Blau Syndrome: Challenging Molecular Genetic Diagnostics of Autoinflammatory Disease

Abstract

The aim of this study was to describe the clinical and molecular genetic findings in seven individuals from three unrelated families with Blau syndrome. A complex ophthalmic and general health examination including diagnostic imaging was performed. The NOD2 mutational hot spot located in exon 4 was Sanger sequenced in all three probands. Two individuals also underwent autoinflammatory disorder gene panel screening, and in one subject, exome sequencing was performed. Blau syndrome presenting as uveitis, skin rush or arthritis was diagnosed in four cases from three families. In two individuals from one family, only camptodactyly was noted, while another member had camptodactyly in combination with non-active uveitis and angioid streaks. One proband developed two attacks of meningoencephalitis attributed to presumed neurosarcoidosis, which is a rare finding in Blau syndrome. The probands from families 1 and 2 carried pathogenic variants in NOD2 (NM_022162.3): c.1001G>A p.(Arg334Gln) and c.1000C>T p.(Arg334Trp), respectively. In family 3, two variants of unknown significance in a heterozygous state were found: c.1412G>T p.(Arg471Leu) in NOD2 and c.928C>T p.(Arg310*) in NLRC4 (NM_001199139.1). In conclusion, Blau syndrome is a phenotypically highly variable, and there is a need to raise awareness about all clinical manifestations, including neurosarcoidosis. Variants of unknown significance pose a significant challenge regarding their contribution to etiopathogenesis of autoinflammatory diseases.

Keywords: Blau syndrome; NOD2; autoinflammation; early onset sarcoidosis; neurosarcoidosis; uveitis.

Figure 1

Pedigrees and results of segregation analysis. NM_022162.3 (NOD2), NM_001199139.1 (NLRC4) and NM_001171.6 (ABCC6) were taken as reference sequences. Wt = wild type. Arrows indicate probands.

Figure 2

Clinical findings in the proband from family 1. (A) Granulomatous maculopapular rash on trunk and extremities at 3 months. (B) Pale optic disc and multifocal chorioretinal lesions in the right eye (arrows) located predominantly in the inferior half at 12 years. (C) Anterior segment photograph of subepithelial corneal opacities in the right eye (arrows) and (D) their visualization on SD-OCT corneal section (asterisks) at 14 years. (E) Coronal T2WI and enlargement of parotid glands (asterisks) at 11 years of age. (F) Coronal T1WI + FatSat+ Gd and enlargement of infiltration lacrimal glands, which is more prominent on the left side, at 11 years of age (asterisks).

Figure 3

Clinical findings in the proband from family 2. (A) Corneal opacities in the left eye, located mostly in the inferior half (asterisk). (B) Multiple iris granulomas in the right eye (asterisk). (C) Symmetrical dorsal wrist edema. (D) Posterior iris synechiae in the right eye (arrows). (E) Chorioretinal partially pigmented atrophic lesions located in the inferior half of the retina in the right eye and (F) in the left eye.

Figure 4

Clinical findings in two individuals from family 3. Proband III:1’s (A) corneal opacities (asterisk) in the right eye and (B) inactive chorioretinal lesions in the inferior periphery in the right eye and (C) left eye. Individual II:1’s (D) inactive chorioretinal lesions scattered in the periphery circumferentially in the right eye and (E) optic nerve drusen in the right eye (arrows), with angioid streaks (arrowheads) in the color fundus photo and (F) in the fundus autofluorescence photo.