OAS-1-associated polymorphic autoinflammatory disorder with distinct cutaneous manifestations and multisystem inflammation: Further expanding the spectrum with a phenotype resembling Behcet’s disease

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Oligoadenylate synthetase (OAS) proteins, activated by interferons (IFN) in response to viral infections, play a key role in cellular defense.^1,2 OAS1-associated polymorphic autoinflammatory immunodeficiency disorder (OPAID) is a recently described monogenic autoinflammatory immunodeficiency disorder caused due to heterozygous OAS1 gain-of-function variants.³ Herein, we describe a case of OPAID presenting with recurrent oral and genital ulcers, periungual lesions, episcleritis, and hepatitis.

A 21-year-old man presented with recurrent painful oral and genital ulceration; swelling of periungual skin with nail dystrophy and pus discharge; redness of the eyes with watering and photophobia for 3 years. These were preceded by bouts of increased stool frequency, self-resolving abdominal pain, and recurrent fever for 6 months. There was no history of consanguinity or similar family history.

Examination revealed multiple well-defined tender minor oral and genital aphthae [Figure 1]. Ophthalmological examination revealed episcleritis. The finger and toenails showed paronychia, yellowish-brown discolouration, onycholysis, and subungual hyperkeratosis with pus discharge [Figure 2]. A well-defined violaceous plaque with overlying ulceration and crusting was present on the right buttock. The pathergy test was negative. The differential diagnoses considered were Behcet’s disease and cutaneous manifestations associated with inflammatory bowel disease.

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Figure 1:

Multiple minor circular aphthous ulcers over the shaft of the penis and scrotum.

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Figure 2:

Erythema and oedema of proximal and lateral nail folds; dystrophy, yellowish-brown discolouration, and onycholysis of nail plate with friable subungual hyperkeratosis affecting all fingernails.

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Laboratory evaluation [Supplementary table 1] revealed leucopenia (3400/mm³) and an episode of significant transaminitis (aspartate aminotransferase (AST) 759 IU/L, alanine aminotransferase (ALT) 377 IU/L) during admission. Nail clippings were negative for any fungal growth. Human leukocyte antigen (HLA) B-51 was negative. Serum immunoglobulin levels were within normal limits. Ultrasonogram showed multiple hyperechoic lesions in the liver. Triphasic computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI) showed multiple small space-occupying lesions in both liver lobes. Liver biopsy showed occasional foci of lobular inflammation and sinusoidal dilatation. Colonoscopy and guided biopsy from the caecum were within normal limits.

Biopsy from the nail fold showed moderately dense nodular chronic lymphomononuclear dermal infiltrate predominantly around adnexa and vessels [Supplementary figures 1 and 2]. Biopsy from plaque on the buttock showed ulcer bed with dense chronic inflammation and proliferating capillaries [Supplementary figure 3]. Biopsy from the scrotal ulcer revealed leukocytoclastic small vessel vasculitis [Supplementary figure 4].

Whole exome sequencing revealed a novel heterozygous nonsense variant in exon 6 (chr12:g.113357323C>T; NM_016816.2:c.1168C>T; p.Gln390Ter) of the OAS1 gene (variant of uncertain significance), validated using Sanger sequencing [Figure 3].

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Figure 3:

Sanger sequencing data (electropherogram) showing the nucleotide change at chr12: c.1168C>T, (p.Gln390Ter) in the OAS1 gene (highlighted with red oval). The blue line indicates the position of the nucleotide change.

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A final diagnosis of OAS-1-associated polymorphic autoinflammatory immunodeficiency disorder (OPAID) was established, and the patient was treated with tapering oral prednisolone starting from 1 mg/kg/day and colchicine 0.5 mg thrice daily over 6 months. There was complete resolution of mucosal ulcers, reduction in ocular and nail symptoms, and no further bouts of fever/abdominal pain/loose stools one month after treatment initiation. We plan to taper and maintain on the lowest possible dose of colchicine to prevent relapses.

OAS proteins play a crucial role in innate immunity against viral infections.^1,2 Type I IFN-α/β activate the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, where JAK1 and tyrosine kinase 2 (TYK-2) phosphorylation forms interferon-stimulated gene factor 3 (ISGF3), inducing OAS gene transcription.^1,2 The OAS gene has been implicated in viral infections, autoimmune disorders, and cancers.^1,2

A heterozygous missense possible gain-of-function variant in OAS1 c.227C>T (p.Ala76Val) is associated with infantile-onset pulmonary alveolar proteinosis and hypogammaglobulinemia.⁴ Magg et al. reported OPAID caused by de novo heterozygous OAS1 gain-of-function variants.³ The presentation included recurrent fevers, ulcerative skin lesions, interstitial lung disease and pulmonary alveolar proteinosis, diarrhoea, hypogammaglobulinemia, and failure to thrive. Sequencing showed four de novo heterozygous OAS1 missense variants (OAS1-A76V, OAS1-C109Y, OAS1-V121G, OAS1-L198V).³ In contrast, our patient did not have pulmonary involvement or hypogammaglobulinemia. Instead, he had ocular and liver involvement along with cutaneous manifestations. The observed variant OAS1 c.1168C>T(p.Gln390Ter) has not been previously reported, suggesting that it may be novel. Computational prediction suggests it could have a damaging effect on protein structure and function, either through protein truncation or nonsense-mediated mRNA decay. This loss of function would have led to autoinflammatory manifestations without any infection. OAS-1 dampens the pro-inflammatory response, as exaggerated pro-inflammatory cytokines, including tumour necrosis factor-α (TNF-α), occur with IFN stimulation in cells with lowered OAS-1 expression, which could possibly lead to inflammatory manifestations.³ However, given its classification as a variant of uncertain significance, further functional studies are required to establish its pathogenicity and clinical relevance. Segregation analysis was also not performed, which is a limitation. Colchicine was chosen due to its established efficacy in the treatment of autoinflammatory syndromes, Behcet-like phenotype, and its inhibitory effect on leucocyte chemotaxis and TNF-α and interleukin-1β (IL-1β) release.⁵

While Behcet’s disease is a complex, polygenic disorder that causes upregulation of OAS-1, a pathogenic heterozygous nonsense variant in the OAS-1 gene has not been previously associated with it.^6,7 In addition, distinct liver involvement, altered immune profiling, negative HLA B-51 with a likely deleterious de novo OAS-1 variant differentiated OPAID from Behcet’s disease [Supplementary table 2].

In conclusion, our index case presented with atypical cutaneous manifestations and systemic features, expanding the spectrum of OPAIDs.