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X-Linked Agammaglobulinemia

BTK-Deficiency

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.


Presentation

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 [1] [2] [3] [4] [5]. 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 [1] [5]. The clinical presentation usually starts in the first few years of life, but only after the maternal IgG antibodies cease to protect the infant [1] [2] [4]. At some point, first signs and symptoms appear and the mean onset is established to be between 2-3 years of age [3] [6]. The main complaint is in the form of recurrent and persistent infections [1] [5] [6]. Individuals are particularly susceptible to encapsulated organisms such as Haemophilus influenzae, Pseudomonas spp., and Streptococcus pneumoniae [1] [7]. Although the immunological response to viral infections remains largely intact, enteroviral infections do occur and can even be life-threatening [7]. Lower respiratory tract infections are the most common types, whereas otitis media, conjunctivitis, gastrointestinal infections, sinusitis, and cutaneous infections are also frequently reported [1] [3] [6]. Recent advances in treatment have led to markedly improved patient outcomes. Almost 60% of patients are diagnosed when severe, life-threatening infections develop [1].

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]
  • Bruton's agammaglobulinemia is a rare X-linked humoral immunodeficiency manifesting with recurrent bacterial infections early in life. Klinefelter's syndrome caused by an additional X chromosome is the most common sex chromosome disorder.[ncbi.nlm.nih.gov]
  • Abstract Mutations in Bruton's tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA), which is characterized by recurrent bacterial infections, profound hypogammaglobulinemia, and decreased numbers of mature B cells in peripheral[ncbi.nlm.nih.gov]
  • Abstract X-linked Agammaglobulinemia (XLA) is a hereditary immunodeficiency, characterized by an early onset of recurrent bacterial infections, hypogammaglobulinemia and markedly reduced B lymphocytes number.[ncbi.nlm.nih.gov]
  • Patients typically become symptomatic during infancy or early childhood and develop recurrent bacterial infections. We report a Japanese case of XLA diagnosed in a patient who was 27 years of age and who had no history of severe infection.[ncbi.nlm.nih.gov]
Chills
  • Occasionally, individuals with XLA have a reaction to gammaglobulin, consisting of headaches, chills, backache, or nausea.[ncbi.nlm.nih.gov]
Movement Disorder
  • The clinical course of the encephalopathy seems rather uniform: Cognition, especially frontal lobe function, is affected in the early stages, and some patients develop movement disorders.[ncbi.nlm.nih.gov]
Proportionate Short Stature
  • The workup for proportionate short stature revealed isolated growth hormone deficiency.[ncbi.nlm.nih.gov]
Absent Tonsils
  • 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]
  • The physical findings of decreased or absent tonsils and cervical lymph nodes could have alerted physicians to the diagnosis of XLA [ 51 ].[intechopen.com]
Chronic Diarrhea
  • Similarly, 7% of these patients had abdominal pain and 9% chronic diarrhea.[ncbi.nlm.nih.gov]
  • 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]
  • diarrhea ( Giardia ), steatorrhea Associated with gluten -sensitive enteropathy, inflammatory bowel disease Diagnosis : serum IgA level 7 mg/dL , with normal IgG and IgM levels Treatment Prophylactic antibiotics Intravenous infusion of IgA is not recommended[amboss.com]
Recurrent Diarrhea
  • 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 ARUP Lab Tests Tests generally appear in the order most useful for common clinical situations.[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]
Abdominal Pain
  • 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]
  • Similarly, 21% reported symptoms of chronic diarrhea and 17% reported abdominal pain. However, only 4% had been diagnosed with Crohn’s disease.[intechopen.com]
Progressive Sensorineural Deafness
  • Besides the immunodeficiency, our patients exhibited progressive sensorineural deafness.[ncbi.nlm.nih.gov]
Hearing Problem
  • 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]
Subcutaneous Nodule
  • 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]
Skin Edema
  • 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]
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]
Microscopic Hematuria
  • The patient presented with microscopic hematuria, proteinuria (U-pro/Cr: 4.0-4.2) and low serum complement levels (C3: 57.8 mg/dl) 3 years after IVIG treatment and was diagnosed histopathologically as having MPGN type III.[ncbi.nlm.nih.gov]
Mental Deterioration
  • 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]
Flaccid Paralysis
  • 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]

Workup

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 [1] [5] [6] [7] [8]. 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 [1]. 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 [1] [2]. In addition, the number of B lymphocytes in the blood is markedly reduced [1] [2]. 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 [1] [2] [3] [4].

Normocytic Normochromic Anemia
  • Laboratory studies revealed deterioration of renal function, normocytic normochromic anemia and nephrotic range proteinuria. Hepatitis B and C and HIV serology were negative. Ultrasound and CT of abdomen were normal.[ncbi.nlm.nih.gov]
Human Herpesvirus 6
  • In contrast, 50% of individuals were found to carry human herpesvirus 6, showing that they are infectible by another lymphotropic herpesvirus.[ncbi.nlm.nih.gov]
Polyps
  • Helicobacter pylori-associated gastritis, adenomatous polyps, and lymphoid hyperplasia were most frequently encountered; no malignancies were detected. Adenomatous polyps were found in two of the four patients with XLA at a relative young age.[ncbi.nlm.nih.gov]
Lymphocytic Infiltrate
  • 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]

Treatment

  • 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]
  • 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]
  • Clinical outcome resulted in the normalization of clinical and biological parameters under antibiotic treatment by a combination of ceftriaxone, metronidazole, and doxycyclin followed by a 2-week treatment with moxifloxacin and a 2-month treatment with[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]
  • Although hospitalization for intravenous treatment was repeatedly recommended, he obstinately declined it.[ncbi.nlm.nih.gov]

Prognosis

  • 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]
  • Prognosis for patients with chronic enterovirus encephalitis is poor, almost invariably resulting in mortality without specific treatment.[ncbi.nlm.nih.gov]
  • Physicians evaluating patients with arthritis should be aware of this fact so that an early diagnosis can be pursued as it is of extreme importance in the optimal management and prognosis of these patients.[ncbi.nlm.nih.gov]
  • Early molecular analysis gives chance for definitive diagnosis and genetic counselling, but not for predicting the clinical severity and prognosis. 2018 The Foundation for the Scandinavian Journal of Immunology.[ncbi.nlm.nih.gov]
  • For 2 years the patient conducted pharmacological treatment and follow-up for the Nephrology department with poor prognosis and progression of renal function impairment.[ncbi.nlm.nih.gov]

Etiology

  • A progressive encephalopathy of unknown etiology has been described in patients with primary immunodeficiency disorders.[ncbi.nlm.nih.gov]
  • We aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis. 16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis.[ncbi.nlm.nih.gov]
  • However, recent genetic studies suggest a different etiology in some patients.[ncbi.nlm.nih.gov]
  • 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]
  • Although its etiology is unknown, it is noninfectious and thought to involve abnormal immune and neutrophil responses.[jcadonline.com]

Epidemiology

  • Epidemiology The incidence is approximately 1 in 250,000 but this may be an underestimate. [ 1 ] 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]
  • […] 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]
  • Kirsner, MD, PhD, Vice-Chairman and The Stiefel Laboratories Professor of Medical Dermatology, Department of Dermatology and Cutaneous Surgery, Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida[jcadonline.com]
  • Epidemiology The incidence of the classic syndrome is estimated to be between one and ten in one million individuals, although it is likely to be higher. [ 7 ] Being X-linked and potentially lethal, it would be expected almost invariably to affect males[patient.info]
Sex distribution
Age distribution

Pathophysiology

  • 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]
  • […] 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]
  • Sequence and Flow Cytometry -In families where a BTK mutation has already been identified, order BTKMP / Bruton Tyrosine Kinase ( BTK ) Genotype and Protein Analysis, Known Mutation Sequencing and Flow Cytometry Clinical Information Discusses physiology, pathophysiology[mayomedicallaboratories.com]
  • Treatment Antibiotic treatment and prophylaxis IV immunoglobulin therapy IL-12 receptor deficiency Definition : impaired Th response due to IL-12 receptors Etiology : autosomal recessive ; salmonella infections and mycobacterial infections most common Pathophysiology[amboss.com]
  • Wiskott-Aldrich syndrome (WAS) was first described by Wiskott in Germany in 1937 [ 3 ] and later by Aldrich in the USA in 1954. [ 4 ] However, descriptions of the condition go back to the 19th century. [ 5 ] Pathophysiology The underlying mutation is[patient.info]

Prevention

  • 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]
  • The case illustrates that IVIG may not prevent VZV infection.[ncbi.nlm.nih.gov]
  • […] a favorable course of the disease.Simple and inexpensive immuno-globulin measurement during the manage-ment of hospitalized children with community-acquired pneumonia may help in early identification of patients with compromised humoral immunity and prevent[ncbi.nlm.nih.gov]
  • A substantial portion of the mutations in BTK results in splicing defects, consequently preventing the formation of protein-coding mRNA.[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]

References

Article

  1. Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. 2001 Apr 5 [Updated 2016 Aug 4]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  2. Winkelstein JA, Conley ME, James C, Howard V, Boyle J. Status of Adults With X-Linked Agammaglobulinemia: Impact of Disease on Daily Lives, Quality of Life, Educational and Socioeconomic Status, Knowledge of Inheritance, and Reproductive Attitudes. Medicine (Baltimore). 2008;87(5):253-258.
  3. 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.
  4. Ochs HD, Smith CI. X-linked agammaglobulinemia. A clinical and molecular analysis. Medicine (Baltimore). 1996;75(6):287-299.
  5. Sigmon JR, Kasasbeh E, Krishnaswamy G. X-linked agammaglobulinemia diagnosed late in life: case report and review of the literature. Clin Mol Allergy. 2008;6:5.
  6. Chen XF, Wang WF, Zhang YD, Zhao W, Wu J, Chen TX. Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000–2015). Thachangattuthodi. A, ed. Medicine (Baltimore). 2016;95(32):e4544.
  7. 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.
  8. Hashimoto SMT, Futatani T, Kanegane H, et al. Atypical X-linked Agammaglobulinemia Diagnosed in Three Adults. Intern Med. 1999;38:722–725.

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Last updated: 2019-07-11 20:21