eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Sarcoidosis

Author: Avinash Shetty, MD, Department of Pediatrics, Division of Pediatric Infectious Diseases, Assistant Professor of Pediatrics, Wake Forest University School of Medicine
Coauthor(s): Abraham Gedalia, MD, Head, Division of Pediatric Rheumatology, Professor of Pediatrics, Louisiana State University Health Sciences Center, Children's Hospital of New Orleans
Contributor Information and Disclosures

Updated: Jul 7, 2009

Introduction

Background

Sarcoidosis is a systemic granulomatous disease of unknown etiology that most commonly affects young adults, who frequently present with hilar lymphadenopathy, pulmonary infiltration, and ocular and cutaneous lesions. Although the lung is most frequently involved, the disease can affect any organ system of the body. The disease is relatively rare in children. Infants and children younger than 4 years present with the triad of skin, joint, and eye involvement without typical pulmonary disease; in older children, involvement of the lungs, lymph nodes, and eyes predominates.

Despite various hypotheses regarding causative agents, the cause of sarcoidosis still is unknown. The diagnosis of sarcoidosis is firmly established when histopathological evidence of noncaseating granulomata in affected organs and reasonable exclusion of other granulomatous diseases support compatible clinicoradiographic findings.

Frequently observed immunologic features include depression of cutaneous delayed-type hypersensitivity and a heightened helper T cell type 1 (Th1) immune response at sites of disease. Circulating immune complexes along with signs of B-cell hyperactivity may also be found. The illness can be self-limited or chronic, with episodic recrudescence and remissions. The course and prognosis may correlate with the mode of onset and the extent of the disease. This article examines the current understanding of sarcoidosis in children, including the epidemiology, etiology, immunopathogenesis, pathology, clinical manifestations, diagnosis, management, and prognosis.

Pathophysiology

Sarcoidosis is a chronic inflammatory disease characterized by a highly focused exaggerated immune response to an unknown antigen at the target organs. The hallmarks of the disease, sarcoid granulomas, most likely are formed in response to a persistent, poorly degradable, antigenic stimulus. Macrophages bearing increased expression of major histocompatibility class (MHC) II molecules most likely initiate the inflammatory response of sarcoidosis by presenting an unidentified antigen to CD4⁺ Th (helper-inducer) lymphocytes. This results in proliferation and activation of the T cell.

The immunopathology has been best studied in lung disease in which early lesions consist of an alveolitis with a high proportion of activated CD4+ Th1 cells, which may precede granuloma formation. Although the lung lymphocytes usually consist of CD4 memory T cells, in some patients, they are predominantly CD8 cells. Th cells in affected organs are primarily Th1 phenotype, secreting cytokines, including interferon-γ, interleukin (IL) –2, IL-12, and tumor necrosis factor-α (TNF-a), which is likely to favor the granulomatous response at sites of disease activity. Additionally, alveolar macrophages release various cytokines, including TNF-a, IL-1, IL-6, IL-12, IL-15, and growth factors in patients with sarcoidosis and pulmonary disease.

The CD4+ lymphocytes, in association with other immune effector cells, such as macrophages, mast cells, and natural killer cells, perpetuate the inflammatory response by release of cytokines, monocyte chemotactic factors, macrophage migration inhibitory factor, leukocyte inhibitory factor, adhesion molecules (CD49a, CD54, CD102), and growth factors.

As a result of these various immunologic interactions, an acute and often a chronic cascade of inflammation occurs. This is characterized by changes in tissue permeability, cellular influx, and local cell proliferation, resulting in a granuloma. Persistent antigenic stimulation is believed to maintain the pathogenic processes. Other immunologic abnormalities observed in patients with sarcoidosis include circulating immune complexes, B-cell hyperactivity, spontaneous in situ production of immunoglobulins, and depression of cutaneous delayed-type hypersensitivity reactions.

Although sarcoidosis most commonly involves the lungs, it can affect nearly any organ system, including the lymph nodes,¹ eyes, ears,² skin, liver, spleen, kidneys, bone, joints, nervous system, and heart. Granulomas mediate disease by compressing tissues, secreting cytokines that provoke constitutional symptoms, recruiting inflammatory cells whose products injure local tissues, and elaborating growth factors that cause fibrosis. Sarcoid granulomas either resolve or heal by fibrosis. This fibrotic response can result in severe and often irreversible organ damage and physiological dysfunction.

Frequency

United States

The prevalence of sarcoidosis in the adult population ranges from less than 1 case to 40 cases per 100,000 population, with an age-adjusted annual incidence rate of 10.9 per 100,000 for white people and 35.5 per 100,000 in black people. True incidence and prevalence is unknown because of the rarity of the disease and the small number of reported cases in childhood. As in adults, many children with sarcoidosis may be asymptomatic and the disease may remain undiagnosed. More than 70% of childhood cases in the United States have been reported primarily in Virginia, North Carolina, South Carolina, and Arkansas, suggesting that the southeastern and south central states are an endemic area for childhood sarcoidosis.

International

In the United Kingdom, the overall prevalence of sarcoidosis is approximately 20 per 100,000 population. In Europe, the prevalence ranges from 3-50 cases per 100,000 population, with the disease most frequently affecting persons aged 20-40 years. Sweden has the highest reported incidence of sarcoidosis in Europe, ranging from 64 cases per 100,000 population using mass radiographic screening to 641 cases per 100,000 population using autopsy studies.

One review reported that the approximate incidence of clinically recognized sarcoidosis in Danish children younger than 15 years was 0.22-0.27 per 100,000 children per year, corresponding to approximately 3 new cases in Denmark each year. In many other countries, such as Spain, Portugal, India, Saudi Arabia, or South America, the prevalence of sarcoidosis is low, possibly because of the absence of mass chest radiographic screening and also because of the presence of other more commonly recognized granulomatous diseases, especially tuberculosis, that mimic sarcoidosis.

Mortality/Morbidity

Very few studies of the prognosis and natural history of sarcoidosis in children are available because of the rarity of the disease and the small number of reported cases. Thus, long-term prognosis is only speculative;³ however, the overall prognosis of childhood sarcoidosis is reported to be good, with most children experiencing considerable improvement in clinical manifestations and findings on chest radiographs and pulmonary function tests.⁴

Data from 16 patients with childhood sarcoidosis showed improvement of the forced vital capacity (FVC) from 80.3 ± 16.4% predicted at presentation to 97.1 ± 18.8% about 4 years later. In another series, Marcille et al performed a follow-up study on 19 individuals in whom sarcoidosis had been diagnosed in childhood. The mean follow-up period was 21 years (range 8-35 y).⁵  Seven patients (37%) had persistent abnormalities on chest radiograph, 68% had impaired lung function, and 63% had abnormal findings on echocardiography. In another series from the University of North Carolina, most patients improved; however, 40% still were symptomatic and 35% had physical abnormalities after an average follow-up of 5 years.

Although most older children appear to improve, a significant number have sequelae or experience major complications; however, the mortality rate is low. A review of 5 large series of childhood cases of sarcoidosis published over an 18-year period showed that 6 of 176 patients died, for an overall mortality rate of 3%. Asymptomatic cases with hilar adenopathy have a very favorable outcome, with spontaneous resolution in many patients, while those with stage IV disease have a poor prognosis. Symptomatic patients with multisystemic involvement often experience chronic disease, with residua in about 20%, mainly involving the eyes and lungs.

Early onset sarcoidosis with involvement of the eyes, joints, and skin suggests a guarded prognosis with the likelihood of a chronic progressive course; 80-100% of these children develop residua of uveitis, polyarthritis, and other organ involvement. A series of 6 patients with early onset sarcoidosis and a long follow-up with a mean of 14 years (range 0-23 y) reported on the severe outcome of the disease, including blindness (4 patients), growth retardation (3 patients), cardiac involvement (2 patients), renal failure (1 patient), and even death (1 patient). Progressive ocular disease may produce severe disability with secondary glaucoma resulting in blindness. Currently, longitudinal clinical assessment focusing on the severity of the disease in affected organs remains the best approach to prognosis.

Race

The lifetime risk of sarcoidosis on the basis of cumulative incidence estimates is 2.4% for black people in the United States and 0.85% for white people in the United States. The racial distribution of sarcoidosis varies with geographic location. In the pediatric series reported from the southeastern United States, sarcoidosis had a higher incidence among blacks.

In children aged 4 years and younger with sarcoidosis, 7-28% are black, whereas in children aged 8-15 years, the percentage of blacks increases to 72-81%. Studies in military and veteran populations showed that black people are 10-17 times more commonly affected with sarcoidosis than are white people. Outside the United States, sarcoidosis most frequently occurs in the predominant race of the country. Thus, in Scandinavian countries where sarcoidosis is common, almost all cases occur in white people, while in Japan, most patients are Asian.

Sex

No clear sex predominance is recognized in childhood sarcoidosis, although a Japanese study has reported a higher incidence of sarcoidosis in males than in females. In a recent study from Denmark, the male/female gender ratio was close to one. Adult studies have reported a slightly higher disease rate for women. A population-based study of incidence and survival in adults with sarcoidosis reported incidence rates of 5.9 per 100,000 person-years for men and 6.3 per 100,000 person-years for women.

Age

Most reported childhood cases have occurred in patients aged 13-15 years. The disease has also been reported in very young children. The prevalence increases until adulthood when the disease most frequently is found in patients aged 20-30 years. A bimodal distribution has been reported in Scandinavian countries and Japan, with a secondary peak occurring primarily in females older than 50 years.

Clinical

History

Because sarcoidosis is a multisystem disease and affects most organs, the clinical presentation can widely vary.

• In most children, the disease frequently involves the lungs, lymph nodes, eyes, skin, liver, and spleen.
• Almost all childhood cases of sarcoidosis are symptomatic.
• In asymptomatic cases, the diagnosis may be made by chance.
• Most of the reported cases of childhood sarcoidosis are accompanied by nonspecific constitutional symptoms, such as fever, fatigue, malaise, and weight loss, as well as symptoms from particular organs such as lungs, eyes, skin, and lymph nodes.
• Pulmonary symptoms usually are mild and often consist of a dry hacking cough with or without mild-to-moderate dyspnea and occasionally chest pain.
• Less common symptoms include bone pain, headache, dyspnea, and abdominal pain. Patients with sarcoidosis may rarely present with fever of unknown origin.

Physical

Two distinct forms of childhood sarcoidosis are noted. Older children usually present with a multisystem disease similar to the adult manifestation with frequent lymphadenopathy and pulmonary involvement, as well as generalized signs and symptoms, such as fever and malaise. In contrast, early onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis⁶ in presenting patients who are younger than 4 years.

• Lung
  • The lung is the organ most commonly involved in sarcoidosis. Pulmonary disease and abnormal findings on chest radiography are more common in children with sarcoidosis who are aged 8-15 years, occurring in 94-100% of patients. In contrast, approximately 22% of children with sarcoidosis who are younger than 4 years have pulmonary involvement.
  • Bilateral hilar adenopathy is the most common chest radiographic finding in children and occurs in almost all cases. Other radiographic findings include paratracheal adenopathy (75-88%) and subcarinal adenopathy (42%). The hilar lymphadenopathy is typically symmetrical, although it may appear unilateral in rare instances.
  • Pulmonary parenchymal involvement is common and predominantly appears radiographically as an interstitial pattern, although nodular, alveolar, and fibrotic patterns have also been described.
  • Other uncommon manifestations include pleural effusion, pneumothorax, pleural thickening, calcification, atelectasis, and cor pulmonale.
  • Nearly half of all children with sarcoidosis demonstrate restrictive lung disease on static and dynamic pulmonary function tests, including a reduction in total lung capacity (TLC), forced vital capacity (FVC), functional residual capacity (FRC), and transfer factor (DL CO). These changes are believed to be secondary to early alveolitis progressing to fibrosis.
  • An obstructive ventilatory pattern has been reported in approximately 15% of children with sarcoidosis. Airway obstruction may be secondary to airway hyperactivity, intrabronchial sarcoid granuloma, hilar and/or mediastinal lymph node compression of the airways, or bronchiectasis.
• Lymphatic system: The most common clinical feature in childhood sarcoidosis is peripheral lymph node enlargement. About 40-70% of children with sarcoidosis have palpable peripheral lymph glands. Lymph nodes are typically firm, nontender, discrete, and freely movable. They do not ulcerate and do not form draining sinuses. The most frequently involved glands are cervical, axillary, epitrochlear, and inguinal. In the neck, the posterior triangle nodes are affected more commonly than the nodes in the anterior triangle. The enlarged peripheral lymph nodes are the most accessible tissue for biopsy, providing a high diagnostic yield.¹
• Liver and spleen: Hepatosplenomegaly occurs in as many as 43% of children with sarcoidosis at some point in their clinical course; however, clinically significant hepatic dysfunction is rare. Mild elevation in biochemical liver function test values (eg, serum bilirubin, serum alanine transferase, alkaline phosphatase) is common, but severe liver involvement with cirrhosis and portal hypertension or splenic involvement with RBC sequestration is unusual in children.
• Eyes: Ocular involvement is extremely common in children with sarcoidosis, and a complete ophthalmologic evaluation, including a slitlamp examination, is crucial, particularly in young children. Any part of the eye or orbit may be affected.
  • Anterior uveitis (also known as iritis or iridocyclitis) is the most frequently observed lesion, occurring in about 58-90% of early-onset sarcoidoses as compared with 24-54% of sarcoidosis cases in older children. The frequency of ocular involvement in adults with sarcoidosis ranges from 25-50% in most series.
  • Sarcoid-associated uveitis can be acute or chronic and can vary from an isolated iridocyclitis to a bilateral panuveitis syndrome.
    • Chronic granulomatous uveitis of sarcoidosis is characterized by firmly edged "mutton-fat" keratitic precipitates occurring preferentially in the limbus, but they may be present as a ring or confluent cellular aggregates and form "snow banking" inferiorly. These precipitates of inflammatory cells can also be present on the iris pupil margin, where they are called Koeppe nodules, and they become a site of synechia formation. The iritis of juvenile rheumatoid arthritis (JRA) may also produce few symptoms; however, the corneal cellular aggregates are more centrally located and the edges are less firm and distinct. In addition, the synechia formation is more diffuse in JRA and tends to be more focal in sarcoidosis. If left untreated, the disease may result in synechiae, corneal opacities, glaucoma, and, eventually, blindness.
    • An acute nongranulomatous type of anterior uveitis may also occur, which typically is characterized by eye pain, blurred vision, photophobia, redness, and excessive lacrimation.
  • Conjunctival granulomas are the second most common ocular manifestation in sarcoidosis, and they may appear as tiny, translucent, pale yellow nodules. A bulbar conjunctival biopsy can be valuable, yielding a diagnosis in 50% of cases.
  • Other forms of ocular lesions include interstitial keratitis, band keratopathy (because of calcium deposition), dacryocystitis, retinal vasculitis, lacrimal gland enlargement, choroiditis, and orbital infiltration, which may result in proptosis.⁶
• Skin
  • Cutaneous involvement occurs in about 24-40% of older children with sarcoidosis and in 77% of young children with sarcoidosis. The most frequent cutaneous eruptions include soft, red–to–yellowish brown, or violaceous flat-topped papules, most frequently found on the face. In children, erythematous macular lesions with scarring and ichthyosiform rashes are frequently encountered. Larger, violaceous, plaquelike lesions may be found on the trunk, extremities, and buttocks. Other skin lesions of sarcoidosis include nodules, hyperpigmented lesions, hypopigmented lesions, ulcers, subcutaneous tumors, and erythema nodosum. Rarely, "scar sarcoidosis" (ie, infiltration of old scars with sarcoid granuloma in the active phase of the disease) may present in children.
  • Cutaneous involvement occurs in about 25% of all adult patients with sarcoidosis. Two clinically important and easily identifiable sarcoid skin lesions in adults (but unusual in children) include erythema nodosum and lupus pernio. Lupus pernio, a violaceous indurated skin lesion occurring principally on the cheeks, nose, lips, and ears, represents chronic sarcoidosis in older women, especially West Indian and black women. Erythema nodosum, the hallmark of acute sarcoidosis, is commonly observed in European, Puerto Rican, and Mexican patients, particularly in women of childbearing age. The entity is rare in Japanese and African American patients. Erythema nodosum consists of ill-defined, tender, red nodules on the anterior aspects of the legs and may be associated with swollen and painful adjacent joints. The lesions typically resolve over 2-3 weeks with characteristic bruising. Rarely, erythema nodosum may be a presenting sign of childhood sarcoidosis.
  • Lofgren syndrome is a classic presentation of acute sarcoidosis typically observed in young adult females, primarily white females, and characterized by fever, bilateral hilar adenopathy, erythema nodosum, and arthralgia. The ankle and knee joints are most frequently involved. This presentation remains less common in children than in adults. Prognosis is excellent, and complete resolution is observed in more than 90% of patients.
• Musculoskeletal system
  • In childhood sarcoidosis, arthritis occurs with a frequency of 45-58%. Musculoskeletal features of sarcoidosis include joint pain, joint effusions, and, rarely, bone lesions. Bone lesions are more likely to be found if chronic cutaneous lesions are present. The arthritis of childhood sarcoidosis, which can easily be confused with JRA in preschool-aged children, is characterized by boggy tenosynovitis with relatively painless effusion and good range of movement. Multiple large joints on the upper and lower extremities are often involved. The joints are swollen but are usually without tenderness or erythema of the skin.
  • Bone involvement is rarely noted in children with sarcoidosis; the common sites include the hands and the feet. When small destructive cystic lesions are present in the distal ends of the phalanges, metacarpals, and metatarsals, a lacy reticular trabecular pattern or acro-osteolysis has been noted. Sarcoid lesions have also been reported to occur in the long bones, spine, and skull. Osteolytic bone lesions or erosive changes are rarely observed today in association with musculoskeletal manifestations of childhood sarcoidosis.
  • Symptomatic muscle involvement in sarcoidosis is unusual in children. Adult studies have reported symptomatic muscle involvement in 1.4% of known cases of sarcoidosis. The clinical spectrum most frequently can vary from an asymptomatic state to nodular myopathy in which findings on MRI and gallium scintigraphy, acute myositis, and chronic myopathy may indicate the lesions. In symptomatic cases, muscle involvement may be evident because of pain, tenderness, weakness, and elevated muscle enzymes (eg, creatine kinase, aldolase). The presence of sarcoid granulomas can be detected in 50% of affected adults on muscle biopsy.
• Renal and endocrine systems
  • Renal involvement occurs infrequently in children and adults with sarcoidosis. Renal disease can be attributed to granulomatous interstitial infiltration or to disorders of calcium homeostasis, including hypercalcemia and hypercalciuria with or without nephrocalcinosis and nephrolithiasis. Clinically, variable renal disease occurs in 5-10% of adult cases. Renal involvement is not well characterized in the published series of childhood sarcoidosis. Only 32 isolated cases of sarcoidosis with renal involvement have been reported in children since 1941.
  • The clinical manifestations in reported cases of renal granulomatous sarcoidosis include proteinuria, leukocyturia, hematuria, concentration defect, hypertension, and renal failure. In a previous review, decreased creatinine clearance was found in more than 60% of children with sarcoidosis, although other evidence of renal dysfunction, such as abnormal urinalysis results, elevated BUN levels, and elevated serum creatinine values were found in less than 40% of children.
  • Histopathological studies have revealed epithelioid granuloma formation, interstitial infiltration by mononuclear cells, interstitial fibrosis, tubulitis, tubular atrophy, mesangial hyperplasia, glomerular fibrosis, membranous nephropathy, and vascular involvement.
  • Granulomas have been found in the kidneys in 15-40% of adult patients with sarcoidosis. Incidence in children is unknown but is believed to be lower. Children who have a partial response to corticosteroid therapy and who develop arterial hypertension have a poor prognosis.
  • Derangement in calcium metabolism manifesting as hypercalcemia and/or hypercalciuria occurs in up to 30% of children. In vitro experiments of cultured alveolar macrophages from patients with sarcoidosis and of homogenized sarcoid lymph node tissue have demonstrated that the sarcoid macrophage is able to synthesize 1,25-dihydroxyvitamin D via 25-hydroxyvitamin D3-1-alpha hydroxylating activity. The excess circulating 1,25-dihydroxyvitamin D produced extrarenally causes increased intestinal absorption of calcium, enhanced bone resorption, and resultant hypercalciuria with or without hypercalcemia.
  • Additionally, granulomatous production of parathyroid hormone–related protein may also play a role. This process can ultimately result in nephrocalcinosis and renal failure. Nephrolithiasis and nephrocalcinosis have been reported in several cases of childhood sarcoidosis with hypercalcemia and hypercalciuria. Hypercalcemia of sarcoidosis often becomes clinically manifest during the summer months because the production of provitamin D in the skin is accelerated by exposure to sunlight. Intense sunlight exposure, as occurs during prolonged sunbathing in subtropical or tropical countries, may induce severe hypercalcemia in some patients with sarcoidosis. Hypercalcemic crisis has been reported as the presenting sign in childhood sarcoidosis.
• Heart: Sarcoidosis involving the heart has been well documented in adults but rarely in children.
  • The most common cardiac abnormalities include conduction abnormalities and dysrhythmias due to granulomatous infiltration of the heart. Sudden deaths have been reported in as many as 60% of adults with untreated cardiac sarcoidosis. Half of the patients with cardiac sarcoidosis have electrocardiographic abnormalities of rhythm, conduction, and repolarization, warranting 24-hour Holter monitoring. A high index of suspicion and early diagnosis is crucial because aggressive treatment with prolonged steroids may result in decreased mortality rates.
  • Other manifestations of cardiac sarcoidosis include infiltrative cardiomyopathy with congestive heart failure, valvular disease, pericardial effusion, and papillary-muscle dysfunction. A combination of myocardial scintigraphy with thallium Tl 201 and gallium Ga 67 is recommended to evaluate disease status and predict possible response to corticosteroids.
• Nervous system
  • Little is known about neurosarcoidosis in children because of the rarity of the disorder in this age group. Sarcoidosis may affect virtually any axis of the nervous system in adults. The disease is apparent in approximately 5% of patients of all ages, often in a clinically silent form.
  • In a review of 29 pediatric neurosarcoid cases, the authors noted that the clinical presentation of neurosarcoid in prepubertal children is different when compared with adults. Children are more likely to have seizures, less likely to have cranial nerve palsies, and more likely to present with space-occupying lesion. The pediatric cases evolve into adult patterns of disease, with more frequent cranial nerve palsies and less frequent seizures as children progress to adulthood.
  • Cranial neuropathies are the most common manifestation of adult neurosarcoidosis, and facial nerve palsy is the most frequent abnormality, followed by abnormalities that affect the optic and acoustic nerves.
  • Sarcoid granulomas primarily involve the basilar leptomeninges, leading to obstructive hydrocephalus and seventh nerve palsy.
  • Other reported manifestations of neurosarcoidosis include meningitis, seizures, hypopituitarism, diabetes insipidus, cerebellar ataxia, isolated intramedullary spinal cord or cauda equina involvement, and peripheral neuritis.
• Parotid glands: Parotid gland enlargement is a frequent finding in children with sarcoidosis. In early onset sarcoidosis, involvement of the parotid gland is reported in 13% of cases. Unilateral or bilateral parotitis with swollen painful enlargement of the gland occurs in less than 6% of adult patients with sarcoidosis and is self-limiting in about 40% of these patients. Heerfordt syndrome (a combination of fever, parotid enlargement, anterior uveitis, and cranial nerve palsies) is often observed in adult patients and has been reported in childhood sarcoidosis.
• Hematologic manifestations
  • Sarcoidosis can affect the bone marrow. The toxicity may result from mechanical disruption of the marrow by granulomas as well as an indirect effect from the variety of cytokines released. Several studies of adult patients with sarcoidosis have shown one or more hematologic abnormalities in over half of the cases. Anemia occurs in 4-20% of patients with sarcoidosis. Leukopenia occurs in as many as 40% of patients but rarely is severe. In the absence of splenomegaly, leukopenia may reflect bone marrow involvement. Other hematologic abnormalities, such as leukemoid reaction, eosinophilia, autoimmune hemolytic anemia, and thrombocytopenia, are rare.
  • Bone marrow involvement in sarcoidosis often is asymptomatic. In severe cases, children may present with fever of unknown origin, localized bone pains, anemia, and leukopenia, mimicking a number of infectious, inflammatory, and neoplastic processes. In such cases, MRI may reveal multiple small nodular lesions within the marrow, even in the presence of normal findings on plain radiographs and normal findings on bone scan. MRI can help localize sarcoid lesions for diagnostic marrow biopsy.
• Other sites of involvement
  • The incidence of GI tract sarcoidosis is reported to be less than 1% in adults. The stomach is the most frequent site of involvement, whereas the esophagus, small bowel, appendix, rectum, and pancreas are very rarely affected. Involvement of the GI tract in childhood sarcoidosis is very unusual.
  • Rarely, the sarcoid granulomatous process may involve the reproductive system in adults and children, often mimicking a tumor.
  • Few cases of isolated laryngeal sarcoidosis have been described in the pediatric literature.
  • Endocrine manifestations, such as anterior pituitary involvement, growth hormone deficiency, and delayed puberty, are rare.
• Early onset childhood sarcoidosis
  • Early onset childhood sarcoidosis (ie, with onset in the first 4 y of life) is a rare disease and appears to be different from sarcoidosis in older children and adolescents. A striking predominance of white patients is observed in early-onset disease unlike that found in older children with sarcoidosis. Patients with early-onset sarcoidosis frequently present in the first year of life with the characteristic triad of rash, uveitis, and arthritis occurring in children younger than 4 years. Hetherington reviewed 28 cases of early-onset disease and noted that a red maculopapular rash (78%) may precede joint symptoms (58%) by months.⁷ Uveitis, which occurs in about 58-90% cases of early onset disease, is described in about 20-30% of patients with later-onset disease. Pulmonary involvement, the leading feature of late-onset disease, is unusual in early onset sarcoidosis and was noted in only 22% of children.
  • Early onset sarcoidosis may be overlooked because of its similarity to systemic-onset JRA. Both entities may be associated with systemic manifestations such as fever, weight loss, and fatigue. Skin changes may help to distinguish between the two diseases at the onset. The rash of JRA is pink, evanescent, and macular, whereas the rash of sarcoidosis usually is a persistent follicular or nodular rash with scaling.
  • Joint involvement in early onset sarcoidosis typically begins as early morning stiffness with minimal functional impairment and is characterized by painless boggy effusions with synovial thickening that commonly affects the wrists and knees. Fusiform swelling of the finger joints and skeletal abnormalities are more common in this age group. Sarcoid arthritis typically is persistent and nondestructive, affecting predominantly the large joints; however, painful destructive polyarthritis with functional impairment indistinguishable from that associated with JRA has also been described in early-onset sarcoidosis.
  • Uveitis is a useful differentiating feature. In JRA, the corneal cellular aggregates are more centrally located and the edges are less firm and distinct. In addition, the synechia formation is more diffuse in JRA and tends to be more focal in sarcoidosis. Furthermore, uveitis is very unusual in systemic-onset JRA, which is most often confused with early-onset sarcoidosis.
  • The other organs involved in preschool children with sarcoidosis include liver and spleen (52%), lymph nodes (42%), parotid gland (13%), bone (13%), and lung (13%). Because liver involvement occurs in approximately half of the cases, liver biopsy is an important diagnostic tool in patients in whom findings on other tissue biopsies are not helpful or in whom affected organs are not easily accessible.
  • Cardiac, renal, and CNS involvement have been reported infrequently in early onset disease. The cardiac manifestations include pericarditis, myocarditis, and intraventricular thrombosis with significant clinical effects.
  • A few case reports describing vasculitis involving renal arteries and aortic arch disease also appear in the literature.
  • Blindness is a rare but severe late complication in early onset sarcoidosis.

Causes

• Despite the world occurrence of sarcoidosis, the etiology of sarcoidosis is still unknown. Attempts to elucidate the cause of sarcoidosis have been disappointingly thwarted by lack of an animal model and the failure to identify the antigen.
• Despite extensive research, no identifiable agent has been demonstrated to account for the granulomata that characterize the disease. Infectious agents, chemicals, drugs, autoimmunity, and genetic factors have all been explored as potential causes. Most experts think that sarcoidosis results from exposure of genetically susceptible hosts to specific environmental agents that trigger an exaggerated cellular immune response, leading to granuloma formation. Case clustering suggests that an infectious agent may be responsible.
• Mycobacteria, including Mycobacterium tuberculosis and other atypical species, have received the greatest amount of attention. The detection of mycobacterial DNA and RNA in sarcoid lesions by polymerase chain reaction (PCR), demonstration of components of the mycobacterial cell wall (eg, tuberculostearic acid, muramyl dipeptide) in sarcoid nodules, and the growth of acid-fast L-forms from the blood of patients with sarcoidosis lend support to that association. However, several investigators have fiercely contested the results obtained by PCR. Furthermore, attempts to fulfill the Koch postulates have failed, and the role of mycobacteria in sarcoidosis remains a controversial issue.
• Besides M tuberculosis, many different antigens are under suspicion, including other bacteria such as Propionibacterium acnes, Streptococcus species, Borrelia burgdorferi, Mycoplasma species, and Nocardia species. Viruses (eg, Epstein-Barr virus, herpesvirus, Coxsackie B virus, cytomegalovirus, retrovirus) and noninfectious environmental chemicals (eg, beryllium, aluminum, zirconium, titanium, pine pollen, peanut dust, clay ingestion) are also under suspicion.
• Variant human herpesvirus 8 (HHV-8) DNA sequences were detected from multiple sample sites in all patients with sarcoidosis. The significance of this finding is not clear and further studies are necessary to determine whether the association between HHV-8 and sarcoidosis is causal.
• The striking racial variation in sarcoidosis incidence suggests a genetic predisposition to develop sarcoidosis. The strongest support for a genetic susceptibility to sarcoidosis comes from numerous reports of familial clustering of cases. In the United States, familial clusters more frequently are observed in blacks, with a rate of at least 19% in affected black families as compared to 5% in white families. Segregation and linkage analyses have not been performed. When sarcoidosis has been observed in twins, monozygotic twins are 2-4 times more concordant for disease than dizygotic twins. The most common familial relationship is sibling pairs, followed by parent-offspring. The hereditary differences in candidate genes that promote susceptibility may reside in loci that influence regulation of antigen presentation or recognition, T cell function, or the regulation of matrix deposition that favors granuloma formation and progressive fibrosis.
• Genetic factors may also be important in defining the pattern of disease presentation, its severity, and prognosis. Several investigators have searched for associations with human leukocyte antigen (HLA)–related genes that may confer susceptibility to sarcoidosis. HLA analyses of affected families suggest a polygenic mode of inheritance of risk for sarcoidosis; the most commonly found alleles include class I HLA-A1 and B8 and class II HLA-DR3 in whites. Of the association studies reported so far, the study of blacks found no association with HLA alleles associated with sarcoidosis in the white population. Reports have demonstrated that association studies may be performed best with families in whom the ethnic background can be controlled. Examination of other genetic loci, such as those encoding polymorphisms for immunoregulatory cytokines, growth factors, and angiotensin-converting enzyme (ACE), may prove equally important.

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