Agammaglobulinemia (Review) D81.4

Primary agammaglobulinemia is either an X-linked recessive or an autosmal recessive/dominant inherited immunodeficiency characterized by very low or absent serum antibodies and low or absent circulating B cells due to early blockade of B cell development. Affected individuals develop severe infections in the first few years of life.

The most common form of primary agammaglobulinemia is X-linked agammaglobulinemia (AGMX1, XLA; 300755), also known as Bruton disease, which is caused by a mutation in the BTK gene (300300). AGMX1 accounts for 85 to 95% of male patients with the characteristic findings (Ferrari et al., 2007).

An autosomal recessive inheritance in agammaglobulinemias results in a phenotype similar to that seen in the X-linked form. This phenoytp has been observed in a small number of families and accounts for up to 15% of patients with agammaglobulinemia (Ferrari et al., 2007).

Primary antibody deficiency syndromes are characterized by a genetically determined deficiency of immunoglobulins. Primary immunodeficiencies that lead to antibody deficiency syndrome (AMS) include:

• AGMX1 ( X-linked agammaglobulinemia; XLA; Bruton syndrome; Bruton-type agammaglobulinemia; mutations in the BTK gene at the Xq22 locus.
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• AGM1 (agammaglobulinemia type 1, autosomal recessive), mutations in the IGHM gene at 14q32.33
• AGM2 (agammaglobulinemia type 2, autosomal recessive), mutations in the IGLL1 gene at 22q11.23
• AGM3 (agammaglobulinemia type 3, autosomal recessive), mutations in the CD79A gene at 19q13.2[5]
• AGM4 (agammaglobulinemia type 4, autosomal recessive), mutations in the BLNK gene at 10q24.1
• AGM5 (agammaglobulinemia type 5, autosomal dominant), mutations in the LRRC8A gene at 9q34.11
• AGM6 (agammaglobulinemia type 6, autosomal recessive), mutations in the CD79B gene at 17q23.3

• AGM9 (agammaglobulinemia 9, autosomal recessive), mutation in SLC39A7

Furthermore, hypogammaglobulinemia is frequently associated with the following conditions:

• WHIM syndrome
• due to primary B-cell immunodeficiencies in trisomy 18, Jacobsen syndrome, or congenital transcobalamin II deficiency
• VODI syndrome

1. Cellier C et al (2000) Regional enteritis associated with enterovirus in a patient with X-linked agammaglobulinemia. N Engl J Med 342: 1611-1612
2. Conley ME, Howard V (2002) Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr 141: 566-571.
3. Fancher KMet al.(2020) Drug interactions with Bruton's tyrosine kinase inhibitors: clinical implications and management. Cancer Chemother Pharmacol 86: 507-515.
4. Howard V et al (2003) Stem cell transplants for patients with X-linked agammaglobulinemia. Clin Immunol 107: 98-102
5. Jo EK et al (2003) Identification of mutations in the Bruton's tyrosine kinase gene, including a novel genomic rearrangements resulting in large deletion, in Korean X-linked agammaglobulinemia patients. J Hum Genet 48: 322-326