Platelet Abnormalities With Eosinophilia And Immune-Mediated Inflammatory Disease

A number sign (#) is used with this entry because of evidence that platelet abnormalities with eosinophilia and immune-mediated inflammatory disease (PLTEID) is caused by homozygous mutation in the ARPC1B gene (604223) on chromosome 7q22.

Description

PLTEID is an autosomal recessive immune-mediated inflammatory disease with highly variable manifestations. More severely affected individuals have recurrent infections, vasculitis, and thrombocytopenia, whereas other patients have mild vasculitis and normal numbers of small platelets without severe infections. Laboratory studies show platelets with abnormal shape, decreased dense granules, and impaired spreading ability, as well as immune dysregulation with increased eosinophils, B cells, IgA and IgE, and autoantibodies (summary by Kahr et al., 2017).

Clinical Features

Kahr et al. (2017) reported 3 patients from 2 unrelated families with a multisystem disorder characterized by platelet abnormalities, vasculitis, eosinophilia, and predisposition to inflammatory diseases. Patient 1, born of consanguineous parents of South Asian descent, had a more severe disorder, with recurrent infections beginning in early infancy, immunodeficiency, microthrombocytopenia, and a severe cutaneous papular nodular rash consistent with vasculitis and associated with deposition of IgG, IgM, and C3. Other features included inflammatory bowel disease with eosinophilic infiltration, cervical lymphadenopathy, and joint limitations progressing to bony erosions. He did not have opportunistic infections. Laboratory studies showed autoantibodies (positive antinuclear antibodies, ANA and ANCA), and bone marrow biopsy showed adequate megakaryocytes and increased eosinophils. At age 9 years, he was maintained on IV Ig infusions, immunosuppression, and prophylactic antibiotics; biochemical markers indicated increased inflammation. Patients 2 and 3, who were sibs, had a skin rash and normal platelet counts, but small platelets. One sib had leukocytoclastic vasculitis with deposition of IgM and C3 and was ANA and ANCA positive. He was treated with IV Ig and immunosuppression. His brother had an intermittent eczematous-like rash, 1 episode of pneumonia at 1 to 2 years of age, and asthma. He had persistently increased C-reactive protein and was positive for ANCA. Immunologic work-up of all 3 patients showed eosinophilia, lymphocytosis, and increased numbers of circulating B cells with increased IgA and IgE; T-cell number and function appeared normal in all patients. Other findings included increased erythrocyte sedimentation rate, suggestive of enhanced inflammation. All patients had failure to thrive early in life. Platelets derived from all 3 patients were small and dysmorphic compared to controls; dysmorphic features included odd shapes, collapse or loss of circumferential microtubule coils, and decreased dense granules. The findings were similar to those observed in Wiskott-Aldrich syndrome (WAS; 301000).

Inheritance

The transmission pattern of PLTEID in the families reported by Kahr et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient, born of consanguineous parents of South Asian descent, with severe PLTEID, Kahr et al. (2017) identified a homozygous truncating mutation in the ARPC1B gene (604223.0001). Immunoblot analysis of patient platelet lysates showed absence of the ARPC1B protein, consistent with a complete loss of function. Two sibs with less severe manifestations of PLTEID were homozygous for a missense mutation (A105V; 604223.0002). Immunoblot analysis of the sibs' platelet lysates showed greatly reduced levels of the ARPC1B protein, consistent with a loss of function. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies showed that patient platelets had aberrant and decreased spreading with formation of spiky structures with tubulin-rich tips that contained fewer and elongated F-actin fibers and little evidence of podosome-like nodule formation. The findings were consistent with a loss of actin branching required for lamellipodia formation. Complete knockdown of the ARPC1B gene in a megakaryocyte cell line resulted in a decrease in proplatelet formation, which may explain the thrombocytopenia observed in the patient with a homozygous truncating mutation and complete absence of the ARPC1B protein.