Clinical and Osteopetrosis-Like Radiological Findings in Patients with Leukocyte Adhesion Deficiency Type III.
FERMT3
JMML
KINDLIN3
MDS
bleeding diathesis
osteopetrosis
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
12
07
2022
accepted:
25
03
2023
medline:
21
7
2023
pubmed:
5
4
2023
entrez:
4
4
2023
Statut:
ppublish
Résumé
Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III. To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III. This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients. The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/μL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS). In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.
Sections du résumé
BACKGROUND
Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III.
AIM
To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III.
METHODS
This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients.
RESULTS
The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/μL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS).
CONCLUSION
In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.
Identifiants
pubmed: 37014583
doi: 10.1007/s10875-023-01479-7
pii: 10.1007/s10875-023-01479-7
doi:
Substances chimiques
Integrins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1250-1258Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Yaz I, Ozbek B, Bildik HN, Tan C, Oskay Halacli S, Soyak Aytekin E, et al. Clinical and laboratory findings in patients with leukocyte adhesion deficiency type I: a multicenter study in Turkey. Clin Exp Immunol. 2021;206(1):47–55.
pubmed: 34310689
pmcid: 8446394
Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994;76(2):301–14.
pubmed: 7507411
Kuijpers TW, van Bruggen R, Kamerbeek N, Tool AT, Hicsonmez G, Gurgey A, et al. Natural history and early diagnosis of LAD-1/variant syndrome. Blood. 2007;109(8):3529–37.
pubmed: 17185466
Hanna S, Etzioni A. Leukocyte adhesion deficiencies. Ann N Y Acad Sci. 2012;1250(1):50–5.
pubmed: 22276660
Cagdas D, Yılmaz M, Kandemir N, Tezcan İ, Etzioni A, Sanal Ö. A novel mutation in leukocyte adhesion deficiency type II/CDGIIc. J Clin Immunol. 2014;34:1009–14.
pubmed: 25239688
Roos D, van Leeuwen K, Madkaikar M, Kambli PM, Gupta M, Mathews V, et al. Hematologically important mutations: leukocyte adhesion deficiency (second update). Blood Cells Mol Dis. 2023;102726
Fan Z, Ley K. Leukocyte arrest: biomechanics and molecular mechanisms of β2 integrin activation. Biorheology. 2015;52(5-6):353–77.
pubmed: 26684674
pmcid: 4869873
Kuijpers TW, Van Lier RA, Hamann D, de Boer M, Thung LY, Weening RS, et al. Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins. J Clin Invest. 1997;100(7):1725–33.
pubmed: 9312170
pmcid: 508355
Kambli PM, Bargir UA, Yadav RM, Gupta MR, Dalvi AD, Hule G, et al. Clinical and genetic spectrum of a large cohort of patients with leukocyte adhesion deficiency type 1 and 3: a multicentric study from India. Front Immunol. 2020;11:612703.
pubmed: 33391282
pmcid: 7772426
Bakhtiar S, Salzmann-Manrique E, Blok H-J, Eikema D-J, Hazelaar S, Ayas M, et al. Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III. Blood Adv. 2021;5(1):262–73.
pubmed: 33570653
pmcid: 7805328
Robert P, Canault M, Farnarier C, Nurden A, Grosdidier C, Barlogis V, et al. A novel leukocyte adhesion deficiency III variant: kindlin-3 deficiency results in integrin- and nonintegrin-related defects in different steps of leukocyte adhesion. J Immunol. 2011;186(9):5273–83.
pubmed: 21441448
Goldstein B. International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6(1):2–8.
pubmed: 15636651
Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, et al. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009;113(19):4740–6.
pubmed: 19064721
Kilic SS, Etzioni A. The clinical spectrum of leukocyte adhesion deficiency (LAD) III due to defective CalDAG-GEF1. J Clin Immunol. 2009;29(1):117–22.
pubmed: 18709451
Haskoloğlu ZŞ, Bal SK, Islamoğlu C, AKB B, Beşli D, Aytekin C, et al. Evaluation of clinical, immunological characteristics, treatment and follow-up of 14 patients with the diagnosis of leukocyte adhesion defect (type-I and type-III). Türkiye Çocuk Hast Derg/Turkish J Pediatr Dis. 2020;14:286–94.
Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, et al. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009;15(3):313–8.
pubmed: 19234460
pmcid: 2857384
Sabnis H, Kirpalani A, Horan J, McDowall A, Svensson L, Cooley A, et al. Leukocyte adhesion deficiency-III in an African-American patient. Pediatr Blood Cancer. 2010;55(1):180–2.
pubmed: 20213844
Elhasid R, Kilic SS, Ben-Arush M, Etzioni A, Rowe JM. Prompt recovery of recipient hematopoiesis after two consecutive haploidentical peripheral blood SCTs in a child with leukocyte adhesion defect III syndrome. Bone Marrow Transplant. 2010;45(2):413–4.
pubmed: 19584822
Crazzolara R, Maurer K, Schulze H, Zieger B, Zustin J, Schulz AS. A new mutation in the KINDLIN-3 gene ablates integrin-dependent leukocyte, platelet, and osteoclast function in a patient with leukocyte adhesion deficiency-III. Pediatr Blood Cancer. 2015;62(9):1677–9.
pubmed: 25854317
Palagano E, Slatter MA, Uva P, Menale C, Villa A, Abinun M, et al. Hematopoietic stem cell transplantation corrects osteopetrosis in a child carrying a novel homozygous mutation in the FERMT3 gene. Bone. 2017;97:126–9.
pubmed: 28095295
Meller J, Malinin NL, Panigrahi S, Kerr BA, Patil A, Ma Y, et al. Novel aspects of Kindlin-3 function in humans based on a new case of leukocyte adhesion deficiency III. J Thromb Haemost. 2012;10(7):1397–408.
pubmed: 22564402
pmcid: 3583563
Alon R, Aker M, Feigelson S, Sokolovsky-Eisenberg M, Staunton DE, Cinamon G, et al. A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow. Blood. 2003;101(11):4437–45.
pubmed: 12595312
Mory A, Feigelson SW, Yarali N, Kilic SS, Bayhan GI, Gershoni-Baruch R, et al. Kindlin-3: a new gene involved in the pathogenesis of LAD-III. Blood. 2008;112(6):2591.
pubmed: 18779414
McDowall A, Svensson L, Stanley P, Patzak I, Chakravarty P, Howarth K, et al. Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro. Blood. 2010;115(23):4834–42.
pubmed: 20357244
Jurk K, Schulz AS, Kehrel BE, Rapple D, Schulze H, Mobest D, et al. Novel integrin-dependent platelet malfunction in siblings with leukocyte adhesion deficiency-III (LAD-III) caused by a point mutation in FERMT3. Thromb Haemost. 2010;103(5):1053–64.
pubmed: 20216991
Harris ES, Smith TL, Springett GM, Weyrich AS, Zimmerman GA. Leukocyte adhesion deficiency-I variant syndrome (LAD-Iv, LAD-III): molecular characterization of the defect in an index family. Am J Hematol. 2012;87(3):311.
pubmed: 22139635
Shahid S, Zaidi S, Ahmed S, Siddiqui S, Abid A, Malik S, et al. A novel nonsense mutation in FERMT3 causes LAD-III in a Pakistani family. Front Genet. 2019;10:360.
pubmed: 31068971
pmcid: 6491447
Essa MF, Elbashir E, Alroqi F, Mohammed R, Alsultan A. Successful hematopoietic stem cell transplant in leukocyte adhesion deficiency type III presenting primarily as malignant infantile osteopetrosis. Clin Immunol. 2020;213:108365.
pubmed: 32092470
Harris ES, Shigeoka AO, Li W, Adams RH, Prescott SM, McIntyre TM, et al. A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins. Blood. 2001;97(3):767–76.
pubmed: 11157496
Stepensky PY, Wolach B, Gavrieli R, Rousso S, Ben Ami T, Goldman V, et al. Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation. J Pediatr Hematol Oncol. 2015;37(4):264–8.
pubmed: 25072369
Suratannon N, Yeetong P, Srichomthong C, Amarinthnukrowh P, Chatchatee P, Sosothikul D, et al. Adaptive immune defects in a patient with leukocyte adhesion deficiency type III with a novel mutation in FERMT3. Pediatr Allergy Immunol. 2016;27(2):214–7.
pubmed: 26359933
Qureshi S, Mir F, Junejo S, Saleem K, Zaidi S, Naveed AB, et al. The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan. World Allergy Organ J. 2020;13(7):100133.
pubmed: 32793328
pmcid: 7414008
Yahya AM, AlMulla AA, AlRufaye HJ, Al Dhaheri A, Elomami AS, Al-Hammadi S, et al. Case report: a case of leukocyte adhesion deficiency, type III presenting with impaired platelet function, lymphocytosis and granulocytosis. Front Pediatr. 2021;9:713921.
pubmed: 34485203
pmcid: 8415448
Schmidt S, Nakchbandi I, Ruppert R, Kawelke N, Hess MW, Pfaller K, et al. Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption. J Cell Biol. 2011;192(5):883–97.
pubmed: 21357746
pmcid: 3051823
Wolach B, Gavrieli R, Wolach O, Stauber T, Abuzaitoun O, Kuperman A, et al. Leucocyte adhesion deficiency-A multicentre national experience. Eur J Clin Invest. 2019;49(2):e13047.
pubmed: 30412664
Kinashi T, Aker M, Sokolovsky-Eisenberg M, Grabovsky V, Tanaka C, Shamri R, et al. LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds. Blood. 2004;103(3):1033–6.
pubmed: 14551137
Pasvolsky R, Feigelson SW, Kilic SS, Simon AJ, Tal-Lapidot G, Grabovsky V, et al. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med. 2007;204(7):1571–82.
pubmed: 17576779
pmcid: 2118641
Slatkin M. Linkage disequilibrium—understanding the evolutionary past and mapping the medical future. Nat Rev Genet. 2008;9(6):477–85.
pubmed: 18427557
pmcid: 5124487
GnomAD 2022 [Available from: https://gnomad.broadinstitute.org/variant/11-64496517-G-T?dataset=gnomad_r2_1 . .
Born G, Grayton HM, Langhorst H, Dudanova I, Rohlmann A, Woodward BW, et al. Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors. Front Synaptic Neurosci. 2015;7:3.
pubmed: 25745399
pmcid: 4333794
Ganesh A, Al-Zuhaibi SS, Bialasiewicz A, Ahmed S, Al-Tamemi S, E-Nour IB. Necrotizing Pseudomonas infection of the ocular adnexa in an infant with leukocyte adhesion defect. J Pediatr Ophthalmol Strabismus. 2007;44(4):199–200.
pubmed: 17694822
Singh P, Chen C, Pal-Ghosh S, Stepp MA, Sheppard D, Van De Water L. Loss of integrin α9β1 results in defects in proliferation, causing poor re-epithelialization during cutaneous wound healing. J Invest Dermatol. 2009;129(1):217–28.
pubmed: 18633440
Lee T-H, Seng S, Li H, Kennel SJ, Avraham HK, Avraham S. Integrin regulation by vascular endothelial growth factor in human brain microvascular endothelial cells: role of α6β1 integrin in angiogenesis. J Biol Chem. 2006;281(52):40450–60.
pubmed: 17085437
Majorana A, Notarangelo LD, Savoldi E, Gastaldi G, Lozada-Nur F. Leukocyte adhesion deficiency in a child with severe oral involvement. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87(6):691–4.
pubmed: 10397659
Koivisto L, Heino J, Hakkinen L, Larjava H. Integrins in wound healing. Adv Wound Care. 2014;3(12):762–83.
Karow A, Baumann I, Niemeyer CM. Morphologic differential diagnosis of juvenile myelomonocytic leukemia—pitfalls apart from viral infection. J Pediatr Hematol Oncol. 2009;31(5):380.
pubmed: 19415027
Strauss A, Furlan I, Steinmann S, Buchholz B, Kremens B, Rossig C, et al. Unmistakable morphology? Infantile malignant osteopetrosis resembling juvenile myelomonocytic leukemia in infants. J Pediatr. 2015;167(2):486–8.
pubmed: 25982139
Hacettepe University Institute of Population Studies, 2018 Turkey Demographic and Health Survey. https://hips.hacettepe.edu.tr/en/2018_tdhs_analysis_and_report-262 . Accessed 11 March 2023