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Leukocyte adhesion deficiency type 1
LAD1 is caused by a fault in the ITGB2 gene, which impacts how certain white blood cells (leukocytes) can reach infection sites. This leads to severe, recurrent infections starting in infancy, often affecting the skin, mouth, and respiratory system.
Overview
Leukocyte Adhesion Deficiency Type 1 (LAD1) is a rare, inherited condition that weakens the immune system. It specifically affects certain white blood cells, called leukocytes, which are crucial for fighting off infections. In individuals with LAD1, these white blood cells cannot properly adhere to blood vessel walls and move into infected tissues [PMID:30130230]. This impaired function means the body struggles to mount an effective immune response, leading to persistent and recurrent infections.
LAD1 typically presents in early infancy, often with severe infections that may be slow to heal. The condition can range in severity, with some individuals experiencing life-threatening complications if not diagnosed and managed appropriately. While rare, understanding LAD1 is important for timely diagnosis and management.
Symptoms & clinical features
The symptoms of LAD1 usually appear shortly after birth or in early infancy. A hallmark symptom is recurrent bacterial infections, particularly affecting the skin, mouth, and respiratory tract. These infections may be severe and can be difficult to treat with standard antibiotics.
Common signs include delayed separation of the umbilical cord stump, often by more than 30 days, which is a key early indicator [PMID:20301416]. Other symptoms can include gum inflammation (gingivitis) and periodontitis, which are severe infections of the gums and supporting structures of the teeth. Individuals with LAD1 may also experience skin infections that present as non-pus-forming lesions or ulcers that heal very slowly. They may not show typical signs of inflammation, such as pus formation, even when severe infection is present.
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Affected organs
LAD1 primarily affects parts of the body prone to infection and where white blood cells are critical for defence. The skin is commonly affected, leading to persistent sores, boils, and slow-healing wounds. The mucous membranes, particularly in the mouth and gastrointestinal tract, are also frequently involved, causing gum disease and potential issues with intestinal infections.
The respiratory system, including the lungs and airways, is often a site of recurrent infections, such as pneumonia and bronchitis. The immune system itself is functionally impaired, meaning that white blood cells struggle to function effectively in any organ system where an infection might arise. While the condition does not directly damage organs, the chronic and severe infections can lead to secondary organ damage over time.
Risks & severity
LAD1 severity varies, but it is generally a serious condition. The severity of the disease often depends on the level of functional protein produced by the ITGB2 gene. More severe forms are associated with almost no functional protein and can be life-threatening in infancy or early childhood due to overwhelming infections [PMID:30130230]. Milder forms, where some functional protein is present, may lead to less severe but still recurrent infections, allowing individuals to live longer.
Without appropriate management, there is a significant risk of severe, life-threatening bacterial infections, including sepsis. The exact prevalence of LAD1 is not well established, but it is considered a very rare disorder, estimated to affect approximately 1 in 1,000,000 newborns. Early diagnosis and intervention are crucial for improving outcomes and reducing the risks associated with severe infections.
Genetic causes
Leukocyte Adhesion Deficiency Type 1 is caused by genetic changes in the ITGB2 gene. This gene provides instructions for making a protein called CD18, which is a vital part of a larger protein complex known as beta-2 integrin. Beta-2 integrins are found on the surface of white blood cells.
The normal function of beta-2 integrins is to help white blood cells stick to other cells and to the walls of blood vessels. This 'stickiness' is essential for white blood cells to move out of the bloodstream and travel to sites of infection or inflammation in the body. When there are pathogenic changes in the ITGB2 gene, the CD18 protein, and thus the beta-2 integrin complex, is either absent or doesn't function correctly [PMID:30130230]. This impairs the ability of white blood cells to migrate effectively, leaving the body vulnerable to recurrent and severe infections.
- ITGB2 integrin subunit beta 2
Inheritance pattern
LAD1 is inherited in an autosomal recessive pattern. This means that a person must inherit two altered copies of the ITGB2 gene - one from each parent - to develop the condition. Individuals who inherit only one altered copy of the gene are known as carriers. Carriers typically do not show symptoms of LAD1 themselves because their one functional copy of the gene is usually sufficient to produce enough functional CD18 protein.
If two carriers have children, there is a 25% chance with each pregnancy that their child will inherit two altered copies of the gene and therefore be affected by LAD1. There is also a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two normal copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
The diagnosis of LAD1 is often suspected based on the characteristic clinical features, such as recurrent severe infections, especially delayed umbilical cord separation. Blood tests can provide initial clues, such as a persistently high white blood cell count (leukocytosis), even when there is no active infection [PMID:20301416].
A definitive diagnosis of LAD1 is confirmed through specialised laboratory tests that assess the function and presence of CD18 on white blood cells, such as flow cytometry. Genetic testing, which involves analysing the ITGB2 gene, can identify the specific pathogenic changes and confirm the diagnosis. In the UK, such testing is part of the NHS Genomic Medicine Service, typically following a referral to a clinical genetics service or immunology specialist. The relevant R-codes for genetic testing would be initiated by specialist clinicians.
Management & lifestyle
Management of LAD1 primarily focuses on preventing and treating infections, as well as supporting the immune system. This often involves aggressive and prolonged antibiotic treatment for bacterial infections. Some individuals may receive prophylactic antibiotics (taken regularly to prevent infections) and antifungals.
In severe cases, the only curative treatment option is a haematopoietic stem cell transplant, often referred to as a bone marrow transplant. This procedure replaces the faulty immune cells with healthy ones from a donor. Decisions about transplant are complex and are made by a multidisciplinary team of specialists, considering the individual's specific condition and the availability of suitable donors. Regular follow-up with immunologists and other specialists within the NHS framework is crucial to monitor health and manage symptoms.
UK care pathway
In the UK, individuals suspected of having LAD1 would typically be referred by their GP or paediatrician to specialist services, such as immunology or clinical genetics teams, within the NHS. Genetic testing to confirm a diagnosis falls under the NHS Genomic Medicine Service (GMS) pathways. Once diagnosed, care is coordinated by specialist consultants. Genetic counsellors are available to provide support, information, and discuss inheritance patterns and family planning options.
Frequently asked questions
What is the umbilical cord issue associated with LAD1?
One of the earliest and most distinctive signs of LAD1 is a significantly delayed separation of the umbilical cord stump after birth, often taking more than 30 days to fall off. This is due to the impaired immune response at the site.
Can LAD1 be cured?
For severe forms of LAD1, a haematopoietic stem cell transplant (also known as a bone marrow transplant) is currently the only curative treatment option. This procedure replaces the affected immune cells with healthy donor cells.
Are there different types of Leukocyte Adhesion Deficiency?
Yes, there are different types of Leukocyte Adhesion Deficiency (LAD), including LAD-I, LAD-II, and LAD-III. Each type is caused by changes in different genes and affects different aspects of white blood cell function, but all lead to problems with fighting infections.
How does LAD1 affect daily life?
Individuals with LAD1 often need careful monitoring and proactive management to prevent and treat infections. This can involve regular medical appointments, long courses of antibiotics, and lifestyle adjustments to minimise exposure to pathogens. The impact varies greatly depending on the severity of the condition.
If I am a carrier for LAD1, will my children be affected?
If you are a carrier for LAD1, you have one altered copy of the ITGB2 gene but do not have the condition. For your children to be affected, they would need to inherit two altered copies of the gene, meaning their other parent would also need to be a carrier of an altered ITGB2 gene.
References
- Booth C, Sevilla J, Almarza E. Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1. The New England journal of medicine. 2025. PMID: 40305711
- Spodzieja K, Olczak-Kowalczyk D. Premature Loss of Deciduous Teeth as a Symptom of Systemic Disease: A Narrative Literature Review. International journal of environmental research and public health. 2022. PMID: 35329073
- Pettigrew HD, Teuber SS, Gershwin ME. Clinical significance of complement deficiencies. Annals of the New York Academy of Sciences. 2009. PMID: 19758139
- Bashir MM, Hussain M, Ahmad D. Leukocyte Adhesion Deficiency Type 1 with Low Expression of CD 11b. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2018. PMID: 29866230
- Klaus T, Wilson AS, Vicari E. Impaired Treg-DC interactions contribute to autoimmunity in leukocyte adhesion deficiency type 1. JCI insight. 2022. PMID: 36346673
- Fazlollahi MR, Hamidieh AA, Moradi L. Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2023. PMID: 37492921
- Cox DP, Weathers DR. Leukocyte adhesion deficiency type 1: an important consideration in the clinical differential diagnosis of prepubertal periodontitis. A case report and review of the literature. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2008. PMID: 17618138
- Sasahara Y, Wada T, Morio T. Impairment of cytokine production following immunological synapse formation in patients with Wiskott-Aldrich syndrome and leukocyte adhesion deficiency type 1. Clinical immunology (Orlando, Fla.). 2022. PMID: 35973636