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Hypomorphic Rag mutations can cause destructive midline granulomatous disease
Suk See De Ravin1, Edward W Cowen, Kol A Zarember
1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. sderavin@niaid.nih.gov
Blood
|May 22, 2010
Summary
A rare genetic disorder, Recombination activating gene-1 (Rag1) deficiency, caused severe facial destruction in an adolescent. This case expands understanding of Rag1 deficiency presentations and immune dysregulation.
Area of Science:
- Immunology
- Genetics
- Pediatrics
Background:
- Destructive midline granulomatous disease (DMGD) of the head and neck typically results from autoimmune conditions, infections, or substance abuse.
- Wegener granulomatosis, lymphomas, and infections are common causes of DMGD.
- Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions.
Observation:
- An adolescent with myasthenia gravis, post-thymectomy, developed extensive DMGD affecting facial structures, palate, nasal septum, airways, and epiglottis.
- The patient presented with normal lymphocyte counts, immunoglobulin G levels, and T-cell receptor (TCR) repertoire.
- Genetic analysis revealed compound heterozygous mutations in Recombination activating gene-1 (Rag1), including a novel deletion and a missense mutation.
Findings:
- The patient's Rag1 mutations resulted in absent and reduced recombinase activity.
- The thymus was dysplastic, lacking autoimmune regulator (AIRE) and Foxp3(+) regulatory T cells, despite normal T-cell numbers.
- This Rag1-deficient phenotype demonstrated immune dysregulation with granulomatous hyperinflammation and autoimmunity.
Implications:
- This case expands the spectrum of clinical presentations for Rag1 deficiency.
- It highlights a distinct phenotype characterized by immune dysregulation, hyperinflammation, and autoimmunity in the context of relatively normal lymphocyte counts and TCR diversity.
- Understanding this phenotype is crucial for diagnosing and managing similar rare immune disorders.
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