Discussion

Selective IgM deficiency has been characterized as a rare form of PID, defined as a low serum IgM level (less than 2SDs below healthy controls), and normal serum IgA and IgG levels [14]. There are over 300 cases published in the literature. The prevalence ranges from 0.03% in a community-based study to 3% in allergy and immunology clinics [15, 8, 9]. In our study, the ratio of sIgMD is found as 0.12% among the patients that were followed up in pediatric immunology out-patient clinic for a definite period (33 out of 27,000 patients) [6].
SIgMD was first described by Hobbs et al in 1967 in a case report of two patients with fulminant meningococcal meningitis [7]. Although URTI were the most common clinical symptoms in sIgMD in literature, the patients presented also with various other infections; such as sepsis and meningitis [4]. In our series, URTI (60.6%) were the most common type of infection, followed by otitis media (42,4%) and pneumonia (36,3%).
It has been reported in the literature that sIgMD is more common in male sex. In our series, 74% of our patient population was male in accordance with the literature [6]. There are publications showing that sIgMD is more common in atopic and allergic people, and IgE levels may be high in patients with sIgMD [11]. In our study, six patients (13%) had high IgE levels; five had atopy.
In Goldenstein’s retrospective cohort, 36 adults with sIgMD were evaluated, the frequency of presentation symptoms were; recurrent URTI in 77%; asthma in 47%; allergic rhinitis in 36%; vasomotor rhinitis in 19%; angioedema in 14%; and anaphylaxis in 11%, and there was no patient who developed lymphoproliferative disease, or panhypogammaglobulinemia, and none died of life-threatening infections, malignancy, or fulminant autoimmune-mediated diseases [15]. Chovancova presented another adult cohort with 17 sIgMD patients. Most common manifestations were increased susceptibility to infections, especially involving recurrent URTI, pneumonia, urinary tract infections, sinusitis, otitis media and furuncles [10]. Allergic disorders included allergic rhinitis, drug allergy, bronchial asthma, atopic dermatitis, urticaria. Autoimmune manifestations including Sjögren’s syndrome, systemic lupus erythematosus (SLE), thyreopathy and alopecia; malignancies including rectal adenocarcinoma, melanoma, and thymoma were also seen in this cohort [10]. Yel and her friends reported 15 adult symptomatic patients, their findings were similar with the previous studies, but they pointed out that impaired specific antibody response to pneumococcal antigens was seen in half of the patients, and IgM-deficient patients who present with recurrent/severe infections may benefit from immunoglobulin treatment, particularly in the presence of impaired pneumococcal antibody responses [16]. The results of our cohort was compatible with these reports. We observed infection susceptibility, chromosomal diseases, autoimmune/inflammatory, and allergic diseases associating with sIgMD. According to our findings, the follow-up of patients with low IgM is very important as about ¼ has got the diagnosis of PID in the follow-up. IgM deficiency may accompany CID [17]. The reason that we emphasized the group of 13 patients with defined PID was to highlight the low IgM levels that we come across in these group of patients.
Clinical associations of sIgMD with 22q11.2 deletion (DiGeorge Syndrome), ring chromosome 18 and chromosome 1 deletion were reported in literature [18]. The reason of the association of sIgMD and these deletions is not yet known, their association may also be a coincidence [11], or the genetic background of sIgMD may be related with these genetic locations. In our study; nine patients had an atypical facial appearance. Among five (14%) patients with syndromes, two patients had trisomy 21, one patient was diagnosed with DiGeorge syndrome, one had Cohen syndrome (COH-1 mutation), and one had 1p deletion.
SIgMD criteria of ESID includes normal IgG subclass levels, and normal vaccination responses with low IgM levels [5]. In some case series IgG subclass deficiency was detected in one fourth of patients [19, 15]. Hepatitis B vaccination response of six (18.1%) patients were negative in our cohort. Janssen et al classifies selective IgM deficiency as follows: “true sIgMD” who met ESID registry criteria, “possible sIgMD” where ESID registry criteria were not fulfilled completely because data on IgG subclasses and/or vaccination response were not available, and “unclassified primary antibody deficiency” since other abnormalities of antibodies, IgG subclass deficiency, and/or impaired response to vaccine were present [20]. Patients of our cohort meet “possible sIgMD” according to this classification due to lack of Ig G subclass and vaccination responses. Gupta et al. explained that terminology of “true”, “possible”, and “unclassified” selective IgM deficiency should not be used, because this definition would exclude a sizeable number of patients, including those with complete absence of serum IgM, from the diagnosis of selective IgM deficiency [21]. Thus, we think that selective IgM deficiency should be defined only according to serum antibody levels and age [21].
In addition to providing early defense against microbes, IgM plays an important role in immune homeostasis, and provides protection from consequences of autoimmunity and inflammation [9]. There is an increased prevalence of autoimmune diseases in patients with sIgMD [7]. Autoimmune diseases associated with sIgMD are SLE, rheumatoid arthritis, Hashimoto’s thyroiditis, autoimmune hemolytic anemia (AHA), Celiac disease, vitiligo, polymyositis, autoimmune glomerulonephritis, and chronic ITP [7]..In our cohort, six patients (9,5%) with sIgMD was also diagnosed with autoimmune and inflammatory disease, such as, Behcet’s disease, ITP, Gullian-Barre syndrome, diabetes mellitus and Crohn disease. According to the reports, autoimmune diseases are more common in adults rather than children [9]. In our cohort, two out of four patients with autoimmune diseases were older than eighteen years old; one of them had Behçet’s diseases, the other had ITP.
A number of malignancies were described in sIgMD patients as case series, including clear cell sarcoma, non-Hodgkin’s lymphoma, promyelocytic leukemia and hepatocellular carcinoma [7]. In our series, malignancy developed in three (8,8%) patients, they were AML, neuroblastoma and tubuler adenoma in sigmoid colon.
There are also reports in the literature showing the relationship between sIgMD and chronic inflammatory diseases, such as Crohn, ulcerative colitis and Celiac disease associating protein-losing enteropathy. We don’t know the reason why only IgM levels, not IgG levels, decreased in patients with protein loosing enteropathy. All these diseases may possibly associate with PID. Some sIgMD patients, having IgM levels improved after treatment of primary disease (e.g. gluten-poor diet) have also been reported. In our cohort, there was one patient with Crohn disease, but there was no improvement in the IgM levels after the treatment [7].
Intravenous immunoglobulin treatment’s beneficial effects on sIgMD patients were reported [16]. Goldenstein et al. showed clinical improvement with high dose IVIG in patients with comorbidity of asthma and bronchiectasis. In our cohort, none of the patients with sIgMD needed IVIG treatment.
Immunologic evaluation should be recommended to the family members who had frequent infections and autoimmune, inflammatory and lymphoproliferative/malign disease.
As a result, the etiology, pathogenesis, clinical course of sIgMD is not clear yet. In the literature, only about three percent of patients with sIgMD were completely asymptomatic both in the adult age and in pediatric age groups; whereas in our series this rate was 24% (n=8) [15, 11]. We observed in our series that about ¼ had PID, and 10% had CID. These findings should be supported by further studies. Patients should have regular follow-up in immunology clinics even if they do not have clinical symptoms.