NORD gratefully acknowledges Prof. Ravi Savarirayan, Consultant Clinical Geneticist, Victorian Clinical Genetic Services, Musculoskeletal Research Group Leader, Murdoch Childrens Research Institute; Professor, University of Melbourne, for assistance in the preparation of this report.
Pycnodysostosis is a rare genetic disorder characterized by distinctive facial features and skeletal malformations. Affected individuals may have osteosclerosis, a condition characterized by abnormal hardening and increased density of bone. The abnormality of the bones of affected individuals cause the bones to be fragile and brittle. Affected individuals are prone to repeated fractures. Affected individuals may fail to grow and can be shorter than would otherwise be expected (short stature). Intelligence is not affected and the disorder is not believed to be life-threatening. The severity of the disorder including the frequency of fractures, final adult height, and specific symptoms can vary greatly among affected individuals. Pycnodysostosis is caused by changes (mutations) in the cathepsin K (CTSK) gene and is inherited in an autosomal recessive trait.
Pycnodysostosis belongs to a larger group of diseases known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks. Low levels or inactivity of an enzyme called cathepsin K results in the abnormal accumulation (storage) of toxic materials in lysosomes. Pycnodysostosis is similar to osteopetrosis and they are sometimes discussed in the medical literature together. Osteopetrosis is a disorder characterized by abnormally dense bones that are brittle and prone to fracture. Osteopetrosis is sometimes associated with skeletal malformations.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of the potential associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
Infants with pycnodysostosis may experience delayed closure of the sutures of the skull. An infant’s skull has seven bones and several joints called sutures. Sutures are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull usually fuse together until around age two or later. In infants with pycnodysostosis, the sutures take longer to fuse together, which can affect the proper development of the skull. The skull is often larger than normal.
Distinctive facial features are common and include an abnormally prominent forehead (frontal bossing), a pointed nose, a highly-arched roof of the mouth (palate), prominent eyes with blue discoloration to the whites of the eyes (bluish sclerae), and a small jaw due to underdevelopment of the bones of the jaw (hypoplasia of the maxilla and mandible). Affected individuals may have several dental problems including delayed eruption of baby (deciduous) teeth, and then persistence of these teeth after they come in. They also experience delayed eruption of the permanent teeth. Some individuals may be missing teeth because the teeth fail to develop (hypodontia).
Individuals with pycnodysostosis may also have malformation of the collarbone (clavicular dysplasia) and breakdown of bone (osteolysis), particularly the outermost bones of the fingers and toes (acroosteolysis). The fingers may be small and stubby, and the fingernails may be absent or abnormally small. People with pycnodysostosis experience abnormal hardening and density of bone (osteosclerosis). Osteosclerosis causes bone to be fragile and affected individuals are prone to repeated fractures with minimal trauma or without trauma (spontaneously). The legs are most commonly affected by fracturing. Some people may have abnormal curvature of the spine such as having an s-shaped spine (scoliosis). Lower back pain due to stress fractures of the lower spinal bones (vertebrae) can occur. There may be deformities of chest development, which can cause breathing (respiratory) issues. Some individuals may snore, while others may have sleep apnea. Sleep apnea is a condition where a person will momentarily stop breathing during sleep. Sometimes, sleep apnea can be severe.
Some individuals with pycnodysostosis have growth hormone deficiency and deficiency of another hormone called insulin-like growth factor 1 (IGF-1), which also plays a role in growth during childhood. Affected individuals reach an adult height that is shorter than would otherwise be expected (short stature). The arms and legs of affected individuals are usually abnormally short.
Less often, pycnodysostosis may occur with other symptoms such as loose (lax) joints, underdevelopment (hypoplasia) of the sinuses, enlargement of the liver and spleen (hepatosplenomegaly), and underdevelopment of the pituitary gland.
Pycnodysostosis is caused by a change (mutation) in the cathepsin K (CTSK) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Pycnodysostosis is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
In certain populations, pycnodysostosis has occurred in families where the parents are closely related. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
The CTSK gene produces an enzyme called cathepsin K. This enzyme is a lysosomal enzyme and its job is to break down certain substances in the body include bone matrix proteins, certain types of collagen and other substances. This enzyme is predominantly found in osteoclasts, which are bone cells that absorb bone tissue during growth and healing. Basically, osteoclasts break down bone, a normal process called resorption. Bone is a dynamic system continuously engaged in a remodeling process of resorption and formation. Bone resorption refers to the breakdown of bone followed by the formation of new bone. In pycnodysostosis, some of these materials are not completely broken down and build up in lysosomes of cell. When enough of these materials build up, they become toxic to the affected cells and tissues of the body.
Pycnodysostosis is an extremely rare disorder that affects both males and females. About 200 people have been reported in the medical literature with this disorder. It is estimated to affect about 1 in 1.7 million people in the general discussion. Pycnodysostosis may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
A diagnosis of pycnodysostosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and x-ray studies. X-ray studies can show many of the characteristic bone changes that are associated with this disorder.
Molecular genetic testing can confirm a diagnosis of pycnodysostosis. Molecular genetic testing can detect mutations in the CTSK gene that causes the disorder, but is available only on as a diagnostic service at specialized laboratories.
The treatment of pycnodysostosis is directed toward the specific symptoms that are apparent in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat bone disorder (orthopedists), orthopedic surgeons, specialists who diagnose and treat hormonal disorders (endocrinologists), dental specialists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with pycnodysostosis.
Individuals with pycnodysostosis will need orthopedic care when fractures occur. There are no standard guidelines on the best method or surgical intervention for fracture treatment in pycnodysostosis. Specialized dental care should be provided and craniofacial surgery may be warranted.
Pycnodysostosis can potentially complicate the use of anesthesia in some people because of abnormalities affecting the jaw and the roof of the mouth (palate). Affected individuals should be evaluated before undergoing procedures that require anesthesia.
Some children with pycnodysostosis have been treated with growth hormone therapy because short stature is a common finding in this disorder. Initial results have shown positive results in individuals’ final adult height.
Researchers are studying specific medications called enzyme inhibitors for the treatment of pycnodysostosis and similar bone disorders. These medications work by inhibiting the activity of a specific enzymes in the body to block negative or harmful effects that these enzymes may cause because of an underlying genetic abnormality.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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