Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality

Lougaris, Vassilios; Soresina, Annarosa; Baronio, Manuela; Montin, Davide; Martino, Silvana; Signa, Sara; Volpi, Stefano; Zecca, Marco; Marinoni, Maddalena; Baselli, Lucia Augusta; Dellepiane, Rosa Maria; Carrabba, Maria; Fabio, Giovanna; Putti, Maria Caterina; Cinetto, Francesco; Lunardi, Claudio; Gazzurelli, Luisa; Benvenuto, Alessio; Bertolini, Patrizia; Conti, Francesca; Consolini, Rita; Ricci, Silvia; Azzari, Chiara; Leonardi, Lucia; Duse, Marzia; Pulvirenti, Federica; Milito, Cinzia; Quinti, Isabella; Cancrini, Caterina; Finocchi, Andrea; Moschese, Viviana; Cirillo, Emilia; Crescenzi, Ludovica; Spadaro, Giuseppe; Marasco, Carolina; Vacca, Angelo; Cardinale, Fabio; Martire, Baldassare; Trizzino, Antonino; Licciardello, Maria; Cossu, Fausto; Matteo, Gigliola Di; Badolato, Raffaele; Ferrari, Simona; Giliani, Silvia; Pession, Andrea; Ugazio, Alberto G.; Pignata, Claudio; Plebani, Alessandro

doi:10.1016/j.jaci.2020.03.001

Cited by 62 publications

(69 citation statements)

References 36 publications

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“…Thus, it is important for clinicians to consider the possibility of a deletion of the last exon 19 in the BTK gene in patients suspected of having DDON syndrome, and to further test for the existence of the neighboring TIMM8A gene to allow for an effective therapeutic strategy. Applying to Italian, Chinese, American, and African cohort studies (4,12,24,25) (19,20,(26)(27)(28)(29)(30)(31)(32) including our patients P14 and P15, only one of five with a deletion of the last exon 19 in the BTK gene and the whole TIMM8A gene succumbed to pneumonitis and respiratory failure because of rapid progressive severe spasticity at 6 years of age. In contrast, the other four who had larger deletions expanding from exon 6 in the BTK gene seemed to have gradual psychomotor retardation, speech impairment, and sensorineural hearing loss.…”

Section: Discussionmentioning

confidence: 94%

“…Referred from the Taiwan Foundation of Rare Disorders (TFRD), 19 of 29 male patients (from 26 unrelated families) with hypogammaglobulinemia, low B cell populations, and infections were diagnosed with XLA. The prevalence of XLA based on approximately 3,200,000 live births during the 16-year study period ( https://www.ncbi.nlm.nih.gov/books/NBK448170/ ) is estimated around 1 case per 170,000 live births in Taiwan, close to that of Norway (1/100,000–1/285,000) ( 22 ) and Switzerland (1/200,000) ( 23 ), but higher than Italy (1/250,000) ( 24 ) and USA (1/379,000) ( 4 ). As well as geno-geographic diversity for higher prevalence, our national health insurance (NHI) and medicine strategy covering such rare disorders encourage affected patients to urge effective management for life-quality improvement.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Distinct Clinical Features and Novel Mutations in Taiwanese Patients With X-Linked Agammaglobulinemia

et al. 2020

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Background: X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase (BTK) gene and is the most common genetic mutation in patients with congenital agammaglobulinemia. The aim of this study was to analyze the clinical features, genetic defects, and/or BTK expression in patients suspected of having XLA who were referred from the Taiwan Foundation of Rare Disorders (TFRD). Methods: Patients with recurrent bacterial infections in the first 2 years of life, serum IgG/A/M below 2 standard deviations of the normal range, and ≦2% CD19+B cells were enrolled during the period of 2004-2019. The frequency of infections, pathogens, B-lymphocyte subsets, and family pedigree were recorded. Peripheral blood samples were sent to our institute for BTK expression and genetic analysis. Results: Nineteen (from 16 families) out of 29 patients had BTK mutations, including 7 missense mutations, 7 splicing mutations, 1 nonsense mutation, 2 huge deletions, and 2 nucleotide deletions. Six novel mutations were detected: c.504G>T [p.K168N], c.895-2A>G [p.Del K290 fs 23 * ], c.910T>G [p.F304V], c.1132T>C [p.T334H], c.1562A>T [p.D521V], and c.1957delG [Del p.D653 fs plus 45 a.a.]. All patients with BTK mutations had obviously decreased BTK expressions. Pseudomonas sepsis developed in 14 patients and led to both Shanghai fever and recurrent hemophagocytic lymphohistiocytosis (HLH). Recurrent sinopulmonary infections and bronchiectasis occurred in 11 patients. One patient died of pseudomonas sepsis and another died of hepatocellular carcinoma before receiving optimal treatment. Two patients with contiguous gene deletion syndrome (CGS) encompassing the TIMM8A/DDP1 gene presented with early-onset progressive post-lingual sensorineural Deafness, gradual Dystonia, and Optic Neuronopathy syndrome (DDON) or Mohr-Tranebjaerg syndrome (MTS). Conclusion: Pseudomonas sepsis was more common (74%) than recurrent sinopulmonary infections in Taiwanese XLA patients, and related to Shanghai fever and Yeh et al. Unique in Taiwanese BTK Patients recurrent HLH, both of which were prevented by regular immunoglobulin infusions. Approximately 10% of patients belonged to CGS involving the TIMM8A/DDP1 gene and presented with the DDON/MTS phenotype in need of aggressive psychomotor therapy.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Distinct Clinical Features and Novel Mutations in Taiwanese Patients With X-Linked Agammaglobulinemia

et al. 2020

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“…Despite immunoglobulin G replacement therapy (IgGRT) which limits the recurrence of (respiratory) infections (13), 16-25% of CVID patients develop structural airway disease (AD) and 3-19% develop interstitial lung disease (ILD) (14)(15)(16), causing significant morbidity and mortality in these patients (14). XLA patients are also treated with IgGRT and remain prone to develop AD [in 32-47%, (17)(18)(19)], but generally do not develop ILD (20).…”

Section: Introductionmentioning

confidence: 99%

Low IgA Associated With Oropharyngeal Microbiota Changes and Lung Disease in Primary Antibody Deficiency

et al. 2020

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Common Variable Immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are primary antibody deficiencies characterized by hypogammaglobulinemia and recurrent infections, which can lead to structural airway disease (AD) and interstitial lung disease (ILD). We investigated associations between serum IgA, oropharyngeal microbiota composition and severity of lung disease in these patients. In this cross-sectional multicentre study we analyzed oropharyngeal microbiota composition of 86 CVID patients, 12 XLA patients and 49 healthy controls (HC) using next-generation sequencing of the 16S rRNA gene. qPCR was used to estimate bacterial load. IgA was measured in serum. High resolution CT scans were scored for severity of AD and ILD. Oropharyngeal bacterial load was increased in CVID patients with low IgA (p = 0.013) and XLA (p = 0.029) compared to HC. IgA status was associated with distinct beta (between-sample) diversity (p = 0.039), enrichment of (Allo)prevotella, and more severe radiographic lung disease (p = 0.003), independently of recent antibiotic use. AD scores were positively associated with Prevotella, Alloprevotella, and Selenomonas, and ILD scores with Streptococcus and negatively with Rothia. In clinically stable patients with CVID and XLA, radiographic lung disease was associated with IgA deficiency and expansion of distinct oropharyngeal bacterial taxa. Our findings highlight IgA as a potential driver of upper respiratory tract microbiota homeostasis.

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“…Different mutations in the BTK gene, classified according to their severity by Conley and Howard ( 12 ), may influence the severity of the disease ( 13 ) and result in a considerable heterogeneity in the clinical spectrum of XLA ( 14 ); however, genotype-phenotype correlation has not been clearly established ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: A Case of X-Linked Agammaglobulinemia With High Serum IgE Levels and Allergic Rhinitis

et al. 2020

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X-linked Agammaglobulinemia (XLA) is a rare genetic disorder of B-lymphocyte differentiation, characterized by the absence or paucity of circulating B cells, markedly reduced levels of all serum immunoglobulin isotypes and lack of specific antibody production. Bruton Tyrosine Kinase (BTK) gene encodes a cytoplasmic tyrosine kinase involved in the B cell maturation and its mutation, blocking B cell differentiation at the pre-B cell stage, and is responsible for XLA. All domains may be affected by the mutation, and the many genotypes are associated with a wide range of clinical presentations. Little is known about genotype-phenotype correlation in this disorder, and factors influencing the phenotype of XLA are not clearly understood. In this report we present a unique case of a young patient affected by XLA. The disease was genetically diagnosed at birth due to a family history of XLA, but during follow up, it was characterized by a CD19+ B cell percentage consistently greater than 2%. He never suffered severe infections, but at two years of age, he developed persistent rhinitis. Thus, total serum IgE levels were measured and detected over the normal range, and specific allergic investigations showed sensitization to dust mites. Further immunological tests (BTK expression, functional "in vitro" B cell proliferation upon CpG stimulation, B cell subset analysis) explained these findings as possible manifestations of a mild XLA phenotype. XLA patients rarely present with allergic manifestations, which could warrant further investigation. High serum IgE levels could be a sign of a mild phenotype, but their role and the mechanisms underlying their production in XLA need to be clarified.

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Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality

Cited by 62 publications

References 36 publications

Distinct Clinical Features and Novel Mutations in Taiwanese Patients With X-Linked Agammaglobulinemia

Distinct Clinical Features and Novel Mutations in Taiwanese Patients With X-Linked Agammaglobulinemia

Low IgA Associated With Oropharyngeal Microbiota Changes and Lung Disease in Primary Antibody Deficiency

Case Report: A Case of X-Linked Agammaglobulinemia With High Serum IgE Levels and Allergic Rhinitis

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