Case Of X-linked Agammaglobulinemia Research Articles

Co-Occurring X-Linked Agammaglobulinemia and X-Linked Chronic Granulomatous Disease: Two Isolated Pathogenic Variants in One Patient

We present a unique and unusual case of a male patient diagnosed with two coexisting and typically unassociated X-linked conditions: he was initially diagnosed with X-linked agammaglobulinemia (XLA) followed by a diagnosis of X-linked chronic granulomatous disease (XCGD) and an as of yet unpublished hypomorphic gp91phox variant in the CYBB gene. The latter was tested after the finding of granulomatous gingivitis. Hematopoietic stem cell transplant (HSCT) was performed due to severe colitis and nodular regenerative hyperplasia (NRH) of the liver. Following transplant, complete donor engraftment was observed with the restoration of a normal oxidative burst and full restoration of normal levels of circulating, mature CD19+ B cells. This case is singular in that it does not involve a contiguous gene syndrome in which deleted genes are in close proximity to either BTK and CYBB, which has been previously reported. To our knowledge, this is the first reported case of XLA and XCGD co-existing in a single patient and of having both inborn errors of immunity successfully treated by HSCT.

B cell repertoire in patients with a novel BTK mutation: expanding the spectrum of atypical X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is caused by mutations in the Bruton tyrosine kinase) BTK) gene. Affected patients have severely reduced amounts of circulating B cells. Patients with atypical XLA may have residual circulating B cells, and there are few studies exploring these cells' repertoire. We aimed to study the B cell repertoire of a novel hypomorphic mutation in the BTK gene, using the next generation sequencing (NGS) technology. Clinical data was collected from our clinical records. Real-time PCR was used to determine KREC copies, and NGS was used to determine the immunoglobulin (Ig) heavy chain (IgH) repertoire diversity. Both patients had a relatively mild clinical and laboratory phenotype, residual BTK protein expression, and the same novel mutation in the BTK gene, c.1841T > C, p. L614P. Signal-joint kappa-deleting recombination excision circles (sj-KREC) for both patients were completely absent reflecting lack of naïve B cells. The intron RSS-Kde coding joints (cj) were significantly reduced, reflecting residual replicating B cells. NGS displayed restricted IgH repertoire with highly uneven distribution of clones, especially for Pt2. We report a novel BTK mutation, c.1841T > C (p. L614P) that is associated with a relatively mild phenotype. We conclude that the IgH repertoire in atypical XLA is restricted with highly uneven distribution of clones. This phenomenon may be explained by extremely reduced to non-existent levels of BTK in B cells. This report sheds further light on atypical cases of XLA.

X-linked Agammaglobulinemia (XLA) Associated with Progressive Neurodegenerative Syndrome: A Case Report

Primary immune deficiency disorders (PIDs) are not an uncommon entity, but the diagnosis is often delayed or even missed due to lack of awareness. Central nervous system involvements due to various reasons are documented in patients with PIDs. This case report describes a 10- year old boy, diagnosed as X-linked agammaglobulinemia (XLA) who developed progressive encephalopathy. He had severe cognitive impairment along with cerebellar and pyramidal dysfunction. MRI of the brain showed generalized cerebral and cerebellar atrophy. Therefore, this boy was diagnosed as a case of XLA with progressive neurodegenerative syndrome.
 BANGLADESH J CHILD HEALTH 2021; VOL 45 (1) : 55-58

Treatment for X-Linked Agammaglobulinemia with Allogeneic Umbilical Cord Blood Stem Cell Transplantation from HLA-Matched Sibling Confirmed Healthy through Prenatal Diagnosis

Background X-linked agammaglobulinemia (XLA) is a rare congenital humoral immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19+ B-cells which was caused by mutations in Bruton's tyrosine kinase (BTK). We herein describe the first case of XLA transplanted from HLA-matched sibling allogeneic umbilical cord blood donor.Method The patient was an 8-year-old boy with XLA who previously had life-threatening infectious episodes and diagnosed by direct sequencing of BTK gene mutations (c.992-923delGAN(NM-000061)) when he was 3 years old. He was treated with the regular replacement of immunoglobulin G (IgG) products. Taking into consideration significant infectious complications and the prompt availability of HLA-matched sibling umbilical cord blood, he underwent HLA-matched sibling UCBT. The FC conditioning regimen consisting of Flu (30mg/m2/d×4 days) and CTX (30mg/kg/d×4 days) was provided for the patient. The source of stem cells was umbilical cord blood of his younger brother who was confirmed completely healthy through prenatal diagnosis with villi at the fetus period of 4 months. The number of infused total nucleated and CD34+ cells was 6.51×108/L and 2.67×106/L, respectively. He received a combination of CsA, short-term MTX and MMF for GVHD prophylaxis.Result Hematopoietic engraftment was rapidly achieved, with an absolute neutrophil count of >0.5×109/L on day 15 and platelet count of >20×109/L on day 20. The patient was discharged on day 45 and has been followed as an outpatient without any infectious episodes for more than 180 days. No expected toxicities were observed. Regarding immune constitution, CD19+ cells, IgA and IgM, which were undetectable before transplantation, started to increase in number 10 days after transplantation and continued to increase for more than 3 months. The patient did not exhibit any GVHD manifestations. He is currently alive and doing well at six months post-transplant, and he is free of any infection episodes.Conclusion The above results provide strong evidence that HLA-matched sibling UCBT may be safe and technically feasible for the treatment of XLA when an appropriately matched related or unrelated donor is unavailable. The umbilical cord blood could be considered being frozen, especially in the era of “the second child” in China.Keywords X-linked agammaglobulinemia; HLA-matched sibling donor; allogeneic umbilical cord blood stem cell transplantation; immune recovery. DisclosuresNo relevant conflicts of interest to declare.

Authors Response: Tuberculosis and pulmonary candidiasis co-infection present in a previously healthy patient

In response to the note about the case described 1, we fully agree that immunodeficiency is not only the relationship with HIV infection, and that there are pathologies and different immunological and genetic conditions associated with it 2-4; the main ones were discarded in the patient.In the patient of the presented clinical case, there is no family history of primary immunodeficiencies. And in her personal history, there were not found any data related to recurrent infectious processes, either in childhood or present, which does not lead to suspicion of diseases with primary immunodeficiencies, in which recurrent infections would be expected as in the case of recurrent pneumonia, lung, spleen and liver abscesses, cervical, axillary and inguinal lymphadenitis, or bone and skin infections, as in the case of chronic granulomatous disease 5.For other primary immunodeficiencies provided by the reader, such as the case of X-linked agammaglobulinemia, this is a congenital disease that affects males and involves B lymphocytes and plasma cells, which are not the primary immune line in tuberculosis6, nor does it correspond to our case.

Gastric Adenocarcinoma in a Patient with X-Linked Agammaglobulinemia and HIV: Case Report and Review of the Literature

X-linked agammaglobulinemia (XLA) is an X-linked inherited disease usually caused by a germline mutation in the BTK gene leading to Bruton’s tyrosine kinase deficiency, which results in the impaired development of B-lymphocytes and a subsequent lack of immunoglobulin production. Patients with XLA have an increased susceptibility to bacterial and viral infections, and multiple case reports have been published regarding an association between XLA and gastrointestinal (GI) malignancy. Here, we describe a case of a 25-year-old man with XLA and HIV, who developed gastric adenocarcinoma. Previously reported cases of XLA and GI malignancy are also reviewed and summarized.

X Linked Agammaglobulinemia: A Single Centre Experience from India

The authors report a series of seven cases of X-linked Agammaglobulinemia, diagnosed and receiving treatment at a tertiary care centre in Mumbai. The ages of the patients ranged from 15mo to 15y. After diagnosis at a mean age of 3 ½ y, all were advised intravenous immunoglobulin (IvIg) infusion therapy in doses of 400-600mg/kg every 3-4wk. They were followed up for an average duration of 9y, throughout which the complications and overall response to immunoglobulin therapy have been observed. The clinical profiles of each of these cases were retrospectively analysed with respect to age at diagnosis, frequency and severity of infections before and after initiation of treatment, co-morbidities and response to therapy. The results demonstrate the importance of early diagnosis and its correlation with decreased complications.

Debilitating progressive encephalitis in a patient with BTK deficiency

X-linked agammaglobulinemia (XLA), also known as Bruton's tyrosine kinase (BTK) deficiency, is a primary antibody deficiency, characterized by low number of B cells, agammaglobulinemia and increased susceptibility to a variety of infections. Herein, we report a case of XLA with confirmed BTK mutation that developed neurological deficits. While we could not detect any responsible microorganism in spite of comprehensive workup, brain magnetic resonance imaging revealed moderate brain atrophy. The diagnosis of progressive encephalitis was made for this patient. Patients with XLA have a higher chance of encephalitis compared with other primary antibody deficiencies. Given the violent nature of encephalitis, it is a concern among XLA patients.

Clinical features of 11 cases of X-linked agammaglobulinemia

Objective To investigate the clinical features of X-linked agammaglobulinemia (XLA)in children,and to improve the early diagnostic rate.Methods The medical records of 11 children with XLA between Dec 2003 and Nov 2011 were reviewed.Results The smallest age of 11 cases with XLA presenting the first symptoms was 0.4 years old and the oldest age was 4 years old with a mean of 2.4 years old.The first diagnosis time was at the age of 3.5 to 13 years old,with a mean of 7 years old.The age at first diagnosis in 63.6％ ( 7/11 ) of patients was more than 7 years old.Two patients ( 18.2％ ) had the family history of the similar disease.Two patients were died from the infection and 1 patient was missed.The other 8 patients were survived.Respiratory infections occurred in 100％ of the 11 patients.54.5％ (6/11 )of the patients were suffered with otitis media and digestive infections were seen in 36.4％ (4/11 ) of the patients.The levels of lgA,IgM and IgG in the serum of the pauents were all decreased.The levels of IgG in the serum of 9 patients were less than 2 g/L and in the serum of the other 2 patients were less than 2.4 g/L.The levels of CD19 in the serum were all less than 1％ and an inversed ratio of CD4/CD8 was observed in 9 patients.Eight patients were diagnosed as XLA by gene detection.Conclusion The age presenting first symptoms in children with XLA in this study is earlier than the reported data and the age at first diagnosis is later.Respiratory infection is the most common manifestation.High prevalence of otitis media and digestive infections are common.The patients with XLA rarely have the family history.The early diagosis and long-term treatment with the intravenous immunoglobulin may improve the prognosis of XLA. Key words: Primary agammaglobulinemia; Tyrosine kinase; X-linked disorder; Children

Transient myelodysplastic syndrome in X‐linked agammaglobulinemia with a novel Btk mutation

X-linked agammaglobulinemia (XLA) is a rare disorder in which recurrent infections occur due to low serum globulins and circulating B lymphocytes caused by a mutation in the Bruton tyrosine kinase (Btk) gene. While myelodysplastic syndrome (MDS) associated with low B lymphocyte counts has been described, clonal cytogenetic abnormalities in confirmed cases of XLA have never been reported. We describe a case of XLA with a novel Btk mutation who also had a persistent clonal population in the bone marrow with abnormal cytogenetics in multiple chromosomes that resolved 1(1/2) years after treatment with IVIG, mimicking a picture of transient MDS.

A Case of X-Linked Agammaglobulinemia with Btk Gene Intron 2 Mutation

저자들은 발열, 기침, 객담을 주소로 입원한 24세 남환의 임상증상, 이학적 검사, 혈청학적 및 면역학적, 유전자 검사상 X연관 무감마글로불린혈증으로 진단된 예를 관찰하였기에 문헌 고찰과 함께 보고 하는 바이다. 반복적인 감염을 보이는 젊은 성인 환자에서 유전자 이상(Btk gene mutation)에 의한 면역결핍질환(X-linked agammaglobulinemia)의 가능성을 꼭 의심해 보아야 한다.

X-Linked Agammaglobulinemia Diagnosed in Adulthood: A Case Report

X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by mutations in Bruton's tyrosine kinase (BTK). 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. The patient's serum immunoglobulin (Ig) G, IgA, and IgM levels were 132,7, and 17 mg/dL, respectively. The percentage of positive cells for CD19 and CD20 was 0.03% and 0.02%, respectively. The patient's brother and sister had no abnormalities. Flow cytometric analysis showed a partially reduced expression of BTK protein in the patient's peripheral monocytes. Sequencing of the BTK. gene revealed a missense mutation (230C>T,T33I). Given this data, this patient was diagnosed as having rare, late onset XLA with a missense mutation in the BTK gene.

A case of X-linked agammaglobulinemia caused septic arthritis of hip in children

A case of X-linked agammaglobulinemia caused septic arthritis of hip in children

A case of X-linked agammaglobulinemia with T cell infiltration to multi-organs, deficiency of CD4 + T-lymphocytes and PML-like CT scan finding

A case of X-linked agammaglobulinemia with T cell infiltration to multi-organs, deficiency of CD4 + T-lymphocytes and PML-like CT scan finding

Mutation analysis of the gene encoding Bruton's tyrosine kinase in a family with a sporadic case of X‐linked agammaglobulinemia reveals three female carriers

Bruton's tyrosine kinase (Btk) has been identified as the protein responsible for the primary immunodeficiency X-linked agammaglobulinemia (XLA). We and others have cloned the gene for Btk and recently reported the genomic organization. Nineteen exons were positioned within the 37 kb gene. With the sequence data derived from our genomic map, we have designed a PCR based assay to directly identify mutations of the Btk gene in germline DNA of patients with XLA. In this report, the assay was used to analyze a family with a sporadic case of XLA to determine if other female relatives carry the disease. A four base-pair deletion was found in the DNA of the affected boy and was further traced through three generations. With the direct identification of the mutations responsible for XLA, we can now diagnose conclusively the disease and identify the immunologically normal female carriers. This same technique can easily be applied to prenatal diagnosis in families where the mutation can be identified.

Carrier detection and prenatal diagnosis of X-linked agammaglobulinemia.

We investigated the pregnant mother of a boy with X-linked agammaglobulinemia (XLA) but with no family history of immune disease. The X-inactivation pattern was found, using a methylation-sensitive probe, to be skewed in the maternal B cells but random in the polymorphonuclear cells, indicating carrier status and a 50% risk of inheritance for her male fetus. Using probes assigned to regions on either side of the XLA locus and defining RFL polymorphism, we excluded for the first time a diagnosis of XLA on a chorionic villus sample, with a risk of error less than 0.003. Immunological studies performed at the 19th week of gestation and 3 days after birth confirmed normality. Carrier detection based on the X-chromosome inactivation pattern, together with prenatal studies using probes close to the disease locus, thus permits prenatal diagnosis in families with isolated cases of XLA.