To the Editor:

Pediatric granulomatous arthritis (PGA) is an autosomic-dominant disease characterized by a triad of granulomatous arthritis, uveitis, and dermatitis¹. The diagnosis rests on the finding of noncaseating giant cell granulomas in synovium, conjunctiva, or dermis^1,2. The disease can be familial (Blau syndrome) or sporadic (early onset sarcoidosis) and in both cases is associated with a mutation in or in the vicinity of the NACHT domain of NOD2, a protein involved in nuclear factor-kB and caspase activation³.

An expanded phenotype involving diverse organs was recognized before the mutation was described^1,4,5. However, some of those manifestations are now emerging among patients with documented mutations⁶, as shown by the experience with the International Registry of Pediatric Granulomatous Arthritis (2005).

We describe the first case of interstitial and glomerular granulomatous nephritis in a patient with arginine to glutamine substitution in position 334 (R334Q) of NOD2.

A 4-year-old Caucasian girl presented symmetrical polyarthritis of wrists, hips, knees, and ankles as well as intermittent nonspecific fever. There was thickening of the synovium and prominent tenosynovitis. Over the next 2 years she developed a maculopapular, evanescent, and at times urticarial exanthema in trunk and upper extremities histologically corresponding to a nongranulomatous leukocytoclastic vasculitis. Initial routine laboratory assessments are given in Table 1. Antinuclear antibodies and rheumatoid factor were negative. Knee and hand radiographs showed periarticular osteopenia.

Table 1. Laboratory findings.

At the age of 8, she developed an asymptomatic nongranulomatous bilateral anterior uveitis with vitreous involvement. Flares associated with red eye led to posterior synechiae, and subsequent visual impairment (OD 9/10, OS 5/10). At age 9 she presented a worsening dermatitis, arthritis, fever, mild pericarditis, and splenomegaly. She received corticosteroids and methotrexate for articular disease, but corticosteroid dependency ensued. Etanercept was introduced, with marginal response.

At age 10 she developed leukocyturia, granular casts, raised serum creatinine 13.9 mg/l (3–7 mg/l), creatinine clearance of 34 ml/min, proteinuria (1 g/24 h), and elevated urinary ß₂-microglobulin at 5.63 µg/ml (1.01–1.73 µg/ml). The angiotensin-converting enzyme level was normal at 18 IU/l. Her erythrocyte sedimentation rate was elevated to 98 mm/h.

A percutaneous renal biopsy showed central granulomatous lesions constituted by epithelioid cells, multinucleated giant cells, and lymphocytes in 3 of 9 glomeruli. Fibrosis in Bowman's space was found in 2 glomeruli and fibroepithelial crescents were observed in 2. There were interstitial granulomas with severe fibrosis and infiltrating lymphocytes, histiocytes, neutrophils, and eosinophils. There was no vascular damage. Tubules presented atrophy and dilated morphology with epithelial degeneration and hyaline and white cell casts (Figure 1). Infliximab therapy (3 mg/kg/dose, every 8 wks) was instituted, with excellent response in renal function and arthritis, starting with the fourth infusion (Table 1). Genotyping of NOD2 revealed a R334Q substitution confirming the diagnosis of PGA.

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Figure 1. Pathologic changes in kidney (original magnification ´40). A. Central granulomatous lesions in glomeruli, chronic interstitial infiltrate, and fibrosis (Pas Shiff technique). B. Interstitial fibrosis, tubules with atrophy, and epithelial degeneration, and hyaline and white cell casts (Masson trichromic).

PGA is the name recently proposed to encompass the familial and sporadic forms of early onset arthritis, with uveitis and dermatitis (usually below age 5 yrs), associated with mutations at the NACHT domain of NOD2⁶. Renal involvement has been reported infrequently in this disease, yet at the time of the diagnosis or later during the course of the disease, mainly as interstitial granulomatous nephritis. However, these reports preceded the availability of genetic testing, hence the presence of NOD2 mutations could not be documented.

Ting, et al were the first to document a family with Blau phenotype, in which the mother of the proband developed acute nephritis at age 27 years. The renal biopsy showed interstitial involvement including giant cell granuloma and glomerulosclerosis resulting in significant renal impairment⁷.

In the French series of Coutant, et al, 11 children with sarcoid nephritis were reported⁸, but the authors do not differentiate between adult and childhood forms (PGA). It should be noted that 3 patients presented arthritic symptoms, suggesting the possibility of PGA, although the adult form can rarely be associated with arthritis as well. Also 7/11 patients had uveitis.

Between 10% and 50% of patients with PGA phenotype are not associated with identified mutations in the NOD2 gene^9,10. Hence the importance of the current report in which we document the first case of a young girl with classical PGA carrying a mutated form of NOD2 (R334Q), who developed a rather significant form of granulomatous nephritis leading to renal impairment. Thus, granulomatous nephritis becomes an established component of disease phenotype. This adds to the growing evidence supporting an expanded phenotype for PGA, a disease for which a mutation in NOD2 has been well documented in the literature, and also alerts the clinician on the need to watch for sudden development of internal organ involvement. Although the term PGA was recently suggested by the authors⁶, the expansion of the phenotype suggested by our report may call for the substitution of the word "systemic" to reflect the newly documented clinical manifestations.

SILVIA MÓNICA MEIORIN, MD; GRACIELA ESPADA, MD, Department of Rheumatology; CHRISTIAN ELIAS COSTA, MD, Department of Ophthalmology; ALEJANDRA TARTARA, MD; ELENA DE MATTEO, MD, Hospital de Niños Ricardo Gutierrez, Buenos Aires, Argentina; CARINE WOUTERS, MD, University Hospital Gasthuisberg, Leuven, Belgium; TAMMY M. MARTIN, MD, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon; CARLOS D. ROSE, MD, Thomas Jefferson University, Department of Pediatrics, Wilmington, Delaware, USA. Address reprint requests to Dr. S. Meiorin, Department of Rheumatology, Hospital de Niños Ricardo Gutierrez, Gallo 1330 Pabellón L, Buenos Aires 1425, Argentina. E-mail: smeiorin@hotmail.com

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