Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Genetic and Flow Cytometry Analysis
3. Results
3.1. Patients
3.2. Infections in APDS-1 Patients
3.3. Lymphoproliferation in APDS-1 Patients
3.4. Other Clinical Features
3.5. Immunological Features at Onset
3.6. PIK3CD Genetic Analysis and Phospo-S6 Kinase Assays
3.7. Therapeutic Strategies
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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P1 | P2 | P3 | P4 | P5 | P6 | P7 | P8 | |
---|---|---|---|---|---|---|---|---|
Gender | Male | Male | Male | Female | Male | Male | Female | Female |
Status at last clinical visit | Alive | Alive | Alive | Alive | Alive | Alive | Alive | Alive |
Current age * | 20.7 | 29.7 | 14.0 | 48.8 | 12.8 | 9.3 | 15.8 | 6.5 |
Follow-up time † | 1.0 | 16.7 | 7.0 | 21.7 | 1.0 | 4.0 | 3.0 | 2.5 |
Onset of infection * | 4.5 | 0.5 | 0.7 | 20.5 | – | 3.4 | 8.0 | 1.0 |
Onset of lymphoproliferation * | 19.0 | 27.7 | 11.0 | – | 12.0 | 5.2 | 8.0 | 1.5 |
Onset of autoimmunity * | – | 12.0 | 4.7 | – | 11.2 | – | 13.0 | – |
First immunological evaluation § | 2019 | 2002 | 2011 | 1998 | 2019 | 2016 | 2017 | 2016 |
First immunological evaluation * | 19.7 | 12.0 | 4.7 | 27.0 | 12.0 | 5.3 | 13.2 | 1.7 |
APDS-1 diagnosis * | 19.7 | 29.0 | 7.6 | 43.2 | 12.0 | 5.3 | 13.8 | 2.2 |
Diagnostic delay † | 0.7 | 15.0 | 2.9 | 16.2 | 0.8 | 0.1 | 0.8 | 0.7 |
P1 | P2 | P3 | P4 | P5 | P6 | P7 | P8 | |
---|---|---|---|---|---|---|---|---|
Symptom leading to immunological evaluation | Lymphoproliferation | RRTI | EN, Pneumonia | RRTI | HLH | Lymphoproliferation | Lymphoproliferation | RRTI |
Initial diagnostic hypothesis | Lymphoma | CVID-like | CVID | CVID | HLH | Lymphoma | Lymphoma | CID |
Sinopulmonary infections | Otitis, Pneumonia, | Pneumonia | Pneumonia | Otitis, Pneumonia | – | Otitis, Pneumonia | Pneumonia | Otitis, Pneumonia |
Infections other than URTI | Sepsis, episodic Candidiasis, recurrent | Dental abscess Gastroenteritis | – | – | – | – | Otomastoiditis | – |
Viral infection | VZV, episodic | EBV, episodic | HSV-1, episodic | – | – | CMV, episodic | – | EBV, persistent |
Lymphadenopathies | Diffuse | Diffuse | Diffuse | – | Diffuse | Diffuse | Diffuse | Cervical |
Hepato/splenomegaly | Hepatosplenomegaly | Hepatosplenomegaly | Hepatosplenomegaly | – | Hepatosplenomegaly | Hepatosplenomegaly | Hepatosplenomegaly | Splenomegaly |
Autoimmunity | – | Psoriatic dermatitis | EN, Leucopenia, Thrombocytopenia, Thyroiditis | – | Arthritis, Rash | – | Hemolytic anemia Recurrent parotiditis | – |
Allergy and asthma | Asthma | – | Asthma | – | – | Asthma | – | Wheezing |
Gastrointestinal involvement | – | – | IBD | – | – | – | – | – |
Neurodevelopmental delay | – | – | – | – | – | – | – | – |
Others | – | – | – | – | – | – | FTT, Delayed puberty | – |
Malignancy | – | – | – | – | – | – | – | – |
P1 | P2 | P3 | P4 | P5 | P6 | P7 | P8 | |
---|---|---|---|---|---|---|---|---|
Date of biopsy | 2019 | 2019 | 2017 | / | 2019 | 2016 | 2017 | / |
Lymph node region | Cervical | Cervical | Cervical | / | Inguinal | Cervical | Axillary | / |
Lymph node histology | Atypical polyclonal lymphoproliferation, EBV-negative | Polyclonal paracortical hyperplasia, EBV-negative | Reactive lymphoproliferation | / | Reactive predominantly paracortical hyperplasia, HSV-1, HSV-2, CMV, EBV negative | Atypical marginal zone hyperplasia with scattered EBV+ cells | Interfollicular hyperplasia | / |
P1 | P2 | P3 | P4 | P5 | P6 | P7 | P8 | ||
---|---|---|---|---|---|---|---|---|---|
WBC ×103/µL (4.0–10.8) | 11.25 | 6.90 | 7.18 | 4.18 | 6.14 | 8.8 | 8.51 | 8.06 | |
Neutrophils ×103/µL (1.5–8.0) | 9.40 | 3.40 | 4.93 | 2.93 | 4.58 | 5.33 | 6.43 | 4.90 | |
Lymphocytes ×103/µL (0.9–4.0) | 1.51 | 2.30 | 1.42 | 0.785 | 1.21 | 2.38 | 1.27 | 2.12 | |
IgG, mg/dL (700–1600) | 855 | 1452 | 282 † | 495 | 2119 ߇ | 362 ƒ§ | 2056 ߇ | 725 ∂# | |
IgA, mg/dL (70–400) | 227 | 80 | 55 † | 10 | 207 ߇ | 38 ƒ§ | 287 ߇ | 15 ∂# | |
IgM, mg/dL (40–230) | 2332 | 145 | 170 † | 7 | 127 ߇ | 414 ƒ§ | 155 ߇ | 228 ∂# | |
Anti-HBs IgG (>10 IU/L) | 30 IU/L | n.a. | absent | absent | 584 IU/L | absent | n.a. | n.a. | |
Anti-tetanus IgG (>0.1 IU/mL) | 0.5 IU/L | 2.5 IU/L | absent | absent | 0.6 IU/mL | absent | n.a. | 1.0 UI/L | |
CFSE-base T cells Proliferation assay | |||||||||
Anti-CD3 | normal | n.a. | normal | n.a. | n.a. | CD4+ normalCD8+ reduced | n.a. | n.a. | |
Anti-CD3 + IL-2 | normal | n.a. | normal | n.a. | n.a. | normal | n.a. | n.a. | |
PHA | reduced | n.a. | normal | n.a. | n.a. | CD4+ normalCD8+ reduced | n.a. | n.a. |
Patients No. | PIK3CD_MUT | PIK3CD_EFF | pS6K |
---|---|---|---|
1 | c.1570T > G | p.Y524D | Increased |
2 | c.3061G > A | p.E1021K | Increased * |
3 | c.3061G > A | p.E1021K | Increased * |
4 | c.1973C > T | p.P658L | Increased * |
5 | c.323C > G | p.R108L | Increased * |
6 | c.3061G > A | p.E1021K | Increased * |
7 | c.1574A > C | p.E525A | Increased * |
8 | c.3061G > A | p.E1021K | Increased * |
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Tessarin, G.; Rossi, S.; Baronio, M.; Gazzurelli, L.; Colpani, M.; Benvenuto, A.; Zunica, F.; Cardinale, F.; Martire, B.; Brescia, L.; et al. Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients. J. Clin. Med. 2020, 9, 3335. https://doi.org/10.3390/jcm9103335
Tessarin G, Rossi S, Baronio M, Gazzurelli L, Colpani M, Benvenuto A, Zunica F, Cardinale F, Martire B, Brescia L, et al. Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients. Journal of Clinical Medicine. 2020; 9(10):3335. https://doi.org/10.3390/jcm9103335
Chicago/Turabian StyleTessarin, Giulio, Stefano Rossi, Manuela Baronio, Luisa Gazzurelli, Michael Colpani, Alessio Benvenuto, Fiammetta Zunica, Fabio Cardinale, Baldassarre Martire, Letizia Brescia, and et al. 2020. "Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients" Journal of Clinical Medicine 9, no. 10: 3335. https://doi.org/10.3390/jcm9103335