Pediatric Sarcoidosis Clinical Presentation

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 are usually 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 in rare cases present with fever of unknown origin.

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 arthritis^[6] in presenting patients who are younger than age 4 years.

Lung

The lung is the organ most commonly involved in sarcoidosis. 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 the cervical, axillary, epitrochlear, and inguinal glands. 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.^[4]

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 red blood cell (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

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) are 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 that is typically observed in young adult females, primarily white females; it is 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 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 magnetic resonance imaging [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.

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.

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 that in 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 fewer 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.

Other sites of involvement

The incidence of gastrointestinal (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. A 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, in contrast to 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 et al reviewed 28 cases of early onset disease and noted that a red maculopapular rash (78%) may precede joint symptoms (58%) by months.^[14] 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 2 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%), bones (13%), and lungs (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 central nervous system (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.