In 1878, French physician Joseph Marie Jules Parrot coined the term achondrodysplasia, which is now considered a rare genetic disorder [1]. It is caused by a gain-of-function point mutation in the FGFR-3 gene, leading to overexpression of the FGFR3 receptor pathway and inhibiting chondrocyte proliferation responsible for cartilage formation [1–4]. The specific mutation in the FGFR3 gene that causes achondroplasia is a substitution of glycine with arginine at codon 380, disrupting normal bone formation and leading to disproportionate short stature [5–8]. Restricted growth, particularly in the arms and legs, leads to disproportionate short stature [5,6]. It affects about one in every 26,000–28,000 live births. Achondroplasia is the most common form of short stature, caused by a dominant FGFR3 gain-of-function mutation that activates the FGFR3 and MAPK signaling cascade, inhibiting chondrocyte differentiation and growth plate activity [1,9,10]. This leads to complications like spinal stenosis and airway narrowing. Treatment recommendations aim to reduce morbidity and mortality, especially in infants and young children [6,11]. External symptoms include short upper arms and thighs, broad hands and feet, and a long trunk. Breathing and hearing issues are common due to chest size and narrow nasopharynx. Physical development may be delayed, but intelligence is not affected. Leg axis changes and spinal curvature may occur, with growth typically ending around 120–140 cm. Early gene mutation suspicion led to the discovery of achondroplasia. Fibroblast growth factor receptor 3 is a receptor tyrosine kinase that binds fibroblast growth factors, regulating cell proliferation, differentiation, and migration. It plays a crucial role in bone ossification and cartilage remodeling. In achondroplasia, an overactive FGFR3 signaling pathway is present, affecting cell growth and differentiation. FGFR3 interacts with adapter proteins like GRB2 and Sos, forming complexes that link to the MAPK pathway. The activation of FGFR3 leads to phosphorylation of proteins like phospholipase C-γ, influencing cell signaling.

Vosoritide (BMN111) is a treatment for achondroplasia in patients over 2 years old with open epiphyses [9,12,13]. Marketed as Voxzogo, it comes in powder and solvent form for injection. Vosoritide acts as an agonist of NPR-B, promoting bone growth by inhibiting the MAPK pathway [5,14]. It is well-absorbed and metabolized via catabolic pathways [14]. The recommended dosage is weight-based to ensure consistent exposure. Common side effects include injection site reactions, vomiting, hypotension, dizziness, and syncope [9,13]. Vosoritide has minimal drug interactions due to its recombinant peptide nature. TransCon CNP is a modified form of CNP-38 attached to polyethylene glycol for sustained release in achondroplasia treatment. It offers continuous exposure to CNP, enhancing bone growth efficacy compared to intermittent exposure. Studies show it is well-tolerated with minimal cardiovascular effects.

The prolonged exposure to CNP with TransCon CNP reduces the risk of hypotension. Recifercept targets FGFGR3 to treat achondroplasia by downregulating specific signaling pathways, improving bone growth, skeletal development, skull proportions, and reproductive capacity [15–17]. It also shows promise in reducing atypical visceral obesity in achondroplasia. Further research is needed to understand its full efficacy and safety in humans. Vofatamab is a monoclonal antibody targeting FGFR3, studied for urothelial carcinoma treatment. It blocks FGF ligand attachment to inhibit cancer cell growth. While considered for achondroplasia, its large size may limit its effectiveness in dense extracellular matrices. Clinical trials are ongoing for urothelial neoplasms and multiple myeloma. Erdafitinib, an FGFR inhibitor, is effective in treating certain cancers by inhibiting FGFR subtypes and other tyrosine kinases. Approved by the FDA in 2019, it is used for metastatic or locally advanced urothelial carcinoma with specific gene mutations. Common side effects include stomatitis, diarrhea, abdominal pain, nausea, constipation, and dysgeusia. Recent publications in the New England Journal of Medicine and the Lancet shed light on oral infigratinib as a valuable milestone in the treatment of achondroplasia [2,5,6,9,11–13].

Therapeutic strategies aim to reduce excessive signals from the FGFR3 gene, with potential treatments including C-Type Natriuretic Peptide (CNP), FGFR3-binding peptides, soluble FGFR3, meclizine, statin, and FGFR inhibitors [18]. Vosoritide, a stable form of CNP, has shown positive effects on growth in clinical trials. Targeting FGFR3 with Tyrosine Kinase Inhibitors (TKIs) is another potential strategy, although current inhibitors are not specific to FGFR3. Research is ongoing to develop more specific inhibitors for FGFR3 [13]. Treatment in childhood is crucial, but current therapies do not cure all symptoms associated with achondroplasia. The current treatments are life-long treatments without curing the patients with this rare disease in childhood.

Future research may focus on mutation repair methods to correct the gene defect, a point mutation on chromosome 4 in a one-time approach [13]. Point mutations, which are changes in the DNA that affect only a single base, can in principle be repaired, and there are various methods to try to do this [6, 7,10,11]. Repair possibilities include cellular repair mechanisms, where cells have built-in mechanisms to detect and repair DNA damage, including point mutations. These mechanisms can perform spontaneous repairs, but sometimes they are not sufficient to fix severe damage. For certain genetic diseases caused by point mutations, gene therapy may be considered. In this approach, the normal gene function is attempted to be restored by introducing an intact gene copy into the cells or directly repairing the faulty DNA. CRISPR/Cas technology is a relatively new method that allows for targeted modification of DNA and correction of point mutations. There are different approaches where either the faulty base is directly replaced or repaired with a template.

Repairing point mutations requires high precision to ensure that only the intended site is altered and no further damage occurs. From the point of efficacy, not all point mutations can be efficiently repaired with the available methods. Off-target effects are also important to evaluate, when using CRISPR/Cas, unintended changes can also occur at other locations in the genome. The applicability of the methods depends on various factors, such as the type of mutation, the affected tissue, and the underlying disease. In summary, it can be said that point mutations are in principle repairable, but the methods and their efficiency can vary.

Overall, further research should focus on mutation repair methods as early as possible, possibly as a prenatal intrauterine one-time approach in achondroplasia [19]. This could be the future to cure pediatric patients with achondroplasia. All other treatment options do not cure but treat the child, help to gain weight in a different degree with sometimes serious toxic side effects depending on the individual mechanism of action of the drug. Especially tyrosine kinase inhibitors should be more selective for FGFR3 signaling pathway, most often they inhibit other FGFR pathways with serious toxic side effects. Discovery of a potent FGFR2/3 Inhibitor to overcome mutation resistance and treat achondroplasia was published recently by a Chinese group of researchers and could be a valuable milestone to treat achondroplasia in childhood [20]. Another recently published interesting study is focused on CDK-8 inhibitors in achondroplasia model mice [21]. Further effective and selective drugs can be TYRA-300 and LOXO-435 as selective FGFR3-tyrosine kinase inhibitors [22–24]. Non-selective tyrosine kinase inhibitors like infigratinib, which include other inhibitory efficacy on other signaling pathways then the FGFR3 signaling pathway will have serious toxic side effects and are not the future for treatment in achondroplasia [7,10,22,25,26]. In conclusion, there are many different targets to treat achondroplasia on the one hand, of which a few shows toxic side effects beside the inhibition of the FGFR3-signaling pathway and, on the other hand, options to cure these children by pre-or postnatal one-time gene therapy approach. This must be the future.

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