30 Granulomatous Disease
Noninfectious granulomatous disease is rare in children, with the exception of Crohn disease (see Chapter 110). This group of diseases includes sarcoidosis, granulomatous vasculitides (Wegener granulomatosis [WG] and Churg-Strauss syndrome [CSS]), and familial juvenile systemic granulomatosis (Blau syndrome).
Sarcoidosis
Sarcoidosis is an uncommon multisystem disorder of uncertain etiology involving granulomatous infiltrates in affected organs. Sarcoidosis occurs in children worldwide without gender predominance. The incidence ranges from 0.22 to 0.9 per 100,000 children in Denmark and Japan, respectively. Race predilection follows the predominant race of the country (e.g., whites in Scandinavian countries and Asians in Japan); however, there is a higher prevalence in 8- to 15-year-old black children of the southeastern United States. The incidence in children in the United States is unclear owing to lack of systematic evaluation.
Etiology and Pathogenesis
Despite considerable research, the cause of sarcoidosis is unknown. Inheritance is multigenic with relatively weak human leukocyte antigen associations varying with populations studied. An infectious cause has been considered but not confirmed. Interestingly, mycobacterial DNA has been detected by polymerase chain reaction in sarcoidosis lesions. A candidate mycobacterial antigen, Mycobacterium tuberculosis catalase-peroxidase protein (mKatG), has been proposed as a trigger for an adaptive immune response that leads to granuloma formation. Other microbes, including Propionibacterium acnes, have been implicated, but not confirmed, by independent studies.
Sarcoidosis is characterized by granulomas consisting of tightly packed epithelioid cells and macrophages surrounded by lymphocytes (Figure 30-1). In the lung, CD4+ T cell-mediated alveolitis occurs early followed by granuloma formation. Granulomas may resolve without sequelae or may heal with residual fibrosis.
Clinical Presentation
Sarcoidosis in children occurs in two distinct forms. Older children (age 8-15 years) typically present with symptoms resembling the adult form of disease, including lymphadenopathy, lung involvement (often asymptomatic), systemic signs (fever, weight loss), and hypercalcemia, but rarely with joint involvement. In children younger than 5 years, the onset typically consists of the triad of rash, arthritis, and uveitis. Sarcoidosis commonly presents with lymphadenopathy and may affect a wide range of organs (Figure 30-2).
Lymphoreticular System Manifestations
Lymphadenopathy is the most common presenting sign in childhood sarcoidosis. Enlarged nodes are generally nontender, firm, and mobile. Hepatosplenomegaly occurs less commonly.
Pulmonary Manifestations
Pulmonary involvement is often asymptomatic, consisting of hilar adenopathy and pulmonary infiltrates. Chronic dry cough is the most common pulmonary symptom, but children are often asymptomatic despite having restrictive disease on pulmonary function testing (PFT).
Ocular Manifestations
Uveitis (anterior, posterior, or panuveitis) is the most common ocular manifestation and is typically bilateral and asymptomatic, with occurrence of redness, pain, photophobia, or blurry vision in fewer than 30% of patients with uveitis. Keratic precipitates (tightly packed lymphocytic accumulations) are characteristic and occur at the corneal edge or pupil–iris junction. Synechiae may occur, typically between the lens and iris, resulting in irregular pupils. Conjunctival granulomas (small, pale yellow, translucent nodules), keratitis, glaucoma, or retinitis may also occur.
Skin Manifestations
Typical rashes include yellow-brown erythematous papules on the face or larger violaceous plaques on the trunk, extremities, and buttocks. Other skin involvement includes nodular (e.g., erythema nodosum), papular, macular, or ichthyosiform lesions; hypopigmentation; hyperpigmentation; or ulceration.
Musculoskeletal Manifestations
The arthritis of sarcoidosis is characterized by boggy tenosynovitis with effusion that is minimally painful or painless. Joint involvement may be oligoarticular (i.e., in few joints) initially but frequently progresses to polyarthritis over time. Associated stiffness and limited range of motion, typical in other forms of chronic arthritis, are generally minimal at diagnosis; however, with increased duration of disease, they become more apparent. Bony involvement is rare, but in the right setting, vertebral sarcoidosis should be considered in a child with back pain. Additionally, the small bones of the hands and feet may be involved. Nodular or inflammatory muscle lesions are rare.
Central Nervous System Manifestations
Central nervous system (CNS) disease includes cranial nerve abnormalities (e.g., optic neuritis or facial nerve palsy), encephalopathy, seizures, and mass lesions.
Other Manifestations
Salivary or lacrimal gland involvement may present similarly to Sjögren syndrome (recurrent parotitis, sicca syndrome, or lacrimal gland enlargement). Pancreatitis is very rare. Renal involvement is usually the result of nephrocalcinosis and nephrolithiasis rather than direct granulomatous inflammation. Heart block, cardiomyopathy, or ventricular arrhythmias may occur but are less common in children. Cytopenias may result from granulomatous infiltrates in bone marrow. Vasculitis affecting any sized vessel has been reported but is rare.
Differential Diagnosis
Sarcoidosis should be considered in any child presenting with nonspecific findings, including fever, weight loss, and lymphadenopathy, especially if accompanied by rash, arthritis, or hilar adenopathy, or in any child with fever of unknown origin (see Chapter 86, Figure 86-1). Other conditions that must be considered in a child suspected of having sarcoidosis include infections, malignancies, and other rheumatic illnesses (vasculitides, systemic lupus erythematosus [SLE], mixed connective tissue disease [MCTD], Sjögren syndrome, juvenile idiopathic arthritis [JIA]). Hilar adenopathy with constitutional symptoms may mimic lymphoma. After granulomatous inflammation has been established, infections must be ruled out before initiation of immunosuppressive medications (Box 30-1).
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