Clinical characteristics.

X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifesting as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum immunoglobulin G to be achieved, and more liberal use of antibiotics.

Diagnosis/testing.

The diagnosis of XLA is established in a male proband with characteristic clinical and laboratory findings and a hemizygous BTK pathogenic variant identified by molecular genetic testing. The diagnosis of XLA can be established in a female proband with characteristic clinical and laboratory findings and a heterozygous pathogenic variant in BTK identified by molecular genetic testing. Females with a heterozygous pathogenic variant in BTK extremely rarely have clinical and laboratory findings of XLA.

Management.

Targeted therapy: The mainstay of treatment is gammaglobulin substitution therapy (by weekly subcutaneous injection or intravenous infusion every two to four weeks) to prevent bacterial infections.

Treatment of manifestations: Generous use of antibiotics can decrease the incidence of chronic sinusitis and lung disease. Prophylactic antibiotics can be considered to prevent infections. Vaccines, apart from live vaccines, are recommended to prevent infection. Inactivated polio vaccine (as opposed to live oral polio vaccine) should be given to affected individuals and their family contacts.

Surveillance: Complete blood count with differential and quantitative serum immunoglobulins at least annually; chest and sinus imaging as needed to assess for chronic lung and/or sinus disease.

Agents/circumstances to avoid: Live viral vaccines, particularly oral polio vaccine.

Evaluation of relatives at risk: Molecular genetic testing of at-risk male relatives as soon after birth as possible ensures that gammaglobulin substitution therapy is initiated as soon as possible in affected individuals and administration of live viral vaccines can be avoided.

Genetic counseling.

By definition, XLA is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother: if the mother has a BTK pathogenic variant, the chance of transmitting the BTK pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected. Affected males transmit the BTK pathogenic variant to all of their daughters and none of their sons. Once the BTK pathogenic variant has been identified in an affected family member, carrier testing for at-risk female relatives, prenatal testing, and preimplantation genetic testing are possible.

Suggestive Findings

X-linked agammaglobulinemia (XLA) should be suspected in probands with the following clinical, laboratory, and family history findings.

Clinical findings

• Recurrent otitis, pneumonitis, sinusitis, and conjunctivitis starting before age five years
• A severe life-threatening bacterial infection such as sepsis, meningitis, cellulitis, or empyema
• Paucity of lymphoid tissue (small adenoids, tonsils, and lymph nodes on physical examination)

Laboratory findings

• Marked reduction in all classes of serum immunoglobulins [Lederman & Winkelstein 1985, Conley et al 2005]
  • The serum IgG concentration is typically <200 mg/dL (2 g/L). Most but not all individuals with XLA have some measurable serum IgG, usually between 100 and 200 mg/dL, and ~10% of individuals have serum concentration of IgG >200 mg/dL.
  • The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency.
• Markedly reduced numbers of B lymphocytes (CD19⁺ cells) in the peripheral circulation (<1%) [Conley 1985, Nonoyama et al 1998]
• Antibody titers to vaccine antigens. Individuals with XLA fail to make antibodies to vaccine antigens like tetanus, H influenzae, or S pneumoniae. Vaccination using SARS-CoV-2 also does not generate antigen-specific antibodies, but cellular immune responses are normal and likely provide protection against severe disease [Gao et al 2022].
• Severe neutropenia in ~10%-25% of individuals at the time of diagnosis, usually in association with pseudomonas or staphylococcal sepsis [Conley & Howard 2002]

Family history of immunodeficiency consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Male proband. The diagnosis of XLA is established in a male proband with suggestive findings and a hemizygous pathogenic (or likely pathogenic) variant in BTK identified by molecular genetic testing (see Table 1).

Female proband. The diagnosis of XLA can be established in a female proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in BTK identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous BTK variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Males with X-linked agammaglobulinemia (XLA) are usually well for the first few months of life because they are protected by transplacentally acquired maternal immunoglobulin. Typically, affected males develop recurrent bacterial infections in the first two years of life and are recognized as having immunodeficiency before age five years [Conley et al 2009, Hernandez-Trujillo et al 2023].

Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. Because males with XLA fail to make antibodies to vaccine antigens like tetanus, H influenzae, or S pneumoniae, the latter two organisms are the most commonly seen prior to diagnosis of XLA, and they may continue to cause sinusitis and otitis even after diagnosis and the initiation of gammaglobulin substitution therapy [Conley et al 2005, Hernandez-Trujillo et al 2023].

Individuals with XLA are not vulnerable to the majority of viral infections; however, they are susceptible to severe and chronic enteroviral infections (often manifesting as dermatomyositis or chronic meningoencephalitis) [Wilfert et al 1977, Bearden et al 2016]. In the past, 5%-10% of individuals with XLA developed vaccine-associated polio after vaccination with the live attenuated oral polio vaccine. Since the mid-1980s, when gammaglobulin substitution therapy became available, the incidence of chronic enteroviral infection has markedly decreased in individuals with XLA. However, some individuals still develop enteroviral encephalitis, and some have neurologic deterioration of unknown etiology [Misbah et al 1992, Ziegner et al 2002].

Like all individuals with antibody deficiencies, persons with XLA are highly susceptible to giardia infection. They may also develop persistent mycoplasma infections. Infections with unusual organisms, like Flexispira or Helicobacter cinaedi, may also be troublesome [Cuccherini et al 2000, Simons et al 2004].

Approximately 10% of males with a hemizygous BTK pathogenic variant are not recognized as having immunodeficiency until after age ten years and some not until adulthood [Howard et al 2006, Conley et al 2008]. Some affected males have higher serum immunoglobulin concentrations than expected, but all have very low numbers of B cells.

The prognosis for individuals with XLA has improved markedly in the last 35 years [Howard et al 2006] as a result of earlier diagnosis, more liberal use of antibiotics, and the development of preparations of gammaglobulin that allow gammaglobulin substitution therapy to achieve normal concentrations of serum immunoglobulin (Ig) G. Most individuals lead a normal life. However, approximately 10% develop significant infections despite appropriate therapy, and many have chronic pulmonary changes [Quartier et al 1999].

Heterozygous females. Two females with XLA have been reported. They demonstrated preferential use of an X chromosome carrying BTK mutations [Takada et al 2004, Garcia-Prat et al 2024].

Genotype-Phenotype Correlations

No strong correlation is observed between the specific BTK pathogenic variant and the severity of disease; however, individuals who have amino acid substitutions or splice defects that occur at sites that are conserved (but not invariant) tend to be older at the time of diagnosis, and have higher serum concentrations of IgM and slightly more B cells in the peripheral circulation [López-Granados et al 2005, Broides et al 2006].

Nomenclature

Bruton called the disorder that he first described in 1952 "agammaglobulinemia" (despite low levels of detected immunoglobulins). The X-linked pattern of inheritance was noted shortly after that time.

In the 1950s, 1960s, and 1970s, the disorder was sometimes called congenital agammaglobulinemia, familial hypogammaglobulinemia, infantile agammaglobulinemia, or simply agammaglobulinemia.

Prevalence

Prevalence of X-linked agammaglobulinemia is approximately 3-6:1,000,000 males in all racial and ethnic groups.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with XLA, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Live viral vaccines, particularly oral polio vaccine, should be avoided in individuals with XLA.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of at-risk male relatives as soon after birth as possible so that gammaglobulin substitution therapy can be initiated promptly in affected individuals and administration of live viral vaccines can be avoided.

Note: Additional clinical evaluations can include analysis of the percentage of B cells in the peripheral circulation and physical examination with a focus on lymphoid tissues. Serum immunoglobulins will not be helpful in the evaluation of a newborn or infant because maternal IgG crosses the placenta.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Research studies exploring virus-mediated and oligonucleotide gene therapy for XLA have been conducted in mice [Kerns et al 2010, Ng et al 2010, Sather et al 2011, Bestas et al 2014], but it is not clear when this type of treatment may be available for humans. Gene editing of hematopoietic stem cells is also being developed but to date is not clinically available for XLA treatment [Gray et al 2021].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

By definition, X-linked agammaglobulinemia (XLA) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the BTK pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a female has more than one affected child and no other affected relatives and if the BTK pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism [Sakamoto et al 2001, Rivière et al 2020].
• If a male is the only affected family member (50% of affected males represent simplex cases), the mother may be a heterozygote (carrier), the affected male may have a de novo BTK pathogenic variant (in which case the mother is not a carrier), or the mother may have somatic/gonadal mosaicism.
  • In about 80%-85% of families, the mother of an affected male is heterozygous for a BTK pathogenic variant.
  • About 15%-20% of affected males have XLA as the result of a de novo pathogenic variant.
• Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment.

Sibs of a male proband. The risk to sibs of a male proband depends on the genetic status of the mother:

• If the mother of the proband has a BTK pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected.
  • Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see Clinical Description, Heterozygous females).
• If the proband represents a simplex case and the BTK pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism. Gonadal mosaicism has been observed [Sakamoto et al 2001, Rivière et al 2020]. Thus, if an affected male represents a simplex case and the BTK pathogenic variant cannot be detected in the leukocyte DNA of his mother, male sibs are still at increased risk (<5%) of being affected.

Offspring of a male proband. Affected males transmit the BTK pathogenic variant to:

• All of their daughters, who will be carriers and highly unlikely to be affected;
• None of their sons.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having a BTK pathogenic variant.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Carrier Detection

Identification of female heterozygotes requires either prior identification of the BTK pathogenic variant in the family or, if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Note: Females who are heterozygous (carriers) for this X-linked disorder are highly unlikely to be affected.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the BTK pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for XLA is possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

BTK encodes tyrosine-protein kinase BTK (BTK), a tyrosine kinase that is expressed in hematopoietic progenitors, myeloid cells and platelets, and B lineage cells. Although BTK is expressed in several hematopoietic cell types, it is primarily needed for signaling from the antigen-specific B-cell receptor. Its downstream substrate is phospholipase Cγ2, which among other things activates NF-κB signaling. Activation of NF-κB is needed for B cell survival.

More than 1,000 different pathogenic variants in BTK have been reported [Väliaho et al 2006, Schaafsma et al 2023]. Two thirds of pathogenic variants are premature stop codons, splice defects, or frameshift variants. These variants result in improper processing of the BTK message. Therefore, no BTK message can be identified in the cytoplasm.

Several deep intronic pathogenic variants that would not be detected by routine sequence analysis have been reported [Kralovicova et al 2011, Mohiuddin et al 2013, Rattanachartnarong et al 2014].

Approximately 3%-5% of affected individuals who have a large deletion that extends through neighboring genes have XLA and deafness-dystonia-optic neuropathy syndrome (DDON, also called Mohr-Tranebjærg syndrome; see Genetically Related Disorders).

Mechanism of disease causation. Loss of function

Author Notes

BTKbase

Acknowledgments

We are indebted to Dr Mauno Vihinen, University of Lund, who curates the BTKbase mutation database, and to Dr Peter Bergman, Karolinska Institutet, for clinical advice. This work was supported by the Swedish Cancer Society (CAN2013/389; 22 2361 Pj 01 H), the Swedish Medical Research Council (K2015-68X-11247-21-3) and the Swedish County Council (ALF-project 2012006; FoUI97465), and Center for Innovative Medicine (CIMED).

Author History

Mary Ellen Conley, MD; St Jude Children’s Research Hospital (2001-2016)
Vanessa C Howard, RN, MSN; St Jude Children’s Research Hospital (2001-2016)
CI Edvard Smith, MD, PhD (2016-present)
Anna Berglöf, PhD (2016-present)

Revision History

• 27 June 2024 (sw) Comprehensive update posted live
• 4 August 2016 (bp) Comprehensive update posted live
• 17 November 2011 (me) Comprehensive update posted live
• 30 July 2009 (me) Comprehensive update posted live
• 21 December 2005 (me) Comprehensive update posted live
• 3 October 2003 (me) Comprehensive update posted live
• 5 April 2001 (me) Review posted live
• December 2000 (mec) Original submission

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