Hypochondroplasia

A primary bone dysplasia with micromelia characterized by disproportionate short stature, mild lumbar lordosis and limited extension of the elbow joints.

Epidemiology

Hypochondroplasia estimated incidence is 1/50,000. The exact prevalence is unknown.

Clinical description

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. Children usually present as toddlers or school-age children with decreased growth velocity leading to short stature and limb disproportion. However, some more severe cases are detected prenatally, at birth or in early infancy. Other features also become more prominent over time.

Etiology

The disorder is caused by mutations in the fibroblast growth factor receptor-3 gene (FGFR3; 4p16.3).

Diagnostic methods

Hypochondroplasia is diagnosed by the recognition of characteristic clinical and radiologic findings that remain controversial. DNA-based testing is possible and about 70% of affected individuals are heterozygous for a pathogenic variant in FGFR3. The most frequent variant is NM_000142.4:c.1620C>A; p.Asn540Lys (p.N540K), which accounts for approximately 60% of affected individuals.

Differential diagnosis

Hypochondroplasia closely resembles achondroplasia (also caused by variants in the FGFR3 gene). Differential diagnosis also includes mild forms of mesomelic dwarfism, mild forms of spondyloepiphyseal-metaphyseal dysplasias, Leri-Weill dyschondrosteosis, Pseudohypoparathyroidism and pseudopseudohypoparathyroidism.

Genetic counseling

The disorder is transmitted in an autosomal dominant manner. Genetic counseling should be proposed to individuals having the disease-causing variant informing them that there is 50% risk of passing the variant to offspring.

Management and treatment

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. Laminectomy relieves symptoms of spinal stenosis; about 70% of individuals experience relief of symptoms following decompression without laminectomy. Developmental milestones are followed closely during early childhood so that cognitive impairments are addressed with special educational programs. Epilepsy is treated in the standard fashion.

Prognosis

Final adult height varies between 132 and 147 cm and life expectancy is normal.