Pycnodysostosis (Pyknodysostosis)

• Pycnodysostosis is an inherited disorder of the bone.
• Pycnodysostosis causes short stature.
• Pycnodysostosis causes abnormally dense brittle bones.
• Pycnodysostosis causes the "soft spot" of a baby's skull to stay widely open.
• Pycnodysostosis is due to a defect in an enzyme: cathepsin K.
• Growth hormone treatment may increase growth in pycnodysostosis.

Pycnodysostosis is perhaps best known as the diagnosis given retrospectively to the late 19th century French artist Henri de Toulouse-Lautrec (portrayed by Jose Ferrer in the 1952 film "Moulin Rouge").

Pycnodysostosis is a genetic (inherited) disease of the bone. Its pattern of inheritance follows the classic rules of genetics (see below).

Pycnodysostosis consistently causes short stature. The height of adult males with the disease is less than 150 cm (59 inches, or 4 feet 11 inches). Adult females with pycnodysostosis are even shorter.

Pycnodysostosis causes the bones to be abnormally dense (osteosclerosis); the last bones of the fingers (the distal phalanges) to be unusually short; and delays the normal closure of the connections (sutures) of the skull bones in infancy, so that the "soft spot" (the fontanel) on top of the head remains widely open.

Pycnodysostosis causes brittle bones which easily break (fracture). The bones in the legs and feet tend to fracture. The jaw and collar bone (clavicles) are also particularly prone to fractures.

The precise frequency of pycnodysostosis has never been determined. Pycnodysostosis can be classified in the large group of genetic diseases that are individually uncommon, but collectively important because of the sum of their numbers, their heavy impact upon affected individuals, and the equally heavy burden they place upon their families.

The name for this disease was coined by the French physicians Maroteaux and Lamy in 1962. They described the disorder in a report entitled "La pycnodysostose." (They were not the only discoverers of the disease. Andren and colleagues independently described the condition in 1962.) Maroteaux and Lamy put "pyknos," from the Greek meaning "dense" together with the compound word "dysostosis" meaning abnormal bone formation. The name "pycnodysostosis" was designed to convey the abnormally dense bone that is a hallmark of the disease.

Although the original Maroteaux and Lamy spelling was with a 'c', it has been written variably with a 'c' or a 'k'. Here we use the original spelling with a 'c'. No matter which way it is spelt, the name has stuck and is utilized worldwide today to designate this disease.

Pycnodysostosis causes abnormalities other than short stature, dense brittle bones, short fingers, and the wide open soft spot of the skull (see above). These other abnormalities involve the head and face, teeth, collar bones, skin, and nails. The front and back of the head are prominent. Within the open sutures of the skull, there may be many small bones (called wormian bones). The midface is less full than usual. The nose is prominent. The jaw can be small. The palate is narrow and grooved. The baby teeth are late coming in and may be lost much later than usual. The permanent teeth can also be slow to appear. The permanent teeth are commonly irregular and teeth may be missing (hypodontia). The collar bones are often underdeveloped and malformed. The skin over the back of the fingers is very wrinkled. The nails are flat and grooved.

Pycnodysostosis also causes problems that may become evident with time. Aside from the broken bones, the last bones of the fingers (the distal phalanges) and the collar bone can undergo slow progressive deterioration. Vertebral defects may permit the spine to curve laterally (resulting in scoliosis). The tooth problems often require orthodontic care and dental cavities are common.

Pycnodysostosis is an autosomal recessive condition. It is autosomal in that the gene for pycnodysostosis is situated on one of the non- sex chromosomes (autosomes). Pycnodysostosis is recessive in that a single edition of the pycnodysostosis gene is not enough to cause the disease. Two copies of the abnormal gene (one from each parent) must be present for the disease to develop. The presence of a normal gene from one or both parents prevents the disease.

Pycnodysostosis is a rare disease so that, if there is no family history of the disease, the risk for a child to have pycnodysostosis is very low.

However, with a inbred (consanguineous) union, the risk of pycnodysostosis rises a little. This means that if one parent carries a rare gene like that for pycnodysostosis, the chance that a mate of theirs who is actually related also carries the same rare gene is increased compared to an unrelated mate.

In a family with a child with pycnodysostosis, the risks are much higher. The parents of a child with pycnodysostosis have no signs of the disease themselves but they each carry a single edition of the pycnodysostosis gene and, with a given pregnancy, each has a half chance of transmitting the pycnodysostosis gene (versus the normal paired gene). It is like tossing a coin. The chance for the child to have pycnodysostosis is one-half (from one parent) times one-half (from the other parent). The overall risk of pycnodysostosis in the offspring of parents carrying the gene is, therefore, one-quarter (25%). Just as coins have no memory of a prior toss, the 25% odds of having a pycnodysostosis child apply to every pregnancy conceived together by these parents, irrespective of the status of any of their other children.

In 1995, the gene for pycnodysostosis was first charted by Gelb and associates. It was found to travel preferentially with gene markers known to be in chromosome region 1q21. (This tendency for genes to travel together is termed linkage). Once the location of the pycnodysostosis gene was identified by linkage analysis, genes in that region that seemed logical candidates were seriously scrutinized. Among them was cathepsin K, which is active in bone. Cathepsin K qualified as a "candidate gene."

In 1996, patients with pycnodysostosis were shown by Gelb and coworkers consistently to have mutational changes in the gene for cathepsin K. The defective cathepsin K gene was thus demonstrated to be the gene responsible for pycnodysostosis. Pycnodysostosis is now clearly recognized as being due to cathepsin K deficiency.

What does cathepsin K normally do? Cathepsin K is an enzyme (a catalyst for a reaction of body metabolism) of the type called a cysteine protease. This protease is important in cells of normal bone (osteoclasts) that are responsible for bone reabsorption (or resorption). It is thought that osteoclasts in patients with pycnodysostosis are hampered by a lack of cathepsin K and cannot adequately reabsorb that component of bone called the organic matrix. (This process is essential for normal bone maintenance; a process referred to as remodeling). Because of this inadequate resorption, the bones in pycnodysostosis are abnormally dense and brittle.

Both pycnodysostosis and osteoporosis cause brittle bones. However, pycnodysostosis is a disease with abnormally dense bones, whereas osteoporosis is exactly the opposite, a disease with washed-out porous bones. There would seem to be no conceivable connection between pycnodysostosis and osteoporosis.

The new findings about cathepsin K and pycnodysostosis have made it clear that cathepsin K is a major protease in bone resorption. Given this function, it may well have a role in osteoporosis. Cathepsin K may, in fact, provide a rational basis for a new approach to the treatment of osteoporosis. This is an excellent illustration of how research on a rare disease may bring benefits to those affected by a common disease.

Bone fractures are a big problem for patients with pycnodysostosis. They can occur with minimal stress. It is important that the disease be diagnosed and the tendency to fractures be recognized so that (1) fractures can be minimized, if not entirely prevented; and (2) the parents and other caregivers are not falsely accused of child abuse! As with any condition causing brittle bones, the infant should be handled with a reasonable degree of care. The older child should be encouraged to engage in safer forms of exercise such as swimming rather than, for example, jumping on a trampoline.

In 1996, Soliman and colleagues reported that there is defective secretion of growth hormone in pycnodysostosis. Replacement treatment with growth hormone was then tested. It was found to increase the growth of the length of bones (linear growth). Since short stature is an important consequence of pycnodysostosis, growth hormone treatment may prove very useful.