Schuetz et al. (2008) reported 3 unrelated girls with combined cellular and humoral deficiencies and multiple granulomas. The first patient presented at age 2.5 years with multiple facial papulonodular lesions composed of epithelioid cells with a strong lymphocytic ... Schuetz et al. (2008) reported 3 unrelated girls with combined cellular and humoral deficiencies and multiple granulomas. The first patient presented at age 2.5 years with multiple facial papulonodular lesions composed of epithelioid cells with a strong lymphocytic infiltrate. She was originally diagnosed with a T-cell lymphoma, but there was a poor response to chemotherapy. Extensive laboratory evaluation showed profound hypogammaglobulinemia, decreased T cells, and defective T-cell function. Bone marrow transplant was successful. The second patient developed severe infections in infancy and later developed skin, tongue, and lung lesions consistent with noninfectious granulomas. Immunophenotyping showed low numbers of B and T cells. Bone marrow transplant was successful. The third patient presented at age 10 years with a history of severe infections and massive splenomegaly. She was found to have hypogammaglobulinemia and defective T-cell function. Noninfectious granulomas were present in the spleen and lungs. None of the patients had a thymus visible on ultrasonography. Schuetz et al. (2008) noted that the phenotype in these patients was distinct from classic SCID and from Omenn syndrome (603554). The relatively late onset and lack of repeated life-threatening infections suggested that the T-cell repertoire was sufficient to offer some residual protection. Perks and Petheram (1978) reported a brother and sister of Maltese ancestry who had recurrent respiratory infections. Investigations showed combined cellular and humoral immune defects and noncaseating granulomas in lungs, liver, lymph nodes, and skin. The brother presented at age 16 years with iritis and died at age 25 from gram-negative septicemia. The sister presented at age 25 with pulmonary complaints. Progressive deterioration of pulmonary and hepatic function was observed in both. The phenotype in these patients resembled that described by Schuetz et al. (2008). - Clinical Variability De Ravin et al. (2010) reported a 14-year-old boy who presented with destructive midline granulomatous disease of the head and neck. The patient had a complicated medical history. He had a history of myasthenia gravis with thymectomy at age 10 years, and a history of recurrent ear and sinus infections. The thymus showed dysplastic features and absence of autoimmune regulator, indicating a defect in thymocyte maturation. Laboratory studies showed a decrease of IgG subclasses 2 and 4 and mild CD8+ T cell lymphopenia, whereas CD3+ T cells, CD19+ B cells, and NK cells were normal. He was treated for Wegener granulomatosis with chemotherapeutic agents, but developed severe lymphopenia and continued to have relapses of noninfectious granulomas. In vitro studies showed dysregulated cellular inflammatory responses to various stimuli, including increased production of IL1B (147720) and IL8 (146930). An older sister had autoimmune cytopenias and antinuclear antibody-positive collagen vascular disease, with death at age 5 years. Molecular analysis of the proband identified compound heterozygous mutations in the RAG1 gene: W522C (179615.0024), which retained about 50% residual activity, and a null mutation (1621delC; 179615.0025). De Ravin et al. (2010) concluded that the proband had a phenotypic variant of RAG1 deficiency, with some residual enzyme activity being responsible for the later presentation and milder phenotype. The authors suggested a dysregulation of the inflammatory response to environmental antigens in this patient.
In 2 unrelated patients with childhood onset of cellular and humoral deficiencies associated with granuloma formation, Schuetz et al. (2008) identified compound heterozygous mutations in the RAG1 gene (179615.0018-179615.0021). A third affected child had compound heterozygous mutations in ... In 2 unrelated patients with childhood onset of cellular and humoral deficiencies associated with granuloma formation, Schuetz et al. (2008) identified compound heterozygous mutations in the RAG1 gene (179615.0018-179615.0021). A third affected child had compound heterozygous mutations in the RAG2 gene (179616.0009 and 179616.0010).