Compound Heterozygeous RAG-1 Mutations in 2 Patients Presenting with Chronic Disfiguring Granulomatous Skin Lesions.

Introduction

Mutations of the recombinase activating genes (RAG) cause a severe combined immunodeficiency (SCID) characterized by absent or low T and B cells due to defective T/B cell receptor rearrangement and failure of lymphocyte maturation. Presenting clinical features commonly are failure to thrive and opportunistic infections in early infancy. We observed 2 patients with RAG mutations where partial T- and B-cell immunity is preserved. These patients did not suffer from severe infections but presented with unusual symptoms and signs, e.g. unexplained lymphogranulomatous skin lesions mimicking malignant lymphoma and lupus vulgaris.

Case presentation

Both patients, who are offsprings of unrelated German parents, underwent genetic screening because of unclear primary immunodeficiencies and were found to have compound heterozygeous RAG-1 mutations (Patient 1: R507W, R737H; R314W and patient 2: R778Q; R975W). Both have no evidence of thymic tissue on ultrasound and have persistant lymphopenia with low T-cell numbers, but are capable of mounting positive antibody responses to tetanus toxoid. In both patients unusual skin lesions were leading clinical abnormalities.

Patient 1, a 6 year-old girl, has been suffering from progressive papulonodular skin lesions of extremities and face since the age of 1 year. Biopsy showed highly monomorphous T-cell infiltrates leading initially to a diagnosis of cutaneous T-cell lymphoma treated with chemotherapy. As progression occurred chemotherapy was stopped and the lesions were reinterpreted as poorly organised sarcoid-like granulomas of unknown etiology. At 5 years of age the girl developed an EBV lymphoma of her right tonsil treated with rituximab. The patient is undergoing at present hematopoetic stem cell transplantation (HSCT).

Patient 2 is an 8 year-old girl, who at the age of 2 years developed persistant ulcerative skin lesions on her face and extremities. Granulomatous epitheloid tissue was found in skin biopsies, and later also in lung and tongue biopsies. No pathogens including mycobacteria were isolated. No improvement was seen on immunosuppression. Skin grafting was necessary in her lower extremity twice after partial destruction of the Achilles tendon by progressive ulceration. HSCT is planned in the near future.

Conclusion

RAG mutations may be associated with a combined immunodeficiency where uncontrolled granuloma formations of the skin, but not opportunistic infections, are leading clinical findings. It is unclear whether these disfiguring lesions are caused by pathogens such as mycobacteria which are difficult to culture or whether they represent reactive sarcoid-like granulomas as seen in other primary IDs, e.g. common variable immunodeficiency.