Large vessel vasculopathy: An underrecognized complication in Wiskott–Aldrich syndrome

Patients with Wiskott–Aldrich syndrome (WAS) are at an increased risk for developing autoimmunity and malignancy. Although the exact mechanism for this increased susceptibility remains incompletely understood, around 30–70% of patients develop some form of autoimmune disease, especially if they do not undergo hematopoietic stem cell transplantation (HSCT) (1). Reported autoimmune complications include autoimmune cytopenia, vasculitis, arthritis, inflammatory bowel disease, and IgA nephropathy. Among these, vasculitis is the second most common manifestation. While small vessel vasculitides such as Henoch–Schoenlein purpura and IgA nephropathy are more frequently reported (2, 3), large vessel vasculitis remains an extremely rare, but life-threatening, complication.

This case series aims to describe the clinical, radiological, and genetic features of four pediatric patients diagnosed with WAS who developed large vessel vasculopathy. It is highlighted that in two of these four patients, initial diagnosis of Takayasu arteritis was established; however, persistent thrombocytopenia prompted screening for WAS.

Of the 80 patients with WAS registered at our center, in our follow-up clinic, four patients were identified to have large vessel vasculopathy resembling Takayasu arteritis. Details of these patients are as follows.

A 5-year-old boy presented with complaints of acute febrile encephalopathy, seizures, and acute-onset deviation of angle of the mouth to the left. He had a history of recurrent sinopulmonary infections, generalized eczematous rash, recurrent epistaxis, and skin bleeds since infancy. Examination revealed petechiae, eczema, generalized lymphadenopathy, hepatosplenomegaly, and signs of meningeal irritation with bilateral lateral rectus palsy and right-sided lower motor neuron facial nerve palsy. Cerebrospinal fluid analysis was cellular with hypoglycorrhachia, but culture was sterile (Table 1). Magnetic resonance imaging (MRI) brain did not reveal any intracranial bleed. In view of history of recurrent infections with persistent thrombocytopenia, the possibility of WAS was considered. The WAS protein (WASP) expression was reduced, and genetic testing revealed a pathogenic variant in the WAS gene (c.1021+2T>G [intron 10, IVS10+2]). He improved following treatment with intravenous ceftriaxone. Replacement intravenous immunoglobulin (IVIg) therapy and evaluation for hematopoietic stem cell transplantation (HSCT) were advised. However, the child was lost to follow-up. He continued to have intermittent bleeding episodes, recurrent otitis media, and pulmonary infections, which were managed at a local health care facility with antimicrobials. He was readmitted to our institute at 16 years of age with complaints of intermittent, severe left chest pain and congestive heart failure. Examination revealed absent pulsations in the left upper limb arteries with differential blood pressures (left upper arm supine: not recordable due to lower limb hypertension), peripheral signs of aortic regurgitation, and hepatosplenomegaly. Investigations are summarized in Table 1. Computed tomography (CT) angiogram showed complete occlusion of left subclavian artery and left common carotid (with collaterals), aneurysmal dilatation of aorta extending from the aortic root up to suprarenal part of the abdominal aorta, and right main renal artery narrowing at the ostium (Fig. 1). He was also noted to have left lower lobe consolidation, right-sided pleural effusion, and necrotic mediastinal lymphadenopathy. Positron emission tomography was suggestive of increased uptake in the cervical, supraclavicular, mediastinal, axillary, and abdominopelvic lymph nodes, omental–serosal deposits, and pleural effusion. Epstein-Barr virus (EBV) viral load was high in the blood; a possibility of EBV-associated lymphoproliferation or lymphoma or disseminated tuberculosis was kept. The clinical condition rapidly deteriorated and developed altered sensorium and acute right hemiparesis within a week of admission. MRI brain showed evidence of multiple microhemorrhages suggesting vasculitic infarcts. He was initiated on corticosteroids with rituximab (375 mg/m²) as rescue therapy but had progressive neurological deterioration and eventually succumbed to the illness.

A 3.5-year-old boy was diagnosed to have WAS when he presented with blood-stained diarrhea since the neonatal period. There was family history of multiple male infant deaths. He was negotiated for HSCT; however, it could not be proceeded further due to the nonavailability of a matched donor and financial constraints. He continued to have intermittent bleeding episodes and infections despite replacement IVIg and cotrimoxazole prophylaxis. At the age of 10 years, he presented with complaints of abdominal pain for 7 days and vomiting. Examination revealed cervical lymphadenopathy, ear discharge with perforation of the tympanic membrane, eczematous lesion over the body with extensive molluscum contagiosum, differential pulses and differential blood pressures between upper limbs and lower limbs, and pulsatile mass in the epigastric region. Laboratory investigations (summarized in Table 2) revealed elevated inflammatory markers. Ultrasonographic assessment of the abdomen revealed a fusiform dilatation in the abdominal aorta, which was later confirmed by CT angiography with a maximum transverse caliber of 27 mm, extending from the diaphragmatic hiatus to its bifurcation. Variable lengths of proximal parts of the coeliac trunk, smooth muscle actin (SMA), and left renal artery show fusiform dilatation (Fig. 2). Pus from the ear showed growth of Pseudomonas aeruginosa, which was treated with sensitive antibiotics for 2 wk. Viral serologies (herpes simplex virus [HSV], hepatitis B virus [HBV], hepatitis C virus [HCV] IgM) and workup for tuberculosis were negative. EBV viral load was found to be elevated (38,880 copies/ml). He received pulse methylprednisolone and IVIg and was initiated on oral methotrexate, warfarin for large vessel vasculopathy, and was reinitiated on prophylactic IVIg and cotrimoxazole. On follow-up at 4 mo, he developed acute abdominal pain with diarrhea and was detected to have a thrombus in the aneurysmal segment of the abdominal aorta. Methylprednisolone pulses reinitiated along with anticoagulation with low molecular weight heparin, however, succumbed to illness.

An 11-year-old boy was referred to our Paediatric Rheumatology Clinic for evaluation of progressive refractory vasculitis with renal disease. The child had been symptomatic for past 3 years, and evaluation performed at the referring center showed severe anemia, neutrophilic leukocytosis, elevated inflammatory markers, and hypertension with nephrotic range proteinuria without active urinary sediments. He was also noted to have low ejection fraction (20–22%). Suspecting underlying vasculitis, a CT angiogram was done, which showed concentric wall thickening of the abdominal aorta, celiac artery, right renal artery stenosis with compensatory hypertrophy of the left kidney, and severe stenosis of the right pulmonary artery. Considering a diagnosis of Takayasu arteritis, he was commenced on pulsed methylprednisolone followed by cyclophosphamide pulses with antihypertensive medications. As intermittent fever persisted with proteinuria, he was referred to our institute. CT angiography and positron emission tomography study are described in Fig. 3. He was worked up for viral etiologies such as CMV, EBV, HSV, which were negative. The screen of all his blood records revealed persistent thrombocytopenia. On detailed history, he had two episodes of acute febrile illness, which were treated as dengue fever due to thrombocytopenia in past. However, he never had major clinical bleeds or serious infections. Whole-exome sequencing revealed hemizygous pathogenic mutation in exon 2 of the WAS gene, c.256C>T, p. Arg86Cys. WASP expression was also reduced. He was started on mycophenolate mofetil and maintenance IVIg, and cotrimoxazole prophylaxis and was being planned for HSCT, however succumbed to his illness at home following sudden-onset respiratory distress.

Another 11-year-old boy was referred to our center with diagnosis of Takayasu arteritis when he presented with complaints of recurrent abdominal pain, and neck and left upper limb pain with features of claudication. CT angiography had shown thickening of bilateral common carotid artery, complete opacification of left subclavian, origin at narrowing of the celiac trunk, and complete opacification of superior mesenteric artery with collaterals from inferior mesenteric artery. Methotrexate and oral corticosteroids were initiated. He had been previously well, and did not have bleeding manifestations, infections, or eczema in past. On evaluation at our institute, thrombocytopenia and leukopenia were noted, and attribute to methotrexate toxicity. Withdrawal of methotrexate and folinic acid supplementation resulted in recovery of leukopenia; however, thrombocytopenia persisted raising the suspicion of WAS. Moreover, mean platelet volume (MPV) was low, and serum immunoglobulins showed elevated IgA and IgE with low IgM levels. Estimation of WASP showed normal expression of protein but genetic sequencing revealed variant in exon 1 c.103C>T p. Leu35Phe. Urgent HSCT was advised, but on screening of the family, both brothers were also found to be affected. He was initiated oral steroids and mycophenolate and is awaiting a haploidentical HSCT.

Besides the classical triad of eczema, immunodeficiency, and microthrombocytopenia, patients with WAS are known to exhibit a spectrum of immunological abnormalities. Our case series adds to the limited literature by presenting four pediatric patients with WAS who developed large vessel vasculopathy, involving the aorta and its major branches. Vasculopathies in WAS can manifest as thoracic aortic aneurysms and dissections (TAADs), coronary artery disease, ischemic strokes, and even death, as seen in our patients.

Sullivan et al. reported vasculitis in 13% of patients in their multi-institutional study on WAS (5). However, multicenter cohort study from India reported vasculitis in a smaller subset (9.5%), predominantly affecting small vessels although autoimmune manifestations were observed in 40% of the cohort (13). The earliest description of large vessel vasculopathy in WAS was given by Lau et al. who reported a 5-year-old boy with Takayasu arteritis affecting the abdominal and renal arteries (16). Later Pellier et al. described five children with WAS who developed aortic aneurysms, predominantly involving the thoracic aorta and abdominal aorta (17). Four of these cases were asymptomatic, with aneurysms detected incidentally following radiological imaging; only one presented with acute chest pain. A summary of previously published cases of large vessel vasculopathy in WAS is provided in Table 2. The low number of reported cases may reflect the impact of early diagnosis and timely HSCT. All four patients in our series were older than 10 years and had not undergone HSCT until then. Patients 1 and 2 were symptomatic; their diagnoses had been established earlier, but HSCT was not performed due to financial constraints. Patients 3 and 4 exhibited vascular symptoms without significant infection or bleeding tendencies and likely represent an milder phenotype. This is further supported by the presence of missense mutations in exons 1 and 2, which are categorized as class 1 variants.

Immune dysregulation is thought to underlie the predisposition to vasculitis in WAS. Immune complex deposition within vessel walls may lead to necrotizing vasculitis. Alternatively, infectious triggers are well documented in vasculitis, and WAS patients are vulnerable to a broad range of pathogens. Pellier et al. found varicella-zoster virus, EBV, and human herpesvirus 6 in aortic tissue from a patient with aortic aneurysm (17). Patients 1, 2, and 4 in our series had significant EBV viremia. Patients 1 and 3 also had a pulmonary infection, and considering India’s high tuberculosis prevalence, an extensive workup was done. Although Mycobacterium tuberculosis could not be isolated, empirical antitubercular therapy was initiated. Patient 1 also had generalized lymphadenopathy raising the suspicion of lymphoma, though biopsy could not be obtained. Vasculitis secondary to lymphoma was considered, and he was treated with high-dose IVIg and rituximab for EBV.

Vasculopathies have also been reported in other actinopathies. Mutations in the ACTA2 gene, encoding alpha-smooth muscle actin (α-SMA), are associated with TAADs and other vascular disorders (18, 19). The Arp2/3 complex, which is also implicated in actin regulation, when disrupted, can cause vasculitis and inflammatory complications. α-SMA is essential for vascular smooth muscle cell (SMC) contraction and vessel wall integrity. ACTA2 mutations lead to SMC dysfunction, resulting in vessel wall remodeling, oxidative stress, hyperplasia, and fibrosis (18, 19, 20). Likewise, members of the DOCK family have been known to modulate downstream effectors involved in rearrangements of the actin cytoskeleton (21). Vascular abnormalities involving great vessels have been reported in Hyper IgE syndromes secondary to DOCK8 deficiency (22, 23, 24, 25). Additionally, actinopathies can impair immune cell function contributing to immune dysregulation and thus inflammation seen in vasculitis.

Evidence guiding the management of aortic aneurysms in WAS is limited to case reports (Table 2). Ilowite et al. reported resolution of vascular involvement with methylprednisolone and cyclophosphamide in a patient with aortic aneurysm and valvular regurgitation (4). Johnston et al. used azathioprine and surgical aortic root replacement in a 17-year-old WAS patient, achieving favorable outcomes (8). Surgical repair has been successful in several cases (6, 9, 10, 11, 12, 13, 14, 15), but is associated with heightened bleeding and infection risk due to underlying thrombocytopenia and immunodeficiency. All four of our patients received immunosuppression in the form of pulse methylprednisolone, methotrexate (patient 2), cyclophosphamide (patient 3), mycophenolate (patient 4), and rituximab (patient 1) but was ineffective. Endovascular intervention/surgical repair was contemplated in patients 1 and 2; however, it could not be done due to severe thrombocytopenia and extensive disease. HSCT could not be pursued because of financial constraints and lack of matched donors.

This study was conducted in the Allergy Immunology Unit of the Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, a tertiary care center in Northern India. We retrospectively reviewed the records of children diagnosed with WAS from January 2005 to June 2025 who presented with features of large vessel vasculopathy at the Pediatric Immunology clinic. Data on demographic details, clinical presentation, detailed family history, laboratory investigations, immunological profile, radiological findings, genetic results, and outcomes were collected and tabulated in an Excel sheet.

All patients underwent assessment of complete blood counts including estimation of MPV by automated analyzers (COULTER HmX AL Analyzer, Beckman Coulter; or COULTER LH780 Hematology Analyzer, Beckham Coulter) standardized for MPV estimation. The MPV value between 7.5 and 11 fl was considered normal, and microplatelets were defined if MPV was <7.5 fl.

Serum IgG, IgM, and IgA were estimated by nephelometer (MININeph, semiautomated nephelometer, The Binding Site), while serum IgE was estimated by enzyme immunoassay. Surface immunophenotyping of lymphocyte subsets was performed on peripheral blood using fluorochrome-conjugated monoclonal antibodies. T cells were identified using anti-CD3-phycoerythrin (PE)-Cy7 (Becton Dickinson, BD), B cells with anti-CD19-fluorescein isothiocyanate (FITC) (BD), and natural killer (NK) cells with anti-CD56-APC/CD16-APC (BD). Within the CD3⁺ T cell population, helper (CD4-FITC) and cytotoxic (CD8-APC) subsets were delineated. Regulatory T cells were defined phenotypically as CD4⁺CD25⁺CD127⁻ cells. Data acquisition was performed on a BD LSRFortessa flow cytometer (BD Biosciences), and analysis was conducted using FlowJo software (Tree Star Inc.).

Intracellular staining of WASP using PE-labeled anti-human WASP antibody (sc-13139, PE [clone: B-9], Santa Cruz Biotechnology) was carried out on nonerythroid blood cells derived from the peripheral blood. Cells were gated using side scatter vs. CD45 labeled with FITC (555482; BD, A07782; Beckman Coulter Life Sciences). Lymphocytes were acquired on a flow cytometer (BD LSRFortessa). Median fluorescence intensity and stain index in stimulated and unstimulated samples were calculated.

Genetic tests were carried out to confirm the diagnosis after obtaining informed consent from parents or caregivers. Genomic DNA was isolated from peripheral blood samples using Qiagen kits (QIAamp DNA Blood Mini Kit, 51106; Qiagen Ltd.). A targeted next-generation sequencing was performed for primary immnue deficincy disease (PID) patients using a gene panel comprising 44 genes including the WAS gene on the Ion S5 platform (Ion Torrent S5, Thermo Fisher Scientific). One patient (patient 4) underwent whole-exome sequencing through a commercial laboratory.

Computed tomography angiography was performed in-house using a 192-detector dual-source CT scanner (Siemens SOMATOM Force), except for patient 1, whose scan was performed externally. Scans were acquired in the systemic arterial phase following intravenous administration of nonionic iodinated contrast. Image acquisition parameters were optimized for pediatric patients to minimize radiation exposure while maintaining diagnostic quality. Multiplanar and three-dimensional reconstructions were generated for detailed assessment of the aorta and its major branches. Figs. 1, 2, 3, and 4 are composite images illustrating features of vascular involvement. In some panels, scale bars could not be provided due to the process of creating composite figures.

To conclude, vasculitis in WAS tends to be progressive and destructive, and relapses have been noted. As many patients may remain asymptomatic, vasculitis may be underdiagnosed. Although most reported cases are in older patients, there are also reports of early-onset disease during infancy. Incidental discovery of WAS gene mutation in two of our patients with Takayasu arteritis with milder phenotype adds up to the spectrum of manifestations. This article highlights the importance of early screening and timely HSCT in all WAS patients, including those with mild or atypical features, to reduce the risk of vasculopathy.

This study was performed in line with the principles of the Declaration of Helsinki. The Departmental Review Board of the Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, approved the manuscript (DRB87/25 dated 05/09/25), and informed consent was obtained from the parents of the children included in this study.

Data are available on request to the corresponding author.

The authors gratefully acknowledge the role of all faculty members, clinical fellows, nursing officers, and research and technical staff who have been involved in the care of these patients.

Author contributions: Deepti Suri: conceptualization, investigation, methodology, supervision, and writing—original draft, review, and editing. Pallavi L. Nadig: data curation, investigation, methodology, project administration, visualization, and writing—original draft, review, and editing. Dev Desai: data curation and writing—original draft. Yamini Sharma: conceptualization, data curation, formal analysis, and methodology. Ahmed Jamal: data curation, investigation, resources, and writing—review and editing. Gayathri C. Vaitheeswaran: resources. Himanshi Chaudhary: writing—original draft, review, and editing. Murugan Sudhakar: conceptualization, investigation, methodology, resources, and writing—original draft, review, and editing. Ridhima Aggarwal: writing—original draft. Suprit Basu: data curation, investigation, methodology, resources, and writing—original draft. Pratibha Suku: investigation. Vibhu Joshi: methodology. Rashmi Rikhi: investigation. Anmol Bhatia: investigation, methodology, resources, validation, and writing—review and editing. Akshay Saxena: investigation, methodology, supervision, and writing—review and editing. Manphool Singhal: investigation, resources, visualization, and writing—review and editing. Manpreet Dhaliwal: investigation, methodology, and resources. Saniya Sharma: investigation, methodology, and resources. Rakesh Kumar Pilania: data curation, formal analysis, investigation, methodology, resources, and supervision. Ankur Kumar Jindal: conceptualization, data curation, formal analysis, and writing—review and editing. Vignesh Pandiarajan: data curation and supervision. Amit Rawat: investigation and resources. Anju Gupta: project administration, resources, and supervision. Surjit Singh: conceptualization, project administration, supervision, and writing—review and editing.