X-linked agammaglobulinemia is a disorder of primary immunodeficiency that induces poor production of B lymphocytes. The clinical presentation starts in late infancy and early childhood as maternal antibodies provide adequate protection during the first several months of life. Various forms of recurrent bacterial infections (and enteroviral infections) are the main manifestation of X-linked agammaglobulinemia, which may be life-threatening in the absence of an early therapy. The diagnosis rests on clinical suspicion, laboratory workup, and genetic studies that confirm Bruton tyrosine kinase (Btk) mutations.
X-linked agammaglobulinemia is a form of primary immunodeficiency caused by mutations in the Btk gene, which plays a key role in the maturation and proliferation of B cells     . Given the X-linked recessive mode of inheritance, the condition appears almost exclusively in males and the prevalence rate is established to around 1 in 10,000 in the general population  . The clinical presentation usually starts in the first few years of life, but only after the maternal IgG antibodies cease to protect the infant   . At some point, first signs and symptoms appear and the mean onset is established to be between 2-3 years of age  . The main complaint is in the form of recurrent and persistent infections   . Individuals are particularly susceptible to encapsulated organisms such as Haemophilus influenzae, Pseudomonas spp., and Streptococcus pneumoniae  . Although the immunological response to viral infections remains largely intact, enteroviral infections do occur and can even be life-threatening . Lower respiratory tract infections are the most common types, whereas otitis media, conjunctivitis, gastrointestinal infections, sinusitis, and cutaneous infections are also frequently reported   . Recent advances in treatment have led to markedly improved patient outcomes. Almost 60% of patients are diagnosed when severe, life-threatening infections develop .
Entire Body System
Recurrent Bacterial Infection
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]
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]
Occasionally, individuals with XLA have a reaction to gammaglobulin, consisting of headaches, chills, backache, or nausea. [ncbi.nlm.nih.gov]
Proportionate Short Stature
The workup for proportionate short stature revealed isolated growth hormone deficiency. [ncbi.nlm.nih.gov]
bacterial skin infections (Pseudomonas, Helicobacter pylori), sepsis, arthritis, inflammatory bowel disease, enteroviral meningoencephalitis and dermatomyositis Physical exam: Minimal lymphatic tissue (small or absent tonsils, adenoids and lymph nodes [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]
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]
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]
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]
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]
Infections that cause chronic diarrhea are also common. Recurrent infections can lead to organ damage. [ghr.nlm.nih.gov]
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]
Commonly diagnosed infections include lung infections (pneumonia and bronchitis), middle ear infections, conjunctivitis, sinus infections, various skin infections, and infections that are associated with chronic diarrhea. 0001508 Fatigue Tired Tiredness [rarediseases.info.nih.gov]
Similarly, 7% of these patients had abdominal pain and 9% chronic diarrhea. [ncbi.nlm.nih.gov]
Giardia may cause abdominal pain, diarrhea, poor growth or loss of serum proteins like gamma globulin. Some patients with agammaglobulinemia also have problems with skin infections. [primaryimmune.org]
The main symptoms are (1, 8-10, 12): – recurrent respiratory tract infections (ears, nose, conjunctivae, sinuses, lungs), – digestive tract infections (Giardia lamblia), causing abdominal pain, diarrhea, body mass loss, growth restriction, – inflammation [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]
Similarly, 21% reported symptoms of chronic diarrhea and 17% reported abdominal pain. However, only 4% had been diagnosed with Crohn’s disease. [intechopen.com]
Other infections reported included sinusitis, bronchiectasis, arthritis, skin infections, meningitis, and recurrent diarrhea. [ncbi.nlm.nih.gov]
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]
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]
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]
The clue to an associated hearing problem was delayed development of speech in one patient and post-lingual deafness noticed between the age of 3-4 years in the other two. [ncbi.nlm.nih.gov]
Progressive Sensorineural Deafness
Besides the immunodeficiency, our patients exhibited progressive sensorineural deafness. [ncbi.nlm.nih.gov]
The symptoms of pain, edema of muscles of the right shank with skin edema and discoloration after mild injury were noted in a 13-year-old boy. [ncbi.nlm.nih.gov]
The patient also had characteristic features of von Recklinghausen disease, such as numerous subcutaneous nodules, café-au-lait spots, Lisch nodules in the iris and spinal scoliosis. Biopsy of a subcutaneous nodule confirmed a neurofibroma. [ncbi.nlm.nih.gov]
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 . [intechopen.com]
At 5 years of age, he presented with symptoms of mental deterioration and gait disturbance. He had no history of infection of the central nervous system. [ncbi.nlm.nih.gov]
Type 3 immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) were isolated from a 15-month-old Iranian boy with acute flaccid paralysis (AFP) who was subsequently diagnosed with X-linked agammaglobulinemia (XLA). [ncbi.nlm.nih.gov]
Suspicion toward a primary immunodeficiency must be raised in the presence of recurrent infections in early life, particularly because of the life-threatening risk that is established in this patient population. Moreover, a misdiagnosis until adulthood has been reported. The early recognition can significantly improve the quality of life     . For this reason, physicians should take a detailed patient history, during which the onset of symptoms and their progression should be revealed, whereas a family history must also be obtained . After a physical examination, a detailed laboratory investigation needs to be employed. All classes of serum immunoglobulins are usually decreased in patients suffering from X-linked agammaglobulinemia  . In addition, the number of B lymphocytes in the blood is markedly reduced  . To confirm the diagnosis, however, molecular genetic studies must be performed. Btk protein testing that detects either mutation (missense, splice, and nonsense mutations have all been recognized) or reduced expression is considered to be a definitive method for establishing X-linked agammaglobulinemia as the underlying cause    .
A renal biopsy specimen showed dense CD3-positive lymphocytic infiltration in the tubulointerstitium and tubular atrophy, while no IgG4-bearing cell infiltration was found. Fibrosclerosis and crescent formation were evident in some glomeruli. [ncbi.nlm.nih.gov]
Granulomatous Dermatitis (GD) is defined by an infiltration of mononuclear and multinucleate giant cells in the skin, with or without lymphocyte infiltration (Mohan et al. 2006). [lymphosign.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]
Local antibiotic treatment (drops, lotions) are preferred over systemic treatment (pills) for long-term treatment, if possible. One of the future prospects of XLA treatment is gene therapy, which could potentially cure XLA. [en.wikipedia.org]
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]
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]
Etiology XLA is caused by mutations in the BTK gene (Xq21.33-q22) involved in B lymphocyte differentiation and maturation. [orpha.net]
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]
Scope Introduction Epidemiology Mechanism of disease: Pathogenesis Clinical manifestations Diagnosis: Laboratory findings Management Complications Prognosis 3. INTRODUCTION 4. [slideshare.net]
Epidemiology The incidence is approximately 1 in 250,000 but this may be an underestimate. One third of cases are thought to arise from new mutations. [patient.info]
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]
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]
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]
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Pathophysiology In the absence of BTK, B lymphocytes do not differentiate or mature. Without mature B lymphocytes, antibody-producing plasma cells are also absent. [emedicine.medscape.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]
This prevents the cells responsible for making antibodies (B cells) from developing normally. The immune system relies on antibodies to fight off infection. [sneeze.com]
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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- 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.
- Hashimoto SMT, Futatani T, Kanegane H, et al. Atypical X-linked Agammaglobulinemia Diagnosed in Three Adults. Intern Med. 1999;38:722–725.