Neurological manifestations and vasculopathy in PLCG2-associated antibody deficiency and immune dysregulation (APLAID): a case series.
22 affiliations
- 1Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 2Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 3Pediatrics Department, Arabian Gulf University, Manama, Bahrain.
- 4Department of Neurosurgery, Cerebrovascular Surgery and Interventions Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 5Division of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 6Dana Farber/Boston Children's Hospital Cancer and Blood Disorders Center, Boston, MA, USA.
- 7Division of Immunology, British Columbia Children's Hospital, University of British Columbia, Vancouver, Canada.
- 8Division of Rheumatology, British Columbia Children's Hospital, University of British Columbia, Vancouver, Canada.
- 9Division of Neuroradiology, Department of Radiology, British Columbia Children's Hospital, University of British Columbia, Vancouver, Canada.
- 10Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 11Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 12Harvard Medical School, Boston, MA, USA.
- 13Department of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 14Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 15Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 16The University of Texas Southwestern Medical Center, Dallas, TX, USA.
- 17Scottish Rite for Children, Dallas, TX, USA.
- 18Assiut University Faculty of Medicine, Assiut, Egypt.
- 19Division of Allergy/Immunology at Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- 20Translational Genetics and Genomics Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
- 21Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
- 22Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
Abstract
Background
Autosomal dominant pathogenic variants in PLCG2 are associated with autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID), characterized by immunological abnormalities and multi-system inflammation. Descriptions of associated neurological manifestations and vascular anomalies are limited. We describe three patients with APLAID, vasculopathies, neuroinflammation, and cerebral vascular tortuosity. These cases highlight underrecognized and clinically important manifestations of APLAID.Case presentations
All three patients had de novo variants in PLCG2 and early systemic inflammatory and immunodeficiency findings within the spectrum of APLAID (e.g. immune laboratory abnormalities, skin and gastrointestinal inflammation, and frequent infections). Additionally, they had notable neurological and vascular findings. Patient #1 (PLCG2 c.3420T > A; p.Asp1140Glu) is a female who had focal seizures at 16 months old. Magnetic resonance imaging (MRI) revealed right parietal leptomeningeal enhancement with white matter changes. MR angiography (MRA) showed cerebrovascular tortuosity and stenoses without evidence of vasculitis. She had extensive veno-lymphatic malformation in the thorax, abnormal renal vasculature, inferior vena cava (IVC) atresia, and bilateral pulmonary vein stenosis (PVS). Patient #2 (PLCG2 c.2122G > C; p.Ala708Pro) is a male who at four years old had an episode of status epilepticus. MRI revealed a right parietal infarct with surrounding leptomeningeal enhancement and MRA demonstrated abnormal caliber of the right middle cerebral artery (MCA), arterial tortuosity, and carotid aneurysms. His course was complicated by aortic root dilation and bilateral PVS. Patient #3 (PLCG2 c.2122G > C; p.Ala708Pro) is a male who at 16 months had a right sided focal motor seizure. MRI demonstrated infarct with associated sulcal enhancement predominantly in the left cerebral hemisphere. MRA found excessive vascular tortuosity and fenestrations. He has a dilated aortic root and ventricular septal defect (VSD).Conclusion
We present three cases of APLAID complicated by significant cerebrovascular tortuosity and seizure and two with cerebral ischemia. The etiology of stroke and/or seizures in these patients is unclear, but vasculopathy leading to perfusion deficits, neuroinflammation, or thrombosis due to underlying thrombotic diathesis or abnormal vascular anatomy may have contributed. We recommend all patients with APLAID undergo monitoring for neurologic manifestations. Additionally, we highlight important vasculopathic findings such as PVS, where early recognition for directed treatment is critical.
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BibTeX
@article{ashari2026neurological,
title = {{Neurological manifestations and vasculopathy in PLCG2-associated antibody deficiency and immune dysregulation (APLAID): a case series.}},
author = {Kosar Asna Ashari and Rebecca MacRae and David P Hoytema van Konijnenburg and Craig D Platt and Maryam Ashoor and Alfred P See and Agnieszka Kielian and Amy Danehy and Riten Kumar and Elliot James and Kristin Houghton and Sheri Harder and Mark P Gorman and Stacy A Kahn and Ankana Daga and Sadaf H Hussain and Alicia M Johnston and Alicia Casey and Jodie D Ouahed and Wai Wong and Kathy Jenkins and Susan Prockop and Esraa Eloseily and Kimberly Risma and Michael J Ombrello and Fatma Dedeoglu and Milena M Andzelm},
journal = {Pediatric rheumatology online journal},
year = {2026},
month = aug,
doi = {10.1186/s12969-026-01227-2},
url = {https://europepmc.org/article/MED/42902271},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Neurological manifestations and vasculopathy in PLCG2-associated antibody deficiency and immune dysregulation (APLAID): a case series.
AU - Kosar Asna Ashari
AU - Rebecca MacRae
AU - David P Hoytema van Konijnenburg
AU - Craig D Platt
AU - Maryam Ashoor
AU - Alfred P See
AU - Agnieszka Kielian
AU - Amy Danehy
AU - Riten Kumar
AU - Elliot James
AU - Kristin Houghton
AU - Sheri Harder
AU - Mark P Gorman
AU - Stacy A Kahn
AU - Ankana Daga
AU - Sadaf H Hussain
AU - Alicia M Johnston
AU - Alicia Casey
AU - Jodie D Ouahed
AU - Wai Wong
AU - Kathy Jenkins
AU - Susan Prockop
AU - Esraa Eloseily
AU - Kimberly Risma
AU - Michael J Ombrello
AU - Fatma Dedeoglu
AU - Milena M Andzelm
PY - 2026
DA - 2026/08/01
JO - Pediatric rheumatology online journal
DO - 10.1186/s12969-026-01227-2
UR - https://europepmc.org/article/MED/42902271
AB - Background Autosomal dominant pathogenic variants in PLCG2 are associated with autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID), characterized by immunological abnormalities and multi-system inflammation. Descriptions of associated neurological manifestations and vascular anomalies are limited. We describe three patients with APLAID, vasculopathies, neuroinflammation, and cerebral vascular tortuosity. These cases highlight underrecognized and clinically important manifestations of APLAID.Case presentations All three patients had de novo variants in PLCG2 and early systemic inflammatory and immunodeficiency findings within the spectrum of APLAID (e.g. immune laboratory abnormalities, skin and gastrointestinal inflammation, and frequent infections). Additionally, they had notable neurological and vascular findings. Patient #1 (PLCG2 c.3420T > A; p.Asp1140Glu) is a female who had focal seizures at 16 months old. Magnetic resonance imaging (MRI) revealed right parietal leptomeningeal enhancement with white matter changes. MR angiography (MRA) showed cerebrovascular tortuosity and stenoses without evidence of vasculitis. She had extensive veno-lymphatic malformation in the thorax, abnormal renal vasculature, inferior vena cava (IVC) atresia, and bilateral pulmonary vein stenosis (PVS). Patient #2 (PLCG2 c.2122G > C; p.Ala708Pro) is a male who at four years old had an episode of status epilepticus. MRI revealed a right parietal infarct with surrounding leptomeningeal enhancement and MRA demonstrated abnormal caliber of the right middle cerebral artery (MCA), arterial tortuosity, and carotid aneurysms. His course was complicated by aortic root dilation and bilateral PVS. Patient #3 (PLCG2 c.2122G > C; p.Ala708Pro) is a male who at 16 months had a right sided focal motor seizure. MRI demonstrated infarct with associated sulcal enhancement predominantly in the left cerebral hemisphere. MRA found excessive vascular tortuosity and fenestrations. He has a dilated aortic root and ventricular septal defect (VSD).Conclusion We present three cases of APLAID complicated by significant cerebrovascular tortuosity and seizure and two with cerebral ischemia. The etiology of stroke and/or seizures in these patients is unclear, but vasculopathy leading to perfusion deficits, neuroinflammation, or thrombosis due to underlying thrombotic diathesis or abnormal vascular anatomy may have contributed. We recommend all patients with APLAID undergo monitoring for neurologic manifestations. Additionally, we highlight important vasculopathic findings such as PVS, where early recognition for directed treatment is critical.
SN - 1546-0096
ER -