AD-CMD
AD-CMD is a rare craniotubular bone disorder with only a few hundred cases published worldwide. Inheritance is autosomal dominant with mutations in ANKH. About 40% of patients known to the moderators carry de novo mutations in the ANKH gene (parents don’t have the mutation).
Characteristic for AD-CMD is the progressive diffuse bone thickening (hyperostosis) of cranial bones, which can already be detected in infancy. First diagnosis is often due to nasal obstruction or choanal stenosis, which result in feeding issues within a few months after birth. Also visible early on is a wide nasal bridge, paranasal bossing, widely spaced eyes (hypertelorism) and sometimes signs of facial palsy develop.
Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, which leads to a characteristic facial expression with massive mandibles, paranasal bossing and hypertelorism with and increased zygomatic width. Hyperostosis of craniofacial bones often results in narrowing of cranial foramina (openings where nerves go through the skull bones), including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy (paralysis of facial muscles), blindness, or deafness (conductive and/or sensorineural hearing loss). Foramen magnum encroachment can result in Chiari malformation (type 1) which can result in syringomyelia and severe headaches. Headaches are often reported by patients.
Long bones are abnormally shaped, especially characteristic for AD-CMD is the flaring of femoral and tibial metaphyses. In contrast to cranial bones, long bone metaphyses are under trabeculated and appear radiographically radiolucent. Cortical bone usually does not appear sclerotic.
Life expectancy is normal in individuals with typical uncomplicated AD-CMD; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum.
CCAL2
AD-CCAL2 is a rare familial disorder that is passed on from an affected parent to child in affected families. On average, approximately 50% of offspring of an affected parent may be affected. Fewer than 100 families worldwide have been identified with this disorder. Most individuals who carry a mutation in the ANKH gene, the cause of CCAL2, will be affected in their third decade of life.
CCAL2 is characterized by the acute onset of arthritis in one or more joints. The knees and wrists are most often affected, but other joints may also be affected including the shoulder, the pubis, and the joints of the fingers. Occasionally, soft tissues may be affected. The immediate cause of the pain and disability in the joints of CCAL2 patients is the deposition of calcium-containing crystals, known as CPP crystals, in the affected joints. When patients experience acute attacks, they may also feel feverish with chills, and their joints may be red and warm. They may have an overall feeling of illness and fatigue. After a few weeks, the acute attack of pain will dissipate, but it may recur several months later. Over time, patients can expect to develop degeneration of the cartilage in their joints that is typical of other forms of arthritis.
The diagnosis of CCAL2 requires both clinical and genetic testing. The clinical tests may include X-ray and ultrasound studies, and some synovial fluid from swollen joints may be examined for CPP crystals. This latter study is necessary to distinguish CCAL2 from gout. Genetic tests are done to confirm that the disease is hereditary and to prove that the gene that is mutated in affected family members is the ANKH gene.
Unfortunately, there are no cures for CCAL2, but there are a number of drugs that can help to manage symptoms in affected individuals. Many of these drugs are currently used to treat patients with gout, so we have a great deal of information about their activity and safety profiles. It may be necessary to try different drugs for different patients in order to get the most relief from a patient’s symptoms. Your doctor will evaluate you on a regular basis to determine which drug, or combination of drugs, is best for your condition. CCAL2 is not a fatal condition! You can expect to live a normal lifespan despite your joint disease.
While there are no specific therapies at this time for CCAL2, doctors and researchers are exploring the affect of ANKH mutations, including your family’s mutation, on the initiation and progression of your disease. It is anticipated that a greater understanding of the cause of your disease will allow researchers to soon develop specific therapies to treat this form of arthritis.