Kosar Asna Ashari, Rebecca MacRae, David P. Hoytema van Konijnenburg, Craig D. Platt, Maryam Ashoor, Alfred P. See, Agnieszka Kielian, Amy Danehy, Riten Kumar, Elliot James, Kristin Houghton, Sheri Harder, Mark P. Gorman, Stacy A. Kahn, Ankana Daga, Sadaf H. Hussain, Alicia M. Johnston, Alicia Casey, Jodie D. Ouahed, Wai Wong, Kathy Jenkins, Susan Prockop, Esraa Eloseily, Kimberly Risma, Michael J. Ombrello, Fatma Dedeoglu, Milena M. Andzelm
Boston Children’s Hospital and Harvard Medical School. Arabian Gulf University. British Columbia Children’s Hospital, University of British Columbia. University of Texas Southwestern Medical Center. Scottish Rite for Children. Assiut University. Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine. National Institutes of Health.
United States, Bahrain, Canada and Egypt
Pediatric Rheumatology
Pediatr Rheumatol 2026; 24:
DOI: 10.1186/s12969-026-01227-2
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.
Category
Stenosis or Obstruction of Normal Pulmonary Venous Connections
Absence or Atresia of Normal Pulmonary Venous Connections
Pulmonary Hypertension Associated with Stenosis or Atresia of Pulmonary Veins
Genetic Factors Influencing the Onset, Severity or Outcome of Disease
Year of Publication: 2026
Age Focus: Pediatric
Article Type: Case Reports or Retrospective Observations in Small Groups of Patients (≤10 patients)
Article Access: Free PDF File or Full Text Article Available Through PubMed or DOI: Yes