Autoinflammatory Periodic Fever, Immunodeficiency, and Thrombocytopenia M35.-

Autoinflammatory periodic fever, immunodeficiency and thrombocytopenia, or PFIT for short, is an autoinflammatory disease caused by homozygous missense mutations in the actin regulatory gene WDR1. WDR1 codes for a protein of the same name, WDR1. This leads to impaired actin dynamics in the patient's immune cells. Increased caspase-1 activity in patient monocytes indicates increased inflammasome activity. Apparently, mutant WDR1 mutant protein forms aggregates that lead to pyrin accumulation. This could potentially accelerate inflammasome assembly, leading to excessive IL-18 production (Standing AS et al.2016).

The clinical features of PFIT include recurrent febrile episodes lasting from 3 to 7 days and with a periodicity of 6-12 weeks. The fever is accompanied by oral ulcers, intermittent thrombocytopenia and cellular immunodeficiency, which increases the rate of infection.

Dermatologic manifestations: The primary manifestations are severe oral ulceration and inflammation causing scarring and microstomia.

High serum levels of IL-18 can be found in patients without a corresponding increase in IL-18-binding protein or IL-1β. The WDR1 mutation points to the role of actin regulation in inflammasome activation and human autoinflammation (Kim ML et al. 2015). Furthermore, increased acute phase reactants, leukocytosis, hyperferritinemia and thrombocytopenia have been shown to be observed during seizures (Standing AS et al.2016)

Glucocorticoids, colchicine, conventional immunosuppressants and anakinra have been associated with poor response. Allogeneic hematopoietic stem cell transplants appear to be a therapeutic option (Standing AS et al.2016).

2 Pakistani girls born to consanguineous parents suffered from severe AIDs beginning in the first weeks of life. Both had periodic febrile episodes of 3-7 days duration, every 6-12 weeks, with severe acute phase reactions: C-reactive protein, >270 mg/liter (reference range < 20); serum amyloid A, >200 mg/liter (RR < 10); leukocytosis, 32 × 109/liter (predominantly neutrophil granulocytes); hyperferritinemia, 82-2.679 µg/ml (RR 11-76); and thrombocytopenia, 24-90 × 109/liter; and normalization of these parameters between febrile episodes. Both had severe recurrent oral inflammation, leading to scarring and acquired microstomy in patient IV-2, and recurrent perianal ulceration. Genetic screening for common AIDs (TNFRSF1A, MVK, NLRP3 and MEFV) was negative. Frequent infections were also observed before immunosuppression. Patient IV-1 developed Pneumocystis jiroveci pneumonia at the age of 5 months and septic arthritis of the knee caused by Staphylococcus aureus at the age of 2 years. Patient IV-2 developed necrotizing erysipelas due to streptococcal pneumonia at the age of 13 years. Both developed severe inflammatory reactions to (presumed) viral infections with moderate thrombocytopenia. The mean platelet volume (MPV) was elevated in patient IV-2, while it was in the normal range in IV-4.

The bone marrow aspirate of patient IV-4 showed ultrastructural abnormalities of the megakaryocytes by electron microscopy. A detailed immunologic examination of both children ruled out autoimmunity, common primary immunodeficiency syndromes and primary hemophagocytic lymphohistiocytosis. In patient IV-4, T-cell stimulation with phytohemagglutinin (PHA) was normal, but T-cell activation in response to stimulation with anti-CD3 was decreased, suggesting a defect in adaptive immunity. Patient IV-2 had normal T-cell activation to PHA, but T-cell activation in response to anti-CD3 was not documented. Neutrophil respiratory activity and phagocytosis of opsonized Escherichia coli (in IV-4) were normal.

Both children responded partially to corticosteroids and colchicine, but poor growth and inflammatory episodes persisted. Patient IV-2 responded to several anti-inflammatory and immunosuppressive agents. However, there was some transient steroid-sparing effect in response to anakinra (2-4 mg/kg s.c. daily). Ultimately, however, this did not control the episodes of autoinflammation and the patient died at the age of 14 years from sterile systemic inflammation and multiorgan failure. Patient IV-4 underwent successful allogeneic hematopoietic stem cell transplantation (HSCT) at the age of 8 years and is still healthy 3 years later, without any medication.

1. Figueras-Nart I et al. (2019) Dermatologic and Dermatopathologic Features of Monogenic Autoinflammatory Diseases. Front Immunol 10:2448.
2. Kim ML et al. (2015) Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β. J Exp Med 212:927-938.
3. Li Y et al. (2022) Pathophysiology, clinical manifestations and current management of IL-1 mediated monogenic systemic autoinflammatory diseases, a literature review. Pediatr Rheumatol Online J 20:90.
4. Standing AS et al.(2016) Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1. J Exp Med 214:59-71.