Paediatric MAS/HLH caused by a novel monoallelic activating mutation in p110δ

Lougaris, Vassilios; Baronio, Manuela; Castagna, Andrea; Tessarin, Giulio; Rossi, Stefano; Gazzurelli, Luisa; Benvenuto, Alessio; Moratto, Daniele; Chiarini, Marcho; Cattalini, Marco; Facchetti, Mattia; Palumbo, Laura; Giliani, Silvia; Girelli, Maria Federica; Badolato, Raffaele; Bondioni, Maria Pia; Facchetti, Fabio; Meini, Antonella; Plebani, Alessandro

doi:10.1016/j.clim.2020.108543

Cited by 9 publications

(9 citation statements)

References 9 publications

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“… Abbreviations: APDS-1: Activated Phosphoinositide 3-Kinase Delta Syndrome-1, PIK3CD_EFF: PIK3CD effect, PIK3CD_MUT: PIK3CD mutation, pS6K: phospo-S6 Kinase. Note: * As previously reported [ 1 , 2 , 24 , 25 , 27 ]. …”

Section: Figurementioning

confidence: 74%

“…In one case (P5), lymphoproliferation was complicated by hemophagocytic lymphohistiocytosis (HLH). Functional and genetic analysis ruled out familiar HLH and other possible triggers were excluded (i.e., malignancy, infections) [ 25 ]. All our patients underwent an extended diagnostic work-up in order to exclude malignancy.…”

Section: Resultsmentioning

confidence: 99%

“…In P4, we identified and already described a missense mutation (c.1973C > T) in the highly conserved P658 region resulting in a Proline to Leucine variation ( p .P658L) [ 24 ]. In P5, a novel missense mutation in c.323C > G ( p .R108L) was found, involving the linker region of the adaptor binding domain [ 25 ]. We confirmed the activating nature of the three variants detected in P1, P4 and P5 comparing the phosphorylation pattern of S6K of the patients with healthy controls and patients harboring the classical E1021K mutation: patients’ T-cells showed a significantly increased phosphorylation of S6K when stimulated with a-CD3, which could be downregulated by treating T-cells with CAL-101 (Idelalisib, GS-1101), a selective p110δ in vitro inhibitor Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Oral steroid cycles were often used in four patients (P1, P2, P5, P6) in order to control lymphoproliferative symptoms. Secondary HLH was treated with high dose intravenous steroid therapy [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

“…Retrospective data regarding medical history, clinical and laboratory data were obtained from analysis of medical notes. P2, P4, P5, P8 have already been described as single case reports [ 23 , 24 , 25 , 26 ], follow-up was therefore extended up to the last clinical visit. All patients (or their caregivers in case of pediatric patients) signed an informed consent form for this study according to the Hospital local ethical committee recommendations.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Figurementioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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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Tofacitinib for elderly onset hemophagocytic lymphohistiocytosis with gene mutations: a case report

Liu,

Cheng,

et al. 2024

MedComm

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Systematic review of mortality and survival rates for APDS

Hanson,

Bonnen

2024

Clin Exp Med

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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 variants in the PIK3CD gene, while loss of function 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. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan–Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.

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Paediatric MAS/HLH caused by a novel monoallelic activating mutation in p110δ

Cited by 9 publications

References 9 publications

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

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

Tofacitinib for elderly onset hemophagocytic lymphohistiocytosis with gene mutations: a case report

Systematic review of mortality and survival rates for APDS

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