Skin manifestations are among the main manifestations of Blau syndrome. Beginning in early infancy, patients develop asymptomatic, local or generalized erythematous or brownish papules or papules and nodules (Fig. 1) that can present as a lichenoid eruption. The palms and soles may be affected. Other skin manifestations described in NOD2 disorders include ichthyosiform disorders,2 a form of panniculitis that is very similar to erythema nodosum (Fig. 2), and leukocytoclastic vasculitis. The most common cutaneous manifestation, which should raise suspicion of Blau syndrome, is a mild, early-onset generalized eruption of brownish papules that often resolves spontaneously in the first years of life.3 Histopathologic findings are similar to those observed in sarcoidosis, and include noncaseating granulomas with histiocytes, lymphocytes, eosinophils (Fig. 3), and giant nucleated cells that are strongly positive when stained with periodic acid-Schiff. Electron microscopy shows so-called comma bodies in epithelioid cells.3

Figure 1.

Blau syndrome. Erythematous-brownish papules with a somewhat lichenoid appearance on the arm.

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Figure 2.

Blau syndrome. Erythematous-violaceous nodules in both pretibial areas, with a very similar appearance to erythema nodosum.

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Figure 3.

Blau syndrome. Noncaseifying granulomas with histiocytes, lymphocytes, eosinophils, and giant multinucleated cells (hematoxylin-eosin, original magnification ×20).

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Characteristic associated clinical manifestations include chronic polyarticular synovitis, symmetric hypertrophic tenosynovitis, and recurrent granulomatous anterior uveitis, although panuveitis is more common. Joint involvement is the most common—and severe—noncutaneous manifestation. It begins before the age of 10 years and affects the hands, wrists, ankles, knees, and elbows. The lesions are painless cysts that grow slowly over time and become considerably swollen, although they do not limit mobility until several decades after onset. Granulomatous inflammatory infiltrates formed by giant multinucleated cells are observed in the synovial membrane. Anterior uveitis can be complicated by involvement of the posterior pole, and patients may also develop cataracts, glaucoma, or loss of vision. Ocular involvement is bilateral in most cases.3 The granulomatous infiltrate can also affect, although less frequently, the liver, the salivary glands, the lungs, the kidneys, the nervous system, and the arteries, causing cranial neuropathy, large vessel arteritis, malignant hypertension, and cerebral infarction. The lymph nodes may also be affected, but unlike in sarcoidosis,4 the hilar nodes are not affected, and unlike in other chronic autoinflammatory disorders, secondary amyloidosis is very rare.5

The progressive appearance of hyperpigmented, hypertrichotic plaques (Fig. 4) and marked sclerosis on the extremities and abdomen is a highly characteristic finding in H syndrome. The lower half of the body is more frequently affected. In most cases the condition begins with hyperpigmentation on the internal surface of the thighs, which then spreads, but generally sparing the knees and buttocks. Some patients also develop ichthyosiform scaling. Skin biopsy shows hyperpigmentation of the basal layer with acanthosis and hyperplasia, similar to that seen in seborrheic keratosis, together with marked fibrosis of the dermis and subcutaneous tissue; the fibrosis is mild in the papillary dermis and much more intense in the subcutis, where it causes progressive obliteration of the fat lobules (Fig. 5). The accompanying infiltrate is mainly composed of numerous, small histiocytes (CD68+, S100+, CD1a−)with clear cytoplasm6 and occasional emperipolesis. Characteristic electron microscopic findings include a distended endoplasmic reticulum and sparse lysosomes.

Figure 4.

H syndrome. Hyperpigmented, hypertrichotic plaques on the posterior surface of the lower extremities, accompanied by marked sclerosis.

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Figure 5.

H syndrome. Striking fibrosis in the dermis and subcutaneous tissue, with more severe involvement of the subcutis, resulting in progressive obliteration of the fat lobules (hematoxylin-eosin, original magnification ×20).

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Associated manifestations in H syndrome include deafness, low stature, flexion contractures, dilated veins in the legs and abdominal wall, heart anomalies, early ischemic cardiomyopathy,7 hepatosplenomegaly, scrotal masses, hypogonadism, delayed puberty, azoospermia, and hyperglycemia/diabetes mellitus.8

Cutaneous manifestations of CANDLE syndrome consist of annular edematous, erythematous violaceous plaques with elevated borders that mainly affect the trunk (Fig. 6), although they can also affect the extremities (mainly the interphalangeal joints) and the area around the mouth and the eyes, causing persistent violaceous erythema.11 Although these lesions resolve spontaneously, leaving hyperpigmentation or residual ecchymotic macules, they recur with sufficient frequency to be considered a chronic, persistent skin disorder. Histopathologic findings include dense perivascular and interstitial inflammatory infiltrates in the dermis, with occasional involvement of the subcutaneous tissue, absence of vasculitis, and presence of karyorrhexis, albeit inconsistently. The infiltrate is composed of atypical mononuclear myeloid cells with large mottled, long or kidney-shaped nuclei and scant eosinophilic cytoplasm,11 accompanied by a variable number of neutrophils and eosinophils (Fig. 7). Immunohistochemical studies show positive staining for myeloperoxidase, lysozyme, Mac387, CD68 (KP1), and CD16312,13 (Fig. 8) and a double population of myeloid cells and macrophages. Finally, the presence of plasmacytoid CD123+ dendritic cells, which are powerful producers of type I IFN, indicate that this cytokine has a more than significant role in CANDLE syndrome.

Figure 6.

CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) syndrome. Edematous erythematous-violaceous annular plaques with raised borders on the trunk, together with anterior residual lesions, including hyperpigmented and ecchymotic macules.

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Figure 7.

CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) syndrome. Infiltrate of atypical mononuclear myeloid cells with large, mottled nuclei and scant eosinophilic cytoplasm, accompanied by neutrophils and eosinophils (hematoxylin-eosin, original magnification ×40).

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Figure 8.

CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) syndrome. Positive immunostaining for myeloperoxidase (MPO, original magnification ×20).

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Less frequently, patients develop violaceous nodules that leave residual hyperpigmentation, hypertrichosis, acanthosis nigricans, and alopecia areata.14 Progressive lipodystrophy on the face, upper extremities, and trunk is a highly characteristic, defining feature of CANDLE syndrome.

According to reports in the literature, all patients experience frequent and sometimes even daily episodes of high fever (> 30°C) and are also affected by low weight and short stature.15 Associated clinical manifestations include enlarged lymph nodes, hepatosplenomegaly, arthralgia without arthritis, and multiple other inflammatory events, such as chondritis, conjunctivitis, nodular episcleritis, epididymitis, nephritis, otitis, parotiditis, and aseptic meningitis. Patients with CANDLE syndrome may also have dysmorphic features such as a broad nasal bridge, fat lips, and an everted lower lip.15 Laboratory studies typically show elevated acute phase reactants, chronic anemia, elevated liver enzymes, and transient lymphopenia during flares.

Aicardi-Goutières syndrome is a genetically highly heterogeneous neurodegenerative disorder with a high degree of consanguinity. It is characterized by cerebral and cutaneous involvement. Although mostly transmitted in an autosomal recessive manner, there have been reports of autosomal dominant transmission. Disease-causing mutations have been detected in 7 genes: TREX1, which codes for a 3′-5′ exonuclease, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, IFIH1, and ADAR1.17 The mutations cause deficient destruction of viral genetic material, which is needed to downregulate the production of IFN in infected cells. This dysregulation of IFN-α generates proinflammatory situations that trigger secondary vasculitic conditions, such as encephalopathy or acrocyanosis. Although Aicardi-Goutières can be congenital, onset is more common in the first year of life in healthy term infants.

Patients develop severe subacute encephalopathy that stabilizes after a period of progression and is associated with calcification of the basal ganglia, leukodystrophy, progressive microcephaly, and pyramidal-extrapyramidal dysfunction accompanied by epilepsy and aseptic febrile episodes. There have also been reports of chronic arthroplasty with progressive acral contractures and oral mucosal ulcers.19 Laboratory studies show high levels of IFN-α, neopterin, biopterin,20 and lymphocytosis, which is also observed in cerebrospinal fluid (CSF). Elevated IFN-α in CSF is considered a major diagnostic criterion for Aicardi-Goutières syndrome.21 Patients may also present thrombocytopenia, elevated liver enzymes, and in some cases, hyperpolygammaglobulinemia, and Coombs-positive hemolytic anemia. All these conditions have a highly variable clinical expression and none of them are necessary for diagnosis.19

Familial chilblain lupus is a rare familial form of cold-induced cutaneous lupus erythematosus that may be sporadic, or less frequently, hereditary. It is generally caused by a mutation in TREX1. TREX1 is the major intracellular repair exonuclease and its deficiency leads to the accumulation of nucleic acids and the activation of the innate immune system accompanied by an increase in INF that favors the development of autoimmunity.6

Patients occasionally develop systemic manifestations such as arthralgia and nonerosive arthritis. Laboratory studies show mild pancytopenia, hypergammaglobulinemia, rheumatoid factor, antinuclear antibodies (ANAs), and anti-Ro/SSA antibodies.23 Cryoglobulins and cold agglutinins are negative. Up to 20% of patients develop systemic lupus erythematosus (SLE)24 and there is a lack of consensus on the association with anorexia.

As previously explained, sensing of viral RNA and DNA is the main biological trigger for the activation of STING, which is a transmembrane protein located in the endoplasmic reticulum that induces the production of IFN. STING-associated vasculopathy with onset in childhood is due to gain-of-function mutations in STING.25,26 The protein is widely expressed in endothelial and alveolar cells. STING hyperfunction causes inflammation in endothelial cells, generating vaso-occlusive phenomena and pulmonary lesions, possibly due to the activation of macrophages or alveolar pneumocytes. The release of IFN triggers a positive feedback loop, as it directly triggers the transcription of other proinflammatory cytokines and activates JAK-kinases, which, in turn trigger the phosphorylation and dimerization of STAT1/STAT2, which initiate the transcription of IFN genes.

Patients with STING-associated vasculopathy with onset in infancy have recurrent episodes of low-grade fever and may also experience delayed growth, severe lung disease with enlarged hilar or paratracheal lymph nodes, interstitial fibrosis, and emphysematous changes caused by a lymphocytic inflammatory infiltrate.27 The laboratory study shows increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and on occasions, ANA, cytoplasmic antineutrophil cytoplasmic antibodies, and antiphospholipid antibodies, which tend to normalize with time.

C1q is a protein that forms part of the C1 complex of the complement system. In addition to its role in activating the complement cascade, it inhibits the production of IFN by plasmacytoid dendritic cells and peripheral blood mononuclear cells. Loss-of-function C1q mutations result in a phenotype similar to that seen in SLE in 90% of cases.28

Extracutaneous manifestations of C1q deficiency include segmental mesangial glomerulonephritis (which differs from the typical nephritis seen in SLE), neurological symptoms, and serious recurrent infections caused by deficient functioning of the classic complement pathway. Plasma levels of CH50 and C1q are practically inexistent, contrasting with C2, C4, and C1 inhibitor levels, which are normal or elevated. ANAs, rheumatoid factor, and anti-Smith antibodies are positive. Biopsy of lesions shows basal layer vacuolization, while DIF shows deposits of IgG, IgM, IgA, and C3. The clinical similarities with SLE combined with the presence of clinical features of immunodeficiency are highly suggestive of complement factor deficiency.

Typical clinical manifestations of ADA2 deficiency include changes associated with poor arterial flow, such as livedo reticularis, Raynaud phenomenon, ischemia, and digital necrosis. Biopsy of lesions shows periarteritis, fibrinoid necrosis, and destruction of the elastic lamina of the cutaneous arterioles. There may also be leukocytoclastic vasculitis and panniculitis.

Additional manifestations include febrile episodes and frequent aneurysms in the renal, mesenteric, and coronary arteries. Ischemia can cause renal, gastrointestinal, genital, musculoskeletal, cardiovascular, and neurologic manifestations. Of particular note are renal hypertension and a high risk of cerebral ictus during childhood.31