Pathways to Facilitate Early Recognition and Diagnosis of Hypochondroplasia

Hypochondroplasia (HCH) is a disproportionate short-statured skeletal dysplasia condition caused by gain-of-function pathogenic variants in the fibroblast growth receptor 3 gene (FGFR3). Although HCH typically becomes clinically apparent after the first year of life, when height discrepancy compared with the general population becomes more pronounced, diagnosis is often delayed by several years. Early recognition of HCH is challenging because of wide phenotypic variability and subtle clinical and radiographic features, leading to delayed or missed diagnosis. Furthermore, wide variant heterogeneity and restrictive testing criteria can contribute to diagnostic delays. Early diagnosis may facilitate timely clinical management and psychosocial support. However, no standardized diagnostic criteria for HCH currently exist, nor are diagnostic pathways well described in the literature.

In October 2024, 14 experts across multiple specialties completed an online survey on current clinical practices for diagnosing HCH. A subset convened in person to discuss strategies to optimize clinical diagnostic pathways, which were subsequently refined by the collective group.

Age-specific diagnostic opportunities were identified. Prenatally, sonographic features of HCH may be detectable from approximately 20 weeks' gestation. Postnatally, features suggestive of HCH include a sustained fall in length/height centiles over the first 2 years of life, relative macrocephaly, neonatal seizures, and specific radiographic and neuroimaging findings. Between ages 2-3 years, a characteristic growth pattern including limb shortening and body disproportion may become evident. Neurocognitive involvement including neurodevelopmental challenges may become apparent. HCH should be considered in the differential diagnosis of idiopathic or isolated short stature. Genetic testing panels that include FGFR3 and evaluation of short-statured parents can support diagnosis.

Early diagnosis of HCH is achievable when age-specific key clinical and radiologic features are recognized and supported by molecular testing using appropriate diagnostic platforms. This work represents an important first step towards developing consensus-based diagnostic guidelines for HCH.