Activated phosphoinositide 3-kinase delta syndrome misdiagnosed as anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report

Zhang, Xiaojing; Wang, Jingjing; Zhu, Kun; Jin, Yanyan; Fu, Haidong; Mao, Jianhua

doi:10.1177/03000605211013222

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…Similarly, APDS1 was confirmed in a 7-year-old boy with recurrent sinopulmonary infections, bronchiectasis, lymphoproliferation, and hematuria after an initial diagnosis of ANCA-associated vasculitis three years earlier (38). No cutaneous vasculitic manifestations were reported in these patients (38,42). There was a single report of vertebral vasculitis in an APDS cohort from the United States Immunodeficiency Network (USIDNET) Registry (5).…”

Section: Apds: Autoimmune Clinical Manifestationsmentioning

confidence: 89%

“…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).…”

Section: Discussionmentioning

confidence: 99%

“…In 2021, Lu et al described two pediatric patients with recurrent lung infections, sinusitis, hematuria, and positive PR3-ANCA antibodies who initially were diagnosed with granulomatosis with polyangiitis but were later genetically confirmed to have APDS1 (42). Similarly, APDS1 was confirmed in a 7-year-old boy with recurrent sinopulmonary infections, bronchiectasis, lymphoproliferation, and hematuria after an initial diagnosis of ANCA-associated vasculitis three years earlier (38). No cutaneous vasculitic manifestations were reported in these patients (38,42).…”

Section: Apds: Autoimmune Clinical Manifestationsmentioning

confidence: 99%

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

et al. 2023

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Activated phosphoinositide 3-kinase δ syndrome (APDS) is a combined immunodeficiency with a broad clinical phenotype, including not only an increased propensity for sinopulmonary and herpesviruses infections but also immune dysregulation, such as benign lymphoproliferation, autoimmunity, and malignancy. Autoimmune complications are increasingly recognized as initial presenting features of immune dysregulation in inborn errors of immunity (IEIs), including APDS, so awareness of the spectrum of autoimmune features inherit within these disorders is critical. We present here a patient vignette to highlight cutaneous antineutrophil cytoplasmic antibody (ANCA) vasculitis as an underrecognized autoimmune manifestation of APDS. The genetic defects underlying APDS result in increased PI3Kδ signaling with aberrant downstream signaling pathways and loss of B- and/or T-cell immunologic tolerance mechanisms, which promote the development of autoimmunity. An understanding of the molecular pathways and mechanisms that lead to immune dysregulation in APDS has allowed for significant advancements in the development of precision-medicine therapeutics, such as leniolisib, to reduce the morbidity and mortality for these patients. Overall, this case and review highlight the need to maintain a high index of suspicion for IEIs, such as APDS, in those presenting with autoimmunity in combination with a dysregulated immune phenotype for prompt diagnosis and targeted intervention.

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Section: Apds: Autoimmune Clinical Manifestationsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Apds: Autoimmune Clinical Manifestationsmentioning

confidence: 99%

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

et al. 2023

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Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens

Walsh,

Shah,

Kothapalli

et al. 2024

Nat Biotechnol

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Real-world evidence of mortality and survival rates in 256 individuals with APDS

Hanson

Bonnen

2022

Preprint

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Activated Phosphoinositide 3-kinase Delta Syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function (GOF) variants in the PIK3CD gene while loss of function (LOF) variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 was 87%, age 30 was 74%, age 40 and 50 were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The mortality data suggests that the standard of care treatment for APDS, immunoglobulin replacement therapy, appears to prevent most deaths due to severe infection, however, new treatments are needed to mitigate the risk of death from lymphoma and other cancers. This analysis based on real world evidence gathered from the medical literature is the largest study of survival for APDS to date.

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Activated phosphoinositide 3-kinase delta syndrome misdiagnosed as anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report

Cited by 5 publications

References 25 publications

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

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

Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens

Real-world evidence of mortality and survival rates in 256 individuals with APDS

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