Secondary C1q Deficiency in Activated PI3Kδ Syndrome Type 2

Abstract

Monogenic forms of vasculitis are rare but increasingly recognized. Furthermore, genetic immunodeficiency is increasingly associated with inflammatory immune dysregulatory features, including vasculitis. This case report describes a child of non-consanguineous parents who presented with chronic digital vasculitis early in life, is of short stature, has facial dysmorphia, immunodeficiency (low serum IgA, high serum IgM), recurrent bacterial infections, lymphoproliferation, absence of detectable serum C1q, and low classical complement pathway activity. We identified a previously reported de novo heterozygous pathogenic splice mutation in PIK3R1 (c.1425 + 1G > A), resulting in the skipping of exon 11 of the p85α subunit of phosphatidylinositol 3-kinase and causing activated PI3Kδ syndrome type II (APDS2). This explained the phenotype, with the exception of digital vasculitis and C1q deficiency, which have never been described in association with APDS2. No mutations were identified in C1QA, B, or C, their promoter regions, or in any other complement component. Functional studies indicated normal monocytic C1q production and release, suggesting that the observed C1q deficiency was caused by peripheral consumption of C1q. Since C1q deficiency has never been associated with APDS2, we assessed C1q levels in two unrelated patients with genetically confirmed APDS2 and confirmed C1q deficiency in those two cases as well. This observation suggests C1q deficiency to be an inherent but previously unrecognized feature of APDS2. We speculate that the consumption of C1q is driven by increased apoptotic bodies derived from immune cellular senescence, combined with elevated IgM production (both inherent features of APDS2). Secondary C1q deficiency in APDS2 may further contribute to immunodeficiency and could also be associated with inflammatory immune dysregulatory phenotypes, such as the digital vasculitis observed in our case.

PIK3R1 mutation associated with primary immunodeficiency: a case of a 14-year-old male and review of the literature: case report

“…Increased IgM levels were observed in most (58%) but not all patients. 6 During the last decade, Cases of APDS2 keep reported in the literature [7][8][9][10][11][12][13][14][15][16][17] with very heterogenous clinical phenotypes as shown in this case report of four members of the same family (parents and 2 siblings). While the youngest child presented early in life with marked lymphoproliferation and died later due to EBV-induced diffuse large B cell lymphoma complications, the other sibling and parents had a milder course with recurrent sinopulmonary infections and mild adenotonsillar hypertrophies.…”

“…14 Congenital infections are also reported, as shown in this case report describing disseminated and congenital toxoplasmosis in a mother and child who share a pathogenic mutation in PIK3R1. 32 Chronic digital vasculitis, 17 short stature and failure to thrive, 11,12,14 microcephaly, 10 and other minor facial dysmorphology 14 were reported as associated findings with APDS2. Another rare but significant clinical phenotype that can be associated with mutations in the PIK3R1 gene is Short Syndrome (short stature, hyperextensibility, hernias, ocular depression [deeply set eyes], Rieger anomaly, teething delay, partial lipodystrophy, insulin resistance, and facial dysmorphic signs).…”

Hyper-IgM and acquired C1q complement deficiency in a patient withde novo ATMmutation

“…How these two phenomena may be pathologically linked is unknown. Another report of HIGM and acquired C1q deficiency in activated phosphoinositide 3-kinase delta syndrome (APDS) speculated that increased apoptotic bodies may be a possible mechanism for increased consumption of C1q complement [ 11 ].…”

ANCA vasculitis expands the spectrum of autoimmune manifestations of activated PI3 kinase δ syndrome

“…Spontaneous resolution of the vasculitis was observed similar to the clinical course of uncomplicated primary cutaneous vasculitis (47) though ANCA positivity remained, indicating that the presence of autoantibodies alone is insufficient for disease manifestation. However, in APDS patients with complicated or systemic vasculitic features, immunomodulatory regimens, such as corticosteroids, hydroxychloroquine, azathioprine, mycophenolate, and cyclophosphamide, have been utilized with variable results (38,(40)(41)(42). In one such case, targeting mTOR hyperactivity with sirolimus allowed for improved management of the associated autoimmune vasculitis (41).…”

“…As noted in Table 2, vasculitis is an infrequent autoimmune feature amongst APDS patients. In 2019, Hong et al reported chronic vasculitis affecting the fingers and toes of a pediatric APDS2 patient who was interestingly found to have a C1q deficiency secondary to increased consumption rather than intrinsic production defect or anti-C1q antibodies (40). The etiology of vasculitis was postulated to be secondary to low C1q similar to the lupus-like vasculitis seen in genetic C1q deficiency (43).…”