A rare presentation of type 2 hyper IgM syndrome in a 17-year-old male: a case report and literature review

Introduction

Inborn errors of immunity, formerly known as primary immunodeficiency (PID) diseases, are a heterogeneous group of disorders and include conditions that impair the immune system’s function, regulation, and development [1]. According to the molecular basis of the causative agents, PID diseases are classified into 10 categories by the International Union of Immunodeficiency Societies (IUIS). One of these classifications is the “Predominantly Antibody Deficiency” group. Hyper IgM (HIGM) syndrome is also included in this group [2]. HIGM syndrome is nowadays divided into various subgroups [2, 3]. The first of these, HIGM type 1 (X-linked inheritance), although rare, is the most common form among the HIGM subtypes and most commonly affects males [4]. In addition, HIGM type 2 is a form that can be inherited in both autosomal dominant and autosomal recessive patterns and is associated with mutations in the activation-induced cytidine deaminase (AICDA) gene (AID deficiency).

Furthermore, HIGM type 3 is inherited in an autosomal recessive manner and develops due to mutations in the CD40 gene. On the other hand, HIGM type 4 has very little data available in the literature. Finally, other subgroups/types of HIGM (up to 25 reported gene mutations) are inherited in an autosomal recessive and autosomal dominant manner [2, 3].

HIGM is an immunodeficiency disorder characterized by high levels of serum IgM antibody. Hyper IgM type 2, characterized by high IgM levels and AID enzyme deficiency, is a disease associated with a mutation in the AICDA gene located on the short arm (12p) of chromosome 12. The mutation in this gene renders the AICDA gene dysfunctional [5]. Consequently, the class switch recombination (CSR) mechanism, which allows B cells to convert these antibodies into different isotypes after producing IgM in germinal centers, does not work. At the same time, the somatic hypermutation (SHM) process, which increases antibody affinity, cannot occur due to this mutation [6, 7]. This is the case for autosomal recessive inheritance. However, only CSR is disrupted in autosomal dominant forms of HIGM, while SHM remains intact [7, 8].

In either case, IgM antibodies cannot convert to other immunoglobulin classes (IgG, IgA, IgE). As a result, these patients have normal or elevated IgM levels but low IgG, IgA, and IgE [6]. This immunodeficiency picture predisposes patients to bacterial infections (mostly sinorespiratory and gastrointestinal tract infections), autoimmune diseases, and allergic reactions [3]. Immunoglobulin replacement therapy is the first-line PID disease treatment [5]. In HIGM syndromes, treatment varies depending on the subtype, but all patients can receive immunoglobulin replacement therapy as standard to help prevent recurrent infections [3].

AID deficiency is estimated to affect less than 1 : 1,000,000 people. Even the incidence of all forms of HIGM in Spain is 1 in 20 million live births. All forms of HIGM are thought to account for 0.3–2.9% of all patients with PID disorders. Compared to AID deficiency leading to HIGM syndromes, CD40L and CD40 deficiency are more common genetic diseases [9].

Here, we report the case of a 17-year-old male with autosomal recessive type 2 HIGM, mainly presenting with recurrent sinopulmonary infections at a very early age in his life.

Case report

A 17-year-old boy, consanguineous marriage of aunt’s children (avunculate marriage, first-degree cousin marriage), was brought to us by his parents in 2017 with a history of frequent fever (monthly) and recurrent upper respiratory tract infections since 6 months of age. His infections were often accompanied by severe symptoms, prolonged recovery periods, and repeated courses of antibiotics for each episode. At the age of 6 months, he was even hospitalized and treated for tonsillitis. He developed oral candidiasis several times in the first 6 months of his life, which was not resistant to treatment and did not last long. Moreover, the oral aphthous lesions he developed at 40 days of age did not resolve until he was 2 years old, and intravenous immunoglobulin (IVIG) was started. At that time, he developed cervical and submandibular lymphadenopathy due to these canker sores in his mouth. Due to suspicion of Epstein-Barr virus (EBV) infection, a monospot test was performed, but the result was negative. Subsequently, an excisional biopsy of a cervical lymph node was performed, and the pathological evaluation was interpreted as reactive hyperplasia. Around the age of 2, he had arthralgia that lasted for a few months and affected his walking. The patient underwent tympanostomy 2 times due to recurrent serous otitis media. Bronchitis, tonsillitis, sinusitis, etc., and upper and lower airway infections, recurred in a couple of years, even with IVIG treatment. At the age of 3, a CT scan of the lung showed sequelae of fibrotic changes in the medial segment of the right middle lobe. Although not suggestive of chronic diarrhea, occasional constipation, abdominal pain, and foamy stools occurred at an early age.

The mother had two previous abortions of unknown cause. He himself was born under the threat of abortion. There are three siblings, and the older and younger sisters are healthy. He was born by caesarean section at 3,600 g/51 cm. He was fully vaccinated.

An immunodeficiency was suspected, and blood tests were ordered. The results revealed elevated levels of IgM and low levels of other immunoglobulin isotypes (Table 1). Laboratory tests revealed an elevated IgM level of 604 mg/dl. Isohemagglutinin anti-B titer at 2 years of age: 1/128, IgG: 100 and 200 mg/dl (n: 345–1236), IgA: 5 (n: 14–159), IgM: 295 and 604 (n: 43–207), and IgE: < 2 IU/ml. The patient was initially diagnosed with HIGM syndrome, and antibody replacement therapy was started. He has been on IVIG since he was 1.5 years old. After 5 years of IVIG treatment, he was switched to SCIG. Routine follow-ups were scheduled to monitor his clinical clinical course and immunoglobulin levels. Despite ongoing treatment, the patient continued to experience occasional infections in the following years.

The last physical examination was unremarkable – complete blood count (CBC), routine biochemistry laboratory values were within normal limits. A comprehensive flow cytometry analysis (Table 2) and genetic testing were performed further to evaluate the patient’s condition. Genetic testing revealed a pathogenic missense homozygous mutation (c.70C>T, pArg24Trp, rs104894324) in the AICDA gene on chromosome 12, consistent with autosomal recessive type 2 HIGM immunodeficiency. (Permission was obtained from the child and family for this case presentation.)

Discussion

As noted in the literature, the most common subtype of HIGM syndrome is type 1, which follows an X-linked inheritance pattern and primarily affects males. However, it remains a rare condition overall [4]. HIGM type 2, conversely, can be inherited in either an autosomal dominant or autosomal recessive pattern and is associated with mutations in the AICDA gene [2, 3]. Our patient’s genetic testing revealed an autosomal recessive missense mutation on chromosome 12, consistent with this subtype. The c.70C>T mutation, which we saw in our patient, is a mutation type previously identified in Turkish patients [10].

Although diagnostic delays are experienced in this disease, our patient was diagnosed at a very early age, probably due to the presence of a homozygous missense mutation or because of this mutation feature [11]. In a study organized by Latin American Society for Immunodeficiencies (LASID), the age of disease onset (first clinical signs) in patients with AID deficiency was 4.5 years [12]. In another study, patients’ median age at diagnosis was 4.9 years (range: 0 to 53) [10]. In our patient, complaints and clinical findings started around 6 months of age, and PID was diagnosed and started to be treated at a very early age, around 1.5 years.

The literature also describes HIGM type 2 as elevated IgM levels and a deficiency of the AID enzyme. This condition is associated with mutations in the AICDA gene located on the short arm (12p) of chromosome 12. These mutations result in a dysfunctional AID (activation-induced cytidine deaminase) enzyme [5]. As a result, the CSR mechanism – responsible for enabling B cells to switch from producing IgM to other antibody isotypes within germinal centers – is impaired [6, 7]. This was also shown in our patient, who consistently showed elevated IgM levels over the years, while all other isotypes remained low or undetectable in some blood tests (Table 1). In our patient, although IgG and IgA levels were close to normal initially, serum IgA levels decreased over time. IgA and IgG are low in the reported case series, and IgM is not high in every case. Cases where these are within normal limits have also been described. In one study, serum IgG levels were low in 13/16 patients, IgA levels were low in 14/16, and IgM levels were high in all but 12/16 [13].

According to the literature, autosomal recessive forms of HIGM are characterized by defects in both CSR and SHM. In contrast, autosomal dominant variants typically involve disruption of CSR alone, with SHM remaining intact [7, 8]. In both cases, the failure to switch from IgM to other immunoglobulin classes (IgG, IgA, and IgE) results in persistently normal or elevated IgM levels. In contrast, IgG, IgA, and IgE levels remain low [6]. This immunological profile increases patients’ vulnerability to recurrent bacterial infections – particularly affecting the sinopulmonary and gastrointestinal systems – and is associated with a higher risk of inflammation, autoimmune, and allergic disease development [3]. Consistent with the literature, our patient had a history of severe and recurrent upper and lower airway infections. Additionally, the patient had occasional gastrointestinal tract infections throughout the years, though to a lesser extent.

Upper respiratory tract (URT) infections and bronchitis were the most common features in these patients, followed by gastrointestinal tract infections [10]. In the study reported by Ouadani et al., pulmonary findings such as bronchopneumopathy/pneumonia were observed in 8/13 patients, oral moniliasis in 3/13 cases, and cutaneous abscess in 1/13 patients [13]. In our patient, infections were seen per the report of Ouadani et al. and others. Although some authors have reported chronic diarrhea or recurrent urinary tract infections, they were not observed in our patient [12].

Usually, in early childhood, HIGM patients may present with enlarged lymph nodes and hepatosplenomegaly due to overactivated germinal centers. Some patients with AID deficiency have presented with lymphoid hyperplasia limited to the tonsils. In one study, lymphoid hyperplasia developed in 22/29 patients and persisted in 7/29 at the last follow-up [10]. In these patients, lymphoid hyperplasia was characterized by hyperplasia of the mesenteric lymph nodes, mediastinal lymph nodes, spleen, liver, and tonsils in addition to peripheral lymph nodes in 45% [9]. Recurrent tonsillar hypertrophy, cervical and submandibular lymphadenopathies were also observed in our patient.

Autoimmune or inflammatory diseases in HIGM patients occur in all HIGM syndromes in varying patterns depending on the underlying genetic defect. Autoimmune complications occur frequently (~25%) in patients with AID defects. In a study of 29 AID-deficient patients, inflammation or autoimmune diseases manifested in 6/29 cases, including diabetes mellitus, polyarthritis, autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn’s disease, and chronic uveitis [10]. Quartier et al. reported that 21% of their cohort of AID-deficient patients had autoimmune or inflammatory disorders [10]. In a different study, no autoimmune disease other than hypothyroidism was observed in Turkish cases [10]. In a study reported by Aghamohammadi et al., 1 new patient with AID deficiency was described, and this patient was 15 years old and did not develop autoimmune and other complications like our patient [14]. Another study reported atopic dermatitis, late-onset lymphopenia, and ITP [15]. However, some authors, like Cabral-Marques et al. and Revy et al., did not report it, as in our case and some other series [12, 16]. Our patient did not develop any autoimmune disease or allergic disorder/reaction before or during the follow-up period.

Management of AICDA mutation-associated HIGM syndromes includes multiple therapeutic approaches to control the complications of HIGM syndromes, including immunoglobulin replacement and antimicrobial therapy to prevent recurrent infections. Monitoring the patients for liver function, along with tailored interventions to control inflammation, autoimmunity, and finally hematopoietic stem cell transplantation (HSCT)/gene therapy would be necessary [9, 17]. Due to the variable clinical presentations and genetic factors, treatment plans must be individualized to optimize patient outcomes and quality of life.

Immunoglobulin replacement therapy is the primary treatment for individuals with primary immunodeficiency diseases [5]. In cases of HIGM, the specific treatment approach may differ based on the subtype; however, immunoglobulin replacement remains a standard therapy for all patients. It plays a key role in reducing the frequency of recurrent infections [3]. Our patient has been on intravenous and later subcutaneous immunoglobulin replacement therapies. And during episodes of severe infection, the patient was occasionally treated in an inpatient setting with IVIG for a rapid response.

However, immunosuppressives (corticosteroid therapy, cyclophosphamide, and cyclosporine), CD40 agonist therapy, HSCT, and antimicrobial drugs may also be given to reduce inflammation and autoimmunity in these patients [1, 9]. In addition, since hematologic problems such as anemia and thrombocytopenia may develop in some HIGM subtypes, supportive therapies such as granulocyte colony-stimulating factors (G-CSF) may be administered when necessary [9]. Our patient did not develop chronic inflammation, autoimmunity, or hematologic problems and did not require immunosuppressive or other treatment options.

Registry of the ESID (European Society for Immunodeficiencies) on 56 affected males showed a 20% survival rate in individuals aged ~25 years. The leading cause of death was pneumonia, encephalitis, or malignancy. Other patients died of liver failure secondary to sclerosing cholangitis and cirrhosis [18]. In a national study of morbidity and mortality of 38 Iranian HIGM patients, the 10-year survival rate was 67.8% and the most common cause of death in HIGM patients was respiratory failure [9]. Our patient has not developed any significant disease-related complications or disorders under subcutaneous and IVIG therapy except for infections before treatment until this age [19, 20].

Conclusions

HIGM syndrome is a complex group of immunodeficiencies characterized by defective immunoglobulin class switching, resulting in elevated IgM levels and deficiencies in other antibody isotypes.