Apert syndrome - FGFR2 gene

Apert syndrome, also known as type I acrocephalosyndactyly, is an alteration of genetic origin characterized by premature fusion of the bones of the skull (craniosonostosis), which prevents normal growth of the skull, affecting the shape of the head and face and brain development, also affecting intellectual development. Other alterations associated with this syndrome have been described, such as skeletal involvement in the shoulders, humerus, elbows, hip, knees, rib cage, spine and central nervous system, among others.

In addition to the signs described above, individuals with Apert syndrome usually have distinctive facial features such as hypoplasia of the middle face, pointed nose, wrinkled forehead, cleft palate and an underdeveloped upper jaw that can lead to dental problems such as absence of teeth and irregular tooth enamel; eye abnormalities such as exophthalmos, hypertelorism, descending palpebral fissures, strabismus and ocular proptosis; malformation of ear structures; digit abnormalities such as syndactyly and polydactyly; hyperhidrosis; and breathing difficulties.

Most cases of Apert syndrome are due to mutations in the gene coding for fibroblast growth factor receptor 2, FGFR2 (fibroblast growth factor receptor 2), located on the long arm of chromosome 10 (10q26) . A large variety of craniosynostosis (including Apert syndrome, Pfeiffer, Jackson-Weiss, etc.) are caused by mutations in three of the four genes that code for fibroblast growth factor receptors (FGFR). FGFRs are tyrosine kinase receptors of fibroblast growth factors involved in intercellular signaling pathways when interacting with their ligands, fibroblast growth factors. They are, therefore, signal transduction molecules that extend across the cell membrane that play a central role in signaling events that regulate the fusion of cranial sutures.

At least 10 mutations in the FGFR2 gene have been identified in people with Apert syndrome. These mutations change amino acids in the FGFR2 protein, which alters the three-dimensional structure of the protein. It is estimated that approximately 98% of cases are due to two mutations in the FGFR2 gene. A particular mutation replaces the amino acid serine with the amino acid tryptophan at position 252 of the protein (Ser252Trp). The other mutation replaces the proline amino acid with the amino acid arginine at position 253 (Pro253Arg). Thus, these mutations result in a gain in function of the FGFR2 receptor causing stronger signaling that promotes premature fusion of the bones of the skull, hands and feet. In addition, depending on the mutation that causes Apert syndrome, there are certain well-established phenotypic nuances. For example, the S252W mutation is associated with a higher incidence of cleft palate, while the P253R mutation is associated with more intense syndactyly and greater growth retardation.

This process is inherited with an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to express the process. Almost all cases of this syndrome are due to new mutations in the gene that occur during the formation of reproductive cells or early embryonic development. These cases occur in people with no history of the process in their family.

Tests performed in IVAMI: in IVAMI we detect mutations associated with Apert syndrome, by means of complete PCR amplification of the exons of the FGFR2 gene, and subsequent sequencing.

Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).