Clinical characteristics.

Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and relative macrocephaly. Radiologic features include shortening of long bones with mild metaphyseal flare; a lack of widening or a narrowing of the lumbar interpedicular distances with shortening of the pedicle length and posterior scalloping of the vertebral bodies; short, broad femoral neck; and squared, shortened ilia. The skeletal features are similar to those seen in achondroplasia but tend to be milder. Medical complications common to achondroplasia (e.g., foramen magnum stenosis, spinal stenosis, tibial bowing, obstructive apnea) occur less frequently in hypochondroplasia, but intellectual disability and epilepsy may be more prevalent. Children usually present as toddlers or at early school age with decreased growth velocity leading to short stature and limb disproportion. Other features also become more prominent over time. Infants may present with temporal lobe seizures.

Diagnosis/testing.

The diagnosis of hypochondroplasia is established in a proband with characteristic clinical and radiographic features. Identification of a heterozygous FGFR3 pathogenic variant known to be associated with hypochondroplasia can confirm the diagnosis and help distinguish hypochondroplasia from achondroplasia and other related skeletal dysplasias in individuals with overlapping phenotypes.

Management.

Treatment of manifestations: Management of short stature in hypochondroplasia is influenced by parental expectations and concerns; one approach is to address these concerns rather than trying to treat the child. Foramen magnum stenosis, thoracolumbar kyphosis, genu varum, and spinal stenosis are management by orthopedists and neurosurgeons using similar strategies employed in achondroplasia. Seizures are treated in the standard manner. Developmental and educational support as needed. Connecting families with local resources and support is important.

Surveillance: The following should be performed at routine well-child visits: measurement and assessment of height, weight, and head circumference using hypochondroplasia-standardized growth curves; assessment for signs and symptoms of spinal cord compression, sleep apnea, thoracolumbar kyphosis, and leg bowing; development assessment and monitoring of all developmental domains including speech and language; audiology evaluation if speech and/or hearing concerns arise. Evaluation of social adjustment at well-child visits and then annually, most important during the grade-school years.

Pregnancy management: Vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size; epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy; spinal stenosis may be aggravated during pregnancy.

Genetic counseling.

Hypochondroplasia is inherited in an autosomal dominant manner. The majority of individuals with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a de novo pathogenic variant. An individual with hypochondroplasia who has a reproductive partner of average stature has a 50% chance of having a child with hypochondroplasia. When the proband and the proband's reproductive partner have the same or different skeletal dysplasias, genetic counseling is more complex. In general, if both members of a couple have a 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 potentially poor pregnancy outcome. It is not possible to provide information about prognosis for all at-risk offspring. If one parent has hypochondroplasia and the other parent is of average stature, has hypochondroplasia, or has another dominantly inherited skeletal dysplasia, prenatal and preimplantation genetic testing are possible if the causative pathogenic variant(s) have been identified in the affected parent(s).

Suggestive Findings

Hypochondroplasia should be suspected in individuals with the following clinical and radiographic features and family history.

Classic clinical features

• Short stature (adult height: 128-165 cm; 2-3 standard deviations below the mean in children)
• Stocky build
• Rhizomelic shortening of the extremities
• Limitation of elbow extension
• Broad, short hands and feet with brachydactyly
• Generalized, mild joint laxity
• Relative macrocephaly in comparison to height z score with relatively normal facies

Less common but significant clinical features:

• Increased lumbar lordosis with protruding abdomen
• Learning disabilities
• Mild-to-moderate intellectual disability
• Temporal lobe dysgenesis with or without seizures
• Bowed legs (genu varum; usually mild)
• Acanthosis nigricans

Radiologic features. The most common radiologic features of hypochondroplasia:

• Lack of widening or narrowing of the lumbar interpedicular distance
• Shortening of the lumbar pedicles
• Posterior scalloping / dorsal concavity of the lumbar vertebral bodies
• Shortening of long bones with mild metaphyseal flare (especially femora and tibiae)
• Mild-to-moderate brachydactyly
• Short, broad femoral neck
• Squared, shortened ilia

Less common but significant radiologic features:

• Elongation of the distal fibula
• Shortening of the distal ulna
• Long ulnar styloid (seen only in adults)
• Shallow "chevron" deformity of distal femur metaphysis
• Low articulation of sacrum on pelvis with a horizontal orientation
• Flattened acetabular roof
• Prominence of the deltoid insertion on the proximal humerus

Family history. Proband may represent a simplex case (i.e., an affected individual with no family history of hypochondroplasia) or the family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of hypochondroplasia is established in a proband with the characteristic clinical and radiographic features. Identification of a heterozygous FGFR3 pathogenic variant known to be associated with hypochondroplasia can confirm the diagnosis and help distinguish hypochondroplasia from achondroplasia and other related skeletal dysplasias in individuals with overlapping phenotypes (see Table 1).

Note: A consensus opinion of which or how many of these features must be present to confirm a clinical diagnosis does not currently exist. Radiographic features vary significantly among affected individuals. Many of these features are not present in affected infants but develop later in life. The mild end of the hypochondroplasia phenotypic spectrum may overlap with idiopathic or familial short stature, making it difficult to establish a definitive clinical diagnosis in these individuals.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Growth. The most common presenting feature of children with hypochondroplasia is short stature with disproportionate limbs and relative macrocephaly. Birth weight and length are often within the normal range and the disproportion in limb-to-trunk length is usually mild and easily overlooked during infancy. Typically, these children present to pediatricians or pediatric endocrinologists as toddlers or at early school age with decreased growth velocity leading to short stature. There is a lack of the pubertal growth spurt [Cheung et al 2024, Del Pino & Fano 2024] when the height difference from those with hypochondroplasia and those with average stature may increase. Overall height is usually two to three standard deviations below the mean during childhood, and adult heights range from 138 to 165 cm (54" to 65") for men and 128 to 151 cm (50" to 59") for women [Maroteaux & Falzon 1988, Arenas et al 2018, Cheung et al 2024].

Musculoskeletal. When children begin to walk, exaggerated lumbar lordosis becomes apparent. Genu varum (bowlegs) can also develop and rarely requires surgical intervention. Young children and adults often have a thick, muscular appearance and may be described as "stocky." The hands are relatively short but do not typically exhibit the "trident" appearance that is typical in achondroplasia. Disproportion in the limbs is classically rhizomelic. Joint pain, back pain, and other symptoms of osteoarthritis may occur later in life.

Craniofacial features are usually normal and the classic facial features of achondroplasia (e.g., midface retrusion, frontal bossing) are not generally seen in individuals with hypochondroplasia. The head circumference may overlap with the unaffected population but is large relative to height z score. Monitoring of serial head circumferences is prudent as ventriculomegaly and obstructive hydrocephalus requiring neurosurgical intervention is associated with achondroplasia. Craniosynostosis should be considered if atypical head morphology is present. Multiple-suture craniosynostosis has been reported in hypochondroplasia [Angle et al 1998, Jumayeva et al 2025]

Neurologic features. Although intellectual disability is thought to be more common in individuals with hypochondroplasia there is a paucity of robust data in the literature and this observation has been controversial. Linnankivi et al [2012] assessed neurologic and neuroimaging aspects of 13 Finnish individuals with hypochondroplasia with a confirmed FGFR3 p.Asn540Lys substitution. Eight affected individuals had neurocognitive difficulties, ranging from specific learning disorder (2/13) to mild intellectual disability (5/13) or global developmental delay (1/13). Kim et al [2023] reported developmental delay in 25% of a cohort of 20 molecularly confirmed individuals. The disabilities range from speech and language delay and attention-deficit disorder to global developmental delay needing special education.

Epilepsy can present at various ages in individuals with hypochondroplasia and typically has a temporal lobe focus [Ahmadi et al 2022]. Infants may present with subtle signs such as apneas, cyanosis, eye deviation, and vacant stares. Abnormalities such as three-second spike and wave formation or slowing over the temporal region may be challenging to capture on EEG [Ahmadi et al 2022]. In older children focal tonic-clonic or unilateral seizures may be present or more subtle temporal lobe seizures such as oral automatisms and sensory disturbances [Bernardo et al 2021].

Temporal lobe dysgenesis has been reported in FGFR3-related conditions and in particular incomplete folding of the hippocampus, abnormal cortical folding, and dilatation of temporal horns [Manikkam et al 2018, Bernardo et al 2021].

Unlike achondroplasia, motor milestones are usually not significantly delayed. Symptoms of spinal stenosis may be seen in some adults with hypochondroplasia but occur much less frequently and tend to be milder than those seen in achondroplasia [Wynne-Davies et al 1981].

Acanthosis nigricans is observed occasionally in children and adults with hypochondroplasia [Berk et al 2010, Blomberg et al 2010] and appears to be more prevalent in individuals with specific FGFR3 pathogenic variants (e.g., c.1948A>C [p.Lys650Gln], c.1949A>C [p.Lys650Thr]). The acanthosis nigricans in individuals reported with these pathogenic variants is much milder than that observed in severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) syndrome (caused by FGFR3 pathogenic variant c.1948A>G [p.Lys650Met]). While increased insulin resistance has been reported in one individual with acanthosis nigricans and hypochondroplasia due to a p.Lys650Gln pathogenic variant [Blomberg et al 2010], no evidence of insulin resistance was found in an individual with acanthosis nigricans and hypochondroplasia due to a p.Asn540Lys pathogenic variant [Alatzoglou et al 2009]. Insulin resistance is also not found in SADDAN syndrome [Bellus et al 1999].

Quality of life. Examination of quality of life has been attempted with the inclusion of individuals with hypochondroplasia in a broader cohort. Four individuals with hypochondroplasia were included in a cohort of 86 individuals with short-limbed short stature and reports of pain or numbness were common [Ajimi et al 2022]. In comparison to a reference population of individuals with idiopathic short stature, 26 individuals with hypochondroplasia were included in a cohort of short stature with a genetic basis. The overall quality of life scores for the genetic short stature cohort were lower than the reference population; however, individuals with hypochondroplasia scored higher than those with another genetic cause of short stature [Galetaki et al 2025].

Genotype-Phenotype Correlations

Other than c.1620C>A and c.1620C>G (both resulting in p.Asn540Lys), most FGFR3 pathogenic variants have not been reported in high enough frequencies to make any generalizations about specific genotype-phenotype manifestations.

• c.829A>G (p.Tyr278Cys). Heuertz et al [2006] and Song et al [2012] reported that this pathogenic variant resulted in a phenotype that resembled achondroplasia in the newborn period.
• c.1043C>G (p.Ser348Cys). Three case reports [Hasegawa et al 2016, Couser et al 2017, Bengur et al 2020] have described individuals with phenotypes that resemble mild achondroplasia / severe hypochondroplasia.
• c.1620C>A or c.1620C>G (p.Asn540Lys). In general, it appears that the phenotypes of individuals diagnosed with hypochondroplasia who have FGFR3 pathogenic variants c.1620C>A or c.1620C>G (both resulting in p.Asn540Lys) have more severe manifestations than those with hypochondroplasia who do not have these pathogenic variants [Rousseau et al 1996, Prinster et al 1998, Ramaswami et al 1998]. Fano et al [2005] reported that affected individuals with a head circumference >1.86 standard deviations above the mean had a greater likelihood of possessing a p.Asn540Lys pathogenic variant. No difference exists in phenotype between the FGFR3 c.1620C>A and c.1620C>G pathogenic variants.
• Individuals with c.1948A>C (p.Lys650Gln) or c.1949A>C (p.Lys650Thr) have a higher likelihood of developing acanthosis nigricans (see Clinical Description). The pathogenic variant c.1949A>C (p.Lys650Thr) also appears to be correlated with milder skeletal issues [Muguet Guenot et al 2019].
• Pathogenic variants c.1950G>T (p.Lys650Asn) and c.1948A>C (p.Lys650Gln) are associated with a slightly milder skeletal phenotype than pathogenic variants c.1620C>A or c.1620C>G (p.Asn540Lys). Bellus et al [2000] reported six individuals with c.1950G>T (p.Lys650Asn) or c.1948A>C (p.Lys650Gln) who had a significantly lower average height deficit than 36 individuals with c.1620C>A/c.1620C>G (p.Asn540Lys). In addition, the L1:L4 interpediculate distance and fibula-to-tibia length ratios were closer to normal.

Somatic mosaicism has not been reported in hypochondroplasia.

Penetrance

Because of evidence that the height range in hypochondroplasia may overlap that of the unaffected population, individuals with hypochondroplasia may not be recognized as having a skeletal dysplasia unless an astute physician recognizes their disproportionate short stature. To date, however, all reported individuals with an FGFR3 pathogenic variant have had demonstrable radiographic changes compatible with hypochondroplasia or one of the other phenotypes known to be associated with pathogenic variants in this gene (see Genetically Related Disorders).

Nomenclature

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], hypochondroplasia is designated "FGFR3-related hypochondroplasia" and placed in the FGFR3 chondrodysplasias family. Individuals with clinical features overlapping those of hypochondroplasia but in whom a different genetic etiology is identified are placed in other skeletal dysplasia groups.

Prevalence

No studies attempting to determine the prevalence of FGFR3 and/or non-FGFR3 hypochondroplasia have been published. Ascertainment of affected individuals is problematic as it is thought that many affected individuals present with no symptoms other than short stature and do not seek medical intervention. However, it is generally agreed that hypochondroplasia is a relatively common skeletal dysplasia that may approach the prevalence of achondroplasia (i.e., 1:15,000-40,000 live births). In addition, simplex cases (affected individuals with no family history of hypochondroplasia) have been associated with advanced paternal age.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hypochondroplasia, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

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

Pregnancy Management

There is a paucity of literature regarding pregnancy management in women with skeletal dysplasias. However, a number of women with hypochondroplasia have had unremarkable pregnancies and deliveries.

• In comparison to women who have achondroplasia, vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size.
• Epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy.
• If present, spinal stenosis may be aggravated during pregnancy due to the normal physiologic changes to the shape of the spine that occur as gestation progresses.

Therapies Under Investigation

Mode of Inheritance

Hypochondroplasia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a de novo pathogenic variant. There appears to be a paternal age effect in some simplex occurrences of hypochondroplasia (i.e., affected individuals with no family history of hypochondroplasia) [Walker et al 1971]. It is likely that de novo pathogenic variants occur on the paternally derived chromosome during spermatogenesis, as has been shown in achondroplasia [Wilkin et al 1998] and Apert syndrome [Moloney et al 1996].
• An individual diagnosed with hypochondroplasia may have an affected parent. In some families, both parents have hypochondroplasia.
• If a molecular diagnosis has been established in the proband and the proband appears to represent a simplex case (i.e., the only family member with hypochondroplasia), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent 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.* 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.
    * Parental gonadal mosaicism has not been reported in hypochondroplasia; however, presumed parental gonadal mosaicism for an FGFR3 variant has been reported in rare families in which parents with average stature have more than one child with achondroplasia.
• Some individuals diagnosed with hypochondroplasia may appear to be the only family member with hypochondroplasia because of failure to recognize the disorder in family members (the height range in hypochondroplasia may overlap that of the average range; see Penetrance). Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing (if a molecular diagnosis has been established in the proband) has been performed on the parents of the proband.
• Note: Because the skeletal features of hypochondroplasia are milder than those of achondroplasia and the incidence of disabilities is lower, the reproductive fitness of individuals with hypochondroplasia is most likely greater than that of individuals with achondroplasia.

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

• If one parent of the proband has hypochondroplasia, the risk to the sibs is 50%.
• If both parents have hypochondroplasia or one has hypochondroplasia and the other has a different autosomal dominant skeletal dysplasia, the risk to sibs is more complex (see Offspring of a proband).
• If the proband has a known FGFR3 pathogenic variant that cannot be detected in the leukocyte DNA of either parent and neither parent has an autosomal dominant skeletal dysplasia, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].

Offspring of a proband

• An individual with hypochondroplasia who has a reproductive partner of average stature has a 50% chance of having a child with hypochondroplasia.
• When the proband and the proband's reproductive partner have the same or different skeletal dysplasias, genetic counseling is more complex. In general, if both members of a couple have a 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 potentially poor pregnancy outcome.
  • Individuals who are compound heterozygous for one of the FGFR3 pathogenic variants resulting in p.Asn540Lys (c.1620C>A or c.1620C>G; causing hypochondroplasia) and one of the FGFR3 pathogenic variants resulting in p.Gly380Arg (c.1138G>A c.1138G>C; causing achondroplasia) on different alleles have a severe skeletal phenotype with the potential for serious disability [Huggins et al 1999, Bober et al 2012, González-Del Angel et al 2018].
  • Poor outcomes have been reported for individuals with compound heterozygosity for achondroplasia and spondyloepiphyseal dysplasia congenita [Young et al 1992, Günthard et al 1995] (see Type II Collagen Disorders Overview) or achondroplasia and pseudoachondroplasia [Langer et al 1993] (see COMP-Related Pseudoachondroplasia).
  • Individuals with double heterozygosity for either achondroplasia and Leri-Weill dyschondrosteosis or hypochondroplasia and Leri-Weill dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [Ross et al 2003, Binder G et al 2024].
• Genetic counseling of couples in which both individuals have hypochondroplasia is complicated by (1) genetic heterogeneity and (2) lack of information about the phenotypes and prognosis for offspring who inherit a pathogenic variant from both parents. Therefore, it is not possible to provide information about prognosis for all at-risk offspring.

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

Genetic counseling for hypochondroplasia presents dilemmas relating to ethical and genetic issues. Hypochondroplasia is considered a mild disorder in which the chief physical disability is generally short stature. Many affected individuals do not think of themselves as disabled. However, some parents may consider short stature a significant physical, emotional, and/or social disability. Furthermore, a child with hypochondroplasia may have intellectual disability or a learning disability. An additional issue is genetic heterogeneity (i.e., pathogenic variants in more than one gene causing hypochondroplasia), which may result in an inability to predict phenotype or prognosis and/or make diagnosis difficult.

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 if 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

• Molecular genetic testing. A high-risk pregnancy is one in which one parent has hypochondroplasia and the other parent is of average stature, has hypochondroplasia, or has another dominantly inherited skeletal dysplasia. Prenatal and preimplantation genetic testing are possible if the causative pathogenic variant(s) have been identified in the affected parent(s).
• Fetal ultrasound examination. If the causative variant for a second autosomal dominant skeletal dysplasia present in the couple is not known or if the variant causing hypochondroplasia cannot be identified, ultrasound examination is the only method of prenatal testing. It is often possible to detect an affected fetus with double heterozygosity for two dominantly inherited skeletal dysplasias early in the pregnancy. However, it is difficult to detect hypochondroplasia caused by a heterozygous pathogenic variant or other milder phenotypes using ultrasonography. Signs of disproportionate growth may suggest the diagnosis of hypochondroplasia, but a "normal" third trimester ultrasound examination is not sufficient to exclude a diagnosis of hypochondroplasia. The phenotype of homozygous hypochondroplasia has not yet been described; therefore, no statement can be made regarding prenatal diagnosis of homozygous hypochondroplasia by ultrasound examination.
  If significant macrocephaly is noted, it is appropriate to consider delivery by cesarean section to reduce the risk of potential central nervous system complications associated with a vaginal delivery.

Low-risk pregnancy. Hypochondroplasia may be suspected in a fetus not known to be at increased risk by the identification (typically later in the third trimester) on fetal ultrasound examination of short long bones and larger head circumferences [Sabir et al 2021]. As prenatal imaging may be limited (i.e., all features of hypochondroplasia may not be demonstrated), a broad multigene panel that includes FGFR3 and other genes of interest in the differential diagnosis or comprehensive genomic testing on a fetal sample obtained by amniocentesis can be considered to establish a diagnosis.

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), which is a tyrosine kinase receptor and a member of the fibroblast growth factor receptor family. This family comprises four related genes in mammals (FGFR1-FGFR4) with highly conserved structure. The FGFR genes are all characterized by an extracellular ligand-binding domain consisting of three immunoglobulin (Ig) subdomains, a transmembrane domain, and a split intracellular tyrosine kinase domain [Johnson & Williams 1993]. A stretch of four to eight acidic amino acids termed the acid box (whose function is not known) is found between the first and second Ig domains. Alternative splicing of FGFR transcripts results in several distinct mRNA isoforms that may lack one or more Ig domains, the acid box, or the intracellular tyrosine kinase domain. Some isoforms have regions of alternative sequence within the extracellular Ig domains. Exons 8 and 9 are alternatively spliced and encode different carboxyl termini of the third Ig domain. Alternative splicing of the FGFR genes is thought to modulate the affinity of the numerous fibroblast growth factors for the receptor and may control other aspects of receptor-mediated signaling.

The effects of the FGFR3 pathogenic variants on FGFR3 have been shown to result in constitutive activation of the tyrosine kinase receptor [Naski et al 1996, Webster & Donoghue 1996, Webster et al 1996, Thompson et al 1997, Tavormina et al 1999]. It therefore appears likely that the FGFR3 pathogenic variants found in hypochondroplasia may result in constitutive activation of the tyrosine kinase receptor, but to a lesser degree than these other pathogenic variants. Such appears to be the case in hypochondroplasia resulting from c.1950G>T (p.Lys650Asn) [G Bellus, D Donoghue, M Webster, C Francomano, unpublished results]. The premise that FGFR3 gain-of-function variants cause skeletal dysplasia is supported by the observation that targeted disruption of Fgfr3 in mice results in enhanced growth of long bones and vertebrae, suggesting that FGFR3 normally functions as a negative regulator of bone growth [Colvin et al 1996, Deng et al 1996].

Mechanism of disease causation. Gain of function

Author History

Arthur S Aylsworth, MD, FACMG; University of North Carolina (1999-2005)
Gary A Bellus, MD, PhD (1999-2005; 2013-present)
Michael B Bober, MD, PhD (2013-present)
Moira S Cheung, MD, PhD (2025-present)
Clair A Francomano, MD; National Institutes of Health (2005-2013)
Mahim Jain, MD, PhD (2025-present)
Thaddeus E Kelly, MD, PhD; University of Virginia Hospital (1999-2005)
Sarah M Nikkel, MD (2013-present)
George E Tiller, MD, PhD (2013-present)

Revision History

• 25 September 2025 (sw) Comprehensive update posted live
• 7 May 2020 (sw) Comprehensive update posted live
• 26 September 2013 (me) Comprehensive update posted live
• 12 December 2005 (me) Comprehensive update posted live
• 13 February 2003 (me) Comprehensive update posted live
• 15 July 1999 (pb) Review posted live
• 27 April 1999 (gb) Original submission

Published Guidelines / Consensus Statements

• Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med. 2009;11:127-33. [PubMed]

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