Genetic conditions that cause joint deformities are primarily disorders affecting connective tissues, muscles, or bone development. These conditions often arise from mutations in genes responsible for producing structural proteins like collagen, fibrillin, or enzymes critical for tissue integrity and function. The result is abnormal joint mobility, stiffness, deformities, or instability, which can significantly impact movement and quality of life.
One of the most well-known groups of genetic disorders causing joint deformities is the **Ehlers–Danlos syndromes (EDS)**. EDS comprises multiple subtypes, each caused by mutations in different genes affecting collagen or related proteins. Collagen is a key structural protein in connective tissues, including skin, ligaments, and joints. In EDS, the connective tissues are abnormally fragile or elastic, leading to symptoms such as hypermobile (overly flexible) joints, recurrent joint dislocations, joint pain, and deformities. For example:
– The **classical-like EDS** subtype involves mutations in the *TNXB* gene and is characterized by loose joints that may dislocate, along with soft, velvety skin.
– The **arthrochalasia type** of EDS, caused by mutations in *COL1A1* or *COL1A2* genes, leads to severe joint hypermobility and congenital hip dislocation. This subtype also features fragile skin and skeletal abnormalities like scoliosis.
– **Brittle cornea syndrome**, linked to *ZNF469* or *PRDM5* gene mutations, includes hypermobile joints alongside eye problems and skin fragility.
EDS types vary in severity and inheritance patterns, with some inherited in an autosomal dominant manner (one mutated gene copy causes the disorder) and others autosomal recessive (two copies needed). Joint deformities in EDS arise because the connective tissue that supports joints is weak or overly stretchy, causing instability and abnormal joint shapes.
Another important genetic condition causing joint deformities is **Marfan syndrome**, which results from mutations in the *FBN1* gene responsible for producing fibrillin, a protein essential for connective tissue strength and elasticity. Marfan syndrome often leads to unusually long limbs and fingers (arachnodactyly), joint hypermobility, and skeletal deformities such as scoliosis or chest wall abnormalities. The joints may be loose and prone to dislocation due to weak ligaments. Marfan syndrome also affects the cardiovascular system, but its joint and skeletal manifestations are prominent.
**Osteogenesis imperfecta (OI)** is a genetic disorder characterized by brittle bones due to defects in type I collagen. While primarily known for causing fragile bones and frequent fractures, OI also leads to joint deformities because the collagen abnormalities affect ligaments and tendons, resulting in joint laxity or contractures. Some forms of OI cause bowing of long bones and spinal curvature, which indirectly affect joint alignment and function.
Certain **muscular dystrophies**, especially congenital muscular dystrophies like **Bethlem myopathy** and **Ullrich congenital muscular dystrophy**, also cause joint deformities. These conditions stem from mutations affecting type VI collagen or other muscle-related proteins. Muscle weakness and hypotonia (low muscle tone) impair joint stability and movement, leading to stiffness, contractures (permanent joint tightening), or excessive joint mobility. For instance, Ullrich congenital muscular dystrophy often presents with severe muscle weakness and unusually mobile joints, while Bethlem myopathy causes joint stiffness and progressive mobility problems.
Other rare genetic connective tissue disorders include:
– **Loeys-Dietz syndrome**, caused by mutations in genes affecting the transforming growth factor-beta (TGF-β) pathway, leads to arterial aneurysms and skeletal abnormalities including joint laxity and deformities.
– **Arterial tortuosity syndrome**, which also affects connective tissue, can cause joint hypermobility and skeletal defor