Peripheral eosinophilia in primary immunodeficiencies of actin dysregulation: A case series of Wiskott-Aldrich syndrome, CARMIL2 and DOCK8 deficiency and review of the literature

Kim, David; Üner, Ayşegül; Saglam, Arzu; Chadburn, Amy; Crane, Genevieve M.

doi:10.1016/j.anndiagpath.2019.151413

Cited by 15 publications

(12 citation statements)

References 26 publications

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“…1 In 2016, certain CARMIL2 mutations were found to give rise to a novel primary immunodeficiency syndrome characterized by cytoskeletal disorganization, defective T-cell polarity and migration, absent regulatory T cells, and impaired CD28 co-signaling. [2][3][4][5][6][7] To date, fewer than 50 cases have been reported worldwide with clinical manifestations including failure to thrive, inflammatory bowel disease (IBD), asthma, skin and airway infections, and smooth muscle tumors [2][3][4][5][6][7][8][9][10][11][12] (Table S1). Immune phenotyping of our patient demonstrated normal absolute Tand B-cell counts but decreased NK and regulatory T-cell counts, with significantly decreased B-and T-cell proliferative responses to mitogen stimulation and completely absent T-cell response to candida antigen and tetanus toxoid (Table S2 A-C).…”

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confidence: 99%

“…2,3,6,12 Reported dermatologic manifestations include widespread verrucae, mollusca, eczematous and psoriasiform dermatitis, and palmoplantar hyperkeratosis. [2][3][4][5][6][7][8][9][10][11][12] Widespread verrucae, mollusca, and recurrent superficial bacterial abscesses can be seen in association with T-cell immunodeficiencies [2][3][4][5][6][7][8][9][10][11][12] ; Table S1.…”

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confidence: 99%

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CARMIL2‐related immunodeficiency manifesting with photosensitivity

Shayegan

Garzon

Morel

et al. 2020

Pediatric Dermatology

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We report a case of a newly recognized primary immunodeficiency due to biallelic mutations in CARMIL2 manifesting as an actinic prurigo-like photodermatitis, allergic diathesis and recurrent infections in a child. We present this case to highlight a rare phenotype seen in this T-cell immunodeficiency and provide an overview of other dermatologic manifestations among published reports of this condition.

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confidence: 99%

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confidence: 99%

CARMIL2‐related immunodeficiency manifesting with photosensitivity

Shayegan

Garzon

Morel

et al. 2020

Pediatric Dermatology

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“…His course was complicated by pneumatosis intestinalis, which resolved with conservative management, and progression of the cerebellar and skull base lesions with subclinical seizures and hyponatremia requiring steroids, hypertonic saline, and anti-epileptic medications. He also developed Candidemia, Cryptosporidium enterocolitis, and moderate peripheral eosinophilia (likely reactive to mycobacterial infection, but possibly potentiated by actin dysregulation leading to Th2-skewing) (12).…”

Section: Resultsmentioning

confidence: 99%

A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors

et al. 2020

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CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus smooth muscle tumors (EBV-SMTs). Case reports associated with EBV-SMTs are limited. We describe herein a novel homozygous CARMIL2 variant (c.1364_1393del) in two Saudi Arabian male siblings born to consanguineous parents who developed EBV-SMTs. CARMIL2 protein expression was significantly reduced in CD4+ T cells and CD8+ T cells. T cell proliferation on stimulation with soluble (s) anti-CD3 or (s) anti-CD3 plus anti-CD28 antibodies was close to absent in the proband, confirming altered CD28-mediated co-signaling. CD28 expression was substantially reduced in the proband's T cells, and was diminished to a lesser degree in the T cells of the younger sibling, who has a milder clinical phenotype. Defects in both T and B cell compartments were observed, including absent central memory CD8+ T cells, and decreased frequencies of total and class-switched memory B cells. FOXP3+ regulatory T cells (Treg) were also quantitatively decreased, and furthermore CD25 expression within the Treg subset was substantially reduced. These data confirm the pathogenicity of this novel loss-of-function (LOF) variant in CARMIL2 and expand the genotypic and phenotypic spectrum of CIDs associated with EBV-SMTs.

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“…DOCK8 is an atypical guanine nucleotide exchange factor of the DOCK 180 superfamily, which interact with Rho GTPases regulating cytoskeletal rearrangements [ 1 , 5 , 10 , 11 ], partially explaining phenotypical overlap with other IEIs caused by cytoskeletal dysregulation, especially Wiskott-Aldrich syndrome (WAS) and CARMIL2 deficiency [ 12 , 13 ]. Interaction between DOCK8 and WASP in NK-cells has been reported [ 2 , 14 , 15 ]. In comparison, the IEI caused by STAT3 deficiency, autosomal-dominant HIES, presents with different phenotypical features, such as connective tissue, dental, and skeletal abnormalities, and typically exhibits a less severe immunodeficiency [ 2 , 3 , 5 , 16 – 18 ].…”

Section: Introductionmentioning

confidence: 99%

Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

et al. 2021

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Bi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78 months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning.

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Peripheral eosinophilia in primary immunodeficiencies of actin dysregulation: A case series of Wiskott-Aldrich syndrome, CARMIL2 and DOCK8 deficiency and review of the literature

Cited by 15 publications

References 26 publications

CARMIL2‐related immunodeficiency manifesting with photosensitivity

CARMIL2‐related immunodeficiency manifesting with photosensitivity

A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors

Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

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