Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia
PFIT mutation has been characterized in 7 families with 13 affected individuals of Northern European, Qatari, Pakistani, Turkish, and Syrian lineage. Males and females are equally affected, and the inheritance pattern is autosomal recessive. The genetic defect stems from missense mutations in the actin regulatory gene WD repeat protein 1 (WDR1), which encodes actin-interacting protein 1 (AIP1), a protein that regulates the actin cytoskeleton.
The mutated WDR1 also activates caspase-1, which leads to autoinflammation due to excessive interleukin-18 (IL-18) production by monocytes. These mutations also disrupt the actin cytoskeleton to impact both innate and adaptive immunity, as neutrophil, monocyte / macrophage, B cell, and T cell functions are impaired, resulting in a primary immunodeficiency.
Affected individuals usually exhibit signs in infancy and early childhood and often have decreased life expectancy, although some patients begin to show disease manifestations during their second decade of life.
Clinical features include early onset of recurrent respiratory infections with cough, pneumonia, bronchiectasis, rhinitis, cutaneous infections, stomatitis, otitis media, gingivitis, and fevers. Infections usually arise from bacterial organisms such as Staphylococcus aureus, Streptococcus pneumoniae, Pneumocystis jiroveci, Haemophilus influenzae, Escherichia coli, and Enterococcus, and may result in severe viral infections, including varicella. Patients can have microstomia, oral stenosis, perianal ulceration, hypertrichosis, nodulocystic acne, and generalized poor wound healing.
Some patients demonstrate the predominant clinical picture of innate immunity defect with impaired neutrophil function and severe neutrophilia. Others experience periodic fevers that may last 3-7 days and recur every 6-12 weeks and immunodeficiency, although sometimes without neutropenia / lymphopenia and instead with leukocytosis, chronic thrombocytopenia, and anemia. Lastly, a third distinct profile is characterized with a mostly impaired adaptive immune system, manifesting with profound B-cell lymphopenia and dysfunction and mild defects in T-cell activation. Patients often show poor growth and mild to moderate intellectual disability, although some patients demonstrate normal growth and development.
D70.8 – Other neutropenia
71436005 – Lazy leukocyte syndrome
Differential Diagnosis & Pitfalls
- Chediak-Higashi syndrome – Associated with oculocutaneous albinism and easy bruising.
- Familial Mediterranean fever (FMF) – MEFV gene mutation; associated with serositis, good response to colchicine treatment.
- Wiskott-Aldrich syndrome (WAS) – Increased risk for malignancy, association with thrombocytopenia and eczema.
- WAS interacting protein (WIP) deficiency – Associated with eczema, elevated immunoglobulin E (IgE).
- X-linked neutropenia (XLN) – Congenital neutropenia.
- Leukocyte adhesion defects (LAD1, 2, 3) – Neutrophilia with lack of pus formation.
- Hyperimmunoglobulin D with periodic fever syndrome (HIDS) – MVK gene mutation; associated with arthralgias / myalgias.
- Deficiency of interleukin-1 receptor antagonist (DIRA) – No fever, associated with osteomyelitis.
- Systemic juvenile idiopathic arthritis (sJIA) – Lymphadenopathy and arthritis, serum shows elevated IL-18 binding protein (IL-18BP).
- Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND)
- Hyperimmunoglobulinemia E syndrome – Associated with eczema, eosinophilia, and elevated serum IgE.
- Macrophage activation syndrome (MAS)
- Behçet disease
- Blau syndrome
- Cryopyrin-associated periodic syndromes (CAPS)
- NLRP1-associated autoinflammation with arthritis and dyskeratosis (NAIAD)
- NLRP12 autoinflammatory syndrome (NLRP12-AD)
- TNF receptor-associated periodic fever syndrome (TRAPS)
- Autoinflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID)
- Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome
- Other actinopathies: DOCK8 deficiency, RASGRP1 deficiency, coronin-1A deficiency, DOCK2 deficiency, Rac2 deficiency, beta-actin deficiency, and ARPC1B deficiency