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Leukocyte adhesion deficiency 1(LAD1)

MedGen UID:
98310
Concept ID:
C0398738
Disease or Syndrome
Synonyms: LAD 1; LAD1; LEUKOCYTE ADHESION DEFICIENCY, TYPE I; LFA 1 immunodeficiency; Lymphocyte function-associated antigen 1 immunodeficiency
SNOMED CT: Leukocyte adhesion deficiency - type 1 (234582006); LFA-1 deficiency (234582006); Mo-1 deficiency (234582006); LAD - Leukocyte adhesion deficiency type 1 (234582006); Leukocyte adhesion molecule deficiency - type 1 (234582006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ITGB2 (21q22.3)
 
Monarch Initiative: MONDO:0007293
OMIM®: 116920
Orphanet: ORPHA99842

Definition

Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder of neutrophil function resulting from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule. The leukocyte cell adhesion molecule is present on the surface of peripheral blood mononuclear leukocytes and granulocytes and mediates cell-cell and cell-extracellular matrix adhesion. LAD is characterized by recurrent bacterial infections; impaired pus formation and wound healing; abnormalities of a wide variety of adhesion-dependent functions of granulocytes, monocytes, and lymphocytes; and a lack of beta-2/alpha-L, beta-2/alpha-M, and beta-2/alpha-X expression. Genetic Heterogeneity of Leukocyte Adhesion Deficiency Also see LAD2 (266265), caused by mutation in the SLC35C1 gene (605881), and LAD3 (612840), caused by mutation in the FERMT3 gene (607901). [from OMIM]

Additional description

From MedlinePlus Genetics
Leukocyte adhesion deficiency type 1 is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as viruses, bacteria, and fungi. Starting from birth, people with leukocyte adhesion deficiency type 1 develop serious bacterial and fungal infections.

One of the first signs of leukocyte adhesion deficiency type 1 is a delay in the detachment of the umbilical cord stump after birth. In newborns, the stump normally falls off within the first two weeks of life; but, in infants with leukocyte adhesion deficiency type 1, this separation usually occurs at three weeks or later. In addition, affected infants often have inflammation of the umbilical cord stump (omphalitis) due to a bacterial infection.

In leukocyte adhesion deficiency type 1, bacterial and fungal infections most commonly occur on the skin and mucous membranes such as the moist lining of the nose and mouth. In childhood, people with this condition develop severe inflammation of the gums (gingivitis) and other tissue around the teeth (periodontitis), which often results in the loss of both primary and permanent teeth. These infections often spread to cover a large area. A hallmark of leukocyte adhesion deficiency type 1 is the lack of pus formation at the sites of infection. In people with this condition, wounds are slow to heal, which can lead to additional infection.

Life expectancy in individuals with leukocyte adhesion deficiency type 1 is often severely shortened. Due to repeat infections, affected individuals may not survive past infancy.  https://medlineplus.gov/genetics/condition/leukocyte-adhesion-deficiency-type-1

Clinical features

From HPO
Chronic diarrhea
MedGen UID:
96036
Concept ID:
C0401151
Finding
The presence of chronic diarrhea, which is usually taken to mean diarrhea that has persisted for over 4 weeks.
Hyperfibrinogenemia
MedGen UID:
488952
Concept ID:
C0919890
Finding
Increased concentration of fibrinogen in the blood.
Chronic mucocutaneous candidiasis
MedGen UID:
2426
Concept ID:
C0006845
Disease or Syndrome
Recurrent or persistent superficial Candida infections of the skin, mucous membranes, and nails.
Leukocytosis
MedGen UID:
9736
Concept ID:
C0023518
Disease or Syndrome
An abnormal increase in the number of leukocytes in the blood.
Osteomyelitis
MedGen UID:
10497
Concept ID:
C0029443
Disease or Syndrome
Osteomyelitis is an inflammatory process accompanied by bone destruction and caused by an infecting microorganism.
Periodontitis
MedGen UID:
45815
Concept ID:
C0031099
Disease or Syndrome
Inflammation of the periodontium.
Rectal abscess
MedGen UID:
57700
Concept ID:
C0149770
Pathologic Function
A collection of pus in the area of the rectum.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Recurrent bacterial infections
MedGen UID:
334943
Concept ID:
C1844383
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
Recurrent staphylococcal infections
MedGen UID:
870417
Concept ID:
C4024862
Finding
Increased susceptibility to staphylococcal infections, as manifested by recurrent episodes of staphylococcal infections.
Recurrent gram-negative bacterial infections
MedGen UID:
870743
Concept ID:
C4025198
Finding
Increased susceptibility to infection by gram-negative bacteria, as manifested by a medical history of repeated or frequent infections by these agents.
Elevated circulating C-reactive protein concentration
MedGen UID:
892906
Concept ID:
C4023452
Finding
An abnormal elevation of the C-reactive protein level in the blood circulation.
Gingivitis
MedGen UID:
4895
Concept ID:
C0017574
Disease or Syndrome
Inflammation of the gingiva.
Skin ulcer
MedGen UID:
52369
Concept ID:
C0037299
Disease or Syndrome
A discontinuity of the skin exhibiting complete loss of the epidermis and often portions of the dermis and even subcutaneous fat.
Poor wound healing
MedGen UID:
377525
Concept ID:
C1851789
Finding
A reduced ability to heal cutaneous wounds.
Neonatal omphalitis
MedGen UID:
510678
Concept ID:
C0158947
Disease or Syndrome
An infection of the umbilicus and/or surrounding tissues occurring in the neonatal period.
Delayed umbilical cord separation
MedGen UID:
226769
Concept ID:
C1260438
Pathologic Function
Separation of the umbilical cord occurs at an abnormally late timepoint.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Leukocyte adhesion deficiency 1 in Orphanet.

Professional guidelines

PubMed

Klaus T, Hieber C, Bros M, Grabbe S
Cells 2024 Jan 23;13(3) doi: 10.3390/cells13030212. PMID: 38334604Free PMC Article
Méndez Barrera JA, Rocha Guzmán S, Hierro Cascajares E, Garabedian EK, Fuleihan RL, Sullivan KE, Lugo Reyes SO
Clin Immunol 2023 Oct;255:109759. Epub 2023 Sep 9 doi: 10.1016/j.clim.2023.109759. PMID: 37678719
Lakshman R, Finn A
J Clin Pathol 2001 Jan;54(1):7-19. doi: 10.1136/jcp.54.1.7. PMID: 11271792Free PMC Article

Recent clinical studies

Diagnosis

Kurosawa H, Mizukami T, Nunoi H, Kato M, Sato Y, Okuya M, Fukushima K, Katsuyama Y, Arisaka O
J Pediatr Hematol Oncol 2018 Jan;40(1):63-66. doi: 10.1097/MPH.0000000000000853. PMID: 28538512
Nagendran J, Prakash C, Anandakrishna L, Gaviappa D, Ganesh D
J Dent Child (Chic) 2012 May-Aug;79(2):105-10. PMID: 22828768
Bernard Cher TH, Chan HS, Klein GF, Jabkowski J, Schadenböck-Kranzl G, Zach O, Roca X, Law SK
Biochem Biophys Res Commun 2011 Jan 28;404(4):1099-104. Epub 2010 Dec 31 doi: 10.1016/j.bbrc.2010.12.124. PMID: 21195692
Beals CR, Edwards AC, Gottschalk RJ, Kuijpers TW, Staunton DE
J Immunol 2001 Dec 1;167(11):6113-22. doi: 10.4049/jimmunol.167.11.6113. PMID: 11714770
Uzel G, Kleiner DE, Kuhns DB, Holland SM
Gastroenterology 2001 Oct;121(4):958-64. doi: 10.1053/gast.2001.28022. PMID: 11606509

Therapy

Kurosawa H, Mizukami T, Nunoi H, Kato M, Sato Y, Okuya M, Fukushima K, Katsuyama Y, Arisaka O
J Pediatr Hematol Oncol 2018 Jan;40(1):63-66. doi: 10.1097/MPH.0000000000000853. PMID: 28538512
Peters T, Bloch W, Pabst O, Wickenhauser C, Uthoff-Hachenberg C, Schmidt SV, Varga G, Grabbe S, Kess D, Oreshkova T, Sindrilaru A, Addicks K, Förster R, Müller W, Scharffetter-Kochanek K
Clin Dev Immunol 2012;2012:450738. Epub 2012 Mar 4 doi: 10.1155/2012/450738. PMID: 22474478Free PMC Article
Simon AJ, Lev A, Wolach B, Gavrieli R, Amariglio N, Rosenthal E, Gazit E, Eyal E, Rechavi G, Somech R
PLoS One 2010 Nov 16;5(11):e13659. doi: 10.1371/journal.pone.0013659. PMID: 21103413Free PMC Article
Malawista SE, de Boisfleury Chevance A, Boxer LA
Cell Motil Cytoskeleton 2000 Jul;46(3):183-9. doi: 10.1002/1097-0169(200007)46:3<183::AID-CM3>3.0.CO;2-2. PMID: 10913965
Majorana A, Notarangelo LD, Savoldi E, Gastaldi G, Lozada-Nur F
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999 Jun;87(6):691-4. doi: 10.1016/s1079-2104(99)70162-9. PMID: 10397659

Prognosis

Simon AJ, Lev A, Wolach B, Gavrieli R, Amariglio N, Rosenthal E, Gazit E, Eyal E, Rechavi G, Somech R
PLoS One 2010 Nov 16;5(11):e13659. doi: 10.1371/journal.pone.0013659. PMID: 21103413Free PMC Article
Malawista SE, de Boisfleury Chevance A, Brown EJ, Boxer LA, Law SK
Am J Hematol 2003 Jun;73(2):115-20. doi: 10.1002/ajh.10311. PMID: 12749013

Clinical prediction guides

Peters T, Bloch W, Pabst O, Wickenhauser C, Uthoff-Hachenberg C, Schmidt SV, Varga G, Grabbe S, Kess D, Oreshkova T, Sindrilaru A, Addicks K, Förster R, Müller W, Scharffetter-Kochanek K
Clin Dev Immunol 2012;2012:450738. Epub 2012 Mar 4 doi: 10.1155/2012/450738. PMID: 22474478Free PMC Article
Simon AJ, Lev A, Wolach B, Gavrieli R, Amariglio N, Rosenthal E, Gazit E, Eyal E, Rechavi G, Somech R
PLoS One 2010 Nov 16;5(11):e13659. doi: 10.1371/journal.pone.0013659. PMID: 21103413Free PMC Article
Jurk K, Schulz AS, Kehrel BE, Räpple D, Schulze H, Möbest D, Friedrich WW, Omran H, Deak E, Henschler R, Scheele JS, Zieger B
Thromb Haemost 2010 May;103(5):1053-64. Epub 2010 Mar 9 doi: 10.1160/TH09-10-0689. PMID: 20216991
Malawista SE, de Boisfleury Chevance A, Boxer LA
Cell Motil Cytoskeleton 2000 Jul;46(3):183-9. doi: 10.1002/1097-0169(200007)46:3<183::AID-CM3>3.0.CO;2-2. PMID: 10913965
Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA
Blood 1996 Jul 1;88(1):146-57. PMID: 8704169

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