This study aimed to explore the genotype-phenotype correlations in individuals with Genetic Skeletal Disorders (GSD), evaluate the efficacy of recombinant human Growth Hormone (rhGH) therapy. The retrospective analysis of the medical records of 80 pediatric patients with GSD diagnosed via whole-exome sequencing was conducted. The therapeutic effects of rhGH treatment were analyzed in 30 of these patients who received rhGH therapy. The study included 80 GSD patients, diagnosed at a median age of 4.88 years, with a median height standard deviation score (Ht-SDS) of - 3.58. The most common clinical manifestations included skeletal deformities (87.5%), short stature (81.3%), and distinctive facial features (including triangular face, abnormality of the philtrum, abnormality of the forehead, etc.) (65.0%). A total of 33 pathogenic genes associated with 20 groups of GSD were identified. The most common groups are Type II collagenopathies (related to the COL2A1 gene) (12/80, 15.0%) and the FGFR3-related chondrodysplasia group (12/80, 15.0%). Those with pathogenic genes linked to Fundamental Cellular Processes had more severe short stature and prenatal phenotypes. Thirty patients received rhGH treatment for a median of 2.25 years (0.33-8.92), showing Ht-SDS increases of 0.66 ± 0.42 and 0.84 ± 0.52, after one and two years, respectively (p < 0.001). Eight untreated patients had an average Ht-SDS decrease of - 0.46 ± 0.55. In this cohort, pediatric GSD patients predominantly presented with short stature, skeletal deformities, and distinctive facial features (including triangular face, abnormality of the philtrum, abnormality of the forehead, etc.), indicating a genotype-phenotype correlation. Compared to untreated GSD patients, those receiving rhGH treatment demonstrated varying degrees of height improvement, however, the long-term efficacy of this treatment warrants further investigation.

Achondroplasia is the most frequent FGFR3-related chondrodysplasia, leading to rhizomelic dwarfism, craniofacial anomalies, stenosis of the foramen magnum, and sleep apnea. Craniofacial growth and its correlation with obstructive sleep apnea syndrome has not been assessed in achondroplasia. In this study, we provide a multimodal analysis of craniofacial growth and anatomo-functional correlations between craniofacial features and the severity of obstructive sleep apnea syndrome. A multimodal study was performed based on a paediatric cohort of 15 achondroplasia patients (mean age, 7.8 ± 3.3 years), including clinical and sleep study data, 2D cephalometrics, and 3D geometric morphometry analyses, based on CT-scans (mean age at CT-scan: patients, 4.9 ± 4.9 years; controls, 3.7 ± 4.2 years). Craniofacial phenotype was characterized by maxillo-zygomatic retrusion, deep nasal root, and prominent forehead. 2D cephalometric studies showed constant maxillo-mandibular retrusion, with excessive vertical dimensions of the lower third of the face, and modifications of cranial base angles. All patients with available CT-scan had premature fusion of skull base synchondroses. 3D morphometric analyses showed more severe craniofacial phenotypes associated with increasing patient age, predominantly regarding the midface-with increased maxillary retrusion in older patients-and the skull base-with closure of the spheno-occipital angle. At the mandibular level, both the corpus and ramus showed shape modifications with age, with shortened anteroposterior mandibular length, as well as ramus and condylar region lengths. We report a significant correlation between the severity of maxillo-mandibular retrusion and obstructive sleep apnea syndrome (p < 0.01). Our study shows more severe craniofacial phenotypes at older ages, with increased maxillomandibular retrusion, and demonstrates a significant anatomo-functional correlation between the severity of midface and mandible craniofacial features and obstructive sleep apnea syndrome.

Statins have demonstrated to be effective for treating chondrodysplasia and its effects were believed to be associated with the fibroblast growth factor receptor 3 (FGFR3). Statins promoted the degradation of FGFR3 in studies using disease-specific induced pluripotent stem cells and model mice, however, recent studies using normal chondrocytes reported that statins did not degrade FGFR3. In order to further investigate the effects of statins in endochondral ossification, this study examined the influence of statins on Indian hedgehog (Ihh), another important component of endochondral ossification, and its related pathways. The chondrocyte cell line ATDC5 was used to investigate changes in cell proliferation, mRNA, and protein expression levels. In addition, an organ culture of a mouse metatarsal bone was performed followed by hematoxylin-eosin staining and fluorescent immunostaining. Results indicated that expression level of Ihh increased with the addition of statins, which activated the Ihh pathway and altered the localization of Ihh. Changes in cholesterol modification may have affected Ihh diffusibility; however, further experiments are necessary. A reactive increase in parathyroid hormone-related protein (PTHrP) was observed in addition to changes in the Wnt pathway through secreted-related protein 2/3 and low-density lipoprotein 5/6. This led to the promotion of cell proliferation, increase of the hypertrophic chondrocyte layer, inhibition of apoptosis, and decrease in mineralization. This study demonstrated that statins had an influence on Ihh, and that the hyperfunction of Ihh may prevent premature cell death caused by FGFR3-related chondrodysplasia through an indirect increase in the expression of PTHrP.

Statins are widely used drugs for cholesterol lowering, which were recently found to counteract the effects of aberrant fibroblast growth factor receptor (FGFR3) signaling in cell and animal models of FGFR3-related chondrodysplasia. This opened an intriguing therapeutic possibility for human dwarfing conditions caused by gain-of-function mutations in FGFR3, although the mechanism of statin action on FGFR3 remains unclear. Here, we determine the effect of statins on FGFR signaling in chondrocytes. Cultured chondrocyte cell lines, mouse embryonic tibia cultures and limb bud micromasses were treated with FGF2 to activate FGFR signaling. The effects of atorvastatin, fluvastatin, lovastatin and pravastatin on FGFR3 protein stability and on FGFR-mediated chondrocyte growth-arrest, loss of extracellular matrix (ECM), induction of premature senescence and hypertrophic differentiation were evaluated. Statins did not alter the level of FGFR3 protein expression nor produce any effect on FGFR-mediated inhibition of chondrocyte proliferation and hypertrophic differentiation in cultured chondrocyte cell lines, mouse tibia cultures or limb bud micromasses. We conclude that statins do not inhibit the FGFR signaling in chondrocytes. Therefore the statin-mediated rescue of FGFR3-related chondrodysplasia, described before, is likely not intrinsic to the growth plate cartilage.