Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• GENE/GENE PANEL: FGFR3
• Condition: Hypochondroplasia
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• FGFR3 ⇔ 0007793 (hypochondroplasia): N/A - Insufficient evidence: expert review

Actionability Rationale

A summary report was created to assess the evidence. After review by the expert group, it was decided not to score this gene-disease pair because of insufficient evidence of actionability in the context of a secondary finding.

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

No studies attempting to determine the prevalence of FGFR3 hypochondroplasia have been published. Ascertainment of affected individuals is problematic as it is thought that many 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 (1 in 15,000-40,000 lives births). Hypochondroplasia estimated incidence is stated to be between 1 in 50,000-100,000. [1, 2, 3]

Clinical Features

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. Facial dysmorphism including frontal bossing and mid-facial hypoplasia can occur, but not often. Elbow extension can be limited. Cognitive abilities are usually normal unless complications intervene. Many infants and young children with hypochondroplasia can develop recurrent or persistent middle ear dysfunction with conductive hearing loss. Less common clinical features include scoliosis, genu varum (bowed legs), lumbar lordosis with protruding abdomen, learning disabilities, mild-to-moderate intellectual disability, acanthosis nigricans, temporal lobe dysgenesis, and temporal lobe epilepsy. 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. [1, 2, 4, 5]

Natural History

Children usually present as toddlers or at early school age with decreased growth velocity leading to short stature and limb disproportion. Growth in the first 1-3 years may be near normal. Other features also become more prominent over time. Some investigators have reported the absence of a pubertal growth spurt. When children begin to walk, exaggerated lumbar lordosis and mild genu varum 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 in the arms. 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 males and 128 to 151 cm (50” to 59”) for females. Functional limitations (e.g., operating an elevator, driving a car) are usually less severe than achondroplasia or not an issue. Life expectancy is normal. [1, 2, 5]

2. How effective are interventions for preventing harm?

Patient Management

Management of children with hypochondroplasia does not differ significantly from that of children with normal stature except for genetic counseling issues and addressing parental expectations and concerns about short stature. Genetic counseling for hypochondroplasia presents dilemmas relating to ethical and genetic issues. Many individuals with hypochondroplasia do not think of themselves as disabled. However, some parents may consider short stature a significant physical, emotional, and/or social disability. Address parents’ expectations and prejudices regarding the child’s height rather than attempting to treat the child. Genetic heterogeneity may result in an inability to predict phenotype or prognosis. Because the phenotype of FGFR3 hypochondroplasia may overlap with that of achondroplasia, recommendations for the management of achondroplasia should be considered in children with hypochondroplasia who exhibit more severe phenotypic features. (Tier 4) [1, 2]

To establish the extent of disease and needs in an individual diagnosed with hypochondroplasia, the following evaluations are recommended.
•Measurement of height, weight, and head circumference. Plot growth parameters on achondroplasia- standardized growth curves.
•Clinical assessment for truncal weakness, limited elbow extension, 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 with walking.
•Assess for signs/symptoms of sleep apnea. Refer for polysomnography if needed.
•Neurologic exam for signs of spinal cord compression. MRI or CT of the foramen magnum if spinal cord compression suggested by findings on neurologic exam or central apnea identified on sleep study. Referral to a pediatric neurologist or neurosurgeon if needed.
•Clinical assessment for symptoms suggestive of epilepsy. Referral to pediatric neurologist when indicated.
•Developmental assessment to include motor, adaptive, cognitive, speech and language evaluation. Evaluation for early intervention or special education.
•Consultation with clinical geneticist and/or genetic counselor. (Tier 4) [1]

Those with macrocephaly (above +2 standard deviations) should have baseline neuroimaging in infancy or early childhood to assess ventricle size and volume of extra-axial fluid. (Tier 4) [5]

Parents/caregivers should be educated regarding common seizure presentations. Any child with hypochondroplasia who has apneic episodes or seizure-like events should have both electroencephalography and MRI of the brain. (Tier 4) [1, 5]

Individuals with severe short stature should be assessed for age-appropriate needs such as school adaptions, stools, adaptations for toileting, teacher involvement, and involvement with Little People of America. (Tier 4) [5]

Growth hormone therapy may be considered as a treatment option for those with hypochondroplasia. (Tier 2) [6]

A systematic review and meta-analysis of recombinant human growth hormone (rhGH) therapy included 113 individuals of unknown ancestry with hypochondroplasia from seven studies (only three studies included genetic data). Most of the enrolled patients were prepubertal (Tanner stage 1) or in early pubertal development (Tanner stage 2) at the start of rhGH treatment. In total children (n=93), mean height was subnormal in all seven studies (p<0.0001). Height progressively increased during rhGH treatment with major catch-up growth at 12 months (p<0.0001). Then height improvement remained constant until 36 months of rhGH treatment, but height was still subnormal. (Tier 1) [7]

Surgical limb lengthening procedures have been used to treat hypochondroplasia. Although the complication rate was high initially, outcomes have steadily improved and significant increases in overall height have been reported. While some advocate performing the procedure during childhood, many pediatricians, geneticists, and ethicists advocate postponement until adolescence, when the individual can make an informed decision. (Tier 4) [1]

The Little People of America Medical Advisory Board issued a position summary on limb lengthening. The entire position summary can be accessed here: https://www.lpaonline.org/limb-lengthening-position-statement. In summary, the recommendations are that prospective patients should be of an age to participate fully in these discussions and in the decision-making process. Interested individuals should carefully assess the institution and personnel, as well as all risks and benefits of limb lengthening prior to committing to this procedure. Before, during and after the operative procedure evaluation should include orthopedic assessment, physical therapy assessment, clinical neurological evaluation, peripheral vascular assessment, and psychological evaluation, including self-image, body image, peer relationships, and family relationships. All of these evaluations will require the cooperative involvement of orthopedic surgeons, physical and occupational therapists, medical geneticists, radiologists, psychologists and/or psychiatrists, and social workers in longitudinal management, at an institution with expertise in skeletal dysplasia. (Tier 4) [8]

A systematic review of lower limb lengthening using external fixation included 367 individuals of unknown ancestry with achondroplasia or hypochondroplasia. The average age at lengthening was 14.5 years (range 4 to 35 years). The mean gain in height was 9.5 cm (range 6-12 cm). The average healing index (HI) was 31 days/cm (range 24-41 days/cm). The complication rate per segment lengthened was 487 in 707 or 0.68. Sequelae per segment lengthened was 1.7%. Reported sequelae included stiff ankle, residual peroneal nerve paralysis, knee valgus, and ankle valgus. (Tier 1) [9]

Surveillance

The following are surveillance recommendations for individuals with hypochondroplasia.
•Monitor height, weight and head circumference using achondroplasia-standardized growth curves.
•Behavioral audiometric and tympanometric assessment, first at 9-12 months of age and at least yearly throughout early childhood.
•Neurologic exam for signs/symptoms of spinal cord compression at routine well-child visits.
•Assessment for signs/symptoms of sleep apnea at routine well-child visits.
•Physical exam for thoracolumbar kyphosis at routine well-child visits through age 3 years.
•Physical exam for genu varum. Clinical history should inquire about pain with ambulation, decreased endurance, and decreased activity level. Orthopedic referral if bowing interferes with walking or is associated with marked pain.
•Periodic assessment of development, especially during early childhood, and more formal assessment should suspicion of serious delays arise.
•Assessment of social adjustment at routine well-child visits and then annually. (Tier 4) [1, 2, 5]

Repeat neuroimaging if head growth acceleration or signs/symptoms of hydrocephalus arise. (Tier 4) [5]

Circumstances to Avoid

Information regarding circumstances to avoid was not identified.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [1, 4]

Prevalence of Genetic Variants

The two most common pathogenic variants, c.1620C>A and c.1620C>G, account for 70% to 80% of individuals. (Tier 3) [1]

Most individuals with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a de novo pathogenic variant. (Tier 4) [1]

Penetrance

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. Rare individuals with the common variant have been identified who have body disproportion but ultimate height within the normal range. (Tier 4) [1, 5]

In about 50% of children macrocephaly will be present. In an unknown but probably very tiny minority (i.e. less than 5%) symptomatic hydrocephalus requiring shunting will develop. A small minority, perhaps 5-10%, of individuals with hypochondroplasia have seizures. Learning disabilities may be present in as many as half of children and 10-12% have intellectual disability. Progressive varus at the knees and of the mesial segments of the legs arises in around 10-20% of children. (Tier 4) [5]

Anthropometry data were collected from a cohort of 188 healthy children recruited within Europe <18 years of age with hypochondroplasia based on established radiological and clinical criteria. Eighty-four children underwent genetic testing. By 1 year of age, 75% of females and 50% of males were below the 2nd centile in length. By 4 years, over 90% of females and 75% of males were below the 2nd centile in length. (Tier 5) [3]

In a retrospective cohort of 35 individuals recruited in Japan with genetically confirmed hypochondroplasia from 30 families that presented for care, the mean age at diagnosis in probands was 2 years, ranging from 0 to 6 years. The median height SD score at diagnosis in probands was -3.1, ranging from -5.6 to -0.3. The height SD scores at diagnosis were -2.0 SD in all patients, except in two diagnosed at 4 months of age or younger. Four individuals (11%) were known to have intellectual disability and 6 (26%) had epilepsy. (Tier 5) [10]

In a retrospective cohort of 20 individuals recruited in Europe with hypochondroplasia who presented for care the median age was 12 years (range 2 to 45 years). One individual had a stenosis and underwent surgery at the age of 10 months. One infant developed hydrocephalus and required a shunt at the age of 6 months. Neurological manifestations in the cohort included:
•Epilepsy 10%
•Headache 20%
•Sleep apnea 15%
•Pain back/neck 15%
•Pain lower limbs 35%
•Hypotonia 15%
•Bladder dysfunction 5%
•Hydrocephalus 10% (Tier 5) [11]

Relative Risk

Information regarding relative risk was unavailable.

Expressivity

In general, it appears that the phenotypes of individuals with hypochondroplasia with have FGFR3 pathogenic variants c.1620C>A and c.1620C>G have more severe manifestations than those with hypochondroplasia who do not have these pathogenic variants. (Tier 3) [1]

Pathogenic variants in FGFR3 can also cause achondroplasia, thanatophoric dysplasia, FGFR3 craniosynostosis, and SADDAN syndrome (which share many features, but which vary markedly in severity). Mild achondroplasia and severe hypochondroplasia may have very similar clinical presentations and are thus easily confused. (Tier 4) [1, 5]

The expression of many of the established diagnostic features in individuals with hypochondroplasia is variable. Radiographic features vary significantly among affected individuals. (Tier 4) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

A systematic review and meta-analysis of rhGH therapy included 113 individuals with hypochondroplasia from seven studies. No serious adverse events were reported during rhGH treatment except one study that reported few patients who developed mild scoliosis and worsening of genu varum. Surgical limb lengthening is very invasive and entails considerable disability and discomfort over a long period of time. The possible complications of limb lengthening include nerve injury (usually temporary), infection, angulation, non-union, increased contractures (of the hip, knee and/or ankle), fractures, unequal limb lengths and increased risk for late onset osteoarthritis. [1, 7, 8]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

The disproportion in limb-to-truck length is often mild and easily overlooked during infancy. 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. In relatively mildly affected individuals, near normal growth in the first years of life may result in delay in diagnosis. Because of the 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. Hypochondroplasia can be difficult to diagnose because no single radiologic or clinical feature is unique to hypochondroplasia. Individuals may have a phenotype indistinguishable from and confused with many other inherited disorders with skeletal dysplasia and/or short stature (e.g., spondyloepimetaphyseal dysplasia, pseudohypoparathyroidism, metaphyseal chondrodysplasia, metaphyseal chondrodysplasia). (Tier 4) [1, 5]

Date of Search: 10.07.2024

Reference List

1. Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A. Hypochondroplasia. GeneReviews®. (1993)

2. Hypochondroplasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=429

3. Cheung MS, Cole TJ, Arundel P, Bridges N, Burren CP, Cole T, Davies JH, Hagenäs L, Högler W, Hulse A, Mason A, McDonnell C, Merker A, Mohnike K, Sabir A, Skae M, Rothenbuhler A, Warner J, Irving M. Growth reference charts for children with hypochondroplasia. Am J Med Genet A. (2024) 194(1552-4833):243-252.

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HYPOCHONDROPLASIA; HCH. MIM: 146000: 2022 Nov 02. World Wide Web URL: http://omim.org.

5. Pauli RM. Hypochondroplasia Natural History: Little People of America. (2009) Website: https://www.lpaonline.org/assets/documents/NH%20Hypochondroplasia1.pdf

6. Hoover-Fong J, Scott CI, Jones MC, COMMITTEE ON GENETICS. Health Supervision for People With Achondroplasia. Pediatrics. (2020) 145(1098-4275).

7. Massart F, Miccoli M, Baggiani A, Bertelloni S. Height outcome of short children with hypochondroplasia after recombinant human growth hormone treatment: a meta-analysis. Pharmacogenomics. (2015) 16(1744-8042):1965-73.

8. Board LPoAMA. Extended Limb Lengthening Position Summary. (2006) Website: https://www.lpaonline.org/limb-lengthening-position-statement

9. Kim SJ, Pierce W, Sabharwal S. The etiology of short stature affects the clinical outcome of lower limb lengthening using external fixation. A systematic review of 18 trials involving 547 patients. Acta Orthop. (2014) 85(1745-3682):181-6.

10. T. Ishii, Takagi, M., Nagasaki, K., Ohara, T., Miyai, K., Kosho, T., Takada, F., Nishimura, G., Hasegawa, T. Molecular basis for hypochondroplasia in Japan. Endocrines. (2022) Website: https://keio.elsevierpure.com/en/publications/molecular-basis-for-hypochondroplasia-in-japan

11. Doherty MA, Hertel, N. T., Hove, H. B., Haagerup, A. Neurological symptoms, evaluation and treatment in Danish patients with achondroplasia and hypochondroplasia. Journal of Rare Diseases Research & Treatment. (2019) Website: https://www.rarediseasesjournal.com/articles/neurological-symptoms-evaluation-and-treatment-in-danish-patients-with-achondroplasia-and-hypochondroplasia.pdf