FGFR2 mutations and bone fusion in Apert syndrome

Apert syndrome, also known as acrocephalosyndactyly (ACS) type I, is a rare genetic disorder that causes alterations to the skull and digits. It affects one in every 65,000 to 88,000 newborns, according to the National Library of Medicine or one in every 45,000 to 160,000 live births, according to Seattle Children’s Hospital. In most cases it is not a fatal diagnosis, but it does often require surgical treatment.

Cause of Apert syndrome

Apert syndrome is an autosomal dominant condition, meaning that, if someone with Apert syndrome has children, each child has a 50 percent chance of having the mutation, but most cases are caused by sporadic (also known as spontaneous) mutations in which the parents have no mutation or signs of the disease. The affected gene is the fibroblast growth factor receptor 2 (FGFR2) gene on chromosome 10. The spontaneous mutation of this gene has been associated with older fathers, but male and female children are equally affected.

The FGFR2 protein is part of a signaling system that guides the differentiation of bone cells during embryonic development. A number of disorders associated with aberrant bone growth is associated with mutations in the FGFR2 gene. In particular, there are seven FGFR2 gene mutations that have been found in Apert syndrome, but nearly all cases can be attributed to one of two mutations that change a single amino acid in the FGFR2 protein, altering its structure. One of these mutations is the replacement of proline with arginine at position 253 (Pro253Arg), and the other is the replacement of serine with tryptophan at position 252 (Ser252Trp). These mutations cause FGFR2 to send a stronger signal, causing premature fusion of the bones during development. This premature fusion results in the characteristics of the disease.

Characteristics of Apert syndrome

Most children with this disorder have normal intelligence, according to Boston Children’s Hospital, though some may exhibit mild to moderate cognitive or learning difficulties due to how their skull fused. Early fusion of the skull leads to a tall skull with a high, prominent forehead and a seemingly sunken face (called midface hypoplasia), resulting in prominent eyes, a small nose and an underdeveloped jaw. The issues with jaw development can lead to dental issues such as teeth crowding as the individual ages. Issues with how the eyes sit in the eye sockets can also cause some individuals with Apert syndrome to have vision problems.

But the skull is not the only affected part of the body. Individuals with Apert syndrome also tend to have fused fingers and toes. This can range from webbed digits to the fusion of all digits into the hand or foot (called syndactyly). Though it is not as common, polydactyly, the addition of digits, is seen in some individuals. Some individuals may also have hearing problems, excessive sweating, patches of missing hair (particularly the eyebrows), recurrent ear infections associated with cleft palate and/or fused cervical vertebrae.

Living with Apert syndrome

Children born with Apert syndrome, or other conditions caused by FGFR2 mutations, often undergo numerous surgeries to ensure that the effect of the aberrant bone fusion on their quality of life is minimized. Because the manifestation of the condition varies, no two cases are identical. Many children’s hospitals have craniofacial surgical teams and specialists, but there are also organizations like AboutFace that strive to help children affected by facial abnormalities, and their families, lead normal, healthy lives.