Precision treatment with sirolimus in a case of activated phosphoinositide 3-kinase δ syndrome

Rae, William; Ramakrishnan, Kesava A.; Gao, Yifang; Ashton‐Key, Margaret; Pengelly, Reuben J.; Patel, Sanjay; Ennis, Sarah; Williams, Anthony P.; Faust, Saul N

doi:10.1016/j.clim.2016.07.017

Cited by 29 publications

(19 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar improvements have been noted in a recent case report of a four year old boy also treated with rapamycin68. However, the effect of rapamycin on B cell homeostasis and humoral immune responses in APDS patients remains to be determined.…”

Section: Treatment Options For Patients With Apdssupporting

confidence: 84%

PI3Kδ and primary immunodeficiencies

et al. 2016

View full text Add to dashboard Cite

Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS) or p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

show abstract

Section: Treatment Options For Patients With Apdssupporting

confidence: 84%

PI3Kδ and primary immunodeficiencies

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Activated phosphoinositide 3‐kinase delta syndrome due to GOF variants in PIK3CD can cause lymphoproliferation and autoimmunity disease which is a significant cause of increased mortality . These disease manifestations respond to inhibition of the hyperfunctional PIK3δ‐AKT‐mTOR pathway in lymphocytes of patients with use of mTOR inhibition by sirolimus or with PIK3δ inhibitors, such as idelalisib …”

Section: Resultsmentioning

confidence: 99%

“…54 These disease manifestations respond to inhibition of the hyperfunctional PIK3δ-AKT-mTOR pathway in lymphocytes of patients with use of mTOR inhibition by sirolimus or with PIK3δ inhibitors, such as idelalisib. 33,36 Heterozygous frameshift variants in IFNGR1 cause recurrent infection with low virulence non-tuberculous mycobacteria (NTM) due to expression of a non-functional cell surface receptor on patients' cells that acts as a "decoy receptor" for interferon-γ. 35 This inborn error against NTMs can be improved with use of exogenous interferon-γ to boost signalling through the residual receptors on effector cells.…”

Section: Clinical Management and Treatment Implicationsmentioning

confidence: 99%

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

et al. 2018

View full text Add to dashboard Cite

Primary immunodeficiencies (PIDs) are rare monogenic inborn errors of immunity that result in impairment of functions of the human immune system. PIDs have a broad phenotype with increased morbidity and mortality, and treatment choices are often complex. With increased accessibility of next-generation sequencing (NGS), the rate of discovery of genetic causes for PID has increased exponentially. Identification of an underlying monogenic diagnosis provides important clinical benefits for patients with the potential to alter treatments, facilitate genetic counselling, and pre-implantation diagnostics. We investigated a NGS PID panel of 242 genes within clinical care across a range of PID phenotypes. We also evaluated Phenomizer to predict causal genes from human phenotype ontology (HPO) terms. Twenty-seven participants were recruited, and a total of 15 reportable variants were identified in 48% (13/27) of the participants. The panel results had implications for treatment in 37% (10/27) of participants. Phenomizer identified the genes harbouring variants from HPO terms in 33% (9/27) of participants. This study shows the clinical efficacy that genetic testing has in the care of PID. However, it also highlights some of the disadvantages of gene panels in the rapidly moving field of PID genomics and current challenges in HPO term assignment for PID.

show abstract

“…51 The antiproliferative drug rapamycin has been successful in normalizing the T-cell profiles of patients with APDS and their lymphoproliferative symptoms. 52 Similar to gain-of-function PI3KCD mutations, patients with heterozygous gain-of-function STAT3 mutations typically present with hypogammaglobulinemia, infectious symptoms, and a panoply of autoimmune manifestations, including type 1 diabetes, autoimmune cytopenias, nonmalignant lymphoproliferation, and enteropathy. 53e55 Unlike loss-of-function STAT3 mutations, which cause mucocutaneous candidiasis, STAT3 gain-of-function mutations can present with disseminated nontuberculous mycobacteriosis.…”

Section: Lymphoproliferative Defectsmentioning

confidence: 99%

Birds of a feather

Romberg

Lawrence

2019

Annals of Allergy, Asthma & Immunology

View full text Add to dashboard Cite

Common variable immune deficiency (CVID) is suggested by a clinical phenotype of infectious susceptibility, autoimmunity, and lymphoproliferation. A diagnosis is made with laboratory evidence of antibody failure. Genetic variants likely contributing to CVID can be identified in up to 30% of patients. Genetic mutations are enriched in patients with CVID with any of the following: early-onset manifestations, autoimmune or inflammatory complications, a family history of immunodeficiency, or low B-cell numbers. Identification of a mutation in a CVID-related gene can have direct prognostic and therapeutic implications.

show abstract

Precision treatment with sirolimus in a case of activated phosphoinositide 3-kinase δ syndrome

Cited by 29 publications

References 9 publications

PI3Kδ and primary immunodeficiencies

PI3Kδ and primary immunodeficiencies

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

Birds of a feather

Contact Info

Product

Resources

About