Caffey disease – COL1A1 gene
Caffey disease, also called infantile cortical hyperostosis, is a bone disorder that occurs more frequently in newborns and is characterized by hyperostosis. Bony abnormalities mainly affect the jaw, scapula, clavicles, and shaft. Affected bones can double or triple in width, as can be seen by x-ray images. In some cases, two bones that are next to each other are fused, such as two ribs, the radius and the ulna, or the tibia and the fibula. In addition, affected newborns have swelling of the joints and soft tissues, such as muscles, with pain and redness in the affected areas. Affected children may also have fever and be irritable.
The signs and symptoms of Caffey disease are usually apparent in newborns at around 5 months of age. In rare cases, skeletal abnormalities can be detected by ultrasound during the last weeks of development before birth. For unknown reasons, the swelling and pain associated with Caffey disease usually go away within a few months. Through bone remodeling, excess bone is usually reabsorbed by the body. However, if two adjacent bones have fused, it can lead to complications. For example, fused rib bones can lead to scoliosis or limited chest expansion, which can lead to breathing problems. Most people with Caffey disease have more related problems after early childhood. In some cases, hyperostosis can occur years later. Also, some adults who had Caffey disease in childhood have other abnormalities of the bones and connective tissues. Affected adults may have joint laxity, hyperextensible skin, or hernias.
This process is due to mutations in the COL1A1 gene, located on the long arm of chromosome 17 (17q21.33). This gene encodes part of a large molecule called type I collagen. Collagens are a family of proteins that strengthen and support many tissues in the body, including cartilage, bone, tendons, skin, and sclera. Type I collagen is the most abundant form of collagen in the human body. Specifically, the COL1A1 gene encodes the pro-α1 chain. Collagens start out as procollagen molecules, which must be processed by enzymes outside the cell to remove extra protein segments from their ends. Each procollagen molecule is made up of three chains: two pro-α1 (I) chains, which are encoded from the COL1A1 gene, and one pro-α2 (I) chain, which is encoded from the COL1A2 gene. Once these molecules are processed, the collagen molecules are arranged into long thin fibrils. Inside these fibrils, individual collagen molecules are cross-linked to each other. These cross-links lead to the formation of very strong collagen fibrils, which are found in the spaces around cells.
A mutation in the COL1A1 gene leads to infantile cortical hyperostosis, commonly known as Caffey disease. The mutation responsible for this disease replaces the amino acid arginine with the amino acid cysteine at position 836 of the protein (Arg836Cys or R836C). This mutation leads to the production of type I collagen fibrils that are variable in size and shape, but it is unknown how these changes lead to the signs and symptoms of Caffey disease.
This disease is inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is generally sufficient to express the disease. About 20% of people who have the mutation that causes Caffey disease do not have its signs or symptoms. This phenomenon is called incomplete penetrance. In some cases, an affected person inherits the mutation that causes Caffey disease from a parent. Other cases are the result of new mutations in the gene and occur in people with no history of the disease in their family.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Caffey disease, by means of the complete PCR amplification of the exons of the COL1A1 gene, and their subsequent sequencing.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).