It has been reported that XLA corresponds to 6-11% of all patients with PIDs, that the incidence is approximately 1 in 100,000 to 200,000 live births and the prevalence is 1 in 10,000 (2, 17). Table 4 summarizes some studies with the incidence and prevalence according to the country that reports cases of XLA. In a report from Latin America, the minimal calculated incidence for XLA is reported in Honduras: 0.11 per 100,000 live births and the highest in Argentina: 1.68 per 100,000 live births (1). In a previous study, Costa Rica reports 9 patients with hypogammaglobulinemia and absence of B cells, but not characterized as XLA (1). Our country has a different distribution of PIDs than the reported worldwide (1, 18–20), where 60% of PIDs correspond to well - defined syndromes, where 55% pf patients have Ataxia Telangiectasia (1, 21). A 17% are combined deficiencies and thirdly 11% are antibody deficiencies (21), where XLA corresponds to 5.5% of all IDPs based on the present study.
Table 4
Summary of incidence and prevalence of XLA reported in different countries or regions.
Country or Region | Incidence (x 100.000 born alive) | Prevalence (x 100.000 inhabitants) | Number of Patients | Reference |
Costa Rica | 0.78–1.41 | NR | 9 | 1 |
Argentina | 1.68 | NR | 94 | 47 |
Latin America | 0.11-1.681 | NR | 2342 | 1 |
Spain | 0.96-1.20 | NR | 49 | 18 |
Norway | 5.40 | 0.35 | 15 | 48 |
Central and East Europe | NR | 0.07 | 104 | 22 |
West Europe | NR | 0.11 | 359 | 22 |
USA | 0.26 | 0.07 | 201 | 2 |
China | 80 cases/ year for 16.87 million inhabitants. | NR | 174 | 30 |
It corresponds to patients with hypogammaglobulinemia and absence of B cells. |
2 It corresponds to the minimum incidence in Honduras and the maximum in Argentina. |
According to the literature, 50% of patients are diagnosed with a/hypogammaglobulinemia near 2 years of age although the specific diagnosis of XLA is made several years afterwards. The problem in Costa Rica is that immunoglobulin quantification is mainly done in central hospitals and many doctors from rural or remote areas do not routinely use this laboratory test.
In other series, patients with a family history of XLA are diagnosed significantly earlier (around 2 years) compared to those without a family history (around 5 years), and only 35% of patients who have a family member with XLA were diagnosed before the development of symptoms attributable to their immunodeficiency (2, 19, 22).
According to a study done in the United States, more than 40% of patients with PIDs are not diagnosed until late stages, even though many report serious and chronic health conditions before diagnosis such as: sinusitis, bronchitis and pneumonia (2). The importance of the recognition and management of PIDs is further accentuated by analyzing the rate of pre- and post-diagnosis hospitalization. It is reported that 70% of patients have hospitalizations before diagnosis and only 48% after diagnosis. Multiple reviews emphasize the importance of early diagnosis of PIDs to prevent disease-related morbidity and hence mortality (23–25).
Recurrent infection or infection was presented as the pivot sign in these patients, and it is also the most important characteristic described in most studies: the presence of recurrent bacterial infections in the first years of life (2, 19, 26–27). They also presented arthritis as an initial manifestation that led to the diagnosis. It is striking that neutropenia was not a guiding fact in the Costa Rican population.
The most common cause of morbidity is respiratory infections. Since 1956 there is a report of patients with agammaglobulinemia (both congenital and acquired) and lung disease. It is important to note that many of these manifestations are prior to the onset of IVIG in these patients and in patients where diagnosis is made more than 5 years after onset of symptoms. These patients have recurrent lung disease with pneumonia due to encapsulated bacteria. Bronchiectasis and pulmonary fibrosis develop as long-term complications. It is not possible to establish a relationship between XLA mutation and lung injury because it does not correlate with what is described in the literature (2, 11, 19, 28–30).
The most frequent complications observed were: recurrent acute and / or chronic otitis media, sinusitis, chronic diarrhea; clearly the most common reported in the literature. They are not quantified, nor documented in a standardized way that allows their statistical analysis. With the data, available in the patient files it is impossible to perform this analysis in the population studied. This is a clear limitation of retrospective studies, which suggests that prospective studies of patients with PID should be started to determine the most common infections and agents in this population, especially to improve early clinical care.
It has been shown in multiple studies that the gammaglobulin replacement decreases the frequency and severity of bacterial and viral infections. It also improves morbidity and mortality and decreases the incidence of pneumonia and hospital admissions due to infection (2).
So far, there are more than 500 BTK mutations reported in BTKbase. Mutations are distributed throughout the gene in coding and non-coding regions. Point mutations (∼ 65%), small insertions, deletions (∼ 25%), and large genomic DNA alterations (∼ 10%) have been described. They have also been described along the BTK domains (3, 31). Table 4 describes the mutations found in our patients.
Except by three cases, all pathogenic/likely pathogenic variants have been previously described by other clinical studies (3, 8, 16, 32–38) or specific databases (31). Most of these mutations are missense variants (n=6), followed by nonsense (n=2), and one variant for splicing site, indels, in-frame deletion, frameshift deletion and large deletion. Seven out of 16 (43.7%) patients showed mutations in the kinase domain of BTK (BTK-KD) or SH1 domain, in concordance with previous studies (2, 3, 16, 39). It has been reported that the BTK-KD is highly susceptible to mutation, due to several conserved amino acids residues, such as K430, E445, R641 and motifs that are tightly conserved throughout the eukaryotic protein kinase superfamily. Around 67% of single nucleotide amino acid variations in this region are predicted to be harmful mutations, associated with the complete phenotype of XLA (31, 40).
The novel mutations described in this paper cannot be proved by functional assays because they are not available in Costa Rica. Patient 9 has changes an isoleucine for a phenylalanine in exon 17. This specific site was not previously described but in this exon patients with atypical presentations such as HLH (41) and Pseudomona infections (6) have been published. This could potentially affect the structure of the protein by the introduction of a benzene group, with differential physical-chemical properties. In addition, the nearby residues W581 and A582 are important in the structure and stability of protein binding to the catalytic site (42, 43). The BTK Base review shows mutations at position 579 and 581, but not at this specific site. At site 579 Tóth (16) describes a Macedonian patient. It is proposed that nearby sites (residue 572 to 582) correspond to a cluster of amino acids critical for protein binding. In addition, the nearby sites: 581 and 582 are important in the structure and stability of protein binding to the catalytic site (43). We speculate that this novel mutation causes structural and binding anomalies.
Multiples mutations in exon 14 as in patient 10, have been described to disrupts a highly conserved glycine- rich motif of the ATP binding site (43). Patient 10 presented a modification of an original glutamine by a proline in the exon 14 (p.Gln412Pro), which is an uncharged polar amino acid instead of hydrophobic basic one. Both mutations are in the SH1 domain that, as it is mentioned above, is highly susceptible to missense variants, and a common mechanism of disease. Although this mutation has not been previously described, the site already has two patients with the W421X mutation (31). The effects of these have not been greatly described either in the BTK expression or its function.
In patient 15, a cysteine duplication was detected in nucleotide 99 of exon 2, generating a frameshift modification with a premature stop signal 8 residues downstream. Therefore, it is expected to result in an absent or interrupted protein product at amino acid 42 of 659.
This is the first study of genetic studies conducted in our country for the diagnosis of IDPs, all other tests were performed abroad. It is also the first in Central America. This pioneering study provide relevant information and should be the principle of the detection of other IDPs by molecular methodologies. Moreover, 3 new likely pathogenic/pathogenic variants in BTK gene have been described in our population.