Expanding the clinical features of autoinflammation and phospholipase Cγ2‐associated antibody deficiency and immune dysregulation by description of a novel patient

Abstract

Background Autoinflammation and phospholipase Cγ2‐associated antibody deficiency and immune dysregulation (APLAID) is an exceedingly rare monogenic autoinflammatory disease. To date, only five cases have been reported with four distinct pathogenic mutations. Objectives We present a novel case of APLAID, corroborated by molecular analysis, with newly described clinical findings including central nervous system vasculitis (CNSV); and distinctive histopathological characteristics that may expand our knowledge of this rare disease′s phenotype. Methods This is a case report presentation of a 3‐year‐old boy, seen at a reference paediatric hospital in Mexico. His parents authorized the use of his clinical information and photographs. Results A 3‐day‐old boy presented to the emergency department with a vesiculo‐pustular rash that resolved within 1 week. Two months later, he developed widespread papules and pseudovesicles that evolved into infiltrated plaques. He also had periodical flares of conjunctivitis, diarrhoea and erythematous blistering acral plaques triggered by upper respiratory infections. By the age of 10 months, he experienced seizures and CNSV. Laboratory work‐up showed mild neutropenia, decreased serum levels of immunoglobulins and B‐cell lymphopenia. A skin biopsy revealed a dense, perivascular and interstitial histiocytic and granulomatous infiltrate, with palisading granulomas, and leucocytoclastic vasculitis with karyorrhexis. APLAID syndrome was confirmed by Sanger sequencing of PLCG2 gene [heterozygous genotype LRG_376t1:c.2543T>C or p.(Leu848Pro)]. Conclusions Presence of CNSV has not been previously described in APLAID, however as the number of reported patients with APLAID is very small, it is possible that the overall spectrum of clinical manifestations has not been completely elucidated. The herein identified p.(Leu848Pro) variant was also documented in a Portuguese patient, suggesting that it could be a PLCG2 gene ‘hot‐spot’.

Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations

“…A l a 7 0 8 P r o a n d p.Leu845_Leu848) expands the range of genetic changes that cause this syndrome. Consistent with previous studies [7][8][9], we show that the new PLCG2 variants have higher PLC PBMCs IL-1β and ASC speck forming monocytes upon canonical NLRP3 activation by LPS priming (1 μg/mL, 2 h) followed by 30-min treatment with ATP (3 mM) or nigericin (10 μM) in healthy controls, patients with CAPS, and patients with APLAID. Showed results are representative of duplicate experiments.…”

“…We were particularly interested in sterile inflammatory lesions and their molecular basis. From a clinical perspective, the cutaneous manifestations were the most prominent in both of our patients (patient 1 and 2) since the onset of their diseases as have been also described for the other four published APLAID patients [7][8][9]. These manifestations were initially vesicular and blistering lesions that subsequently evolved to the destruction of elastin fibers leading to large areas of cutis laxa in both patients, a phenomenon also described in the APLAID patient with the p.Leu848Pro PLCG2 variant [8].…”

“…A comprehensive analysis of circulating B cells revealed their near complete absence in patient 1 and an overall decrease of all B cell subpopulations, a decreased response to polysaccharide vaccination, and the absence of autoantibodies in patient 2 ( Table 2 and Supplementary Table S3). Bone marrow aspiration was once performed in patient 1, which revealed that B Table 1 Summary of clinical and immunological features of enrolled patients and comparison with reported APLAID patients (Zhou et al [7]; Neves et al [8]; Morán-Villaseñor et al [9] Present study Zhou et al…”

“…Residues so far found to be mutated only in PLCγ1 are shown in gray. Other residues mutated in APLAID (p.Ser707 and p.Leu848) and Ali14 mice (p.Tyr495) are indicated by orange arrows p.Leu848Pro PLCG2 variant [8,9]. The humoral immunodeficiency of this patient (patient 1) was clinically characterized by severe and recurrent bacterial infections, structural lung lesions, recurrent episodes of acute hemoptysis, and the requirement of surgical lung lobe resection.…”

“…Furthermore, our extensive characterization of clinical manifestations, properties of immune cells, and changes in function of the encoded enzyme, PLCγ2, support a definitive diagnosis of PLCγ2-associated antibody deficiency and immune dysregulation syndrome, designated as APLAID. Previously, only 4 patients from three families have been diagnosed with APLAID [7][8][9] and have been found to share some of the manifestations with Ali5 and Ali14 mouse strains that carry gain-of-function PLCG2 mutations [17,18]. Another two families carrying the same PLCG2 variant in the C2 domain of the protein have been recently described during manuscript reviewing [19].…”