Hypochondroplasia
Summary
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).
Diagnosis
The clinical and radiologic diagnostic criteria for hypochondroplasia remain controversial for several reasons, including the following:
- No single radiologic or clinical feature is unique to hypochondroplasia.
- The expression of many of the established diagnostic features in affected individuals is variable.
- Locus heterogeneity has been established.
Genetic heterogeneity and lack of agreement on a definitive set of diagnostic criteria have made it difficult to compare data from the many studies reported in the literature [Walker et al 1971, Hall & Spranger 1979, Heselson et al 1979, Oberklaid et al 1979, Wynne-Davies et al 1981, Maroteaux & Falzon 1988, Song et al 2012]. Nevertheless, it is clear that a complete radiographic survey including skull, pelvis, anteroposterior and lateral spine, legs, arms, and hands is absolutely necessary to make a clinical diagnosis of hypochondroplasia.
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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of hypochondroplasia, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
Single-gene testing
- Targeted analysis for pathogenic variants c.1620C>A and c.1620C>G can be performed first.
- Sequence analysis of FGFR3 can be performed next if a pathogenic variant is not identified on targeted analysis.
A multigene panel that includes FGFR3 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal dysplasia, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Hypochondroplasia
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| FGFR3 | Targeted analysis for c.1620C>A and c.1620C>G | ~70%-80% 3, 4 |
| Sequence analysis 5 | 70%-90% 4 | |
| Gene-targeted deletion/duplication analysis 6 | None reported 7 | |
| Unknown 8 | NA | 10%-30% |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
The two most common pathogenic variants [Prinos et al 1995, Bellus et al 1996, Rousseau et al 1996, Fofanova et al 1998, Prinster et al 1998, Ramaswami et al 1998, Heuertz et al 2006]
- 4.
Xue et al [2014]
- 5.
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.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No deletions or duplications involving FGFR3 have been reported to cause hypochondroplasia.
- 8.
Using diagnostic criteria based solely on the radiographic finding of decreased interpediculate distance between L1 and L5, Mullis et al [1991] studied 20 children with hypochondroplasia. Two RFLPs identified within introns of IGF1 (12q23) showed a positive LOD score of 3.31 in some families with hypochondroplasia. To date, no further refinement of the genetic locus on 12q23 has been reported and no pathogenic variants have been reported in IGF1.
Clinical Characteristics
Differential Diagnosis
Numerous forms of skeletal dysplasia with disproportionate limbs are recognized and are characterized by clinical and radiologic features that distinguish them from hypochondroplasia and achondroplasia. Many of these disorders are quite rare. The diagnosis of hypochondroplasia is seldom made at birth unless a prior family history exists. Most affected individuals present with short stature as toddlers or young school-age children. Inappropriate diagnoses of hypochondroplasia are often made because the disorder is considered to be relatively common and the radiologic features are variable and may be subtle.
Conditions with a known genetic etiology that may be confused with hypochondroplasia are summarized in Table 3.
Table 3.
Genes of Interest in the Differential Diagnosis of Hypochondroplasia
| Gene(s) | Disorder | MOI |
|---|---|---|
| B3GALT6 | Mild forms of spondyloepimetaphyseal dysplasia (e.g., SEMDJL1; OMIM 271640) | AR |
| FGFR3 | Mild achondroplasia 1 | AD |
| GNAS | Pseudohypoparathyroidism & pseudopseudohypoparathyroidism (see Disorders of GNAS Inactivation) | AD 2 |
| COL10A1 PTH1R | Mild forms of metaphyseal chondrodysplasia (e.g., Schmid metaphyseal chondrodysplasia & Murk Jansen metaphyseal chondrodysplasia; OMIM 156400) | AD |
| SHOX | Mild forms of mesomelic dysplasia (e.g., Langer mesomelic dysplasia; OMIM 249700) | Pseudoautosomal recessive |
| Leri-Weill dyschondrosteosis (see SHOX deficiency disorders) | Pseudoautosomal dominant |
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SEMDJL1 = spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures
- 1.
See Genetically Related Disorders.
- 2.
Disorders of GNAS inactivation are inherited in an autosomal dominant manner with the specific phenotype determined by the parental origin of the defective allele.
Other conditions to consider in the differential diagnosis of hypochondroplasia:
- Short stature caused by disturbances in the growth hormone axis
- Constitutive short stature
Management
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.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with Hypochondroplasia
| System/Concern | Evaluation | Comment |
|---|---|---|
| Growth | Measurement of height, weight, & head circumference | Plot growth parameters on achondroplasia-standardized growth curves. |
| Musculoskeletal | Clinical assessment for truncal weakness or evidence of thoracolumbar kyphosis | Lateral spine films to evaluate for thoracolumbar kyphosis if indicated |
| Clinical assessment for genu varum | Referral to orthopedist if bowing interferes w/walking | |
| Narrow craniocervical junction |
|
|
| Neurology | Clinical assessment for symptoms suggestive of epilepsy | Referral to pediatric neurologist when indicated |
| Development | Developmental assessment |
|
| Spinal cord stenosis | In newly diagnosed adults: neurologic exam for signs of spinal cord stenosis (intermittent, reversible, exercise-induced claudication to severe, irreversible abnormalities of leg function & continence) | If severe signs &/or symptoms of spinal stenosis arise, urgent surgical referral is appropriate. |
| Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
Treatment of Manifestations
Table 5.
Treatment of Manifestations in Individuals with Hypochondroplasia
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Short stature |
| Adult height in hypochondroplasia is considerably greater than achondroplasia & functional limitations (e.g., operating an elevator, driving a car, using an automatic teller machine) usually less severe or not an issue. |
| Narrow craniocervical junction w/spinal cord compression | Referral to pediatric neurosurgeon to consider suboccipital decompression if neurologic status is affected by spinal cord compression | See Achondroplasia for best predictors of need for suboccipital decompression. |
| Thoracolumbar kyphosis | Treatment if necessary per orthopedic surgeon | |
| Genu varum | Treatment if necessary per orthopedic surgeon | |
| Spinal stenosis | Laminectomy 1 | If severe signs &/or symptoms of spinal stenosis arise, urgent surgical referral is appropriate. |
| Epilepsy | Standardized treatment w/AEDs by experienced neurologist |
|
| DD/ID | See Developmental Delay / Intellectual Disability Management Issues | |
| Family/ Community | Connect family with w/local resources & support (LPA) | LPA can:
|
AED = antiepileptic drug; DD/ID = developmental delay / intellectual disability; LPA = Little People of America, Inc.
- 1.
Thomeer & van Dijk [2002] determined that about 70% of symptomatic individuals with achondroplasia experienced total relief of symptoms following decompression without laminectomy. The L2-L3 level most commonly required decompression.
- 2.
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Developmental Disability / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments.
Gross motor dysfunction. Physical therapy is recommended to maximize mobility.
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Surveillance
Table 6.
Recommended Surveillance for Individuals with Hypochondroplasia
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Growth | Height, weight, & head circumference | Monitor using achondroplasia-standardized growth curves |
| Spinal cord compression | Neurologic exam for signs/symptoms | At routine well-child visits through adulthood |
| MRI or CT exam of the foramen magnum if evidence of severe hypotonia, spinal cord compression, or central sleep apnea | ||
| Sleep apnea | Assessment for signs/symptoms | At routine well-child visits through adulthood |
| Thoracolumbar kyphosis | Physical exam | At routine well-child visits through age 3 yrs |
| Genu varum | Physical exam w/orthopedic referral if bowing interferes w/walking | |
| Development | Assessment of developmental milestones | Monitor closely during early childhood. |
| Assessment of social adjustment | At routine well-child visits & then annually |
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
Growth Hormone Therapy
Trials of growth hormone therapy in hypochondroplasia have shown mixed results. Those differences in individual responses published prior to gene discovery in 1995 [Mullis et al 1991, Bridges & Brook 1994] may have resulted from genetic heterogeneity and indicate a need for stratification of affected individuals with regard to genetic etiology (e.g., those with FGFR3 pathogenic variants and those without). Meyer et al [2003] emphasized the importance of considering pubertal development in assessing the response to growth hormone stimulation testing. Tanaka et al [2003] reported data suggesting that children with hypochondroplasia may have a greater response to growth hormone therapy than children with achondroplasia.
Pinto et al [2012] treated 19 children with hypochondroplasia (11/19 with confirmed FGFR3 pathogenic variants, mean age 9.0±3.0 years) with human recombinant growth hormone over a three-year period. Their mean height increased 1.32±1.05 standard deviation score (SDS) compared to a historical cohort of 40 untreated individuals with hypochondroplasia.
Rothenbuhler et al [2012] treated six children with hypochondroplasia (confirmed FGFR3 p.Asn540Lys substitution, mean age 2.6±0.7 years) with human recombinant growth hormone over a six-year period. Their mean height SDS increased by 1.9 during the study period, and trunk/leg disproportion was improved.
Çetin et al [2018] treated six children (mean age 7.8±3.2 years) with hypochondroplasia (confirmed FGFR3 pathogenic variant in a single individual) with human recombinant growth hormone over a mean of 4.45 years. Their mean height SDS increased by 0.26±1.19 during the study period, and trunk/leg disproportion was unchanged.
Since data about final adult height in growth hormone-treated individuals with hypochondroplasia are not available, the ultimate success of this approach remains uncertain. Growth hormone therapy should still be considered experimental and controversial in this condition.
Surgical Limb Lengthening
Surgical limb lengthening procedures have been used to treat achondroplasia and hypochondroplasia for more than 15 years. Although the complication rate was high initially, outcomes have steadily improved and significant increases in overall height have been reported [Yasui et al 1997, Lie & Chow 2009]. Nevertheless, the procedure is very invasive and entails considerable disability and discomfort over a long period of time. While some advocate performing the procedure during childhood, many pediatricians, geneticists, and ethicists advocate postponement until adolescence, when the affected individual is able to make an informed decision. Surgical limb lengthening is controversial, but is achieving greater acceptance with fewer complications as larger numbers of operations have been performed.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.