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 macrocephaly. Radiologic features include shortening of long bones with mild metaphyseal flare; narrowing of the inferior lumbar interpedicular distances; short, broad femoral neck; and squared, shortened ilia. The skeletal features are very similar to those seen in achondroplasia but tend to be milder. Medical complications common to achondroplasia (e.g., 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.

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. Suboccipital decompression if neurologic status is affected by spinal cord compression. Treatment for thoracolumbar kyphosis and/or genu varum as per orthopedic surgeon if necessary. Laminectomy relieves symptoms of spinal stenosis; about 70% of individuals experience relief of symptoms following decompression without laminectomy. Epilepsy is treated in the standard fashion. Developmental milestones are followed closely during early childhood so that cognitive impairments are addressed with special educational programs. Connect family with local resources and support.

Surveillance: Height, weight, and head circumference should be monitored using achondroplasia-standardized growth curves. The following should be performed at routine well-child visits: neurologic examination for signs of spinal cord compression, assessment of signs and symptoms of sleep apnea, physical examination for emerging leg bowing, and monitoring of development and social adjustment. MRI or CT examination of the foramen magnum is indicated if there is evidence of severe hypotonia, spinal cord compression, or central sleep apnea.

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. 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 germline mosaicism. An individual with hypochondroplasia who has a partner of average stature is at a 50% risk of having a child with hypochondroplasia. If an affected individual's partner also has hypochondroplasia (or another dominant form of skeletal dysplasia), genetic counseling becomes more complicated because of (1) the risk for inheriting two dominantly inherited skeletal dysplasias, (2) the high incidence of genetic heterogeneity, and (3) the lack of medical literature addressing these circumstances. Prenatal testing 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.

Clinical features

• Short stature (adult height 128-165 cm; 2-3 SD below the mean in children)
• Stocky build
• Shortening of the proximal or middle segments of the extremities (respectively, rhizomelia or mesomelia)
• Limitation of elbow extension
• Broad, short hands and feet with brachydactyly
• Generalized, mild joint laxity
• Macrocephaly with relatively normal facies

Less common but significant clinical features:

• Scoliosis
• Bowed legs (genu varum) (usually mild)
• Lumbar lordosis with protruding abdomen
• Mild-to-moderate intellectual disability
• Learning disabilities
• Adult-onset osteoarthritis
• Acanthosis nigricans
• Temporal lobe epilepsy

Radiologic features. The most common radiologic features of hypochondroplasia:

• Shortening of long bones with mild metaphyseal flare (especially femora and tibiae)
• Narrowing of the inferior lumbar interpedicular distances (or failure to widen)
• Mild-to-moderate brachydactyly
• Short, broad femoral neck
• Squared, shortened ilia

Less common but significant radiologic features:

• Elongation of the distal fibula
• Shortening (anterior-posterior) of the lumbar pedicles
• Dorsal concavity of the lumbar vertebral bodies
• Shortening of the distal ulna
• Long ulnar styloid (seen only in adults)
• Prominence of muscle insertions on long bones
• Shallow "chevron" deformity of distal femur metaphysis
• Low articulation of sacrum on pelvis with a horizontal orientation
• Flattened acetabular roof

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) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of hypochondroplasia is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with skeletal dysplasia and/or short stature are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Growth. The most common presenting feature of children with hypochondroplasia is short stature with disproportionate limbs. Birth weight and length are often within the normal range and the disproportion in limb-to-trunk length is often mild and easily overlooked during infancy. Typically, these children present to pediatricians or pediatric endocrinologist as toddlers or at early school age with decreased growth velocity leading to short stature. Some investigators have reported the absence of a pubertal growth spurt [Bridges et al 1991]. 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].

Musculoskeletal. When children begin to walk, exaggerated lumbar lordosis and mild genu varum (bowlegs) are often noted. The genu varum is usually transient and rarely requires surgical intervention. With age, limb disproportion usually becomes more prominent in the legs than the arms. Both rhizomelic [Maroteaux & Falzon 1988] and mesomelic [Walker et al 1971] shortening have been reported, although others have reported the predominance of neither [Hall & Spranger 1979]. Young children and adults often have a thick, muscular appearance and may be described as "stocky." The hands are relatively short but do not exhibit the "trident" appearance that is typical in achondroplasia. 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. Head size may be large without significant disproportion.

Neurology. The incidence of intellectual disability is thought to be higher in hypochondroplasia than in achondroplasia or the general population. This observation has been controversial, and several studies have reported conflicting results [Walker et al 1971, Hall & Spranger 1979, Wynne-Davies & Patton 1991]. It is unclear whether these discrepancies result from sampling bias, genetic heterogeneity, or both. 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). Six of 13 affected individuals had a history of epilepsy. Of eight individuals who underwent head MRI, all had temporal lobe dysgenesis, six had peritrigonal white matter reduction, and four had abnormally shaped lateral ventricles.

Unlike achondroplasia, motor milestones are usually not significantly delayed and symptoms resulting from spinal cord compression (e.g., apnea, neuropathy) are less common [Wynne-Davies et al 1981]. Symptoms of spinal stenosis are 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., p.Lys650Gln, 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 (FGFR3 pathogenic variant 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].

Other. Multiple-suture craniosynostosis has been reported in one individual with hypochondroplasia [Angle et al 1998] and the common pathogenic variant p.Asn540Lys.

Genotype-Phenotype Correlations

Other than p.Asn540Lys, most pathogenic variants have not been reported in high enough frequency to make any generalizations about specific genotype-phenotype manifestations.

• p.Tyr278Cys. More recently, both Heuertz et al [2006] and Song et al [2012] reported that a p.Tyr278Cys (c.829A>G) pathogenic variant resulted in a phenotype that resembled achondroplasia in the newborn period.
• 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.
• 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 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 SD above the mean had a greater likelihood of possessing the p.Asn540Lys pathogenic variant. No difference exists in phenotype between the FGFR3 c.1620C>A and c.1620C>G pathogenic variants, as they result in identical mutated proteins, p.Asn540Lys.
• Individuals with p.Lys650Gln or p.Lys650Thr have a higher likelihood of developing acanthosis nigricans (see Clinical Description). The variant p.Lys650Thr also appears to be correlated with milder skeletal issues [Muguet Guenot et al 2019].
• Pathogenic variants resulting in p.Lys650Asn and p.Lys650Gln are associated with a slightly milder skeletal phenotype than pathogenic variants resulting in p.Asn540Lys. Bellus et al [2000] reported six individuals with p.Lys650Asn or p.Lys650Gln who had a significantly lower average height deficit than 36 individuals with p.Asn540Lys. In addition, the L1:L4 interpediculate distance and fibula: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).

Prevalence

No studies attempting to determine the prevalence of FGFR3 and/or non-FGFR3 hypochondroplasia have been published. Ascertainment of cases 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 in 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

Management of children with hypochondroplasia usually does not differ significantly from that of children with normal stature except for genetic counseling issues and dealing with parental concerns about short stature. However, because the phenotype of FGFR3 hypochondroplasia may overlap with that of achondroplasia, recommendations for the management of achondroplasia as outlined by the American Academy of Pediatrics Committee on Genetics [Trotter et al 2005] should be considered in children with hypochondroplasia who exhibit more severe phenotypic features.

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

Surveillance

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 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 [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].
• In some instances, one or both parents have hypochondroplasia.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo FGFR3 pathogenic variant.
• If an FGFR3 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband; another possible explanation is germline mosaicism in a parent. (Note: Parental germline mosaicism has not been reported in hypochondroplasia; however, presumed parental germline mosaicism for an FGFR3 variant has been reported in rare families in which parents with average stature have more than one child with achondroplasia.)
• The family history of some individuals diagnosed with hypochondroplasia may appear to be negative 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 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. It is likely that the number of families with multiple affected members is higher for hypochondroplasia than for achondroplasia, and that the percentage of cases of hypochondroplasia attributable to de novo pathogenic variants is less than the 80% figure stated for 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 is affected, 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 germline mosaicism [Rahbari et al 2016].

Offspring of a proband

• An individual with hypochondroplasia who has a reproductive partner of average stature is at a 50% risk 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 complicated. 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 heterozygotes for FGFR3 variants p.Asn540Lys and p.Gly380Arg (the pathogenic variants that cause hypochondroplasia and achondroplasia, respectively) or individuals in whom the hypochondroplasia results from FGFR3 variant p.Asn540Lys 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 who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [Young et al 1992, Günthard et al 1995] or achondroplasia and pseudoachondroplasia [Langer et al 1993].
  • Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [Ross et al 2003].
• Genetic counseling of couples both of whom 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. No reports address the following phenotypes:
  • Individuals with hypochondroplasia who are homozygous for FGFR3 pathogenic variants or homozygous for non-FGFR3 pathogenic variants
  • Individuals who are compound heterozygotes for an FGFR3 pathogenic variant and a non-FGFR3 pathogenic variant
• Similarly, the following phenotypes have not been described:
  • Individuals who are compound heterozygotes for a non-FGFR3 pathogenic variant causing hypochondroplasia and an FGFR3 pathogenic variant causing achondroplasia
  • Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an FGFR3 pathogenic variant or a pathogenic variant in a different gene) and another dominantly inherited skeletal dysplasia (except individuals who are compound heterozygotes for FGFR3 pathogenic variants causing hypochondroplasia and achondroplasia; see above: Individuals who are compound heterozygotes for FGFR3 variants)
• 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.

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, non-medical 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 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 testing for a high-risk pregnancy 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 early in the pregnancy if the fetus is at risk of being a compound heterozygote with another dominantly inherited skeletal dysplasia. However, it is currently difficult to detect heterozygous hypochondroplasia 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 CNS complications associated with a vaginal delivery.

Low-risk pregnancy. A fetus with a de novo FGFR3 pathogenic variant causing hypochondroplasia who exhibits short limbs may be detected by routine ultrasound examination late in pregnancy [Jones et al 1990]. DNA-based diagnosis (i.e., FGFR3 p.Asn540Lys and p.Gly380Arg analysis for pathogenic variants) via amniocentesis may be helpful in ruling out lethal forms of skeletal dysplasia and establishing a more favorable prognosis for the fetus.

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.

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

Molecular Pathogenesis

Fibroblast growth factor receptor 3 is a receptor tyrosine kinase (FGFR3) 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 FGFs for the receptor and may control other aspects of receptor-mediated signaling.

The effects of the FGFR3 pathogenic variants on FGFR3 function have been shown to result in constitutive activation of the receptor tyrosine kinase [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 receptor tyrosine kinase, but to a lesser degree than these other pathogenic variants. Such appears to be the case in hypochondroplasia resulting from 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)
Clair A Francomano, MD; National Institutes of Health (2005-2013)
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

• 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. Available online. 2009. Accessed 1-24-23.

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