Autoimmune lymphoproliferative syndrome type 3 D81.4

Last updated on: 31.05.2022

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Autoimmune lymphoproliferative syndrome type III, also known as ALPS3, is a rare autosomal recessive immunodeficiency syndrome caused by a homozygous mutation in the PRKCD gene (Protein Kinase C Delta/176977) on chromosome 3p21. The phenotype is variable, but most patients have significant lymphadenopathy associated with various autoimmune manifestations. Recurrent infections may occur in some patients. The accumulation of lymphocytes results from a combination of impaired apoptosis and excessive proliferation (Oliveira 2013)

Case report(s)
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Salzer et al (2013) reported a 12-year-old boy with a primary immunodeficiency syndrome characterized by B-cell deficiency and severe autoimmunity. The patient suffered from recurrent infections affecting most systems (respiratory, urinary, gastrointestinal) since the age of one year. At 15 months of age, he developed autoimmune nephrotic syndrome; a renal biopsy showed membranous glomerulonephritis with deposits of IgG and complement components. At 3 years of age, he developed hepatosplenomegaly and generalized lymphadenopathy associated with herpesviremia. Other autoimmune features included polychondritis and an antiphospholipid syndrome with antinuclear, anti-dsDNA, and anticardiolipin IgG antibodies.

Lab: decreased IgG levels with increased IgA and IgM. The formal criteria for CVID, which include decreased levels of at least two Ig classes, were not met, but the phenotype was consistent with a CVID-like disorder. B-cell studies showed a decrease in CD19+ B cells, a decrease in memory B cells, and an increase in CD21(low)-B cells. T cells showed a slightly decreased proliferative response. Treatment with low-dose steroids and the immunosuppressant mycophenolate mofetil resulted in good disease control in this patient....

At 4 years of age, he was treated with intravenous IgG, which resulted in a decrease in infections, and anti-CD20 therapy. The autoantibodies persisted.

Andre et al (2007) reported on three siblings born to consanguineous parents of European ancestry who suffered from childhood-onset autoinflammatory-accentuated immunodeficiency. The most severely affected child presented at 3 years of age with a lymphoproliferative syndrome with lymphadenopathy and hepatosplenomegaly. She had severe hemolytic anemia and later developed idiopathic thrombocytopenic purpura. Furthermore, manifestations reminiscent of systemic lupus erythematosus (152700) were detectable (erythema, glomerulonephritis, arthralgias). Lab.: ESR elevated, hypergammaglobulinemia and autoantibodies; B cells were elevated, CD4/CD8 T cells were undetectable. The disease was treated with immunosuppressive therapy. The patient's sister and brother presented with SLE features at the age of 10 and 6 years, respectively, but without lymphoproliferative disorder.

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  1. Andre JM et al (2007) Overexpression of the antiapoptotic gene Bfl-1 in B cells from patients with familial systemic lupus erythematosus. Lupus 16: 95-100.
  2. Belot A et al. (2013) Protein kinase C-delta deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum 65: 2161-2171.
  3. Kuehn HS et al (2013) Loss-of-function of the protein kinase C-delta (PKC-delta) causes a B-cell lymphoproliferative syndrome in humans. Blood 121: 3117-3125.
  4. Miyamoto A et al. (2002) Increased proliferation of B cells and auto-immunity in mice lacking protein kinase C-delta. Nature 416: 865-869.
  5. Neehus AL et al (2021) Impaired respiratory burst contributes to infections in PKC-delta-deficient patients. J Exp Med 218: e20210501.
  6. Oliveira JB et al (2013) The expanding spectrum of the autoimmune lymphoproliferative syndromes. Curr. Opin. Pediat. 25: 722-729.
  7. Salzer E et al (2013) B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C-delta. Blood 121: 3112-3116.

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Last updated on: 31.05.2022