DeCure for Bent bone dysplasia syndrome 2

Bent bone dysplasia syndrome 2 is a congenital skeletal disorder caused by dominant mutations in fibroblast growth factor receptor 2 (FGFR2). The FGFR2 mutations in this syndrome enhance nuclear and nucleolar localisation of the receptor. Targeted expression of these mutations in the lateral plate mesoderm of the developing chick induced angulated hindlimbs, bent long bones with shortened bone collars, and in severe cases dysmorphic epiphyses. Epiphyseal changes correlated with joint dislocations and contractures. Histological analysis showed that bent long bones and joint defects were closely associated with irregularities in skeletal muscle patterning and tendon-to-bone attachment. The limb phenotypes were recapitulated by targeted expression of wild-type FGFR2 appended with nuclear and nucleolar localisation signals, indicating that increased nuclear and nucleolar localisation of FGFR2 plays a mechanistic role in the disease phenotype.

Bent bone dysplasias in general are a heterogeneous group. In a cross-sectional cohort from the International Skeletal Dysplasia Registry (1988–2006), 66% of cases with angulated femurs belonged to three groups: campomelic disorders (24.4%), thanatophoric dysplasia (23.9%), and osteogenesis imperfecta (OI) (18.1%). More than 40 distinct disorders were associated with bowed or bent femurs. OI itself can usually be distinguished from other bent bone dysplasias by decreased bone mineralisation and bone fractures. Bruck syndrome type 2, a rare autosomal recessive form of OI caused by biallelic PLOD2 variants, is associated with congenital joint contractures with pterygia. In a 2017 report of six patients from four families with novel PLOD2 variants, all cases had multiple fractures. Features ranged from prenatal lethal severe angulation of the long bones through classical Bruck syndrome to moderate OI with normal joints. Two stillborn siblings with a kyphomelic dysplasia-like phenotype had compound heterozygous PLOD2 variants (p.Asp585Val and p.Ser166*). One infant who died at age 4 months had a bent bone phenotype with mesomelic shortening, camptodactyly, retrognathia, cleft palate, and skin dimples, and was homozygous for the nonsense variant p.Trp561*. Two siblings had various degrees of Bruck syndrome caused by the homozygous missense variant p.His687Arg. A boy with moderate OI had a possibly pathogenic homozygous variant p.Trp588Cys.

No curative treatment exists for most skeletal dysplasias. Supportive therapies include growth-hormone therapy for achondroplasia and hypochondroplasia, and bisphosphonate therapy for OI. Enzyme replacement therapy for hypophosphatasia was on clinical trial as of 2013. For fibrous dysplasia, suramin sodium, which inhibits Gsα activation, has been investigated in a preclinical drug delivery system. In a 2016 study, suramin sodium was loaded into alendronate-conjugated polymeric nanoparticles that showed strong affinity to bone hydroxyapatite in vitro. Against fibrous dysplasia cells in culture, the loaded nanoparticles inhibited proliferation as measured by MTT assay and flow cytometry. No in vivo data or human trials were reported for that system.

What is still missing for bent bone dysplasia syndrome 2 specifically: no drug has been tested in patients or animal models of the FGFR2-driven form. The chick model demonstrates a mechanistic role for nuclear FGFR2, but no therapeutic strategy targeting that mechanism has been reported. There are no clinical trials, no patient-derived cell work with drug screening, and no stratified patient cohorts. Funding for rare skeletal dysplasia drug development and a trial design that accounts for the prenatal or neonatal lethality of severe cases remain absent.