Patients suffering from X-linked hypogammaglobulinemia (XLH) typically present with systemic and recurring infections starting at a very early age. B-cell defects can occur at birth, systemic infections can start at any time. Infections may become more severe even starting at the age of 6-18 months. Most common symptoms in XLH patients are otitis media, sinusitis, pneumonia, bronchitis, sepsis, meningitis, skin abscess, edema, hemolytic anemia, gastrointestinal infections caused by the Giardia parasite presenting with diarrhea and abdominal pain, enteroviral infections (e.g. poliovirus) and dermatomyositis-meningoencephalitis syndrome. Tonsils and lymph nodes are always small in XLH patients. Infections can also invade the bloodstream and affect joints, bones and the brain. Pneumococcus, streptococcus, staphylococcus and H. influenzae bacteria are most prevalent in these infections [1] [2] [3] [4].

XLH has a prevalence of 1 in 250,000 newborn males. Females never present with XLH but have a 50% chance to transmit XLH to their male progeny. Since XLH is a genetic disease, cases can accumulate in families. Spontaneous mutations make up for up to fifty percent of diagnosed cases. XLH is caused by disruptive mutations in the BTK, most of which are missense mutations conducive to protein truncations [5]. Causative mutations can be retrieved online from the BTKbase [6]. Impaired BTK function is conducive to a lower proliferation and maturation rate of B cells. Consequently, the humoral immune response operates at a strongly reduced efficiency. Infection onset due to XLH is highly variable but most likely to begin at the age of six months in male infants.

• 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]

  The diagnosis was delayed due to near-normal levels of serum immunoglobulins, although he presented with severe and recurrent bacterial infections since the age of 1year. [ncbi.nlm.nih.gov]

• Sepsis

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

  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 testing CBC with white blood [arupconsult.com]

  Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD). [ncbi.nlm.nih.gov]

• Short Stature

  The workup for proportionate short stature revealed isolated growth hormone deficiency. [ncbi.nlm.nih.gov]

  stature Decreased body height Small stature [ more ] 0004322 Sinusitis Sinus inflammation 0000246 Skin rash 0000988 Skin ulcer Open skin sore 0200042 30%-79% of people have these symptoms Arthritis Joint inflammation 0001369 Cellulitis Bacterial infection [rarediseases.info.nih.gov]

• Chills

  SCIg is ideal for patients who benefit from maintaining steady serum levels of immunoglobulins or who are unable to tolerate IVIG due to adverse side effects (headache, chills, nausea, thrombotic events). [immunodeficiencysearch.com]

  Sometimes, people with XLA have a reaction to gammaglobulin, which may include headaches, chills, backache, or nausea. These reactions are more likely to occur when they have a viral infection or when the brand of gammaglobulin has been changed. [rarediseases.info.nih.gov]

• Recurrent Respiratory Infection

  Patients with X-linked agammaglobulinaemia may present with: Reduced lymphoid or reticuloendothelial organs, including the tonsil, lymph nodes, spleen, adenoids and intestinal Peyer patches Recurrent respiratory infections, including otitis media, pneumonia [dermnetnz.org]

  Symptoms and Signs The first manifestations are often hemorrhagic (usually bloody diarrhea), followed by recurrent respiratory infections, eczema, and thrombocytopenia. [merck.com]

  From early childhood, they exhibit recurrent respiratory infections such as sinusitis, pneumonia, and otitis media; severe bacterial infections such as septicemia, osteomyelitis, and meningitis may also occur. [frontiersin.org]

  Cedzynski et al. reported an association between relative L-ficolin deficiency and recurrent respiratory infections coexisting with asthma in children [ 34 ]. [hindawi.com]

• Absent Tonsils

  tonsils, adenoids and lymph nodes) Common laboratory features: Hypogammaglobulinemia (markedly low IgG that becomes apparent after the loss of maternal antibodies as well as low or absent IgM and IgA), low or absent specific antibody titers, B-cell lymphopenia [seattlechildrens.org]

  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]

  Physical Examination ◦ Absence of lymph nodes and tonsils (tissues normally highly populated by B cells) distinct from other forms of antibody deficiency ◦ Small or absent tonsils also be seen in patients with some CIDs and other congenital agammaglobulinemia [slideshare.net]

  Diagnosis The diagnosis of agammaglobulinemia should be considered in any individual (male or female) with recurrent or severe bacterial infections, particularly if they have small or absent tonsils and lymph nodes. [primaryimmune.org]

  In the absence of family history of X-SCID and prior to newborn screening for X-SCID, most males with typical X-SCID come to medical attention between ages three and six months with failure to thrive, oral/diaper candidiasis, absent tonsils and lymph [ncbi.nlm.nih.gov]

• Chronic Diarrhea

  Similarly, 7% of these patients had abdominal pain and 9% chronic diarrhea. [ncbi.nlm.nih.gov]

  There is an increased susceptibility to enterovirus infections (polio, coxsackie, echo virus), which can cause chronic diarrhea, meningitis, or fatal disseminated infection. 6. [immunodeficiencysearch.com]

  Showing of 49 | Medical Terms Other Names Learn More: HPO ID 80%-99% of people have these symptoms Abnormality of the tonsils 0100765 Agammaglobulinemia 0004432 Chronic diarrhea 0002028 Chronic otitis media Chronic infections of the middle ear 0000389 [rarediseases.info.nih.gov]

• Abdominal Pain

  Similarly, 21% reported symptoms of chronic diarrhea and 17% reported abdominal pain, however only 4% had been diagnosed with Crohn's disease. [ncbi.nlm.nih.gov]

  On the same day the paediatric patient began to report pain in the anus area during defecation. An ultrasound examination of the abdominal cavity confirmed the presence of perianal abscess (fig. 1). Fig. 1. [czytelniamedyczna.pl]

  At the age of 13 years he was admitted for left-sided abdominal pain and was noted to have lower left abdominal tenderness. [lymphosign.com]

  Arthritis had been diagnosed only in 7% XLA patients, despite 20% reported painful joints and 11% reported swelling of the joints. Similarly, 21% reported symptoms of chronic diarrhea and 17% reported abdominal pain. [intechopen.com]

• Recurrent Diarrhea

  Other infections reported included sinusitis, bronchiectasis, arthritis, skin infections, meningitis, and recurrent diarrhea. [ncbi.nlm.nih.gov]

  diarrhea Cellulitis Life-threatening infections uncommon Sepsis Meningitis/encephalitis Septic arthritis/osteomyelitis References Additional Resources 24795713 Al-Herz W Bousfiha A Casanova JL Chatila T Conley MEllen Cunningham-Rundles C Etzioni A Franco [arupconsult.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. [clinicaladvisor.com]

  Seventy percent of patients had at least 1 episode of otitis, 62% at least 1 episode of pneumonia, 60% at least 1 episode of sinusitis, 23% at least 1 episode of chronic/recurrent diarrhea, 21% at least 1 episode of conjunctivitis, 18% at least 1 episode [intechopen.com]

• Hearing Impairment

  […] more ] 0000750 Diarrhea Watery stool 0002014 Encephalitis Brain inflammation 0002383 Enteroviral dermatomyositis syndrome 0003729 Enteroviral hepatitis 0001412 Epididymitis 0000031 Hearing impairment Deafness Hearing defect [ more ] 0000365 Lymph node [rarediseases.info.nih.gov]

• Arthritis

  Twenty percent of patients with XLA may have arthritis. Septic arthritis may occur, but there is also a form of arthritis that is similar to rheumatoid arthritis or juvenile chronic arthritis. [ncbi.nlm.nih.gov]

  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]

  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

  Data from the USIDNET Registry on 149 patients with XLA, revealed that 12% had pain, swelling or arthralgias, while 18% had been diagnosed with arthritis. Similarly, 7% of these patients had abdominal pain and 9% chronic diarrhea. [ncbi.nlm.nih.gov]

  Data from the United States Immune Deficiency Network (USIDNET) Registry on 149 patients with XLA revealed that 12% had pain, swelling, or arthralgia, while 18% had been diagnosed with arthritis [67]. [intechopen.com]

Diagnosis should build on three cornerstone criteria. First, a thorough analysis of the family history should provide hints about a possibly inherited XLH manifestation. Second, persistent and recurring infections in the context of otitis media, chronic coughs, and pneumonia are a key indication of a possible XLH case. Conclusive evidence can be provided by molecular genetic tests [7] probing for known BTK mutations [6] and by immunologic tests.

A significant reduction in all classes of serum immunoglobulins (IgG, IgE, IgM, IgA) and a small peripheral B lymphocyte count are strong indicators of XLH. Pronounced neutropenia can be observed in up to 25% of XLH patients [8]. Furthermore, antibody titer measurement after vaccination may further corroborate the diagnosis, since XLH patients fail to produce antibodies upon vaccination due to an impaired immune response [9] [10].

XLH cannot be cured. Treatment consists of systemic antibiotic therapies to counter infection symptoms on the one hand and on immunoglobulin therapies on the other hand. Maintenance of an IgG level of 500-800 mg/dL is recommended by intravenous or subcutaneous administration [9].

• Hypogammaglobulinemia

  MATERIALS AND METHODS: Heparinized venous blood samples were collected from some hypogammaglobulinemia adults. [ncbi.nlm.nih.gov]

  X linked hypogammaglobulinemia X-linked agammaglobulinemia X-linked hypogammaglobulinemia Clinical Information X-linked agammaglobulinemia. [icd9data.com]

  A case of Ureaplasma urealyticum septic arthritis in a patient with hypogammaglobulinemia. Clin Infect Dis, 1993; 16(2):293-4. [PubMed] [CrossRef] 19. [journal-imab-bg.org]

  2, record 1, English, congenital%20hypogammaglobulinemia correct Bruton hypogammaglobulinemia 3, record 1, English, Bruton%20hypogammaglobulinemia correct X-linked hypogammaglobulinemia 2, record 1, English, X%2Dlinked%20hypogammaglobulinemia correct [btb.termiumplus.gc.ca]

• Neutropenia

  Eight out of 30 XLA patients (26.7%) developed neutropenia during the course of the disease. In two patients, episodes of neutropenia were identified before or at the time of diagnosis of XLA. [ncbi.nlm.nih.gov]

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

  Neutropenia is a finding in 10 % of patients at presentation and usually occurs with acute infection. The neutropenia typically resolves after the infectious episode is properly treated. [immunodeficiencysearch.com]

  Taking into consideration the location of the infection, leukopenia with neutropenia, as well as an increase in the concentration of P. aeruginosa in the blood, immunodeficiency was proposed. [czytelniamedyczna.pl]

• Immunoglobulin A Decreased

  Patients who begin immunoglobulin replacement therapy before the age of 5 years have a more prolonged survival rate and decreased morbidity. Some patients now survive into their late forties. [patient.info]

  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]

  If the levels of more than two types of immunoglobulin are decreased, XLA should be suspected. 9 Otolaryngologists should also be mindful of this disease when they are caring for otitis media and sinusitis, the most frequent bacterial infections in childhood [doi.org]

  Shabestari et al. [ 23 ] reported a case of a boy with Bruton’s agammaglobulinemia in whom concentrations of main classes of immunoglobulins were decreased within all isotypes including IgE ( BTK gene mutation. [hindawi.com]

Although no curative therapy exists, intravenous immunoglobulin (IVIg) is the mainstay of XLA treatment. [jcadonline.com]

He failed to respond to standard treatment with high dose intravenous immunoglobulin, but showed stabilization and improvement following treatment with fluoxetine. [ncbi.nlm.nih.gov]

Management and treatment There is no curative treatment for XLA but good disease control can be achieved through consistent gammaglobulin therapy. [orpha.net]

The balance between host immunity and the virulence of the causative virus may be involved in the prognosis of meningoencephalitis in XLA. [ncbi.nlm.nih.gov]

Infants who develop polio or persistent viral infections, however, have a poorer prognosis. Prevention Parents of a child with XLA should consider genetic counseling if they are planning to have more children. [medical-dictionary.thefreedictionary.com]

A progressive encephalopathy of unknown etiology has been described in patients with primary immunodeficiency disorders. [ncbi.nlm.nih.gov]

His symptoms resolved with oral tolmetin in the anti-inflammatory dose, and no further evaluations were performed for infectious etiologies. At 12 years of age he presented with pain involving multiple joints. [hindawi.com]

Bruton agammaglobulinemia ( X-linked agammaglobulinemia ) Definition : x-linked recessive disease that causes a complete deficiency of B lymphocytes Epidemiology : appears in boys only Etiology : defect of Bruton's tyrosine kinase expressed in B cells [amboss.com]

Bruton agammaglobulinemia ( X-linked agammaglobulinemia ) Definition : x-linked recessive disease that causes a complete deficiency of B lymphocytes Epidemiology : appears in boys only Etiology : defect of Bruton's tyrosine kinase expressed in B cells [amboss.com]

Summary Epidemiology Estimated prevalence is 1/350,000 to 1/700,000. Annual incidence is not known. The disorder has been reported in various ethnic groups worldwide. Only males are affected and females are asymptomatic carriers. [orpha.net]

[…] 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 immunodeficiency X-linked lymphoproliferative disease HIV Background Epidemiology [arupconsult.com]

Essential features Features of FAP and extraintestinal lesions, including desmoid tumors, bone osteomas and fibromas Due to a mutation in the APC tumor suppressor gene Terminology Rarely also called Plenk-Gardner syndrome Epidemiology Incidence of 1 per [pathologyoutlines.com]

Scope ◦ Introduction ◦ Epidemiology ◦ Mechanism of disease: Pathogenesis ◦ Clinical manifestations ◦ Diagnosis: Laboratory findings ◦ Management ◦ Complications ◦ Prognosis 3. INTRODUCTION 4. [slideshare.net]

Although results are uncertain, they suggest the pathophysiology of Bruton’s XLA may encompass more than simply a B-cell defect. The pathophysiology of PG is also poorly understood. [jcadonline.com]

[…] immunodeficiency 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]

Paediatrics, Neonatology (387) Internal Medicine (386) Pathology and Forensic Medicine (274) Neurology (261) Physiology and Pathophysiology (242) Genetics (224) Surgery, Traumatology and Orthopaedics (183) Medical Chemistry and Biochemistry (174) Infectology [portal.mefanet.cz]

"Brugada" syndrome: clinical data and suggested pathophysiological mechanism. Circulation. 1999 Feb 9. 99(5):666-73. [Medline]. Meregalli PG, Wilde AA, Tan HL. [emedicine.medscape.com]

Despite intense research efforts, as documented by about 5,000 publications on BrS, controversies still exist over its pathophysiology, risk stratification and care. [aerjournal.com]

Although persons with XLA carry the genes to produce immunoglobulins, a genetic defect on the X chromosome prevents their formation. [medical-dictionary.thefreedictionary.com]

High dose intravenous immunoglobulin combined with azithromycin once per week, and a complete avoidance of bacterial reservoirs may be helpful for the prevention of C. lari bacteremia. [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]

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