Pediatric sarcoidosis comprises a spectrum of childhood granulomatous inflammatory conditions with the hallmark being the presence of noncaseating epithelioid giant cell granulomas in a variety of tissues and organ systems. The finding in 2001 of a mutation in the nucleotide-binding oligomerization domain 2/caspase activation recruitment domain 15 (NOD2/CARD15) gene among patients with a history of familial granulomatous arthritis constituted a major advance and revealed the complexity and heterogeneity of the spectrum of pediatric sarcoidosis.
Blau syndrome and early-onset sarcoidosis constitute the familial and sporadic forms of a pediatric disease characterized by a triad of polyarthritis, uveitis, and rash; and a unique association with mutations in or near the central NOD/NACHT domain of the NOD2 gene. The term pediatric granulomatous arthritis (PGA) proposed for both conditions falls short in describing the systemic and visceral manifestations that have been documented in a number of patients with PGA.
Many children with sarcoidosis are NOD2 mutation negative and tend to exhibit systemic and visceral manifestations at presentation. Within this group, the authors identified a distinct entity, infantile-onset panniculitis, with uveitis and systemic granulomatosis.
The form of sarcoidosis observed in adults, characterized mainly by interstitial pulmonary involvement and hilar adenopathy, can also be seen in the pediatric age group but is limited to older children. Certain clinical symptom complexes of granulomatous inflammation, including Löfgren and Mikulicz syndromes, can occur in children. Granulomatous inflammation can be seen secondary to immunodeficiencies, in the context of malignancies and some systemic vasculitides or with certain drug therapies.
Epidemiology
Scarce data exist on the epidemiology of pediatric sarcoidosis. A Danish National Registry study included 48 children within a cohort of 5536 patients with sarcoidosis, resulting in a calculated overall incidence for childhood sarcoidosis of 0.29 per 100,000 per year. The incidence ranged from 0.06 per 100,000 per year for children younger than 5 years old to 1.02 per 100,000 per year for children 14 to 15 years old.
An earlier international registry reported on 53 pediatric patients, of whom 14 had a family history, which yielded a ratio of 1 : 5 for familial to sporadic forms. The International Registry of Pediatric Sarcoidosis, established in 2005, shows no gender difference or geographic predominance; the majority of patients exhibiting the classic triad of arthritis, uveitis, and rash have disease onset before reaching 5 years old.
Etiopathogenesis
The familial cases manifesting the classic clinical triad and an autosomal dominant transmission pattern have been termed Blau syndrome (BS). Using linkage analysis of the original pedigree, the susceptibility locus for BS was mapped to a region of chromosome 16, which was found to contain a gene associated with Crohn’s disease (CD) called IBD1 . The IBD1 gene was later found to be NOD2 . In 2001, Miceli and colleagues identified mutations within the NOD/NACHT domain of the NOD2 gene in four French families with the Blau phenotype. This seminal work revealed that NOD2 substitutions associated with BS were located in a different domain of the protein than those associated with CD. Wang and colleagues reported NOD2 mutations in 50% of 10 pedigrees with the BS phenotype. Later, identical mutations were reported among patients with early-onset sarcoidosis (EOS), a sporadic disease with the same phenotype of granulomatous arthritis, uveitis, and rash. Currently, BS and EOS are considered to be the same disease. Conversely, mutations in NOD2 are not found in variant forms of pediatric sarcoidosis that display a more heterogeneous phenotype, nor are they found in adult sarcoidosis, yet certain NOD2 polymorphisms are reportedly associated with severe pulmonary sarcoidosis.
The NOD2 gene encodes a 1,040 amino-acid protein composed of three main functional domains: two amino-terminal caspase recruitment domains (CARDs), a central nucleotide binding oligomerization domain (NOD/NACHT), and carboxyterminal leucine-rich repeats (LRRs). An expanding number of mutations causing amino-acid substitutions in and near the NOD domain have been documented. Substitutions R334W (arginine to glutamine in position 334) and R334Q (arginine to tryptophan) are by far the most common. Yet mutations in position 802 (LRR region) were seen at least in one patient with BS. Variants associated with CD are concentrated in the carboxyterminal LRR region; although CD and BS/EOS have very different phenotypes, they are both characterized by the presence of giant cell granulomas.
The NOD2 protein is a member of a growing family of NOD-like receptor cytosolic proteins comprising different functional domains and implicated in pathways of inflammation and apoptosis. The two amino-terminal CARD domains of NOD2 have an important role in the mediation of nuclear factor (NF)-κB activation and secretion of proinflammatory cytokines, resulting from CARD–CARD interactions between NOD2 and a pivotal downstream kinase protein receptor-interacting serine/threonine kinase (RICK) also known as RIP2 or CARDIAK. The centrally located NOD domain mediates self-oligomerization of NOD2 proteins and activation of downstream effector molecules. The LRR region is structurally related to the LRR regions of the Toll-like receptors, which are molecules of the innate immune system indispensable for the “sensing” of molecular motifs specific to pathogens, such as lipopolysaccharide. Studies have shown that the moiety recognized by NOD2 is actually muramyldipeptide, a building block of peptidoglycan found in both Gram-positive and Gram-negative bacterial cell walls. NOD2 is expressed constitutively in monocytes, granulocytes, dendritic cells, and in Paneth cells in the villous crypts of the small intestine.
The downstream effects of NOD2 mutations and their relationship with the clinical phenotype are largely unknown. The NOD2 mutations associated with BS involve residues located in the NOD domain and reportedly act as constitutively active NOD2 mutants, which are gain-of-function variants consistent with the autosomal-dominant nature of the disease ( Fig. 39-1 ). Using transfection systems, a constitutive NF-κB activation through an abnormal stabilization of the active conformation in the mutated NOD2 protein has been suggested, although these findings have not been replicated to date. Conversely, experiments using patients’ circulating mononuclear cells could not confirm the expected upregulation and release of interleukin (IL)-1 and other proinflammatory cytokines, an in vitro phenomenon poorly understood that somewhat contradicts the notion of a gain-of-function effect on the mutations and activation of NF-κB.
The pathological hallmark of sarcoidosis is the presence of noncaseating epithelioid granulomas thought to result from an exaggerated immune-inflammatory response to a persistent unidentified antigen. The granulomas consist of a central cluster of monocytes/macrophages in various stages of activation, epithelioid cells aligned in a way reminiscent of epithelial cells, and multinucleated giant cells ( Fig. 39-2 ). A corona of mostly CD4 + T lymphocytes, scattered CD8 + T lymphocytes, and plasma cells surrounds the central region. Immunohistochemistry studies in adult sarcoidosis have demonstrated the presence of T-helper (Th)-1 type lymphokines (IL-2, interferon [IFN]-γ) and proinflammatory cytokines (IL-1, tumor necrosis factor [TNF]-α, IL-6) in situ .
Blau granulomas display a distinct morphology characterized by large polycyclic granulomas with dense lymphocytic coronas. They reflect an exuberant inflammatory response that is in line with a gain-of-function mutation in NOD2 . Using immunohistochemistry, a predominance of CD68 + macrophages and CD4 + T lymphocytes, an abundant inflammatory cytokine expression in situ is typically observed. A prominent expression of IFN-γ is in accordance with an important role for Th1 lymphocytes in granulomatous inflammation. This is seen in association with a very high expression of IL-6, TGF-β, and IL-17, as well as an increased expression of IL-23 receptor on granuloma cells. These findings are suggestive of activation of the Th17 lymphocyte axis in Blau granulomas. Of interest, a role for both Th1 and Th17 cells in adult sarcoidosis has recently been reported as well.
In Blau granulomas, widespread extensive emperipolesis (cell-in-cell phenomenon) of lymphocytes within multinucleated giant cells, associated with multinucleated giant cell death, was seen as well, a finding of interest in view of the recently reported role of NOD2 in autophagy ( Fig. 39-3 ).
The relationship between the formation and persistence of inflammatory granulomas and the effect of NOD2 mutations on inflammatory and apoptosis pathways remains to be elucidated.
Clinical Features
Sarcoidosis Associated With NOD2 Mutation
NOD2 mutation–associated sarcoidosis comprises patients with either BS or EOS manifesting a consistent clinical phenotype with polyarthritis, dermatitis, and uveitis ( Fig. 39-4 ). In recent years, because of the availability of genetic testing, a more protean clinical picture than initially conceived has been observed. That this form of sarcoidosis is different from the better-known adult form should not be forgotten.
The initial manifestations include the typical exanthema followed within months by a symmetrical polyarthritis. Ocular involvement tends to occur toward the second year. The median age at onset in the International Blau Registry was 26 months, with two unusual cases showing an age at onset of 2 months and 14 years old.
Cutaneous Involvement
The rash varies in color from pale pink with varied degrees of tan to intense erythema. The lesions appear on the trunk, mainly dorsally, and extend to the face and limbs with accentuation of the tan color on extensor surfaces, where it may become scaly brownish over time (see Fig. 39-4A ). The lesions are tiny (5 to 7 mm), round, and barely palpable. At onset, the rash often shows a very fine desquamation, which may lead to confusion with atopic dermatitis. Over the course of years the rash waxes and wanes. With time, the desquamation predominates, and, in adolescence, it may mimic ichthyosis vulgaris.
Subcutaneous nodules, often located in the lower limbs, are the second most common dermatological manifestation and may be clinically indistinguishable from erythema nodosum. The nodules are mildly tender and resolve without atrophy or pigmentation, even in patients with recurrent episodes. Erysipelas-like lesions have been observed as well, and in one case an urticarial rash showed typical histological features of leukocytoclastic vasculitis.
Articular Disease
The majority of patients will report a polyarticular symmetrical, generalized, or additive arthritis, affecting large and small peripheral joints and tendon sheaths. The joints most frequently involved comprise wrists, knees, ankles, and proximal interphalangeal (PIP) joints. A characteristic feature of both synovitis and tenosynovitis is the exuberance of the swelling. The distal flexor tendons of the digits, the extensor and peroneal compartments, and the flexor groups of the carpus can reach significant size. The anserine tendon sheath diameter can reach 1 cm in some cases. The synovial outpouching can acquire a cystic appearance in the dorsum of the carpus and tarsus. Despite the prominent “boggy” synovitis, pain and morning stiffness appear to be moderate and are overall well tolerated. Except for the PIP joints, where a characteristic flexion contracture described as “camptodactyly” can be seen, the range of motion is relatively well preserved, at least in childhood (see Fig. 39-4, B ). The course of the arthritis is variable, and erosive changes are mostly modest. However, limited joint mobility and joint contractures may develop with time; ulnar deviations, wrist subluxations, and joint space narrowing have been described. It appears that in addition to the postinflammatory sequelae on radiograph there are a number of other abnormalities suggestive of dysplastic changes. There are limited data on the functional effects of BS arthritis over time. In a recent study it was noted that between one quarter and one third of patients show moderate or severe pain, and moderate to severe functional impairment after a mean follow-up of 16 years.
Ocular Disease
An insidious granulomatous iridocyclitis and posterior uveitis can evolve into a severe destructive panuveitis. Of the clinical triad elements, the ocular disease exhibits the most somber functional prognosis. It tends to start within the first 2 years of disease, and initially there is little to no redness or photophobia. Over time, characteristic iris nodules, focal synechiae, cataract, increased intraocular pressure, and clumpy keratic precipitates at the limbus ensue. Nodules may also occur in the conjunctivae and, in this location, offer an early diagnostic clue and biopsy site. A description of the slit-lamp appearance of sarcoid uveitis compared with juvenile idiopathic arthritis (JIA)-associated uveitis was published by Lindsley and Godfrey. Posterior involvement includes vitritis, multifocal choroiditis, retinal vasculopathy, and optic nerve edema (see Fig. 39-4, C ). Significant visual loss is observed in 20% to 30% of the affected individuals. Ocular disease can be difficult to control. A prospective study on the natural course of the disease showed persistent vitreous inflammation in 60% of patients and anterior segment activity in 30% despite aggressive therapy during the years of disease course.
Visceral Involvement
As our understanding of the disease spectrum evolves, it has become apparent that the clinical phenotype is not restricted to the classic triad. Among patients with sarcoidosis and associated NOD2 mutations, a myriad of clinical manifestations including granulomatous and interstitial nephritis, chronic renal insufficiency, small-vessel vasculitis, interstitial pneumonitis, peripheral and mediastinal (excluding hilar) lymphadenitis, pericarditis, cranial neuropathy (VII cranial nerve), and parotitis have been documented. Visceral manifestations have been described in patients with BS before the NOD2 mutation was known. Systemic manifestations including prolonged fever have been reported at the onset and may recur during first few years of the disease. Large-vessel vasculopathy has been reported in past studies, and in one NOD2 mutated family studied by Wang, but it was not confirmed in more recent series. Severe arterial hypertension without demonstrable vascular involvement by digital imaging has been observed in 25% of patients who had extra-triad manifestations. The mechanism is unknown, but renal vasculopathy was suggested.
Until recently, no cases of asymptomatic mutation carrying have been observed; however, one family with a mutation E383K in four asymptomatic members has been reported.
Sarcoidosis Without NOD2 Mutation
Sarcoidosis with wild-type NOD2 constitutes a heterogeneous group of granulomatous inflammatory disorders with protean manifestations. Within this group, two distinct subsets have been identified, including infantile-onset panniculitis with systemic granulomatosis and pediatric-onset adult sarcoidosis.
Infantile-Onset Panniculitis With Uveitis and Systemic Granulomatosis
Four infants with a unique phenotype, including recurrent lobular nonlipophagic panniculitis, severe systemic involvement with persistent fever, hepatosplenomegaly, and granulomatous inflammation affecting joints, eyes, internal organs, and the CNS, have been described. The disease course is progressive, although a partial response to anti-TNF agents can be seen. This condition has been considered a new clinical and pathological entity.
Pediatric-Onset “Adult-Type” Sarcoidosis
Overall, this form of sarcoidosis is characterized primarily by systemic features: pulmonary and lymph node involvement, rather than articular disease. The incidence increases with age and tends to cluster in early adolescence. A review of published pediatric sarcoidosis cohorts reveals the presence of systemic features (malaise, fever, weight loss) at presentation in 60% to 98% of patients; lung involvement in 90% to 100%; hilar adenopathy in 40% to 67% and peripheral adenopathy in 71% to 76%, and 71% to 76% of patients, respectively. Hepatomegaly and splenomegaly were seen in up to 43% of patients; mild elevation of liver enzymes is common, but severe sarcoid hepatitis rarely occurs. A liver biopsy may show granulomas but also cholestatic, necroinflammatory, and vascular changes. Cutaneous manifestations including erythema nodosum, erythematous macules, papules, and plaques were observed in 25% to 42% of patients ( Fig. 39-5 ); eye involvement was seen in 23% to 51%; and uveitis, the most common ocular manifestation, was observed in 25%. Neurological manifestations, mainly CNS involvement, was seen in 23% of patients.
