Pediatric Sarcoidosis: A Review with Emphasis on Early Onset and High-Risk Sarcoidosis and Diagnostic Challenges

Abstract

Sarcoidosis is a non-necrotizing granulomatous inflammatory syndrome with multisystemic manifestations. We performed a systematic review of sarcoidosis in the pediatric population with particular emphases on early onset sarcoidosis, high-risk sarcoidosis, and newly reported or unusual sarcoid-related diseases. Blau Syndrome and early onset sarcoidosis/ BS-EOS are seen in children younger than five years old presenting with extra-thoracic manifestations but usually without lymphadenopathy and/or pulmonary involvement. The prevalence of high-risk sarcoidosis is very low in children and is further limited by the difficulty of diagnosis in symptomatic children and underdiagnosis in subclinical or asymptomatic patients. Reports of sarcoidal syndromes in users of E-cigarette/marijuana/other flavorings and their induction in cancer immunotherapies are of interests and may be challenging to differentiate from metastatic malignancy. The diagnostic considerations in pediatric sarcoidosis are to support a compatible clinicoradiographic presentation and the pathologic findings of non-necrotizing granulomas by ruling out granulomas of infective etiology. There is no absolutely reliable diagnostic test for sarcoidosis at present. The use of endoscopic bronchial ultrasound (EBUS) and transbronchial fine needle aspiration (TBNA) sampling of intrathoracic lymph nodes and lung, and for superficially accessible lesions, with cytopathological assessment and pathological confirmations provide fair diagnostic yield and excellent patient safety profile in children.

Pulmonary granulomatosis of genetic origin

“…NOD2 is involved in innate immune responses and the inflammative cascade after viral or bacterial infections (via NF-κB and TNF receptor-associated factor 3 (TRAF3)) [101,102]. Gain of function mutations in NOD2 are associated with granulomatous inflammation of affected tissues, though a triggering infection is possibly essential [100,103,104]. Histologic evaluation reveals epithelioid cell-rich, noncaseating granulomas [105].…”

“…Blau syndrome is the inherited form of the disease and early-onset sarcoidosis is caused by de novo mutations in NOD2. The clinical course of the two entities is phenotypically indistinguishable and patients show a triad of granulomatous polyarthritis, dermatitis and uveitis [99,103,[106][107][108] (figure 4). Most patients present under the age of 2 years [109] and about one third to one half of patients have additional manifestations.…”

“…Parameters that have been helpful in diagnosing sarcoidosis are serum levels of angiotensin-converting enzyme (ACE), soluble IL-2 receptor and serum amyloid A [103,115]. For patients with high suspicion of Blau syndrome/early-onset sarcoidosis, genetic analysis should be performed (figure 4) [107].…”

Case Report: Pediatric Renal Sarcoidosis and Prognostic Factors in Reviewed Cases

“…A combination of genetic factors (e.g., CARD15/NOD2-mutation) and environmental exposure with antigens such as infectious agents—mainly mycobacteria ( 4 ), silica, aluminum, or inorganic dusts ( 5 )—is suspected to trigger a CD4+ T-cell response with increased cytokine activities resulting in granuloma formation. Prolonged inflammation may lead to fibrosis and irreversible organ dysfunction ( 6 ). Autonomous expression of 1-alpha-hydroxylase and therefore overproduction of 1,25-vitamin D in activated macrophages may result in hypercalcemia and secondary nephrocalcinosis ( 7 ).…”

Pediatrics: An Evolving Concept for the 21st Century

“…Few cases have been reported of this intriguing disease in children and youth [18]. Chiu et al revised this topic in detail in this issue [19]. These authors focused on early-onset sarcoidosis, high-risk sarcoidosis, and atypical sarcoid-related diseases.…”