Early diagnosis of early-onset sarcoidosis: a case report with functional analysis and review of the literature

Abstract

This study examined the pathogenesis of early-onset sarcoidosis (EOS) in a patient with a rare NOD2 mutation and surveyed the literature to identify the hallmark features for early diagnosis. An infant girl suffering from prolonged fever and skin rash of multiple pinkish papules and subsequent erythema nodosum was referred to our institution. Skin biopsy and DNA sequencing were performed along with cytokine profiling of the patient's serum and stimulated mononuclear cells. NF-κB activation was analyzed using transfected cells. Multiple non-caseating granuloma inclusions were recognized in biopsy specimens obtained from the patient's rash. DNA sequencing revealed a very rare heterozygous Met513Thr (M513T) mutation in NOD2. Mononuclear cells produced a low amount of IL-1β upon stimulation as compared with normal control cells. Mutated NOD2 transfection enhanced NF-κB activation. We suspected that the M513T mutation in NOD2 decreased IL-1β production and enhanced NF-κB activation, which was likely responsible for the patient's granuloma involvement. A comprehensive review of the literature on 30 cases of sporadic type of EOS revealed that all patients had cutaneous manifestations, with all but one displaying granulation. A majority of EOS patients have R334W/Q. But about half of sporadic EOS had NOD2 mutations other than R334W/Q, as in the present case. Accordingly, skin rash with granuloma formation and specific NOD2 mutations may represent early diagnostic hallmarks of EOS in infants with persistent inflammation.

Unique Variant of NOD2 Pediatric Granulomatous Arthritis With Severe 1,25-Dihydroxyvitamin D-Mediated Hypercalcemia and Generalized Osteosclerosis

“…Exchange of the arginine residue at position #334 accounts for >80% of individuals with PGA (12,13,19,33) and, as in our patient, the substituted amino acid is often glycine. (14) Residue #334 occupies the central nucleotide binding and oligomerization domain of NOD2 having ATPase activity.…”

“…Our patient's PGA is explained by a heterozygous missense mutation in NOD2 (c.1001G>A, p.Arg334Gln) that is expected at residue #334 to change the most commonly altered amino acid in this disorder. (19) Yet, she lacked the classic triad of PGA complications (dermatitis, uveitis, arthritis) and instead uniquely manifested severe hypercalcemia together with radiographic and histological findings in keeping with OPT. This conundrum is discussed below.…”

“…Herein, we report a young girl with a NOD2 missense mutation that is common in PGA, yet who lacked its classic triad of complications and instead at presentation had severe 1,25(OH) 2 D‐mediated hypercalcemia, nephrocalcinosis, and compromised kidney function as well as radiological and histopathological findings consistent with OPT …”

Genetic Basis of Myocarditis: Myth or Reality?

“…Cardiac involvement is rare [136][137][138][139][140]. The pathologic hallmark is the non-caseating epithelioid cell Blau granuloma.…”

“…The mutations are systematically collected in the international Infevers Registry [fmf.igh.cnrs.fr/infevers] [139]. Blau syndrome is allelic to early-onset sarcoidosis (EOS) [140,141]. The diagnosis is usually suspected in the clinical context of rheumatology or dermatology or ophthalmology issues.…”