Achondroplasia

Achondroplasia is a skeletal genetic disease caused by autosomal dominant variants in FGFR3, acting through gain-of-function (constitutive receptor activation). Within this volume's rankable burden cohort it sits at residual rank 5 of 23, where established therapy is partially disease-modifying. That order is a provisional [H]-grade prioritisation device, not a registry-locked ranking.

Achondroplasia is inherited as autosomal dominant and acts by gain-of-function (constitutive receptor activation) ([L]). Its pre-treatment burden proxy is 0.7167 and, after the established therapy's efficacy offset e = 0.3000 is applied, its residual burden score is 0.5017 ([H]), placing it at residual rank 5 of 23.

Gene, inheritance, and molecular mechanism

Achondroplasia is inherited as Autosomal dominant inheritance [L] and is classified mechanistically as gain-of-function (constitutive receptor activation) [L]. FGFR3 encodes fibroblast growth factor receptor 3, a negative regulator of bone growth. A recurrent gain-of-function variant leaves the receptor constitutively active, suppressing chondrocyte proliferation at the growth plate.

Inheritance source: medgen:esummary:ModeOfInheritance:2026-06-17. Mechanism source: curated_rule:fgfr3_gof; established molecular genetics; OMIM(row) molecular section; OMIM:100800. These are observed, cited inputs; the inheritance and mechanism classification is the reproducible analysis layer (C-D1).

In-scope clinical involvement

Achondroplasia is the most common skeletal dysplasia: disproportionate short stature with rhizomelic limb shortening, macrocephaly with frontal bossing, midface hypoplasia, and trident hands.

Organ systems [L] from HPO phenotype.hpoa v2026-06-06 (OMIM 100800,134934); P-aspect terms rolled up to HP:0000118 organ-system categories via hp.obo.

Reproducible burden position

Of the five axes, 3 are scored (the rankability cut is ≥ 3 of 5); the pre-treatment composite is the renormalised mean over the scored axes, raw_burden = 0.7167. The registry-grade [L] axes here are onset and severity (onset from the Orphanet AverageAgeOfOnset register / HPO). Mortality remains an [H] inference from the cited clinical definition.

Because those axes carry [H] inferences, this position is a provisional [H] prioritisation device, not a registry-locked ranking.

The natural-history registry passes have been run against Orphanet/Orphadata (CC BY 4.0, R6) and the openly published GBD 2013 disability-weights table (Salomon et al., CC BY, R7). R6 lifts onset to registry-grade [L] across most of the cohort (earliest AverageAgeOfOnset category, entity-anchored per ORPHAcode, Exact OMIM↔ORPHA only); R7 lifts disability to [L] where one dominant untreated sequela maps to a named GBD health state (published disability weight binned by declared cut-points), and independently corroborates a mortality axis from PMC survival literature where a quantitative disease-typical figure exists. Severity now lifts to registry [L] for the one disease whose dominant sequela carries a cited HPO Severity-modifier annotation (the HP:0012824 subtree, R8); for the rest the open HPO severity annotations are feature-level (using one feature as the disease tier would be a category error), so severity stays [H]/[O] with the obstacle named. Progression lifts to registry [L] where a cited PMC open-access source states a disease-level magnitude for the dominant untreated sequela and the frozen R3 tier function derives the tier from that verbatim sentence (R9, curated dominant-sequela join, non-spectrum); for the rest progression stays [H]/[O]. The OMIM clinical synopsis (the disease-level alternative) is API-key-gated and the key is unobtainable for an individual researcher — that path is removed, not guessed.

Achondroplasia perturbs the growth-plate length scale that the carried morphogenesis engine forward-simulates as its normal-development baseline.

Established treatment and residual burden

The established disease-directed approach is CNP analog (vosoritide) for growth, with orthopedic management and foramen-magnum decompression where indicated. Mechanistically: vosoritide antagonizes FGFR3 downstream MAPK signaling to promote endochondral growth [L].

Its effect on natural history is classified disease-modifying (partial), mapping to an efficacy offset e = 0.3000 and a residual factor R_treat = 0.7000. Applied to the pre-treatment proxy this gives the residual burden score 0.5017, moving the disease from raw rank 10 to residual rank 5 (shift 5).

Evidence tier: accession-dated to the GeneReviews NBK1152 Management section [L] (initial posting October 12, 1998; last revision April 9, 2026; retrieved 2026-06-18; corroborating term(s): “analog, vosoritide, growth, orthopedic, decompression”). The natural-history axis grades remain a mix of [L] (GeneReviews-corroborated) and [H] (definition-only), so the burden order is still provisional.