OAS1-associated autoinflammation and immunodeficiency syndrome

2′-5′-oligoadenylate synthetase 1 (OAS1)-associated autoinflammation and immunodeficiency syndrome is a rare genetic condition caused by gain-of-function variants in the OAS1 gene. Affected individuals present early in childhood with variable features, including autoinflammation, pulmonary alveolar proteinosis and recurrent infections secondary to hypogammaglobulinaemia.

Affected individuals present early in childhood with recurrent episodes of fever. The main clinical features of OAS1-associated autoinflammation and immunodeficiency syndrome include:

• pulmonary alveolar proteinosis (PAP), a rare condition caused by accumulation of a surfactant-like substance in alveolae, leading to respiratory distress and failure;
• recurrent fever;
• dermatitis;
• hypogammaglobulinaemia;
• inflammatory bowel disease; and
• failure to thrive.

OAS1-associated autoinflammation and immunodeficiency syndrome is caused by monoallelic (heterozygous) pathogenic variants in the OAS1 gene, which encodes OAS1.

Causative missense variants have a gain-of-function effect, which leads to impaired surfactant catabolism in alveoli and excessive RNA breakdown, which induces interferon-induced autoinflammation.

Note that deleterious variants that have been described have arisen de novo, and that variable penetrance may occur.

Genetic polymorphisms may contribute to susceptibility to viral infection on a population level, though these changes are not by themselves causative of OAS1-associated autoinflammation and immunodeficiency syndrome. The splice-acceptor site single nucleotide polymorphism rs10774671 risk allele produces OAS1 protein with lower enzymatic activity.

PAP is diagnosed following high-resolution chest CT and bronchoalveolar lavage, the latter showing periodic acid-Schiff (PAS) positive material.

Laboratory tests may show:

• hypogammaglobulinaemia with reduced antibody responses;
• raised acute phase reactants; and/or
• raised IL-1 and/or IL-6.

Genomic testing should be carried out in patients presenting with infantile-onset PAP in order to analyse the other genes associated with it: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB and GATA2. PAP may also occur secondary to an autoimmune mechanism.

Genomic testing confirms the diagnosis and differentiates OAS1-associated autoinflammation and immunodeficiency syndrome from other similar conditions. OAS1 is also included on other autoinflammatory and immunodeficiency panels.

For information about testing, see ‘Infant or child with severe, recurrent, persistent and/or unusual infections‘.

OAS1-associated autoinflammation and immunodeficiency syndrome may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services or the National Amyloidosis Centre. Please refer to the local pathway for your region for this condition.

OAS1-associated autoinflammation and immunodeficiency syndrome is a rare genetic condition with an autosomal dominant pattern of inheritance. Pathogenic genetic variants have a gain-of-function effect on the OAS1 protein.

• Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• Incomplete penetrance can occur (that is, not everyone who has the variant develops the disease).

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

OAS1-associated autoinflammation and immunodeficiency syndrome should be managed using a multidisciplinary specialist immunology service.

Initial treatment for PAP includes lung lavage and may require mechanical ventilation. Patients require immunoglobulin replacement with antibiotic prophylaxis.

Patients may require corticosteroids in treatment of acute flares of fever. Patients with isolated fever, dermatitis or inflammatory bowel disease may respond to immunosuppressive agents, such as methotrexate or azathioprine.

Recently, haematopoietic stem cell transplantation (HSCT) has been reportedly successful. However, it should only be considered in more severe, treatment-refractory cases.

OAS1-associated autoinflammation and immunodeficiency syndrome may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• OMIM: 618042 Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia; IMD100

References:

• Magg T, Okano T, Koenig LM and others. ‘Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency‘. Science Immunology 2021: volume 6, issue 60. DOI: 10.1126/sciimmunol.abf9564
• Seidl E, Schramm D, Schön C and others. ‘Pulmonary alveolar proteinosis due to heterozygous mutation in OAS1: Whole lung lavages for long-term bridging to hematopoietic stem cell transplantation‘. Pediatric Pulmonology 2022: volume 7, issue 1, pages 273–277. DOI: 10.1002/ppul.25728

For patients

• Autoinflammatory UK