American Journal of Respiratory and Critical Care Medicine

To the Editor:

Noninfectious granulomatous diseases are commonly encountered in clinical practice and often pose a diagnostic challenge (1). Adult sarcoidosis may be confused with granulomatous autoinflammatory disease (AUID) (2). Herein, we report a unique case of granuloma in the skin and lung associated with a rare nucleotide-binding oligomerization domain–containing protein-2 (NOD2) gene mutation. Some of these studies have been previously published both in the form of an abstract and an article (3, 4).

A 63-year-old, previously healthy white woman with a presumed diagnosis of psoriasis in the past 10 years presented with recurrent nonitchy red patches and plaques on her extremities and bilateral wrist and ankle pain/swelling. There were episodes of dyspnea on exertion without cough and bilateral pleural effusions, which resolved with treatment consisting of a short course of prednisone, 20 mg daily. Reappearance of the dyspnea after discontinuation of prednisone prompted a diagnosis of pneumonitis of unclear etiology requiring home oxygenation.

The patient reported fatigue, slight weight loss, and mild dry mouth without dry eyes, parotid gland enlargement, or fever. Schirmer test results were as follows: right eye, 5 mm/5 min; left eye, 6 mm/5 min. She was of British descent without any family history of AUID, sarcoidosis, or psoriasis. She had no known drug or food allergies, and was taking only multivitamins before the onset of respiratory symptoms. On physical examination, her temperature was 37.3°C, with faint erythematous patches and plaques without scales on the right axilla and bilateral upper thighs. Dry crackles were appreciated, with unremarkable cardiac and abdominal findings. There was mild swelling in the ankle without tenderness and localized tissue swelling in the right distal arm. Laboratory work was normal, including complete blood count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, and angiotensin-converting enzyme as well as urinalysis. Serological testing for a systemic autoimmune disease was negative, including anti-nuclear antibodies, anti–extractable nuclear antigen antibodies, anti–double-stranded DNA antibodies, complement 3/complement 4, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, and serum protein electrophoresis. Genetic testing of the NOD2 gene for mutations by DNA polymerase chain reaction and DNA sequencing of all 12 coding exons was performed in the Center for Genetic Testing at Saint Francis (Tulsa, OK), and it was positive for the heterozygous R703C variant of the NOD2 gene. The chest radiography and computerized tomography scan showed bilateral lower lung interstitial infiltrates and ground-glass attenuation, without hilar, mediastinal, or axillary adenopathy (Figure 1). A transbronchial biopsy showed focal interstitial chronic inflammation and ill-formed nonnecrotizing granulomas, without evidence of infection. Thoracoscopic lung biopsies showed areas of diffuse interstitial chronic lymphoplasmacytic infiltrates with lymphoid aggregates with numerous multinucleated giant cells (Figures 2A–2C). Pulmonary function testing showed decreased diffusing capacity without pulmonary hypertension on echocardiography. Blood cultures for microorganisms and testing for hypersensitivity pneumonitis–related antifungal antibodies were all negative, as was the bronchial alveolar lavage fluid analysis. A minor salivary gland biopsy was normal except for focal atrophy and fibrosis. A skin punch biopsy demonstrated interstitial granulomatous dermatitis with overlying spongiotic dermatitis (Figure 2D).

The characteristic manifestations of this patient consist of granulomatous dermatitis and pneumonitis, pleural effusions, and inflammatory arthritis. These, together with the positive NOD2 gene mutation R703C, may constitute an AUID.

Adult sarcoidosis is an uncommon systemic inflammatory disorder characterized by noncaseating granulomatous inflammation that most commonly affects the lungs, intrathoracic lymph nodes (90%), eyes, and skin (5), but pleuritis is extremely unusual. The cutaneous lesions typically comprise erythematous or flesh-colored papules, plaques, or nodules and erythema nodosum (6). Uveitis occurs in 20% of patients (7) and noncaseating granulomas of the salivary glands in 38–58% (8). Sarcoidosis is a diagnosis of exclusion, and a presumptive diagnosis may be made on the basis of the presence of bilateral hilar adenopathy on the chest radiograph, Löfgren syndrome (erythema nodosum, bilateral hilar adenopathy on the chest radiograph, and often fever/arthritis), or Heerfordt syndrome (uveitis, parotitis, and fever). However, this usually warrants a tissue biopsy (9). On the basis of these data, typical adult sarcoidosis was unlikely in our case. Moreover, adult sarcoidosis has not been associated with NOD2 gene mutations in several studies (1012). In addition, the granulomas of sarcoidosis are well formed, without associated chronic inflammation (13). Although each of the aforementioned unusual clinical manifestations could occur individually in the adult form of sarcoidosis, it would be extremely odd to have all the rare presentations occurring in the same individual. Despite dry mouth, primary Sjögren’s syndrome was unlikely in the absence of xerophthalmia, autoantibodies, and salivary gland inflammation.

Blau’s syndrome is an autosomal dominant AUID in children. It is characterized by the triad of granulomatous dermatitis, inflammatory arthritis, and uveitis (14) with occasional presentation of an atypical form, and is regarded as the same disease as early-onset sarcoidosis (15). Blau’s syndrome is typically familial and occasionally sporadic, and may have sicca-like symptoms with sialadenitis but lacks gastrointestinal (GI) symptoms (16). Blau’s syndrome is linked to the NOD2 gene mutations (17, 18). To our knowledge, only one case of radiographic interstitial pneumonitis has been reported as pediatric Blau’s syndrome associated with R334Q (19), but lung tissue diagnosis was not provided. Our patient underwent lung biopsies that showed diffuse interstitial chronic inflammation with multinucleated giant cells. Nonetheless, adult-onset Blau’s syndrome has never been reported in the literature. The primary pathological differential diagnosis would be subacute hypersensitivity pneumonia, certain drug reactions (most notably methotrexate), and granulomatous lymphocytic interstitial lung disease associated with immunodeficiency (20), although there was meager evidence to support such diagnoses in our case.

We have reported a Blau-like disease, a new category of AUID associated with the NOD2 gene mutations IVS8+158 and R702W, characterized by recurrent dermatitis, inflammatory arthritis, and periodic fevers. GI, sicca-like symptoms, and serositis can happen (4). R703C, which is adjacent to R702W, was initially linked to Crohn’s disease (21) and confirmed in two later studies (22, 23), with 0% of the R703C allele frequency in the healthy population control. Interestingly, the R703C variant also causes gain of function as the gene variants (L469F, R334Q, and R334W) of Blau’s syndrome (24). Our patient also completely lacked GI symptoms, which would argue against Crohn’s disease. Taken together, the data indicate adult-onset Blau-like syndrome, which may be classified as a new category of AUID as reported previously. High-dose prednisone resulted in complete resolution of dyspnea and considerable pulmonary improvement, which were maintained with azathiopurine treatment and low-dose prednisone. This report should alert physicians to the existence of this new entity.

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