Paget’s disease (PDB) is a chronic disorder that disrupts the body’s normal process of bone renewal, resulting in areas of abnormally structured, weak bone. While some cases appear randomly, others cluster within families, raising the question of whether PDB is hereditary. Understanding the genetic risk factors and environmental influences is important for individuals assessing their potential for developing the disease.
Understanding Paget’s Disease of Bone
Paget’s disease of bone is a localized disorder of the skeletal remodeling cycle, the continuous process where old bone tissue is broken down and replaced. This cycle is normally balanced between osteoclasts (resorbing bone) and osteoblasts (forming new bone). In PDB, osteoclasts become overly active, leading to excessive and rapid bone resorption in specific areas.
The bone tissue subsequently produced by the osteoblasts attempts to compensate but is structurally disorganized. Instead of the tight, organized structure of normal bone, the newly formed bone takes on a chaotic, mosaic pattern, often described as “woven bone.” This disorganized growth results in bones that are enlarged, structurally weak, and brittle, making them susceptible to pain and fracture. The disease commonly affects bones in the axial skeleton, particularly the pelvis, spine, skull, femur, and tibia.
Identifying the Genetic Components
While most cases of Paget’s disease are sporadic, a significant number are familial, confirming a strong genetic link. Between 15% and 40% of individuals diagnosed with PDB report having at least one first-degree relative with the condition. This familial form often follows an autosomal dominant inheritance pattern, meaning a person only needs to inherit one copy of the altered gene to be at risk.
The most significant genetic factor identified is a mutation in the SQSTM1 gene (Sequestosome 1). This gene is altered in up to 50% of familial cases and 5% to 30% of sporadic cases. SQSTM1 provides instructions for a protein that regulates the activity of osteoclasts.
Mutations in SQSTM1 typically cluster around the ubiquitin-associated (UBA) domain. These specific mutations result in a gain of function that hyper-activates the osteoclasts, causing the excessive bone breakdown characteristic of PDB. Despite this inheritance pattern, the disease exhibits incomplete penetrance; not everyone who inherits the mutation will develop PDB. Other genes, including TNFRSF11A and ZNF687, have also been associated with the disease, indicating a complex genetic foundation.
The Interplay of Genes and Environment
The incomplete penetrance observed with SQSTM1 mutations suggests that genetics alone are insufficient to trigger the disease. PDB development is often viewed through the “two-hit” hypothesis, requiring both genetic susceptibility and a subsequent environmental trigger. This model helps explain why the disease affects only certain bones and why its prevalence has declined globally.
The most widely studied environmental trigger is chronic viral infection, specifically with paramyxoviruses, such as the measles virus. It is hypothesized that a viral infection may activate genetically susceptible osteoclasts, initiating the abnormal remodeling cycle. Other proposed environmental factors include dietary deficiencies (calcium or vitamin D) and exposure to certain toxins.
Genetic Counseling and Family Risk Assessment
Genetic counseling offers a structured way to assess personal risk for individuals with a known family history of Paget’s disease. This process involves reviewing the family’s medical history, calculating risk, and discussing the implications of genetic testing. Counseling helps individuals understand the autosomal dominant inheritance pattern and incomplete penetrance.
Genetic testing for the SQSTM1 mutation confirms a predisposition, enabling proactive management. For those confirmed to be at high risk, periodic screening is recommended to detect the disease in its earliest, asymptomatic stages. Screening typically involves annual or biennial blood tests to monitor alkaline phosphatase, a marker of high bone turnover. A radionuclide bone scan may also be used to identify early, localized lesions. Early diagnosis allows for prophylactic treatment with medications like bisphosphonates, which can prevent the development or progression of the disease in genetically susceptible individuals.