Muenke syndrome – FGFR3 gene
Muenke syndrome, also known as non-syndromic coronal craniosynostosis of Muenke or coronal sinostosis-associated with FGFR3, is characterized by a broad spectrum of clinical manifestations, with diverse phenotypes that vary from the absence of symptoms in cases of “isolated” craniosynostosis, to overlapping symptoms with other craniosynostosis syndromes, such as Crouzon, Saethre-Chotzen and Pfeiffer syndromes. In any case, the classic presentation of this pathology includes unilateral or bilateral coronal craniosynostosis, macrocephaly, greater size of the toes, as well as carpal and tarsal fusions, hearing loss and developmental delay. Also relevant are exophthalmia and mediofacial hypoplasia, although cephalo-facial anomalies are not always present. In general, this entity affects women more intensely and to a greater extent.
This process is due to a mutation in the FGFR3 (fibroblast growth factor receptor 3) gene, located on the short arm of chromosome 4 (4p16.3). This gene encodes a protein called a fibroblast growth factor receptor 3. This protein is part of a family of fibroblast growth factor receptors that share similar structures and functions. These proteins play a role in several important cell processes, including growth regulation and cell division, cell type determination, blood vessel formation, wound healing and embryo development. The FGFR3 protein crosses the cell membrane, so that one end of the protein remains inside the cell and the other end remains on the outer surface. This positioning of the protein allows it to interact with specific growth factors outside the cell and receive signals that control growth and development. When these growth factors bind to the FGFR3 protein, the protein triggers a cascade of chemical reactions inside the cell that instruct it to carry out certain changes, such as maturation to assume specialized functions. Several isoforms of the FGFR3 protein are encoded from the FGFR3 gene. Different isoforms are found in various tissues of the body and interact with a variety of growth factors. Many isoforms are found in the cells that form the bones. It is believed that the FGFR3 protein in bone cells regulates bone growth through the ossification process, specifically in the long bones. A particular isoform of the FGFR3 protein is specifically found in epithelial cells, including the cells that form the epidermis.
The mutation responsible for Muenke syndrome is located in exon 7 of the FGFR3 gene. It consists in replacing the original proline with an arginine due to a nucleotide change in the triplet that encodes it, located at position 250 of the protein (P250R). This mutation is in the region of the gene that encodes the extracellular domain of the FGFR3 protein, and corresponds exactly to the same mutation in the same residue of the FGFR1 (P252R) and FGFR2 (P253R) genes, which cause other craniosynostosis syndromes, specifically Pfeiffer syndrome and Apert syndrome, respectively. This mutation results in the coding of a receptor that is too active, which causes the bones of the skull to fuse earlier than normal.
Its mode of inheritance is autosomal dominant, although there are cases of asymptomatic heterozygotes probably due to incomplete penetrance and some variability in expression. An autosomal dominant pattern means that one copy of the altered gene in each cell is sufficient to express the condition.
The heterogeneity mentioned above makes it difficult and, at times, makes diagnosis impossible in the absence of molecular tests that, in addition, are also essential for the prediction of risk in the rest of the affected family members, and for the identification of possible associated anomalies.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Muenke syndrome, by means of the complete PCR amplification of the 7th exon of the FGFR3 gene, and their subsequent sequencing.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).