Pyle disease is a disorder of the bones. Its hallmark feature is an abnormality of the long bones in the arms and legs in which the ends (metaphyses) of the bones are abnormally broad; the shape of the bones resembles a boat oar or paddle. The broad metaphyses are due to enlargement of the spongy inner layer of bone (trabecular bone). Although trabecular bone is expanded, the dense outermost layer of bone (cortical bone) is thinner than normal. As a result, the bones are fragile and fracture easily. The bone abnormalities in the legs commonly cause knock knees (genu valgum) in affected individuals.
Other bone abnormalities can also occur in Pyle disease. Affected individuals may have widened collar bones (clavicles), ribs, or bones in the fingers and hands. Dental problems are common in Pyle disease, including delayed appearance (eruption) of permanent teeth and misalignment of the top and bottom teeth (malocclusion).
Pyle disease is caused by mutations in the SFRP4 gene. This gene provides instructions for making a protein that blocks (inhibits) a process called Wnt signaling, which is involved in the development of several tissues and organs throughout the body. In particular, regulation of Wnt signaling by the SFRP4 protein is critical for normal bone development and remodeling. Bone remodeling is a normal process in which old bone is broken down and new bone is created to replace it. Mutations in the SFRP4 gene are thought to prevent the production of functional SFRP4 protein. The resulting dysregulation of Wnt signaling leads to the bone abnormalities characteristic of Pyle disease.
Pyle disease is thought to be a rare disorder, although its prevalence is unknown. More than 25 cases have been described in the medical literature.
Pyle disease is inherited in an autosomal recessive pattern, which means both copies of the SFRP4 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene. While they do not develop the condition, they may have mild abnormalities of the long bones.
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