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KeywordsAgammaglobulinemia Immunoglobulin Replacement Treatment Block Cell Differentiation Lung Physiotherapy Homozygous Frameshift Mutation
B-cell linker protein (BLNK) deficiency (OMIM #613502) is a rare primary immunodeficiency characterized by reduced serum levels of all immunoglobulin classes in the absence of peripheral B cells (peripheral B cells <2%). To date, a small number of patients have been described. BLNK deficiency is caused by biallelic deleterious mutations in the gene encoding for BLNK.
Early B cell development takes place in the bone marrow. An important maturational step is the progression form the pro-B to the pre-B stage (Espeli et al. 2006; Rudin and Thompson 1998; Bartholdy and Matthias 2004). This passage depends on the expression of a functional B cell receptor composed of the μ heavy chain (IGHM; OMIM*147020), Igα (CD79A; OMIM*112205), Igβ (CD79B; OMIM*147245), VpreB, and λ5 (IGLL1; OMIM*146770) that initiates downstream signalling necessary for early B cell differentiation through kinases such as BTK and BLNK (OMIM*604615). Over the years, animal models and in vitro studies have underlined the importance of each of the pre-BCR components and associated transcription factors for the transition from pro-B to pre-B stage of maturation, suggesting that deficiency of these proteins may be responsible for agammaglobulinemia in humans (Conley and Cooper 1998).
BLNK (also called SLP-65) is activated after BCR cross-linking and initiates the downstream signaling cascade. Since mutations in pre-BCR components have been found to cause agammaglobulinemia and BLNK acts downstream of this complex, BLNK was evaluated as a candidate gene. In 1999, Minegishi et al. reported on the first male patient with mutations in BLNK resulting in agammaglobulinemia. Bone marrow analysis showed a specific block at the pro-B to pre-B stage, and additional experiment concluded that BLNK is essential for B cell development once the pre-BCR is expressed. In 2014, the second case of BLNK deficiency was reported by Lagresle-Peyrou et al.: a male patient carrying a homozygous mutation in the BLNK gene leading to a premature stop codon with a B cell differentiation block at the bone marrow at the pre-BI stage. In 2015, Naser Eddin et al. described two siblings with a homozygous frameshift mutation in BLNK resulting in a developmental arrest at the pre-BI to pre-BII stage at the bone marrow.
The first patient with BLNK deficiency described by Minegishi et al. in 1999 presented a clinical history of pneumonia and recurrent otitis media in the first year of life. The first immunological workup evidenced undetectable serum IgG, IgA, and IgM levels in the absence of peripheral B cells. Once on regular IVIG therapy and during an 18-year period of follow-up, his clinical history was complicated with chronic otitis and sinusitis, hepatitis C acquired from immunoglobulin product, and a protein-losing enteropathy episode during adolescence. The patient described by Lagresle-Peyrou et al. presented a clinical history of recurrent otitis and lung infections. Diagnosis of agammaglobulinemia was made at the age of 6 years, Immunoglobulin serum levels were undetectable and peripheral B cells were absent. He was put on IVIG with good clinical response. The male patient described by Naser Eddin et al. was diagnosed with agammaglobulinemia at the age of 6 months. His clinical history included recurrent otitis media, diarrhea, and positive family history. During follow-up, and under IVIG regular treatment, he developed worsening of the intestinal symptoms with associated arthritis, and progessive skin manifestations including hypercheratosis and edema. Peripheral blood PCR resulted positive for enterovirus. His older sister was diagnosed with agammaglobulinemia at the age of 12 months. Her clinical history included recurrent otitis media and sinopulmonary infections. Although IVIG was initiated, lung infections persisted over time leading to the development of bronchiectasis. She is currently on antibiotic prophylaxis and IVIG. Of note, her PCR resulted negative for enterovirus.
Immunological work-up in BLNK deficient patients shows low levels of serum immunoglobulins in the complete absence of peripheral B cells. Once BTK mutations are excluded for male patients, genetic screening for mutations in components of the pre-BCR and downstream signaling molecules such as BLNK should be performed.
As in other forms of primary humoral immunodeficiencies, immunoglobulin replacement treatment should be undertaken once the immunological diagnosis of agammaglobulinemia is established. Currently two options for administration are available: intravenous or subcutaneous. Commonly, a dose of 400 mg/kg/dose every three to 4 weeks is sufficient to maintain pre-infusion IgG levels >500 mg/dl that should be able to reduce the number of infectious episodes, especially that of invasive infections.
Antibiotic usage should be undertaken for every infectious episode, and in some case, prophylactic regimen may also be prescribed.
Considering the limited number of affected patients, long-term follow-up is not well known. Nonetheless, in case of lung involvement (bronchiectasis, chronic lung disease), lung physiotherapy should be taken into consideration.