Fig. 46.1
Boggy synovitis of both knees in child with early-onset sarcoidosis
Fig. 46.2
Skin rash in a child with sarcoidosis following etanercept treatment
Introduction
Sarcoidosis is challenging both to diagnose and treat. It is a multisystem granulomatous disease, which occurs with a frequency of 1–40 per 100,000 individuals [1]. It has a heterogeneous presentation and is characterized by the presence of noncaseating granulomas in various organs like the lungs, skin, lymph nodes, eyes, and joints. Clinical features seen in the pediatric age group are different to those seen in the adult population. The diagnosis of sarcoidosis in children is established when a compatible clinical and radiographic picture is supported by histologic evidence of noncaseating granulomas in affected tissues and when other granulomatous diseases have been excluded.
Epidemiology
Pediatric sarcoidosis is a rare disease. A recent review done in Danish children with sarcoidosis showed that the incidence in children younger than or equal to 15 years was 0.29 per 100,000 person-years, with the incidence rates gradually increasing with age. The median age at diagnosis was 13 years. The male/female ratio in this cohort was 1.18 [2]. The prevalence of sarcoidosis varies according to the geographic area and racial distribution. It is more prevalent in US blacks, Swedes, and Danes and is relatively less frequent in South America, Spain, Portugal, India, Saudi Arabia, and Japan [1, 3]. The disease is thought to be more severe in the blacks than in whites [1].
Etiopathogenesis
The etiology of sarcoidosis remains essentially unknown. It probably occurs due to an environmental or infectious trigger in a genetically susceptible host. Organisms like Mycobacteria, Propionibacterium acnes, and Borrelia burgdorferi have been implicated in the etiopathogenesis, but there is no definite proof of direct causation [4–6]. There is also a genetic component to the pathophysiology of sarcoidosis, which is evidenced by familial clustering of cases. Certain manifestations of sarcoidosis are associated with HLA-AI, HLA-B8, and HLA-DR3, whereas negative association is seen with HLA-B12 and HLA-DR4. HLA-DR3 has been associated with a good outcome [7]. A recent study found three independent association signals in the HLA region, peaking in the BTNL2 promoter region, at HLA-B*0801, and at HLA-DPB1, and another novel independent signal near IL23R [8].
The hallmark of the disease is the formation of the sarcoid granuloma, in response to a persistent, poorly degradable antigenic stimulus [1]. Macrophages from patients with sarcoidosis have an increased expression of MHC II molecules and other co-stimulatory molecules on their cell surface. The antigen is presented by these highly efficient macrophages to T-helper cells, expressing the Th1 phenotype. This leads to proliferation and activation of the T cells [9]. The sarcoid granuloma has activated T cells abundantly present in the internal areas of the granuloma with a layer-like distribution. T-helper cells are present in the internal areas of the granuloma, whereas the periphery comprises of cytotoxic T cells and suppressor/inducer T cells [10]. These cells secrete a variety of cytokines and chemokines including interferon gamma; interleukin (IL)-2, IL-12, and IL-15; tumor necrosis factor-alpha (TNF-α); and growth factors. Two mechanisms are involved in the accumulation of inflammatory cells in tissues affected by sarcoidosis. First, chemoattractant cytokines such as IL-8, IL-16, and RANTES contribute to expand the local pool of CD4 memory cells within the inflamed tissue. The second mechanism is in situ IL-2-mediated proliferation of CD4 T cells [1]. IL-18 has been recently recognized as an IFN γ-inducing factor. It plays an important role in Th1 response induction and may be responsible for disease progression. IL-18 has also been described as a good prognostic marker [11].
A sustained inflammatory response leads to granuloma formation, common sites for which are the lymph nodes, lungs, liver, spleen, and skin. These granulomas resolve or they heal by fibrosis [1].
Clinical Features
There are two forms of pediatric sarcoidosis. The early-onset form is associated with a sporadic genetic mutation in the nucleotide binding oligomerization domain 2/caspase activation recruitment domain 15 (NOD2/CARD15) gene that causes accelerated nuclear factor (NF)-κB activation [12]. The second type is seen in older children and adolescents and is similar to the adult disease with pulmonary manifestations, lymphadenopathy, panniculitis, arthritis, hepatosplenomegaly, parotid swelling, and other systemic features such as weight loss and fever.
Sarcoidosis Associated with NOD2 Mutation
Early-onset sarcoidosis (EOS) and Blau syndrome have a similar genetic etiology, and they represent the sporadic and familial forms of pediatric sarcoidosis, respectively. Lately, the term “pediatric granulomatous arthritis” refers to both EOS and Blau syndrome. It has been recently classified as an autosomal dominant systemic autoinflammatory disease as it is due to defects in the innate immune system.
NOD2 has a tripartite structure which comprises of two N-terminal CARDs (caspase activation and recruitment domains), one centrally located NOD and a C-terminal domain comprised of ten leucine-rich repeat (LRR) motifs. The LRR domain binds muramyldipeptide (MDP), a degradation product of the bacterial cell wall peptidoglycan. This leads to the activation of NOD2. NOD2 is inactive in its unstimulated state via intramolecular interaction between its LRR domains and CARDs. Engagement of MDP ligand leads to unfolding and oligomerization via the exposed NOD making it active. This results in further engagement of Receptor-interacting serine/threonine-protein kinase 2 (RIP 2 kinase) and subsequently of the TAK1 (Transforming growth factor β-activated kinase 1) complex and in consequent activation of the key downstream signaling molecules NF-kB and MAP kinase (Fig. 46.3). This ultimately results in the production of inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α and a variety of other cytokines, chemokines, and adhesion molecules. Enhanced ligand-independent NF-kB activity was demonstrated for NOD2 alleles associated with Blau syndrome and EOS [13–15].
Fig. 46.3
Mechanism of NOD2 activation. NOD2 has a tripartite structure which comprises of two N-terminal CARDs, one a centrally located NOD and a C-terminal domain comprised of LRR motifs. The binding of the LRR domain to MDP of the bacterial cell wall leads to the activation of NOD2. This results in further engagement of RIP2 kinase and consequent activation of the key downstream signaling molecules NF-kB and MAP kinase
Functional alterations in the NOD2/CARD15 gene are responsible for two granulomatous diseases. The loss-of-function mutations in its LRR domain are associated with Crohn’s disease. Blau syndrome and EOS are caused by the gain-of-function mutations in its NOD domain [12].
EOS is seen in young children with disease onset usually before the age of 5 years. Patients with EOS/Blau syndrome have a triad of skin, joint, and ocular manifestations, the onset of which is usually in the order listed. Other manifestations seen are fever, pulmonary lesions, hepatosplenomegaly, and parotid swelling [16].
Scaly erythematous plaques with lichenoid papules are the most commonly observed skin symptom. Others are tan-colored scaly ichthyosiform rash, erythema nodosum-like lesions, scaly eczematoid lesions, ichthyosiform lesions, and leukocytoclastic vasculitis [15–18].
The articular involvement is usually a symmetrical polyarthritis involving the large and small joints. Oligoarticular presentation and camptodactyly have also been described. The arthritis is characteristically a boggy synovitis and tenosynovitis, which is painless, and usually there is no limitation of movement. Typical boggy swellings can be seen at the wrists, the ankles, and sometimes the knees (Fig. 46.4). Erosions and joint deformities occur in the late stages of the disease course.
Fig. 46.4
Boggy tenosynovitis on the dorsum of a child with early-onset sarcoidosis
Ocular involvement does not present as the sole presenting symptom and is usually not present at disease onset [19]. It presents as an insidious granulomatous iridocyclitis with posterior uveitis. It has a potential to evolve into panuveitis and is associated with an increased risk of visual morbidity [15]. Nodules may also occur in the conjunctivae.
Other features seen are persistent fever, generalized lymphadenopathy, hepatosplenomegaly, cranial neuropathies, and interstitial nephritis [17]. The disease can have profound complications, such as visual loss, joint deformities, and growth retardation [17, 19].
An international registry on pediatric granulomatous arthritis was started in 2005. It showed that cutaneous manifestations were the most common presenting symptom, followed by arthritis which was usually polyarticular in nature. Isolated eye symptoms were never the presenting complaints, but around 40 % had severe visual impairment. The best diagnostic approach was the skin biopsy. In this series, all classic pedigrees were carrying the mutation and there was no asymptomatic carriage [18].
Sarcoidosis Without NOD2 Mutation
Within this group, two distinct subsets have been identified, including pediatric-onset adult sarcoidosis and infantile-onset panniculitis with uveitis with systemic granulomatosis.
Pediatric-Onset “Adult-Type” Sarcoidosis
This form of sarcoidosis is characterized by multisystem involvement, similar to that seen in adults. The recent Danish review on pediatric sarcoidosis showed that general symptoms such as weight loss, fever, and abdominal discomfort were present in 98 % of patients, cough in 65 %, skin involvement in 42 %, peripheral lymphadenopathy in 40 %, ocular symptoms in 29 %, neurological manifestations in 25 %, and arthritis in 4.2 % [2].
Lofgren Syndrome
This syndrome, which is characterized by erythema nodosum, arthritis (mainly of the ankles), and hilar adenopathy, is infrequent in pediatric patients.
Mikulicz Syndrome (Parotid and Lacrimal Gland Enlargement)
This syndrome which is seen in the adult population has also been described in the pediatric literature [20].
Heerfordt-Waldenstrom Syndrome
or uveoparotid fever is a rare presentation of sarcoidosis described only in adult literature. It is characterized by fever, anterior uveitis, swelling of parotid gland, and facial nerve palsy and is a close differential of IgG4-related disease.
Several systems can be involved in sarcoidosis and the features are described below.
Respiratory Tract
Cough, exertional dyspnea, and chest pain are the most common symptoms. A Danish study which included 48 children showed that majority of the children (71 %) had isolated bilateral hilar lymphadenopathy. Chest radiograph was normal (stage 0) in 10 % of children. Bilateral hilar adenopathy with pulmonary infiltrates (stage II) and parenchymal infiltrates without hilar adenopathy (stage III) were present in 8.3 % of patients, respectively. None of the children had evidence of fibrosis (stage IV) [2]. Abnormal pulmonary function tests with restrictive and obstructive pattern can be seen in as many as 50 % and 15 % of children, respectively [2]. Gradual improvement may be seen in children over a period of years, and they eventually develop normal lung function [21].
Skin
Cutaneous manifestations are frequently seen. The most common skin lesion is erythema nodosum. Other lesions seen are skin plaques, subcutaneous nodules, maculopapular eruptions, scar lesions, psoriasiform plaques, and hypo- or hyperpigmented areas. Lupus pernio which is frequently seen in adults is rare in children [22, 23].
Eyes
Ocular involvement is one of the most serious complications of the disease. Sarcoidosis can involve almost any ocular structure. It usually presents as insidious-onset, bilateral, granulomatous uveitis. The most common form is anterior uveitis followed by posterior and intermediate uveitis. Panuveitis is seen in about 25 % of cases. The classic findings seen are mutton fat keratic precipitates, iris nodules, focal synechiae, and multifocal choroiditis. Conjunctival nodules can also be seen. Complications include band keratopathy, cataract, glaucoma, optic neuritis, and retinal vasculitis. Around 10 % of patients with sarcoid uveitis may develop unilateral blindness [21, 24].
Nervous System
Neurosarcoidosis is a rare manifestation in the pediatric age group. Granulomata are most commonly seen in the basal area of the meninges and the brain, causing obstructive hydrocephalus and seventh nerve palsy [23]. A recent review of neurosarcoidosis in the pediatric age group found that the most common presenting symptoms were seizures followed by cranial nerve involvement, hypothalamic dysfunction, headache, motor signs, and papilledema. Children are more likely to have seizures and space-occupying lesions and are less likely to have cranial nerve palsies, as compared to adults [25]. The most characteristic feature on MRI is thickening and enhancement of the basilar meninges, intraparenchymal-enhancing nodules, and white matter focal abnormalities [26].
Kidney
Renal involvement is uncommon in children with sarcoidosis. It can be attributed to infiltration of the renal tissues with sarcoid granulomas or related to hypercalcemia and hypercalciuria [21]. It can have varied clinical presentations like proteinuria, hematuria, leukocyturia, concentration defect, membranous nephropathy, and renal failure [27, 28].
Musculoskeletal System
Involvement is seen in 15–58 % of patients with childhood sarcoidosis [2, 29]. Arthritis is more common in the early-onset group than in older children. Typical boggy synovitis involving the joints of upper or lower extremities without any tenderness or limitation of movement is seen. The phalanges are the most common bone to be involved in children, as in adults. Punched-out lesions, lacy reticular trabecular pattern, or acro-osteolysis has been described [30]. Symptomatic muscle involvement has been described but is rare [29].
Cardiovascular System
Cardiac sarcoid is rare in children. Conduction and rhythm disturbances secondary to granulomatous infiltration of the cardiac tissues are the most common presentations. Other manifestations include congestive cardiac failure, pericardial disease, valvular involvement, and myocardial infarction [23]. Though rare, childhood sarcoidosis can be complicated by systemic vasculitis affecting small to large vessels [31].
Infantile-Onset Panniculitis with Uveitis with Systemic Granulomatosis
This is a newly described entity. Four patients, with prolonged high fever, systemic illness, anemia, hepatosplenomegaly, and histologically documented lobular panniculitis, were followed up. They later developed uveitis, arthritis, and granulomatous inflammation which were demonstrated in a variety of organs and tissues. CARD15 or Cold-Induced Auto inflammatory Syndrome 1 (CIAS1 ) gene mutation was not seen. The disease is progressive; anti-tumour necrosis factor (TNF) monoclonal antibody therapy has shown effective disease control [32].
Diagnosis
There is no definite confirmatory laboratory test for the diagnosis of sarcoidosis. Laboratory evaluation may reveal elevated acute phase reactants, anemia, leukopenia, and eosinophilia. Hypergammaglobulinemia is common. Depression of delayed-type hypersensitivity on skin testing is seen [1]. Hypercalcemia and hypercalciuria are also observed due to specific metabolic dysregulation [21].
The levels of serum angiotensin-converting enzyme (ACE) are elevated in over 50 % of children with late-onset sarcoidosis [2]. ACE is produced by the epithelioid cells in granulomas. ACE levels, in children less than 15 years of age, are 40–50 % higher than in adults. The mean ± SD ACE values in children less than 18 years are 118 ± 30 as compared to 100 ± 35 in adults. Adolescent children have higher serum ACE, with boys showing a higher level than girls [33]. The test is not specific for sarcoidosis, and levels may be also elevated in other conditions like primary biliary cirrhosis, tuberculosis, diabetes mellitus, hyperthyroidism, Gaucher disease, myeloma, pulmonary neoplasm, and lymphomas [1, 23]. Angiotensin-converting enzyme (ACE) polymorphism (insertion/deletion) has been associated with susceptibility to sarcoidosis in European and East Asian populations [34].
A recent study has shown that serum adenosine deaminase is useful in detecting sarcoidosis activity, and soluble interleukin-2 receptor (sIL2R) serum levels are useful in exploring the extrapulmonary organ involvement [35].
Chest radiograph should be done to screen for pulmonary involvement. High-resolution chest computed tomography (CT) is a better modality to delineate the extent of parenchymal disease. Bronchoalveolar lavage (BAL) typically demonstrates an increased number of lymphocytes, with around 55 % of the patients showing a high CD4/CD8 ratio. A CD4/CD8 ratio greater than 3.5 is highly specific for sarcoidosis, although the sensitivity is low. Endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA) has been shown to be highly specific [36].
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