Craniometaphyseal dysplasia is a rare condition characterized by thickening (overgrowth) of bones in the skull (cranium) and abnormalities in a region at the end of long bones known as the metaphysis. The abnormal bone growth continues throughout life. Except in the most severe cases, the lifespan of people with craniometaphyseal dysplasia is normal.

Bone overgrowth in the head causes many of the signs and symptoms of craniometaphyseal dysplasia. Affected individuals typically have distinctive facial features such as a wide nasal bridge, a prominent forehead, wide-set eyes (hypertelorism), and a prominent jaw. Excess bone formation in the jaw can delay teething (dentition) or result in absent (non-erupting) teeth. Infants with craniometaphyseal dysplasia may have breathing or feeding problems caused by narrow nasal passages. In severe cases, abnormal bone growth can pinch (compress) the nerves that extend from the brain to various areas of the head and neck (cranial nerves). Compression of the cranial nerves can lead to paralyzed facial muscles (facial nerve palsy), blindness, or deafness.

The x-rays of individuals with craniometaphyseal dysplasia show unusually shaped long bones, particularly long bones in the legs. The ends of these bones are wider and appear less dense than usual in people with this condition.

There are two types of craniometaphyseal dysplasia, which are distinguished by their pattern of inheritance and genetic cause. They are known as the autosomal dominant and autosomal recessive types.

Craniometaphyseal dysplasia is a very rare disorder; its incidence is unknown.

Mutations in the ANKH gene cause autosomal dominant craniometaphyseal dysplasia. The ANKH gene provides instructions for making a protein that plays a role in the development and function of cells that build bones (osteoblasts) and cells that break down bone (osteoclasts). Osteoclasts are involved in bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. In addition, the ANKH protein transports a molecule called pyrophosphate out of cells. The pyrophosphate found outside of cells (extracellular pyrophosphate) helps control bone formation by preventing mineralization, the process by which minerals such as calcium and phosphorus are deposited in developing bones. The ANKH protein may have other, unknown functions.

Mutations in the ANKH gene that cause autosomal dominant craniometaphyseal dysplasia impair the maturation (differentiation) of osteoclasts, which likely disrupts bone remodeling. Reduced breakdown of bone tissue can contribute to the bone thickening characteristic of craniometaphyseal dysplasia. ANKH gene mutations may also reduce the protein's ability to transport pyrophosphate out of cells. A shortage of extracellular pyrophosphate can increase bone mineralization, which may also contribute to the bone abnormalities.

A mutation in the GJA1 gene causes some cases of autosomal recessive craniometaphyseal dysplasia. This gene provides instructions for making a protein called connexin 43, which is involved in the development of many tissues in the body, including bone. The protein may be involved in bone remodeling. It is unclear how a mutation in the GJA1 gene leads to the particular bone abnormalities of craniometaphyseal dysplasia.

The genetic cause of many cases of autosomal recessive craniometaphyseal dysplasia is unknown. It is likely that other, unidentified genes are involved in this form of the disorder.

Normal Function

The ANKH gene provides instructions for making a protein that is involved in skeletal development. The ANKH protein plays a role in the development and function of cells that build bones (osteoblasts) and cells that break down bone (osteoclasts). Osteoclasts are involved in bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. In addition, the ANKH protein transports a molecule called pyrophosphate out of cells to the intricate network of proteins that forms in the spaces between cells (extracellular matrix). This extracellular pyrophosphate helps regulate bone formation by preventing mineralization, the process by which minerals such as calcium and phosphorus are deposited in tissues. The ANKH protein may have other, unknown functions.

Health Conditions Related to Genetic Changes

Craniometaphyseal dysplasia

More than 10 mutations in the ANKH gene have been found to cause autosomal dominant craniometaphyseal dysplasia, a condition characterized by thickening of bones in the skull (cranium) and widening of a region at the end of long bones known as the metaphysis. Some mutations change a single protein building block (amino acid) in the ANKH protein, whereas others insert or delete one or more amino acids in the protein. These changes disrupt the functioning of osteoblasts and osteoclasts. In particular, the maturation (differentiation) of osteoclasts is impaired, which likely disrupts bone remodeling. Reduced breakdown of bone tissue can contribute to the bone thickening characteristic of craniometaphyseal dysplasia. The altered ANKH proteins may also be less able to transport pyrophosphate out of cells. A shortage of extracellular pyrophosphate can increase bone mineralization, which may also contribute to the bone abnormalities.

Other disorders

At least five mutations in the ANKH gene have been found to cause a rare hereditary form of a cartilage disorder called calcium pyrophosphate dihydrate deposition disease (CPPDD). CPPDD, also called chondrocalcinosis or pseudogout, is characterized by the accumulation of calcium pyrophosphate dihydrate crystals in the cartilage, the tough but flexible tissue that covers the ends of bones at the joints. The buildup of these crystals weakens cartilage and causes it to break down more easily. The crystals may cause inflammation in the joints, which can be painful.

Most cases of CPPDD occur in people older than 40, are not inherited, and have an unknown cause. However, inherited mutations in the ANKH gene have been shown to cause CPPDD in a few families. In these families, one altered copy of the ANKH gene in each cell is sufficient to cause the condition. Individuals with familial CPPDD caused by ANKH gene mutations typically form crystal deposits within multiple joints during early adulthood. Researchers believe that these mutations lead to elevated pyrophosphate levels in the extracellular matrix. High levels of pyrophosphate result in excessive formation of calcium pyrophosphate dihydrate crystals within joints.

Studies suggest that certain variations (polymorphisms) in the ANKH gene are associated with the normal differences in bone size and shape among individuals. These polymorphisms probably result in slight changes in the activity of the ANKH protein, affecting the levels of pyrophosphate in the extracellular matrix.

Other Names for This Gene

• ANK
• ANKH_HUMAN
• ankylosis, progressive homolog (mouse)
• FLJ27166
• HANK
• MANK
• progressive ankylosis protein
• SLC62A1

Genomic Location

Normal Function

The GJA1 gene provides instructions for making a protein called connexin 43, which is one of 21 connexin proteins. Connexins play a role in cell-to-cell communication by forming channels, or gap junctions, between cells. Gap junctions allow for the transport of nutrients, charged particles (ions), and other small molecules that carry necessary communication signals between cells. In addition, connexin 43 attaches (binds) several signaling molecules that can relay communication signals inside the cell. Connexin 43 is found in many tissues such as the eyes, skin, bone, ears, heart, and brain, and it plays a role in their normal development and function.

Health Conditions Related to Genetic Changes

Craniometaphyseal dysplasia

A mutation in the GJA1 gene has been found to cause autosomal recessive craniometaphyseal dysplasia in a small number of people. This condition is characterized by thickening of bones in the skull (cranium) and widening of a region at the end of long bones known as the metaphysis. The mutation is present in both copies of the GJA1 gene. It changes a single protein building block (amino acid) in the connexin 43 protein: at position 239, the amino acid arginine is replaced with the amino acid glutamine (written as Arg239Gln or R239Q). It is unknown how this change affects the function of the connexin 43 protein or leads to the bone abnormalities characteristic of craniometaphyseal dysplasia.

Erythrokeratodermia variabilis et progressiva

At least two mutations in the GJA1 gene have been found to cause erythrokeratodermia variabilis et progressiva (EKVP), a skin disorder characterized by areas of hyperkeratosis, which is abnormally thickened skin, and temporarily reddened patches called erythematous areas. The GJA1 gene mutations that cause this disorder are present in one of the two copies of the gene in each cell. Each of the known mutations changes a single amino acid in the connexin 43 protein. These changes lead to the production of an abnormal version of the protein that is unable to reach the cell surface to become part of gap junctions. Instead, after it is produced, the abnormal protein becomes trapped in a cell structure called the Golgi apparatus. It is unclear how a shortage of connexin 43 at the cell surface affects the structure of gap junctions in the outermost layer of skin (epidermis), or how these changes result in the skin abnormalities characteristic of EKVP.

Nonsyndromic hearing loss

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Oculodentodigital dysplasia

At least 76 mutations in the GJA1 gene have been found to cause oculodentodigital dysplasia, a condition characterized by abnormalities of the eyes (oculo-), teeth (dento-), and fingers (digital). The GJA1 gene mutations that cause this disorder are usually present in one of the two copies of the gene in each cell. Most of these mutations change an amino acid in connexin 43. A different type of change in the GJA1 gene causes people to have oculodentodigital dysplasia with palmoplantar keratoderma. Palmoplantar keratoderma is a condition that causes skin on the palms of the hands and the soles of the feet to become thick, scaly, and calloused. The mutation that causes this condition deletes two DNA building blocks (nucleotides) to create a premature stop signal in the instructions for making connexin 43. As a result, an abnormally short, nonfunctional protein is produced.

Gap junctions formed with abnormal connexin 43 proteins are often permanently closed, preventing the transport of any molecules. Some mutations prevent connexin 43 proteins from traveling to the cell surface where they are needed to form gap junctions. These disruptions impair communication between cells, which is thought to cause the eye, tooth, and finger abnormalities characteristic of oculodentodigital dysplasia.

Coloboma

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Critical congenital heart disease

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Heterotaxy syndrome

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Other disorders

Mutations in one copy of the GJA1 gene in each cell can cause isolated syndactyly type III, which is characterized by fusion of the ring and pinky fingers (fourth and fifth fingers) and sometimes shortening of the pinky finger. Syndactyly type III is a characteristic feature in oculodentodigital dysplasia (described above); however, some people have syndactyly type III without other features of oculodentodigital dysplasia, which is known as isolated syndactyly type III. It is unclear why some people with GJA1 gene mutations develop only the finger abnormalities and others have additional developmental abnormalities characteristic of oculodentodigital dysplasia.

A mutation in one copy of the GJA1 gene has been found to cause palmoplantar keratoderma and congenital alopecia 1, a condition characterized by skin problems, an absence of hair from birth (congenital alopecia), and often nail abnormalities. The mutation identified in this disorder leads to production of an altered connexin 43 protein. Channels made with the altered protein open more easily than normal, increasing the transport of molecules. Researchers suggest that abnormal signaling in cells that form the skin, hair, and nails results in the features characteristic of palmoplantar keratoderma and congenital alopecia 1.

Other mutations in one copy of the GJA1 gene in each cell have been found in a small number of people who have died suddenly with no known cause in infancy (sudden infant death syndrome) or early adulthood (sudden unexplained nocturnal death). Doctors suspect that abnormalities of heart function associated with GJA1 gene mutations may contribute to sudden death. It is thought that other genetic and environmental factors, many of which have not been identified, also play a part in determining the risk of these disorders. Mutations in one copy of the GJA1 gene may also contribute to heart malformations, although the role of such a genetic change is unclear.

Other Names for This Gene

• connexin 43
• connexin43
• CX43
• Cx43α1
• CXA1_HUMAN
• gap junction 43 kDa heart protein
• gap junction protein, alpha 1, 43kDa
• gap junction protein, alpha-like

Genomic Location

When caused by mutations in the ANKH gene, craniometaphyseal dysplasia follows an autosomal dominant pattern, which means one altered copy of the ANKH gene in each cell is sufficient to cause the disorder. Individuals with autosomal dominant craniometaphyseal dysplasia typically have one parent who also has the condition. Less often, cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

When caused by mutations in the GJA1 gene, craniometaphyseal dysplasia has an autosomal recessive inheritance pattern, which means both copies of the GJA1 gene in each cell are altered. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the disorder.