Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review

Jamee, Mahnaz; Moniri, Shakiba; Zaki‐Dizaji, Majid; Olbrich, Peter; Yazdani, Reza; Jadidi‐Niaragh, Farhad; Aghamahdi, Fatemeh; Abolhassani, Hassan; Condliffe, Alison M.; Aghamohammadi, Asghar; Azizi, Gholamreza

doi:10.1007/s12016-019-08738-9

Cited by 101 publications

(180 citation statements)

References 69 publications

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“…Patient 009 was a 2-month-old infant male, initially admitted to the inpatient pediatric service with chronic diarrhea and failure to thrive and transferred to the PICU with worsening metabolic acidosis, hypernatremic dehydration and hypoglycemia. The patient’s rCES demonstrated a de novo , heterozygous likely pathogenic variant in PIK3CD , a member of a family of lipid kinases involved in cell growth, proliferation, development, motility, survival and intracellular trafficking expressed in leukocytes [ 20 ]. Heterozygous gain-of-function variants involving PIK3CD have been previously associated with immunodeficiency-14 (OMIM # 615513) [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Rapid exome sequencing in PICU patients with new-onset metabolic or neurological disorders

et al. 2020

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Background: Genomic assessment previously took months to result and was unable to impact clinical care in the pediatric intensive care unit (PICU). The advent of rapid exome sequencing potentially changes this. We investigated the impact of rapid exome sequencing in a pilot study on pediatric patients admitted to a single PICU with new onset metabolic/neurologic disease. Methods: Rapid exome sequencing (7 days to verbal result) was performed on (n=10) PICU patients age <6 years admitted with new onset metabolic/neurologic disease. The primary outcome of interest was inpatient LOS, which served as a proxy for inpatient cost. Results: A significant reduction in median LOS was identified when comparing PICU patients who underwent rapid exome sequencing to historical controls. From those patients who underwent rapid sequencing, 5 had likely pathogenic variants. In 3 cases with diagnostic genetic results, there was a modification to clinical care attributable to information provided by exome sequencing. Conclusions: This pilot study demonstrates that rapid exome sequencing is feasible to do in the PICU, that genetic results can be returned quickly enough to impact critical care decision-making and management. In a select population of PICU patients, this technology may contribute to a decrease in hospital length of stay.

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Section: Resultsmentioning

confidence: 99%

Rapid exome sequencing in PICU patients with new-onset metabolic or neurological disorders

et al. 2020

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“…A characteristic feature of APDS-1 patients is T cell immunosenescence with raised CD8 + CD57 + cells and CD8 + T-cells skewed towards effector memory [ 16 ]. Genetic analysis of APDS-1 patients revealed in the vast majority of cases the recurrent E1021K monoallelic mutation, with a limited number of novel variants reported since the identification of the disorder [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients

Tessarin

Rossi

Baronio

et al. 2020

JCM

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Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients’ clinical management and their quality of life.

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“…Herein, we describe a child of non-consanguineous parents who presented with digital vasculitis from early on in life, C1q deficiency, immunodeficiency, recurrent infections, short stature, and facial dysmorphia. Whole genome sequencing revealed a previously reported (8–10) de novo heterozygous pathogenic splice mutation in a mutation hotspot of PIK3R1 (c.1425 + 1G > A), resulting in the skipping of exon 11 of the p85α subunit of phosphatidylinositol 3-kinase and confirming the diagnosis of activated PI3Kδ syndrome type II (APDS2). This fully explained the phenotype, though with the exception of C1q deficiency, which has never been described in association with APDS2.…”

Section: Introductionmentioning

confidence: 71%

“…Whole genome sequencing revealed a de novo class five mutation in PIK3R1 in the proband: (c.1425 + 1G > A), resulting in the skipping of exon 11 of the p85α subunit of phosphatidylinositol 3-kinase and confirming the diagnosis of activated PI3Kδ syndrome type II (APDS2) (13, 14). This explained the phenotype of absent IgA, elevated IgM, recurrent infections, lymphoproliferation, and dysmorphic features reminiscent of SHORT syndrome ( s hort stature, h yperextensibility of joints and/or inguinal herniae, o cular depression, r ieger anomaly of the eye, and t eething problems), which can also be associated with diabetes and insulin resistance in APDS2 (8, 15). This mutation was also confirmed as the only pathogenic mutation found in the proband using our targeted gene panel (for a full list of genes included, see Supplemental Table 5), which also confirmed that neither parent had the mutation.…”

Section: Whole Genome Sequencing Identification Of De Novo Pik3r1 Mutmentioning

confidence: 98%

“…Consequently, we did not have the opportunity to measure C1q levels in response to sirolimus. At the time of writing, she is being worked up for allogeneic hematopoietic stem cell transplantation (allo-HSCT) (8) since the patient has declined further experimental targeted treatment with the PI3Kδ inhibitor, leniolisib (8, 16).…”

Section: Whole Genome Sequencing Identification Of De Novo Pik3r1 Mutmentioning

confidence: 99%

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Secondary C1q Deficiency in Activated PI3Kδ Syndrome Type 2

et al. 2019

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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.

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Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review

Cited by 101 publications

References 69 publications

Rapid exome sequencing in PICU patients with new-onset metabolic or neurological disorders

Rapid exome sequencing in PICU patients with new-onset metabolic or neurological disorders

Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients

Secondary C1q Deficiency in Activated PI3Kδ Syndrome Type 2

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