Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Sarcoidosis
Sarcoidosis is a rare multisystem granulomatous disease of unknown etiology. The name is derived from a Greek word meaning “flesh-like condition,” in reference to the characteristic skin lesions. There appear to be 2 distinct, age-dependent patterns of disease among children with sarcoidosis. The clinical features in older children are similar to those in adults (pediatric-onset adult sarcoidosis), with frequent systemic features (fever, weight loss, malaise), pulmonary involvement, and lymphadenopathy. In contrast, early-onset sarcoidosis manifesting in children <4 yr of age is characterized by the triad of rash, uveitis, and polyarthritis.
Etiology
The etiology of sarcoidosis remains obscure but likely results from exposure of a genetically susceptible individual to 1 or more unidentified antigens. This exposure initiates an exaggerated immunologic response that ultimately leads to the formation of granulomas. The human major histocompatibility complex is located on chromosome 6, and specific human leukocyte antigen (HLA) class I and class II alleles are associated with disease phenotype. Genetic polymorphisms involving various cytokines and chemokines may also have a role in development of sarcoidosis. Familial clustering supports the contribution of genetic factors to sarcoidosis susceptibility. Environmental and occupational exposures are also associated with disease risk. There are positive associations between sarcoidosis and agricultural employment, occupational exposure to insecticides, and moldy environments typically associated with microbial bioaerosols.
Blau syndrome is an autosomal dominant, familial form of sarcoidosis and is typified by the early onset of granulomatous inflammation involving the skin, eyes, and joints. Missense mutations in the CARD15/NOD2 gene on chromosome 16 have been found in affected family members and appear to be associated with development of sarcoidosis. The 2 most common amino acid substitutions are R334W (arginine to glutamine) and R334Q (arginine to tryptophan). Similar genetic mutations also have been found in individuals with a sporadic early-onset sarcoidosis (EOS) (rash, uveitis, arthritis), suggesting that this nonfamilial form and Blau syndrome are genetically and phenotypically identical (see Chapter 188 ).
Epidemiology
A nationwide patient registry of childhood sarcoidosis in Denmark estimated the annual incidence to be 0.22-0.27 per 100,000 children. The incidence increases with age, and peak onset occurs at 20-39 yr. The most common age of reported childhood cases is 13-15 yr. Annual incidence is about 11 per 100,000 in adult white Americans and is 3 times higher in blacks. There is no clear sex predominance in childhood sarcoidosis. The majority of U.S. childhood sarcoidosis cases are reported in the southeastern and south-central states.
An international registry and Spanish cohort of Blau syndrome and EOS reported the mean age of disease onset as 30 mo and 36 mo, respectively. All but 3 of these young patients presented before 5 yr of age. There does not appear to be a sex predilection in either condition.
Pathology and Pathogenesis
Noncaseating, epithelioid granulomatous lesions are a cardinal feature of sarcoidosis. Activated macrophages, epithelioid cells, and multinucleated giant cells as well as CD4 + T lymphocytes accumulate and become tightly packed in the center of the granuloma. The causative agent that initiates this inflammatory process is not known. The periphery of the granuloma contains a loose collection of monocytes, CD4 + and CD8 + T lymphocytes, and fibroblasts. The interaction between the macrophages and CD4 + T lymphocytes is important in the formation and maintenance of the granuloma. The activated macrophages secrete high levels of tumor necrosis factor (TNF)-α and other proinflammatory mediators. The CD4 + T lymphocytes differentiate into type 1 helper T cells and release interleukin (IL)-2 and interferon (IFN)-γ, promoting proliferation of lymphocytes. Granulomas may heal or resolve with complete preservation of the parenchyma. In approximately 20% of the lesions, the fibroblasts in the periphery proliferate and produce fibrotic scar tissue, leading to significant and irreversible organ dysfunction.
The sarcoid macrophage is able to produce and secrete 1,25-(OH) 2 -vitamin D or calcitriol, an active form of vitamin D typically produced in the kidneys. The hormone's natural functions are to increase intestinal absorption of calcium and bone resorption and decrease renal excretion of calcium and phosphate. An excess of calcitriol may result in hypercalcemia and hypercalciuria in patients with sarcoidosis.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here