Clinical Diagnosis

The diagnosis of X-linked agammaglobulinemia (XLA) is considered in individuals with any of the following:

• 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 tonsils and lymph nodes on physical examination)
• Family history of immunodeficiency consistent with X-linked inheritance

Testing

Testing of Immune Function

Affected individuals. Specific blood tests and findings that help confirm the diagnosis of XLA:

• Concentration of serum immunoglobulins [Lederman & Winkelstein 1985, Conley et al 2005]
  • The serum IgG concentration is typically less than 200 mg/dL. Most but not all individuals with XLA do have some measurable serum IgG, usually between 100 and 200 mg/dL, and approximately 10% of individuals have serum concentration of IgG greater than 200 mg/dL.
  • The serum concentrations of IgM and IgA are typically less than 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 is almost always associated with immunodeficiency.
• Antibody titers to vaccine antigens. Individuals with XLA fail to make antibodies to vaccine antigens like tetanus, H influenzae, or S pneumoniae.
• Lymphocyte cell surface markers. The most consistent feature in XLA is markedly reduced numbers of B lymphocytes (CD 19+ cells) in the peripheral circulation (<1%) [Conley 1985, Nonoyama et al 1998]
• Severe neutropenia is seen in approximately 10%-25% of individuals at the time of diagnosis, usually in association with pseudomonas or staphylococcal sepsis [Conley & Howard 2002]. Neutropenia is generally not seen after the initiation of gammaglobulin therapy.

The immune system is otherwise normal.

Female carriers. Tests of immune function are normal.

BTK Protein Testing

Because most mutations in BTK result in the absence of the BTK protein in monocytes, some research laboratories have developed techniques that allow the detection of BTK protein in monocytes by immunofluorescence or western blot [Futatani et al 1998, Gaspar et al 1998]. This can help confirm the diagnosis of XLA when molecular genetic testing is not available or is unsuccessful at detecting a mutation.

Testing Strategy

To confirm/establish the diagnosis in a proband. When the diagnosis of XLA is suspected because a child has had recurrent, persistent, or severe infections:

• Serum immunoglobulins and titers to vaccine antigens should be measured.
• If these are abnormal or the index of suspicion is high, the percentage of CD19+ B cells in the blood should be determined.
• Molecular genetic testing using sequence analysis/mutation scanning first, and then if a mutation is not identified, by deletion/duplication analysis, should be performed to confirm/establish the diagnosis.

If a newborn or infant is being evaluated because of a positive family history of XLA:

• Serum immunoglobulins will not be helpful because maternal IgG crosses the placenta.
• The percentage of B cells should be analyzed as a first step.
• If the percentage of B cells is low, it is reasonable to pursue molecular genetic testing to determine if the at-risk family member has the family-specific mutation.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and usually do not develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Analysis of X-chromosome inactivation patterns has been helpful in assessing carrier risk of at-risk female relatives in the past. However, given the high sensitivity and specificity of clinical molecular genetic testing in current use, this approach is rarely used.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Contiguous gene deletion syndrome. Approximately 3%-5% of individuals with mutations in BTK have large deletions that remove the 3' end of BTK and the closely linked gene TIMM8A (also called DDP) [Richter et al 2001, Sedivá et al 2007]. These individuals have XLA and deafness-dystonia-optic neuropathy syndrome (DDS, also called Mohr-Tranebjærg syndrome). They are generally recognized as having XLA before they develop hearing loss, which is the first sign of DDS. In individuals with the contiguous gene deletion syndrome, the hearing loss may incorrectly be initially attributed to recurrent otitis media.

Natural History

Individuals 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 & Howard 2002, Plebani et al 2002]. The most common infecting organisms include H influenzae and S pneumoniae. Approximately 10% of individuals with mutations in BTK 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 patients have higher serum immunoglobulin concentrations than expected, but all have very low numbers of B cells.

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 commonly seen organisms prior to diagnosis and they may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin therapy [Lederman & Winkelstein 1985, Conley et al 2005].

Individuals with XLA are not unusually vulnerable to most viral infections; however, they are susceptible to severe and chronic enteroviral infections [Wilfert et al 1977]. 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 intravenous gammaglobulin became available, the incidence of chronic enteroviral infection has markedly decreased in individuals with XLA. However, some patients 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 unusually susceptible to giardia infection. They may also develop problems with persistent mycoplasma infections. Infections with unusual organisms, like Flexispira or Helicobacter cinaedi, may also be troublesome [Cuccherini et al 2000, Simons et al 2004].

The prognosis for individuals with XLA has improved markedly in the last 25 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 normal concentrations of serum IgG to be achieved. Most individuals lead a normal life. However, approximately 10% of individuals develop significant infections despite appropriate therapy and many have chronic pulmonary changes [Quartier et al 1999].

Heterozygotes. One female with XLA has been reported. The father of this child had XLA and analysis of her buccal epithelium and peripheral blood demonstrated exclusive use of the paternally derived X chromosome as the active X [Takada et al 2004].

Genotype-Phenotype Correlations

No strong correlation is observed between the specific mutation in BTK 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 they 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.” The X-linked pattern of inheritance was noted shortly after that time. In the 50s, 60s, and 70s, the disorder was sometimes called congenital agammaglobulinemia, familial hypogammaglobulinemia or infantile agammaglobulinemia, or simply agammaglobulinemia.

Prevalence

Prevalence is approximately three to six per million males in all racial and ethnic groups.

Evaluations Following Initial Diagnosis

A patient with XLA should receive specialty care at a center with expertise in this disorder.

To establish the extent of disease and needs of an individual diagnosed with X-linked agammaglobulinemia (XLA), the following evaluations are recommended:

• A complete blood count with differential
• Chemistries that include renal and liver function tests, total protein, albumin, and CRP
• Quantitative serum immunoglobulins and titers to vaccine antigens
• Base line chest and sinus x-rays
• If the patient is able to cooperate, base line pulmonary function tests

Treatment of Manifestations

If individuals develop acute infections, they should be treated with a course of antibiotics that is at least twice as long as that used in otherwise healthy individuals.

Prevention of Primary Manifestations

Prevention of Secondary Complications

Children with XLA should be given inactivated polio vaccine (IPV) rather than oral polio vaccine.

The siblings of children with XLA should also be given IPV rather than oral polio vaccine (in order to avoid infecting their affected sib with live virus).

Surveillance

At least once a year:

• A complete blood count with differential, chemistries, and quantitative serum immunoglobulins
• Chest x-rays or CTs and sinus films
  Note: Chronic lung disease can develop in the absence of an acute pulmonary infection [Quartier et al 1999].

If the patient is stable, the serum IgG does not need to be evaluated with every infusion of gammaglobulin.

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 evaluate at-risk male relatives as soon after birth as possible by molecular genetic testing for the known family-specific BTK mutation or by analyzing the percentage of B cells in the peripheral circulation, so that gammaglobulin replacement therapy can be initiated as soon as possible and so that administration of live viral vaccines can be avoided.

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

Pregnancy Management

No special precautions need to be taken at the time of delivery of an infant known to have XLA.

Therapies Under Investigation

Research studies exploring gene therapy for XLA have been conducted in mice [Kerns et al 2010, Ng et al 2010], but it is not clear when this type of treatment may be available for humans.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Affected individuals are encouraged to lead a normal, active life including participation in sports.

Mode of Inheritance

X-linked agammaglobulinemia is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of a male proband is neither affected nor a carrier.
• Mothers who have an affected son and one other affected relative in the maternal line (e.g., brother, uncle, nephew) are obligate carriers.
• Fifty percent of males have no family history of XLA. If an affected male is the only affected individual in the family, two possibilities regarding his mother's carrier status and carrier risks of extended family members need to be considered [Conley et al 1998]:
  • The mother is not a carrier and the affected male has a de novo disease-causing mutation (~15%-20% of cases).
  • The mother is a carrier of a disease-causing mutation (~80%-85% of cases).

Sibs of a male proband

• The risk to the sibs depends on the carrier status of the mother.
• If the mother is a carrier, there is a 50% chance of transmitting the BTK mutation in each pregnancy:
  • Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers.
  • Females carrying a BTK mutation are asymptomatic.
• If the proband is the only affected individual in the family and if his mother's carrier status is unknown, she has an approximately 80% chance of being a carrier [Conley et al 1998]. Thus, male sibs have a 40% chance of having XLA and female sibs have a 40% chance of being carriers.
• Germline mosaicism has been observed. Thus, if an affected male represents a single case in a family and if his mother has no evidence of her son's BTK disease-causing mutation in DNA extracted from her leukocytes, the male sibs are still at increased risk (<5%) of being affected.

Offspring of a male proband

• All daughters of a male proband will inherit the mutant BTK allele and will be carriers for XLA. Females carrying a BTK mutation are asymptomatic.
• The sons of a male proband will not inherit the mutant allele, have XLA, or pass it on to their offspring.

Other family members of a male proband. The proband's maternal aunts and their offspring may be at risk of being carriers or being affected (depending on their gender, family relationship, and the carrier status of the proband's mother). Linkage analysis has shown that the maternal grandfather is the source of a de novo mutation in the majority of males who have no family history of XLA and that the maternal grandmothers are carriers less than 20% of the time [Conley et al 1998]. Therefore, the risk that the maternal aunt of a boy with no family history of XLA is a carrier is less than 10%.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation in the family is known.

When the BTK mutation in the proband has not been identified, linkage analysis can be used to provide carrier detection in families with an unequivocal diagnosis of XLA in multiple generations.

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, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks' gestation) or by amniocentesis (usually performed at ~15-18 weeks' gestation). If the karyotype is 46,XY and if the disease-causing mutation has been identified in a family member, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Prenatal testing for conditions which (like X-linked agammaglobulinemia) do not affect intellect and have some treatment available is not commonly requested. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Literature Cited

1. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol. 2004;112:1–7. [PubMed: 15207776]
2. Broides A, Yang W, Conley ME. Genotype/phenotype correlations in X-linked agammaglobulinemia. Clin Immunol. 2006;118:195–200. [PubMed: 16297664]
3. Conley ME. B cells in patients with X-linked agammaglobulinemia. J Immunol. 1985;134:3070–4. [PubMed: 3920309]
4. Conley ME, Broides A, Hernandez-Trujillo V, Howard V, Kanegane H, Miyawaki T, Shurtleff SA. Genetic analysis of patients with defects in early B-cell development. Immunol Rev. 2005;203:216–34. [PubMed: 15661032]
5. Conley ME, Farmer DM, Dobbs AK, Howard V, Aiba Y, Shurtleff SA, Kurosaki T. A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clin Exp Immunol. 2008;152:39–44. [PMC free article: PMC2384053] [PubMed: 18241230]
6. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr. 2002;141:566–71. [PubMed: 12378199]
7. Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J. Mutations in BTK in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998;62:1034–43. [PMC free article: PMC1377085] [PubMed: 9545398]
8. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190–7. [PubMed: 10600329]
9. Cuccherini B, Chua K, Gill V, Weir S, Wray B, Stewart D, Nelson D, Fuss I, Strober W. Bacteremia and skin/bone infections in two patients with X-linked agammaglobulinemia caused by an unusual organism related to Flexispira/Helicobacter species. Clin Immunol. 2000;97:121–9. [PubMed: 11027452]
10. Dobbs AK, Yang T, Farmer D, Kager L, Parolini O, Conley ME. Cutting edge: a hypomorphic mutation in Igbeta (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development. J Immunol. 2007;179:2055–9. [PubMed: 17675462]
11. Ferrari S, Lougaris V, Caraffi S, Zuntini R, Yang J, Soresina A, Meini A, Cazzola G, Rossi C, Reth M, Plebani A. Mutations of the Igbeta gene cause agammaglobulinemia in man. J Exp Med. 2007a;204:2047–51. [PMC free article: PMC2118692] [PubMed: 17709424]
12. Ferrari S, Zuntini R, Lougaris V, Soresina A, Sourková V, Fiorini M, Martino S, Rossi P, Pietrogrande MC, Martire B, Spadaro G, Cardinale F, Cossu F, Pierani P, Quinti I, Rossi C, Plebani A. Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia. Genes Immun. 2007b;8:325–33. [PubMed: 17410177]
13. Futatani T, Miyawaki T, Tsukada S, Hashimoto S, Kunikata T, Arai S, Kurimoto M, Niida Y, Matsuoka H, Sakiyama Y, Iwata T, Tsuchiya S, Tatsuzawa O, Yoshizaki K, Kishimoto T. Deficient expression of Bruton's tyrosine kinase in monocytes from X- linked agammaglobulinemia as evaluated by a flow cytometric analysis and its clinical application to carrier detection. Blood. 1998;91:595–602. [PubMed: 9427714]
14. Gaspar HB, Lester T, Levinsky RJ, Kinnon C. Bruton's tyrosine kinase expression and activity in X-linked agammaglobulinaemia (XLA): the use of protein analysis as a diagnostic indicator of XLA. Clin Exp Immunol. 1998;111:334–8. [PMC free article: PMC1904924] [PubMed: 9486400]
15. Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Backesjo CM, Vihinen M, Hubbard SR, Belohradsky BH, Smith CI, Meindl A. Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics. 1998;101:276–84. [PubMed: 9445504]
16. Howard V, Greene JM, Pahwa S, Winkelstein JA, Boyle JM, Kocak M, Conley ME. The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol. 2006;118:201–8. [PubMed: 16377251]
17. Kerns HM, Ryu BY, Stirling BV, Sather BD, Astrakhan A, Humblet-Baron S, Liggitt D, Rawlings DJ. B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia. Blood. 2010;115:2146–55. [PMC free article: PMC2844021] [PubMed: 20093406]
18. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Medicine (Baltimore). 1985;64:145–56. [PubMed: 2581110]
19. Lindvall JM, Blomberg KE, Valiaho J, Vargas L, Heinonen JE, Berglof A, Mohamed AJ, Nore BF, Vihinen M, Smith CI. Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling. Immunol Rev. 2005;203:200–15. [PubMed: 15661031]
20. López-Granados E, Porpiglia AS, Hogan MB, Matamoros N, Krasovec S, Pignata C, Smith CI, Hammarstrom L, Bjorkander J, Belohradsky BH, Casariego GF, Garcia Rodriguez MC, Conley ME. Clinical and molecular analysis of patients with defects in μheavy chain gene. J Clin Invest. 2002;110:1029–35. [PMC free article: PMC151150] [PubMed: 12370281]
21. López-Granados E, Pérez de Diego R, Ferreira Cerdán A, Fontán Casariego G, García Rodríguez MC. A genotype-phenotype correlation study in a group of 54 patients with X-linked agammaglobulinemia. J.Allergy Clin.Immunol. 2005;116:690–7. [PubMed: 16159644]
22. Misbah SA, Spickett GP, Ryba PC, Hockaday JM, Kroll JS, Sherwood C, Kurtz JB, Moxon ER, Chapel HM. Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. J Clin Immunol. 1992;12:266–70. [PubMed: 1512300]
23. Ng YY, Baert MR, Pike-Overzet K, Rodijk M, Brugman MH, Schambach A, Baum C, Hendriks RW, van Dongen JJ, Staal FJ. Correction of B-cell development in Btk-deficient mice using lentiviral vectorswith codon-optimized human BTK. Leukemia. 2010;24:1617–30. [PubMed: 20574453]
24. Nonoyama S, Tsukada S, Yamadori T, Miyawaki T, Jin YZ, Watanabe C, Morio T, Yata J, Ochs HD. Functional analysis of peripheral blood B cells in patients with X-linked agammaglobulinemia. J Immunol. 1998;161:3925–9. [PubMed: 9780159]
25. Pérez de Diego R, Bravo J, Allende LM, López-Granados E, Rivera J, Ferreira A, Fontán G, García Rodríguez MC. Identification of novel non-pathogenic mutation in SH3 domain of Btk in an XLA patient. Mol Immunol. 2008;45:301–3. [PubMed: 17707910]
26. Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, Cazzola G, Consolini R, De Mattia D, Dell'Erba G, Duse M, Fiorini M, Martino S, Martire B, Masi M, Monafo V, Moschese V, Notarangelo LD, Orlandi P, Panei P, Pession A, Pietrogrande MC, Pignata C, Quinti I, Ragno V, Rossi P, Sciotto A, Stabile A. Italian Pediatric Group for XLA-AIEOP; Clinical, immunological, and molecular analysis in a large cohort of patiens with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002;104:221–30. [PubMed: 12217331]
27. Quartier P, Debre M, De Blic J, de Sauverzac R, Sayegh N, Jabado N, Haddad E, Blanche S, Casanova JL, Smith CI, Le Deist F, de Saint Basile G, Fischer A. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. 1999;134:589–96. [PubMed: 10228295]
28. Richter D, Conley ME, Rohrer J, Myers LA, Zahradka K, Kelecic J, Sertic J, Stavljenic-Rukavina A. A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness. Pediatr Allergy Immunol. 2001;12:107–11. [PubMed: 11338284]
29. Sedivá A, Smith CI, Asplund AC, Hadac J, Janda A, Zeman J, Hansíková H, Dvoráková L, Mrázová L, Velbri S, Koehler C, Roesch K, Sullivan KE, Futatani T, Ochs HD. Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. J Clin Immunol. 2007;27:640–6. [PubMed: 17851739]
30. Simons E, Spacek LA, Lederman HM, Winkelstein JA. Helicobacter cinaedi bacteremia presenting as macules in an afebrile patient with X-linked agammaglobulinemia. Infection. 2004;32:367–8. [PubMed: 15597229]
31. Takada H, Kanegane H, Nomura A, Yamamoto K, Ihara K, Takahashi Y, Tsukada S, Miyawaki T, Hara T. Female agammaglobulinemia due to the Bruton tyrosine kinase deficiency caused by extremely skewed X-chromosome inactivation. Blood. 2004;103:185–7. [PubMed: 12958074]
32. Väliaho J, Smith CI, Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Hum Mutat. 2006;27:1209–17. [PubMed: 16969761]
33. van Zelm MC, Geertsema C, Nieuwenhuis N, de Ridder D, Conley ME, Schiff C, Tezcan I, Bernatowska E, Hartwig NG, Sanders EA, Litzman J, Kondratenko I, van Dongen JJ, van der Burg M. Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. Am.J.Hum Genet. 2008;82:320–32. [PMC free article: PMC2427306] [PubMed: 18252213]
34. Vihinen M, Kwan SP, Lester T, Ochs HD, Resnick I, Väliaho J, Conley ME, Smith CI. Mutations of the human BTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia. Hum Mutat. 1999;13:280–5. [PubMed: 10220140]
35. Wilfert CM, Buckley RH, Mohanakumar T, Griffith JF, Katz SL, Whisnant JK, Eggleston PA, Moore M, Treadwell E, Oxman MN, Rosen FS. Persistent and fatal central-nervous-system ECHOvirus infections in patients with agammaglobulinemia. N Engl J Med. 1977;296:1485–9. [PubMed: 301244]
36. Ziegner UH, Kobayashi RH, Cunningham-Rundles C, Español T, Fasth A, Huttenlocher A, Krogstad P, Marthinsen L, Notarangelo LD, Pasic S, Rieger CH, Rudge P, Sankar R, Shigeoka AO, Stiehm ER, Sullivan KE, Webster AD, Ochs HD. Progressive neurodegeneration in patients with primary immunodeficiency disease on IVIG treatment. Clin Immunol. 2002;102:19–24. [PubMed: 11781063]

Revision History

• 17 November 2011 (me) Comprehensive update posted live
• 30 July 2009 (me) Comprehensive update posted live
• 21 December 2005 (me) Comprehensive update posted to live Web site
• 4 November 2004 (mec) Revision: test availability
• 3 October 2003 (me) Comprehensive update posted to live Web site
• 5 April 2001 (me) Review posted to live Web site
• December 2000 (mec) Original submission