Signs and symptoms of agammaglobulinemia (often referred as X-linked agammaglobulinemia, or XLA) start to appear several months after birth (between 7-9 months of age in most cases) when maternal immunoglobulins in the child slowly begin to disappear, and are completely absent at the end of the child's first year of life [1] [2]. Having in mind the complete or near-complete dysfunction of B-cells due to mutations in the Bruton tyrosine kinase (BTK) protein, situated on the X chromosome (resulting in almost exclusive appearance of the disease in males), infants are predisposed to numerous infections of bacterial, viral and fungal origin, and their recurrent appearance is usually the first and most important clinical presentation [3] [4]. In particular, patients are most susceptible to infections caused by encapsulated bacteria (such as streptococcus pneumoniae, haemophilus influenzae, and pseudomonas aeruginosa), mycoplasma spp., enteroviruses and giardia lamblia [4] [5]. Recurrent infections of the respiratory system (pneumonia and less commonly sinusitis), skin, the gastrointestinal tract (caused by rotavirus, salmonella spp., and campylobacter spp., in addition to giardiasis) are typical for agammaglobulinemia patients, and recurrent otitis media is described in the vast majority of cases [1] [4] [6]. Central nervous system (CNS) infections, both meningitis, and encephalitis, as well as sepsis and infections of the musculoskeletal system (osteomyelitis and arthritis), can develop in the absence of a timely diagnosis [1] [4] [6]. Hand-foot-and-mouth disease, hepatitis, opportunistic infections (pneumocystis jiroveci pneumonia - PCP) and polio vaccine-related poliomyelitis (as a result of depleted B-cells) are very rare manifestations of agammaglobulinemia but have been reported by certain authors [1] [4] [7].

• Recurrent Infection

  Because gamma globulin is so important in the production of antibodies and the body's ability to defend itself against infection, a deficiency or absence of gamma globulin results in severe and recurrent infections, usually bacterial ones that are difficult [web.archive.org]

  These patients are at risk for frequent recurrent infections, which may become fatal if untreated. Patients have increased susceptibility to encapsulated pyogenic bacteria. [ncbi.nlm.nih.gov]

  Chronic cryptosporidia infection may be particularly problematic in X-linked hyper-IgM. Patients with WAS start experiencing recurrent bacterial infections during the first year of life. [emedicine.com]

  However, recurrent infections related to XLA will likely require careful attention and aggressive treatment. They can cause organ damage and be life-threatening. [sparrow.org]

• Sepsis

  Unexplained sepsis in patients with agammaglobulinemia warrants specific investigation to identify fastidious bacteria such as Spiroplasma spp. [ncbi.nlm.nih.gov]

  Concurrently, and following the administration of human globulin (3.2 gm. gamma globulin) at monthly intervals, he has been free of pneumococcal sepsis for more than a year, whereas he had experienced clinical sepsis at least 19 times in the previous [pediatrics.aappublications.org]

  Other severe infections may include empyema, meningitis, sepsis, or septic arthritis. [orpha.net]

  Tabs Content Clinical Overview Diagnosis Indications for Testing Recurrent infections in males during infancy or early childhood Respiratory tract (lungs, ears, sinuses) Meningitis Sepsis Gastrointestinal Cutaneous infections Laboratory Testing Nonspecific [arupconsult.com]

• Recurrent Bacterial Infection

  IgA more than 2 SD below normal for age Absent isohemagglutinins Spectrum of disease Most patients with XLA develop recurrent bacterial infections, particularly otitis, sinusitis and pneumonia, in the first two years of life. [esid.org]

  This syndrome is featured by (a) a history of recurrent bacterial infections, (b) absence of acquired antibodies, (c) lack of isohemagglutins, (d) extremely low to absent gamma globulin, although total serum proteins are within normal range, (e) failure [annals.org]

  Recurrent bacterial infections of the skin, lungs and the gastrointestinal tract appearing in infancy are the main clinical presentation. The diagnosis is made based on clinical and laboratory criteria, as well as genetic studies. [symptoma.com]

  X-linked agammaglobulinaemia was the first described entity of this group and is characterised by early onset of recurrent bacterial infections, profound deficiency of all immunoglobulin isotypes and markedly reduced number of peripheral B-lymphocytes [biomed.papers.upol.cz]

• Fever

  Which symptoms you or your child has will depend on what infections you get, but they can include: coughing sore throat fever ear pain congestion sinus pain diarrhea nausea and vomiting abdominal cramps joint pain Several gene changes (mutations) have [healthline.com]

  Further history revealed that he was born at term without complication but was hospitalized at 3 weeks of age for fever, and sepsis workup revealed rhinovirus and neutropenia (ANC 900 cells/mm3). [frontiersin.org]

  Call the healthcare provider if your child has: Symptoms that don’t get better, or get worse Fever New symptoms Key points about X-linked agammaglobulinemia in children X-linked agammaglobulinemia is a rare genetic disease. [urmc.rochester.edu]

  At 7 months he was admitted with cough and fever with small ulcers noted on his lips. Investigations showed bilateral lung infiltrates on chest x-rays, profound neutropenia on blood count, and C-reactive protein of 222 mg/L (Normal 0–8 mg/L). [pediatrics.aappublications.org]

• Increased Susceptibility to Infections

  Neither increased susceptibility to infections nor agammaglobulinemia have been described as a manifestation of terminal 14q32.33 deletion. [ncbi.nlm.nih.gov]

  An increased susceptibility to infection is the clinical hallmark of the disorder. [clinicaladvisor.com]

  Similarly, XLA should be included in the differential diagnosis of the child with an increased susceptibility to infection and neutropenia7,10,18,26,42. [journals.lww.com]

• Pneumonia

  In particular, patients are most susceptible to infections caused by encapsulated bacteria (such as streptococcus pneumoniae, haemophilus influenzae, and pseudomonas aeruginosa), mycoplasma spp., enteroviruses and giardia lamblia. [symptoma.com]

  Epidemiology and etiology of childhood pneumonia. Bulletin of the World Health Organization 2008; 86: 408-416 9 Stein RT, Marostica PJ. Community-acquired pneumonia: a review and recent advances. [thieme-connect.com]

  The parents say that the child has had these symptoms multiple times in the past couple of months and a throat swab sample reveals the presence of Streptoccocus pneumoniae. [step1.medbullets.com]

  TABLE 2: Etiology of Pneumonia TABLE 3: Etiology of Chronic/Recurrent Diarrhea TABLE 4: Etiology of Meningitis/Encephalitis TABLE 5: Etiology of Sepsis TABLE 6: Etiology of Hepatitis Pneumonia The majority of patients (84%) with pneumonia did not have [journals.lww.com]

• Absent Tonsils

  Affected boys have a profound defect in B lymphocyte development resulting in severe hypogammaglobulinemia, absence of circulating B cells, small to absent tonsils, no palpable lymph nodes and abnormal lymph node architecture ( 2-5 ). [journals.lww.com]

  Diagnosis of XLA Diagnosis of XLA or ARA should be considered in patients with recurrent or severe bacterial infections that also have small or absent tonsils and lymph nodes. [immunedisease.com]

  Testing XLA testing is usually recommended for any child with recurrent or severe bacterial infections, particularly if the patient has small or absent tonsils and lymph nodes. First, an evaluation of serum immunoglobins may be conducted. [rh.perkinelmer.com]

  Diagnosis of X-Linked Agammaglobulinemia and Autosomal Recessive Agammaglobulinemia The diagnosis of agammaglobulinemia should be considered in any child with recurrent or severe bacterial infections, particularly if the patient has small or absent tonsils [primaryimmune.org]

• Chronic Diarrhea

  Common Symptoms Serial bacterial infections (including frequent bronchitis episodes), chronic diarrhea, conjunctivitis, otitis media, pneumonia, sinusitis, skin infections, and upper respiratory tract infections. [autoimmuneinstitute.org]

  diarrhea respiratory infections These frequent infections will start showing up within the first couple years of your life. [healthblurbs.com]

  Symptoms Symptoms include frequent episodes of: Bronchitis (airway infection) Chronic diarrhea Conjunctivitis (eye infection) Otitis media (middle ear infection) Pneumonia (lung infection) Sinusitis (sinus infection) Skin infections Upper respiratory [ufhealth.org]

  Symptoms include frequent episodes of: Bronchitis (airway infection) Chronic diarrhea Conjunctivitis (eye infection) Otitis media (middle ear infection) Pneumonia (lung infection) Sinusitis (sinus infection) Skin infections Upper respiratory tract infections [nlm.nih.gov]

• Recurrent Diarrhea

  diarrhea Cellulitis Life-threatening infections uncommon Sepsis Meningitis / encephalitis Septic arthritis/osteomyelitis ARUP Lab Tests Tests generally appear in the order most useful for common clinical situations. [arupconsult.com]

  Chronic and/or Recurrent Diarrhea Over half of the patients with chronic and/or recurrent diarrhea had an organism identified. [journals.lww.com]

  Conjunctivitis, chronic recurrent diarrhea, and skin infections are also common. These individuals have undeveloped secondary lymphoid organs, such as lymph nodes because of the absence of mature B-cells. [cancertherapyadvisor.com]

• Failure to Thrive

  […] to thrive and a chronic asymmetrical polyarthritis. [patient.info]

  Growth charts may show evidence of failure to thrive especially in older children. [ncbi.nlm.nih.gov]

  He received his scheduled 2, 4-, and 6-month vaccines without complications and parents denied recurrent skin infections, eczema, failure to thrive, or chronic diarrhea. [frontiersin.org]

• Ecthyma

  CASE REPORT Pseudomonas aeruginosa SEPTIC SHOCK ASSOCIATED WITH ECTHYMA GANGRENOSUM IN AN INFANT WITH AGAMMAGLOBULINEMIA João Fernando Lourenço de ALMEIDA, Jaques SZTAJNBOK, Eduardo Juan TROSTER & Flávio Adolfo Costa VAZ SUMMARY Ecthyma gangrenosum (EG [scielo.br]

  Juvenile ecthyma gangrenosum caused by Pseudomonas aeruginosa revealing an underlying neutropenia: case report and review of the literature. [frontiersin.org]

  Concomitant diagnosis of immune deficiency and Pseudomonas sepsis in a 19 month old with ecthyma gangrenosum by host whole-genome sequencing. Cold Spring Harb Mol Case Stud. 2018 Dec;4(6) [PMC free article: PMC6318772] [PubMed: 30559311] 2. [ncbi.nlm.nih.gov]

  […] quality of life is poor. [12][13][14](Level V) References [1] Sanford E,Farnaes L,Batalov S,Bainbridge M,Laubach S,Worthen HM,Tokita M,Kingsmore SF,Bradley J, Concomitant diagnosis of immune deficiency and {i}Pseudomonas{/i} sepsis in a 19 month old with ecthyma [statpearls.com]

• Arthritis

  Disorders of connective tissue such as scleroderma, arthritis, and lupus erythematosus are also frequent complications. common variable agammaglobulinemia common variable immunodeficiency. [web.archive.org]

  Molecular diagnosis of ureaplasma urealyticum septic arthritis in a patient with hypogammaglobulinemia. Arthritis Rheum, 1992; 35(4):443-448. [ PubMed ] 18. Forgacs P, Kundsin RB, Margles SW, Silverman ML, Perkins RE. [journal-imab-bg.org]

  Risk of infectious arthritis Acute Infectious Arthritis Acute infectious (septic) arthritis is a joint infection that evolves over hours or days. [msdmanuals.com]

  Some patients have a family history of rheumatoid arthritis or allergies. This seems to indicate the presence of genetic factors in the development of agammaglobulinemia. Symptoms. [medical-dictionary.thefreedictionary.com]

  Arthralgia, monoarticular or oligoarticular arthritis of the large joints with sterile effusions and septic arthritis may occur. Anaphylaxis or other severe reactions following transfusion of blood products may indicate an underlying IgA deficiency. [patient.info]

The diagnosis of agammaglobulinemia can be made only if physicians recognize the recurrent nature of infections in infancy and early childhood and order a thorough laboratory investigation. Despite evident clinical criteria for some form of immunodeficiency, however, up to 20% of children are not diagnosed by school age, indicating that clinical suspicion is probably the most important factor in detecting agammaglobulinemia [1] [3] [6]. A detailed patient history focused on the interview with the parents (as children are often too young to provide relevant information) can provide vital clues for the physician. A detailed family history is equally important and may be quite useful in determining whether close family members have or had the diagnosis or experience of similar symptoms, as a significant number of patients have a confirmed family member suffering from agammaglobulinemia [6]. Initial laboratory testing reveals neutropenia in about 15% of cases, whereas reductions in serum immunoglobulins (IgG, IgM and IgA) are readily encountered [1] [5] [6] [8]. A key diagnostic feature of agammaglobulinemia is a markedly lower number of CD19+ B cells (< 2%), while absent isohemagglutinins and/or poor vaccine responses are also important features that make the diagnosis of this primary immunodeficiency highly likely [1] [8]. Confirmation of agammaglobulinemia, however, is achieved by detecting BTK mutations through genetic studies in both the patient and in one of his maternal cousins [1].

• Hypogammaglobulinemia

  This is known as transient hypogammaglobulinemia of infancy and is discussed in detail in a separate article. [emedicine.com]

  ICD-10-CM Diagnosis Code D80.1 Nonfamilial hypogammaglobulinemia 2016 2017 2018 2019 Billable/Specific Code Applicable To Agammaglobulinemia with immunoglobulin-bearing B-lymphocytes Common variable agammaglobulinemia [CVAgamma] Hypogammaglobulinemia [icd10data.com]

  Evaluating and managing hypogammaglobulinemia. Cleve Clin J Med. 2006;73:133-37, 140, 143-44. Lawrence T, Puel A, Reichenbach j, et al. Autosomal-dominant primary immunodeficiencies. Curr Opin Hematol. 2005;12:22-30. [rarediseases.org]

  There is susceptibility to a broader range of infections than with hypogammaglobulinemia alone. [online.epocrates.com]

  SHERMANBANASEDWARDSMACMAHONPATTERSON JDJSTLHEJF: A syndrome of diarrhea, thymoma, and hypogammaglobulinemia. Gastroenterology 51: 681, 1966. CrossrefMedlineGoogle Scholar 23. MCCARTHYAUSTADREAD CFWIAE: Hypogammaglobulinemia and steatorrhea. Amer. J. [acpjournals.org]

• Neutropenia

  His neutropenia was initially treated with GCSF. [frontiersin.org]

  The mechanism of neutropenia is poorly understood. [pediatrics.aappublications.org]

  such as obstruction to hollow viscera and diminished blood supply, changes in the reactivity of the tissues in such metabolic disturbances as scurvy, cortisone therapy and diabetes, and failure of the normal defense mechanisms, as in patients with neutropenia [nejm.org]

  Initial laboratory testing reveals neutropenia in about 15% of cases, whereas reductions in serum immunoglobulins (IgG, IgM and IgA) are readily encountered. [symptoma.com]

• Immunoglobulin A Decreased

  Over time, their immunoglobulin levels begin to decrease because they cannot successfully produce their own. As the immunoglobulin levels decrease, the baby becomes increasingly vulnerable to bacterial infections. [healthofchildren.com]

• Colitis

  HAMMERASHURSTNAISH BPJ: Diseases associated with ulcerative colitis and Crohn's disease. Gut 9: 17, 1968. CrossrefMedlineGoogle Scholar 13. ALMYSHERLOCK TPP: Genetic aspects of ulcerative colitis and regional enteritis. [acpjournals.org]

  They can include: autoimmune disorders such as Crohn’s disease and ulcerative colitis damage to the heart, lungs, nervous system, or digestive tract increased risk for cancer repeated infections slowed growth in children Getting treated for infections [healthline.com]

  […] agammaglobulinemia (XLA). ( 30698158 ) Tavasolian P...Rezaei N 2019 3 Pseudomonas aeruginosa severe skin infection in a toddler with X-linked agammaglobulinemia due to a novel BTK mutation. ( 30882382 ) Riccardi N...Castagnola E 2019 4 Cytomegalovirus Colitis [malacards.org]

  Even with treatment, patients can expect to have chronic pulmonary infections, skin disease, inflammatory bowel disease ( ulcerative colitis and Crohn disease ), and central nervous system complications due to enteroviral infection. [emedicine.medscape.com]

  A few patients with refractory C. difficile colitis have been treated successfully with human IVIG (200 to 400 mg/kg). [cmr.asm.org]

Prolonged suboptimal treatment may cause bacterial resistance to β-lactam antibiotics in H. cinaedi. It is possible that this resistance may have contributed to the treatment failure. [ncbi.nlm.nih.gov]

• Early diagnosis and treatment would improve the survival. • Intravenous immunoglobulin (IVIG) and antibiotic prophylaxis were the conventional treatments which resulted in an increasing survival rate. • Gene therapy of XLA could be considered as a [slideshare.net]

Without treatment, most severe infections are deadly. [ufhealth.org]

Prognosis It is difficult to generalize about the prognosis in hypogammaglobulinemia, as there is a variety of possible underlying diseases, and the prognosis is often dictated by the underlying condition. [online.epocrates.com]

Normal prognosis with regular intravenous immunoglobulin (IVIG) therapy and early detection Please rate this review topic. [step2.medbullets.com]

Prevention, and Complications Prognosis normal prognosis with regular IVIG therapy and early detection Prevention screening in newborns regular IVIG to prevent infections Complications small risk of malignancy Please rate topic. [step1.medbullets.com]

Prognosis The prognosis depends on the age at diagnosis, compliance with therapy and the development of complications. Most patients on treatment can lead a normal life. [orpha.net]

TABLE 2: Etiology of Pneumonia TABLE 3: Etiology of Chronic/Recurrent Diarrhea TABLE 4: Etiology of Meningitis/Encephalitis TABLE 5: Etiology of Sepsis TABLE 6: Etiology of Hepatitis Pneumonia The majority of patients (84%) with pneumonia did not have [journals.lww.com]

Etiology Defects in B lymphocyte development and maturation appear to underlie agammaglobulinemia. [orpha.net]

Introduction Clinical definition primary humoral immunodeficiency characterized by decreased immunoglobulins Epidemiology Demographics boys etiology Pathogenesis defective maturation of B-cells impaired signaling from pre-B cell receptor ↓ B-cells ↓ production [step2.medbullets.com]

Summary Epidemiology Prevalence is estimated to be about 1/250,000 to 1/500/000. Isolated agammaglobulinemia has been reported worldwide in all ethnic groups. [orpha.net]

Introduction Clinical definition primary humoral immunodeficiency characterized by decreased immunoglobulins Epidemiology Demographics boys etiology Pathogenesis defective maturation of B-cells impaired signaling from pre-B cell receptor ↓ B-cells ↓ production [step2.medbullets.com]

Vach 3 Clinical Epidemiology, Institute of Medical Biometry and Medical Informatics, University Medical Centre, University of Freiburg, Germany, M. [thieme-connect.com]

[…] cytometry – if protein expression is absent or reduced, suggests X-linked agammaglobulinemia (XLA) in males Differential Diagnosis X-linked hyper IgM syndrome X-linked severe combined immunodeficienc y X-linked lymphoproliferative disease HIV Background Epidemiology [arupconsult.com]

[…] at Clinical Trials.gov US National Guidelines Clearinghouse NICE Guidance FDA on X-linked agammaglobulinemia pathophysiology CDC on X-linked agammaglobulinemia pathophysiology X-linked agammaglobulinemia pathophysiology in the news Blogs on X-linked [wikidoc.org]

[…] immunodeficienc y X-linked lymphoproliferative disease HIV Background Epidemiology Incidence – estimated 1/250,000-700,000 male births Age 50% diagnosed by 2 years 80% diagnosed by 5 years Sex – >99% male Ethnicity – most commonly diagnosed in Caucasians Pathophysiology [arupconsult.com]

Describe the pathophysiology of Bruton agammaglobulinemia. Describe how to counsel a patient with Bruton agammaglobulinemia. [ncbi.nlm.nih.gov]

Frequently called Bruton's Agammaglobulinemia, XLA is caused by a genetic mistake in a gene called Bruton's Tyrosine Kinase (BTK), which prevents B cells from developing normally. [aaaai.org]

These mutations prevent the development and regulation of B lymphocytes Pre-B-lymphocytes are unable to mature into B lymphocytes. [dovemed.com]

It should be noted here that children with Agammaglobulinemia should not get live vaccinations as the child may end up having the disease for which vaccinations were given instead of preventing it. [epainassist.com]

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2. Ozturk C, Sutcuoglu S, Atabay B, Berdeli A. X-Linked Agammaglobulinemia Presenting with Secondary Hemophagocytic Syndrome: A Case Report. Case Reports in Medicine. 2013;2013:742795.
3. Sigmon JR, Kasasbeh E, Krishnaswamy G. X-linked agammaglobulinemia diagnosed late in life: case report and review of the literature. Clinical and molecular allergy : CMA. 2008;6:5.
4. Chen X-F, Wang W-F, Zhang Y-D, Zhao W, Wu J, Chen T-X. Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000–2015). Medicine (Baltimore). 2016;95(32):e4544.
5. Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, et al. Autoimmunity and Inflammation in X-linked Agammaglobulinemia. J Clin Immunol. 2014;34(6):627-632.
6. Winkelstein JA, Marino MC, Lederman HM, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006;85(4):193-202.
7. Jongco AM, Gough JD, Sarnataro K, et al. X-linked agammaglobulinemia presenting as polymicrobial pneumonia, including Pneumocystis jirovecii. Ann Allergy Asthma Immunol. 2014;112(1):10.1016/j.anai.2013.10.008.
8. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.