Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency
Main Article Content
Keywords
CARMIL2 deficiency , primary immunodeficiency, Gastrointestinal stenosis , clinical vigilance
Abstract
CARMIL2 deficiency is a rare autosomal recessive combined immunodeficiency classically associated with dermatitis, inflammatory bowel disease (IBD), recurrent infections, and Epstein–Barr virus-related tumors. Gastrointestinal (GI) stenosis remains an underrecognized but potentially life-threatening complication. We report a consanguineous Moroccan family in which all three siblings with CARMIL2 deficiency developed early-onset, severe, and progressive GI stenoses, including pyloric and esophageal involvement. The striking consistency and severity of this phenotype within a single family highlight the clinical importance of early recognition and timely intervention to prevent irreversible GI damage.
References
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19. Shamriz O, Simon AJ, Lev A, Megged O, Ledder O, Picard E, et al. Exogenous interleukin-2 can rescue in-vitro T cell acti-vation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation. Clin Exp Immunol. 2020 Jun;200(3):215–27. https://doi.org/10.1111/ cei.13432
20. Shayegan LH, Garzon MC, Morel KD, Borlack R, Vuguin PM, Margolis KG, et al. CARMIL2-related immunodeficiency manifesting with photosensitivity. Pediatr Dermatol. 2020 Jul;37(4):695–7. https://doi.org/10.1111/pde.14173
21. Yonkof JR, Gupta A, Rueda CM, Mangray S, Prince BT, Rangarajan HG, et al. A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors. Front Immunol. 2020;11:884. https:// doi.org/10.3389/fimmu.2020.00884
2. Lévy R, Gothe F, Momenilandi M, Magg T, Materna M, Peters P, et al. Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency. J Exp Med. 2023 Feb 6;220(2):e20220275. https:// doi.org/10.1084/jem.20220275
3. Schober T, Magg T, Laschinger M, Rohlfs M, Linhares ND, Puchalka J, et al. A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat Commun. 2017 Jan 23;8:14209. https://doi.org/10.1038/ncomms14209
4. Wang Y, Ma CS, Ling Y, Bousfiha A, Camcioglu Y, Jacquot S, et al. Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations. J Exp Med. 2016 Oct 17;213(11):2413–35. https://doi.org/10.1084/jem.20160576
5. Béziat V, Rapaport F, Hu J, Titeux M, Bonnet des Claustres M, Bourgey M, et al. Humans with inherited T cell CD28 defi-ciency are susceptible to skin papillomaviruses but are otherwise healthy. Cell. 2021 Jul 8;184(14):3812–3828.e30. https://doi.org/10.1016/j.cell.2021.06.004
6. Lanier MH, Kim T, Cooper JA. CARMIL2 is a novel molecu-lar connection between vimentin and actin essential for cell migration and invadopodia formation. Mol Biol Cell. 2015 Dec 15;26(25):4577–88. https://doi.org/10.1091/mbc.E15-08-0552
7. Lanier MH, McConnell P, Cooper JA. Cell Migration and Invadopodia Formation Require a Membrane-binding Domain of CARMIL2. J Biol Chem. 2016 Jan 15;291(3):1076–91. https:// doi.org/10.1074/jbc.M115.676882
8. Magg T, Shcherbina A, Arslan D, Desai MM, Wall S, Mitsialis V, et al. CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease. Inflamm Bowel Dis. 2019 Oct 18;25(11):1788–95. https://doi.org/10.1093/ibd/izz103
9. Alazami AM, Al-Helale M, Alhissi S, Al-Saud B, Alajlan H, Monies D, et al. Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency. Front Immunol. 2018;9:203. https://doi. org/10.3389/fimmu.2018.00203
10. Marangi G, Garcovich S, Sante GD, Orteschi D, Frangella S, Scaldaferri F, et al. Complex Muco-cutaneous Manifestations of CARMIL2-associated Combined Immunodeficiency: A Novel Presentation of Dysfunctional Epithelial Barriers. Acta Derm Venereol. 2020 Jan 23;100(1):adv00038. https://doi. org/10.2340/00015555-3370
11. Sorte HS, Osnes LT, Fevang B, Aukrust P, Erichsen HC, Backe PH, et al. A potential founder variant in CARMIL2/ RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction. Mol Genet Genomic Med. 2016 Nov;4(6):604–16. https://doi.org/10.1002/mgg3.237
12. Bosa L, Batura V, Colavito D, Fiedler K, Gaio P, Guo C, et al. Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease. Sci Rep. 2021 Mar 15;11(1):5945. https://doi.org/10.1038/s41598-021-85399-9
13. Chan A, Feuille E, Bassetti J, Pereira E, Demirdag Y. M232 Variable Phenotypes Associated With P.H648tfsx20 Pathogenic Variant In Carmil2 Gene: A Report Of Two Cases. Annals of Allergy, Asthma & Immunology. 2019 Nov 1;123(5):S104. https://doi.org/10.1016/j.anai.2019.08.204
14. Frede N, Rojas-Restrepo J, Caballero Garcia de Oteyza A, Buchta M, Hübscher K, Gámez-Díaz L, et al. Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis. J Clin Immunol. 2021 Nov;41(8):1804–38. https://doi.org/10.1007/ s10875-021-01086-4
15. Kim D, Uner A, Saglam A, Chadburn A, Crane GM. Peripheral eosinophilia in primary immunodeficiencies of actin dysreg-ulation: A case series of Wiskott-Aldrich syndrome, CARMIL2 and DOCK8 deficiency and review of the literature. Ann Diagn Pathol. 2019 Dec;43:151413. https://doi.org/10.1016/j. anndiagpath.2019.151413
16. Kurolap A, Eshach Adiv O, Konnikova L, Werner L, Gonzaga-Jauregui C, Steinberg M, et al. A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant. J Clin Immunol. 2019 May;39(4):430–9. https://doi.org/10.1007/s10875-019-00631-6
17. Maccari ME, Speckmann C, Heeg M, Reimer A, Casetti F, Has C, et al. Profound immunodeficiency with severe skin disease explained by concomitant novel CARMIL2 and PLEC1 loss-of-function mutations. Clin Immunol. 2019 Nov;208:108228. https://doi.org/10.1016/j.clim.2019.06.004
18. Rao LP, Kothiwale V, Radhakrishnan P, Rangaswamy D, Shukla A, Bhat V. Secondary Membranous Nephropathy and Immunodeficiency due to a Novel Biallelic Variant in CARMIL2. Indian J Nephrol. 2024;34(6):667–9. https://doi. org/10.25259/ijn_542_23
19. Shamriz O, Simon AJ, Lev A, Megged O, Ledder O, Picard E, et al. Exogenous interleukin-2 can rescue in-vitro T cell acti-vation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation. Clin Exp Immunol. 2020 Jun;200(3):215–27. https://doi.org/10.1111/ cei.13432
20. Shayegan LH, Garzon MC, Morel KD, Borlack R, Vuguin PM, Margolis KG, et al. CARMIL2-related immunodeficiency manifesting with photosensitivity. Pediatr Dermatol. 2020 Jul;37(4):695–7. https://doi.org/10.1111/pde.14173
21. Yonkof JR, Gupta A, Rueda CM, Mangray S, Prince BT, Rangarajan HG, et al. A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors. Front Immunol. 2020;11:884. https:// doi.org/10.3389/fimmu.2020.00884