Another way the Norris lab is attempting to find this gene is by looking at genes involved in the formation of the aorta and mitral valves, as these valves are often prolapsed or malformed as a symptom of EDS. Because hEDS is such a complex, multi-organ disease, focusing on one hallmark trait has proven successful. One gene found this way is DZIP1, which regulates cardiac valve development in mammals through a Cby1-beta-catenin mechanism. Mutations at this gene affect the beta-catenin cascade involved in development, causing malformation of the extra-cellular matrix, resulting in loss of collagen. A lack of collagen here is both consistent with hEDS and explains the "floppy" mitral and aortic valve heart defects. A second genetic study specific to mitral valve prolapse focused on the PDGF signaling pathway, which is involved in growth factor ligands and receptor isoforms. Mutations in this pathway affect the ability to localize cilia in various cell types, including cardiac cells. With the resulting ciliopathies, structures such as the cardiac outflow tract, heart tube assembly, and cardiac fusion are limited and/or damaged. Classical EDS
Classical EDS (formerly categorized as type 1) is characterized by extremely elastic skin that is fragile and bruises easily and hypermobility of the joints. Molluscoid pseudotumors (calcified hematomas that occur over pressure points) and spheroids (cysts that contain fat occurring over forearms and shins) are also often seen. A side complication of the hyperelasticity presented in many EDS cases makes wounds closing on their own more difficult. Sometimes, motor development is delayed and hypotonia occurs.
Further out into the fibrous shell there is a zone that contains T cells and plasma cells in association with blood vessels. The histology of pulmonary nodules are similar to that of subcutaneous nodules, with central necrosis surrounded by palisading macrophages and inflammatory infiltrate. Risk Factors
Rheumatoid nodules develop if a person currently has rheumatoid arthritis. However, not all people with rheumatoid arthritis develop rheumatoid nodules. Some risk factors for rheumatoid nodules for people with rheumatoid arthritis may include:
Smoking (strong association)
Elevated levels of serum rheumatoid factors
HLA-DRB1 gene (weak association)
Trauma to small vessels
Having severe rheumatoid arthritis
Taking Methotrexate over other arthritis drugs

Diagnosis
Differential diagnosis of rheumatoid nodules can be classified from localization, depth pathology, age of onset, persistence, rheumatoid factor, concomitant joint disease, and bone erosions. Diagnosis is typically determined clinically by a rheumatologist. Rheumatoid arthritis associated rheumatoid nodules are typically subcutaneous and occur at extensor sites. The onset typically starts in adulthood and presents with rheumatoid factors and bone erosions, and concomitant joint diseases. The pathology is characterized by central necrosis, palisading mononuclear cells, and perivascular lymphocytic infiltrations.Rheumatoid nodulosis is characterized by multiple subcutaneous nodules presenting with rheumatoid factors but an absence of joint complaints. The nodules are typically small and concentrated on the extensor sites of the hands and feet, sometimes accompanied by bone erosions. The onset typically starts in adulthood with a pathology similar to rheumatoid arthritis associated rheumatoid nodules.Benign rheumatoid nodules are often not associated with rheumatoid factors or concomitant joint diseases. They are typically found on the feet, scalp, and pretibial regions.