and its management in children with achondroplasia. Am J
Med Genet. 2017;173:868–78. PubMed PMID: 28239978.
Tofts L, Das S, Collins F, Burton KLO. Growth charts for Australian children with achondroplasia. Am J Med
Genet A. 2017;173:2189–200. PubMed PMID: 28599087.
Trotter TL, Hall JG, et al. Health supervision for children with achondroplasia. Pediatrics. 2005;116:771–83.
PubMed PMID: 16140722.
Tunkel D, Alade Y, Kerbavez R, Smith B, Rose-Hardison D, Hoover-Fong J. Hearing loss in skeletal dysplasia
patients. Am J Med Genet A. 2012;158A:1551–5. PubMed PMID: 22628261.
Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, Cohn DH, Cormier-Daire V, Girisha KM, Hall
C, Krakow D, Makitie O, Mundlos S, Nishimura G, Robertson SP, Savarirayan R, Sillence D, Simon M,
Sutton VR, Warman ML, Superti-Furga A. Nosology of genetic skeletal disorders: 2023 revision. Am J Med
Genet A. 2023;191:1164–209. PubMed PMID: 36779427.
Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3
disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome
with acanthosis nigricans. Endocr Rev. 2000;21:23–39. PubMed PMID: 10696568.
Vivanti AJ, Costa JM, Rosefort A, Kleinfinger P, Lohmann L, Cordier AG, Benachi A. Optimal non-invasive
diagnosis of fetal achondroplasia combining ultrasonography and circulating cell-free fetal DNA analysis.
Ultrasound Obstet Gynecol. 2019;53:87–94. PubMed PMID: 29380944.
Waller DK, Correa A, Vo TM, Wang Y, Hobbs C, Langlois PH, Pearson K, Romitti PA, Shaw GM, Hecht JT. The
population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US.
Am J Med Genet A. 2008;146A:2385–9. PubMed PMID: 18698630.
Achondroplasia 23

Waters KA, Everett F, Sillence DO, Fagan ER, Sullivan CE. Treatment of obstructive sleep apnea in
achondroplasia: evaluation of sleep, breathing, and somatosensory-evoked potentials. Am J Med Genet.
1995;59:460–6. PubMed PMID: 8585566.
Wigg K, Tofts L, Benson S, Porter M. The neuropsychological function of children with achondroplasia. Am J
Med Genet A. 2016;170:2882–8. PubMed PMID: 27605460.
Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, Kaitila I, Loughlin J, Munnich A, Sykes B,
Bonaventure J, Francomano CA. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of
achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet. 1998;63:711–6.
PubMed PMID: 9718331.
Wynn J, King TM, Gambello MJ, Waller DK, Hecht JK. Mortality in achondroplasia study: a 42-year follow-up.
Am J Med Genet A. 2007;143A:2502–11. PubMed PMID: 17879967.
Xu L, Li Y, Sheng F, Zia C, Qui Y, Zhu Z. The efficacy of brace treatment for thoracolumbar kyphosis in patients
with achondroplasia. Spine (Phila Pa 1976). 2018;43:1133–8. PubMed PMID: 29419717.

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