Our report is the first to provide a detailed description on the expanded phenotype of PGA, exclusively among patients with documented NOD2 mutations, hence endorsing the notion that PGA may constitute a systemic granulomatous inflammatory disorder.
In 1985, Jabs and Blau reported two separate multiplex families showing a similar clinical phenotype including early onset polyarticular “boggy” synovitis, severe pan-uveitis and an autosomal dominant pattern of inheritance. The family reported by Blau also presented with a tan-colored maculopapular rash, absent in Jabs’ report while the latter included cranial neuropathy (4
). All patients characteristically showed non-caseating granulomas on tissue biopsy. The BS phenotype was also reported subsequently in a family by Pastores et al (15
). The initial idea that this disease entailed a restricted phenotype was later challenged by the publications of 2 families: one with associated liver granulomatous involvement and another with renal granulomatous disease (7
). Most authors currently accept cranial neuropathies, systemic involvement (fever) and arteritis as part of the disease spectrum. Hence the family reported by Jabs (5
) and earlier families reported by Hafner (9
) and by Rotenstein (10
) could be considered to fall within the BS spectrum. The phenotype of the sporadic form of the disease, formerly known as early onset (childhood) sarcoidosis has itself been expanded to include large vessel vasculitis (11
) and visceral involvement including granulomatous infiltration of the lungs, heart, liver and kidneys (14
Cranial neuropathy had been identified in association with BS before genetic analysis was available (5
). We were able to confirm this complication in our series in one instance with a patient that suffered from transient facial nerve palsy. The same patient presented an inflammatory optic neuropathy complicating severe panuveitis.
We observed leukocytoclastic vasculitis presenting phenotypically as urticarial vasculitis being part of the spectrum of PGA. Large vessel vasculopathy reported in mutation positive patients by Wang (20
) and before by others (11
) was not observed in this series.
This study expanded the cutaneous manifestations of the disease. The dermatitis described as a maculopapular rash with ichthyosiform desquamation and dermal granulomas was documented in 40/45 subjects, hence without a doubt it is a cardinal manifestation. This study confirmed that recurrent erythema nodosum-like panniculitis as well as cutaneous small vessel vasculitis are also part of the spectrum.
Lymphadenitis (excluding hilar adenitis) and interstitial pneumonitis have not been previously reported in PGA associated with NOD2 mutation. In addition, sialadenitis, hepatic and splenic involvements seem to be without clinical consequences at least in the short-term. Hence these manifestations may not require invasive diagnostic procedures when found as an isolated physical finding.
Pericarditis has not been reported in early disease before, in our series it was symptomatic in one and an echocardiographic finding in the other. Cardiomyopathy found in one patient could have be the result of chronic hypertension and not a bona-fide primary manifestation. Pulmonary embolism found in one instance should be regarded with caution since risk factors for pulmonary embolism can be elusive.
Renal disease has been described as interstitial nephritis in a population of patients with childhood sarcoidosis before genetic testing was available (21
); here we show one documented case of acute glomerulonephritis with granulomatous involvement of glomeruli and interstitium. We observed two additional cases of chronic renal failure, however without histologic documentation of granulomatous kidney disease.
Hypertension was previously described in association with renal arteritis (10
). Our findings confirm that systemic hypertension severe enough to require treatment is not uncommon even during the early phases (# 7, #9 and #23) of the disease and should be monitored closely. The mechanism is unclear since the two children who were investigated had normal digital imaging of the renal vasculature, normal renal function and urinary microscopy. Still, we cannot rule out silent granulomatous nephritis as the cause of the observed hypertension.
The expanded manifestations were noted both in sporadic and familial cases, and seemed to cluster in a subset of patients constituting more than one fourth of the cohort. This may suggest the presence of additional phenotype-influencing genes in NOD2-associated PGA as has been demonstrated for other auto-inflammatory diseases (22
). In addition, the longer disease duration in patients with an expanded phenotype implies that the classic triad may evolve in a greater proportion of patients with longer follow-up and that additional features may emerge with time.
In our cohort we observed some patients that were diagnosed at a later age, hence genetic analysis of NOD2 mutations could be considered not only among children but also in adults with a suspicious phenotype.
A comparison of clinical manifestations between patients with and without NOD2 mutations revealed that arthritis, uveitis and skin rash are not exclusively seen in the presence of NOD2 mutations although the characteristic triad is significantly more common in NOD2 mutated individuals. Conversely although we found extended manifestations in the NOD2 mutated group, their frequency was significantly higher among individuals with wild-type NOD2. Still, the presence of overlapping clinical features supports the hypothesis that additional genetic factors may contribute to the phenotype in pediatric granulomatous inflammatory diseases.
Our investigation has some shortcomings, mostly related to the retrospective character of the clinical data collection. First there may be an underestimation of the exact frequency of certain subclinical manifestations found as a result of unrelated investigations. Among those sialadenitis, granulomatous liver disease and pericarditis should be noted. Second, in the absence of histologic demonstration of granulomas, a causal link for the NOD2 mutation and some of the atypical manifestations such arterial hypertension, cardiomyopathy, chronic renal failure and pulmonary embolism cannot be proven.
From the strong association of NOD2 with granulomatous inflammatory disease and from the knowledge of its role in innate immunity one might be tempted to hypothesize that NOD2 has a pathogenic role in the formation of granulomas. Apart from mutations in the central NACHT domain that are strongly associated with PGA, several mutations and polymorphisms in the N-terminal Leucine Rich Repeat domain are known to confer a susceptibility to Crohn’s disease as well. However as our data demonstrate granulomatous disease even in infants can occur with wild-type NOD2 and mutations can also be silent. The phenotype of individuals with NOD2 mutations is clearly more complex than initially thought, requiring work on potential additional genetic factors capable of modulating the phenotype, although as we showed here this clinical variability may partly be related to the length of disease course.
In conclusion, we have described different new clinical manifestations, and confirmed several previously noted manifestations in patients with PGA and a documented NOD2 mutation by combining two cohorts. The obvious systemic nature of this condition may require yet another consideration for an appropriate name such as Juvenile Systemic Granulomatosis which may describe better the nature of the disease.