von Recklinghausen Disease in a Patient with X-linked Agammaglobulinemia.
Daisuke HirataHiroyuki NaraToshihiro InabaRika MUROIHirokazu KaneganeToshio MiyawakiHitoaki OkazakiSeiji Minota
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Abstract:
A 33-year-old man was referred to our hospital because of intractable cellulitis in his left lower leg. He was diagnosed with agammaglobulinemia at the age of 6 years and had been receiving γ-globulin supplementation since then. Laboratory examination revealed a markedly reduced number of B cells, decreased protein amount of Bruton's tyrosine kinase (BTK) in monocytes, and a single base substitution of C994→T(missense mutation of Arg288→Trp) in BTK gene, confirming the diagnosis of X-linked agammaglobulinemia (XLA). The patient also had characteristic features of von Recklinghausen disease, such as numerous subcutaneous nodules, café-au-lait spots, Lisch nodules in the iris and spinal scoliosis. Biopsy of a subcutaneous nodule confirmed a neurofibroma. Although the influence of XLA on the development of von Recklinghausen disease is unknown for the moment, this is, to our knowledge, the first report of a patient with XLA who also developed von Recklinghausen disease.(Internal Medicine 41: 1039-1043, 2002)Keywords:
X-linked agammaglobulinemia
X-linked agammaglobulinemia (XLA) is a genetic disorder with mutation in Bruton's tyrosine kinase (BTK). Defects in B cell development and immunoglobulin production lead to recurrent infections following loss of maternal IgG at 6 months of age. A 55-year-old male with a longstanding common variable immunodeficiency diagnosis on infusion therapy presented to the clinic with cutaneous T-cell lymphoma, which inspired overall repeat evaluation. Immunoglobulin levels and lymphocyte markers, family history, and genetic testing prompted a true diagnosis of XLA and novel mutation in the BTK gene. Disease-associated mutations have been noted in all five domains of BTK, with missense variants most commonly cited among the 100s of reported genetic alterations. The BTK protein is expressed in hematopoietic lineages and plasma cells, with the exception of T lymphocytes. Disruption in the protein function or absence of BTK halts normal B cell development at the pre-B transitional cell stage and induces premature apoptosis. We present the first reported case of a novel hemizygous BTK c.1492C > G mutation in a patient causing XLA.
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Background: X-linked agammaglobulinemia (XLA) is characterized by the absence of immunoglobulin and B cells. Patients suffer from recurrent bacterial infections from early childhood, and require lifelong immunoglobulin replacement therapy. Mutations in BTK (Bruton's Tyrosine Kinase) are associated with this phenotype. Some patients that present XLA do not show typical clinical symptoms, resulting in delayed diagnosis due to the lack of a severe phenotype. This study presents a report of five XLA patients from four different families and attempts to determine a relationship between delayed diagnosis and the occurrence of BTK mutations.Methods: Samples from patients with antibody deficiency were analyzed to determine BTK expression, immunophenotyping and mutation analysis. Clinical and laboratory data was analyzed and presented for each patient.Results: Most patients presented here showed atypical clinical and laboratory data for XLA, including normal IgM, IgG, or IgA levels. Most patients expressed detectable BTK protein. Sequencing of BTK showed that these patients harbored missense mutations in the pleckstrin homology and Src-homology-2 domains. When it was compared to public databases, BTK sequencing exhibited a new change, along with three other previously reported changes.Conclusions: Delayed diagnosis and atypical manifestations in XLA might be related to mutation type and BTK expression.
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Bruton's Tyrosine Kinase (BTK) Is Present in Normal Platelets, and Its Absence Identifies Patients with X-Linked Agammaglobulinemia (XLA) and Carrier Females
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X-linked agammaglobulinemia (XLA) is a heritable immunodeficiency disorder that is caused by a differentiation block leading to almost complete absence of B lymphocytes and plasma cells. The affected protein is a cytoplasmic protein tyrosine kinase, Bruton's agammaglobulinemia tyrosine kinase (Btk). Btk along with Tec, Itk, Bmx and Txk belong to a distinct family of protein kinases. These proteins contain five regions; PH, TH, SH3, SH2 and kinase domains. Mutations causing XLA may affect any of these domains. About 380 unique mutations have been identified and are collected in a mutation database, BTKbase. Here, we describe the structure, function, and interactions of the affected signaling molecules in atomic detail.
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