20080910

X-linked agammaglobulinemia

Agammaglobulinemia is a misnomer, since most of these patients synthesize some immunoglobulins.

Within the same family, some affected males may have substantial levels of IgM, IgG, and IgA, while others are nearly agammaglobulinemic. Btk-deficient patients typically are very deficient in circulating B lymphocytes. The few B lymphocytes that escape the block in pre-B cell differentiation are hyporesponsive, making antibody replacement therapy essential in these patients.

Males with this syndrome often begin to have recurrent bacterial infections in the first year of life when maternally derived immunoglobulins have disappeared. Although B cell progenitors are found in the bone marrow, affected individuals have very few immunoglobulin-bearing B lymphocytes in their circulation and typically lack primary and secondary lymphoid follicles. Mutations of Bruton's tyrosine kinase(Btk) gene are responsible for X-linked agammaglobulinemia. The developmental block due to the deficiency of this pre-BCR and BCR signaling enzyme is evident at the pre-B cell level (Fig. 310-1). B cells in heterozygous female carriers exclusively utilize the X chromosome with the normal Btk gene, while random X chromosome usage occurs in T cells and myeloid cells. A variant disorder, X-linked agammaglobulinemia with growth hormone deficiency, has been associated with Btk mutations that result in a truncated message.

Sinopulmonary bacterial infections constitute the most frequent clinical problem. Mycoplasma infections may cause arthritis in some of these patients. Chronic encephalitis of viral etiology, sometimes associated with dermatomyositis, can be a fatal complication. All of these complications are reduced by treatment with intravenous immunoglobulins.

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