Genetic factors play a crucial role in determining human height. Short stature commonly affects multiple family members and therefore, familial short stature (FSS) represents a significant proportion of growth disorders. Traditionally, FSS was considered a benign polygenic condition representing a subcategory of idiopathic short stature (ISS). However, advancements in genetic research have revealed that FSS can also be monogenic, inherited in an autosomal dominant manner and can result from different mechanisms including primary growth plate disorders, growth hormone deficiency/insensitivity or by the disruption of fundamental intracellular pathways. These discoveries have highlighted a broader phenotypic spectrum for monogenic forms of short stature, which may exhibit mild manifestations indistinguishable from ISS. Given the overlapping features and the difficulty in differentiating polygenic from monogenic FSS without genetic testing, some researchers redefine FSS as a descriptive term that encompasses any familial occurrence of short stature, regardless of the underlying cause. This shift emphasizes the complexity of diagnosing and managing short stature within families, reflecting the diverse genetic landscape that influences human growth.

• Keywords
• autosomal dominant short stature, familial short stature, genetics, growth plate, short stature,
• MeSH
• Phenotype MeSH
• Humans MeSH
• Dwarfism genetics   MeSH
• Growth Disorders * genetics   MeSH
• Body Height * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: Achondroplasia (ACH) is one of the most prevalent genetic forms of short-limbed skeletal dysplasia, caused by gain-of-function mutations in the receptor tyrosine kinase FGFR3. In August 2021, the C-type natriuretic peptide (CNP) analog vosoritide was approved for the treatment of ACH. A total of six other inhibitors of FGFR3 signaling are currently undergoing clinical evaluation for ACH. This progress creates an opportunity for children with ACH, who may gain early access to the treatment by entering clinical trials before the closure of their epiphyseal growth plates and cessation of growth. Pathophysiology associated with the ACH, however, demands a long observational period before admission to the interventional trial. Public patient registries can facilitate the process by identification of patients suitable for treatment and collecting the data necessary for the trial entry. RESULTS: In 2015, we established the prospective ACH registry in the Czechia and the Slovak Republic ( http://www.achondroplasia-registry.cz ). Patient data is collected through pediatric practitioners and other relevant specialists. After informed consent is given, the data is entered to the online TrialDB system and stored in the Oracle 9i database. The initial cohort included 51 ACH children (average age 8.5 years, range 3 months to 14 years). The frequency of selected neurological, orthopedic, or ORL diagnoses is also recorded. In 2015-2021, a total of 89 measurements of heights, weights, and other parameters were collected. The individual average growth rate was calculated and showed values without exception in the lower decile for the appropriate age. Evidence of paternal age effect was found, with 58.7% of ACH fathers older than the general average paternal age and 43.5% of fathers older by two or more years. One ACH patient had orthopedic limb extension and one patient received growth hormone therapy. Low blood pressure or renal impairment were not found in any patient. CONCLUSION: The registry collected the clinical information of 51 pediatric ACH patients during its 6 years of existence, corresponding to ~ 60% of ACH patients living in the Czechia and Slovak Republic. The registry continues to collect ACH patient data with annual frequency to monitor the growth and other parameters in preparation for future therapy.

• Keywords
• Achondroplasia, FGFR3, ReACH, Registry, Skeletal dysplasia, Treatment,
• MeSH
• Achondroplasia * epidemiology   genetics   MeSH
• Child MeSH
• Infant MeSH
• Humans MeSH
• Mutation MeSH
• Child, Preschool MeSH
• Prospective Studies MeSH
• Receptor, Fibroblast Growth Factor, Type 3 genetics   MeSH
• Registries MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Slovakia MeSH
• Names of Substances
• Receptor, Fibroblast Growth Factor, Type 3 MeSH

Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for significantly shortened primary cilia in ACH and TD cartilage growth plates. Using in vivo and in vitro methodologies, our data demonstrate that transient versus sustained activation of FGF signaling correlated with different cilia consequences. Transient FGF pathway activation elongated cilia, while sustained activity shortened cilia. FGF signaling extended primary cilia via ERK MAP kinase and mTORC2 signaling, but not through mTORC1. Employing a GFP-tagged IFT20 construct to measure intraflagellar (IFT) speed in cilia, we showed that FGF signaling affected IFT velocities, as well as modulating cilia-based Hedgehog signaling. Our data integrate primary cilia into canonical FGF signal transduction and uncover a FGF-cilia pathway that needs consideration when elucidating the mechanisms of physiological and pathological FGFR function, or in the development of FGFR therapeutics.

• MeSH
• Achondroplasia genetics   physiopathology   MeSH
• NIH 3T3 Cells MeSH
• Chondrocytes metabolism   MeSH
• Cartilage metabolism   MeSH
• Cilia pathology   physiology   MeSH
• Ciliopathies genetics   physiopathology   MeSH
• Phenotype MeSH
• Fibroblast Growth Factors metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Primary Cell Culture MeSH
• Receptor, Fibroblast Growth Factor, Type 3 genetics   metabolism   MeSH
• Growth Plate metabolism   MeSH
• Signal Transduction physiology   MeSH
• Thanatophoric Dysplasia genetics   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• FGFR3 protein, human MeSH Browser
• Fibroblast Growth Factors MeSH
• Receptor, Fibroblast Growth Factor, Type 3 MeSH

• Keywords
• Chromosome Section, FGFR3, cartilage, chondrosarcoma, growth inhibition,
• MeSH
• Chondroma metabolism   MeSH
• Hedgehog Proteins metabolism   MeSH
• Receptor, Fibroblast Growth Factor, Type 3 metabolism   MeSH
• Up-Regulation * MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Comment MeSH
• Editorial MeSH
• Names of Substances
• Hedgehog Proteins MeSH
• Receptor, Fibroblast Growth Factor, Type 3 MeSH

Fibroblast growth factors (FGFs) deliver extracellular signals that govern many developmental and regenerative processes, but the mechanisms regulating FGF signaling remain incompletely understood. Here, we explored the relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family. We report that FGF1, FGF3, FGF4, FGF6, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 exist as unstable proteins, which are rapidly degraded in cell cultivation media. Biological activity of FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, and FGF20 is limited by their instability, manifesting as failure to activate FGF receptor signal transduction over long periods of time, and influence specific cell behavior in vitro and in vivo. Stabilization via exogenous heparin binding, introduction of stabilizing mutations or lowering the cell cultivation temperature rescues signaling of unstable FGFs. Thus, the intrinsic ligand instability is an important elementary level of regulation in the FGF signaling system.

• MeSH
• Chondrosarcoma genetics   metabolism   pathology   MeSH
• Circular Dichroism MeSH
• Fibroblast Growth Factors chemistry   classification   genetics   metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Mutant Proteins chemistry   metabolism   MeSH
• Tumor Cells, Cultured MeSH
• Bone Neoplasms genetics   metabolism   pathology   MeSH
• Breast Neoplasms genetics   metabolism   pathology   MeSH
• Cell Proliferation * MeSH
• Signal Transduction * MeSH
• Protein Stability MeSH
• Temperature MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fibroblast Growth Factors MeSH
• Mutant Proteins MeSH