IgM Deficiency Associated With Connexin Mutation in an 18-Year-old Male

Abstract

IgM deficiency is characterized by remarkably low serum levels of IgM with normal IgG and IgA levels. These patients clinically present with recurrent infections, autoimmune disorders, and malignancies. While unknown, the proposed mechanisms explain the pathophysiology as an issue due to impaired IgG antibody response. The connexin genes encode for gap junctional proteins where mutations can cause hearing deficits and immune dysregulation. We present a unique case of an 18-year-old patient with recurrent sinusitis, diagnosed connexin-26 mutation and an IgM deficiency. An 18-year-old male with chronic sinusitis, Marfanoid joint hypermobility syndrome, and sensorineural hearing loss due to connexin-26 deficiency with bilateral cochlear implants. This patient's mutation is a GJB2 deletion located on chromosome 13 which encodes for the connexin-26 protein. The patient experienced recurrent infections, and serum immunoglobulins showed a normal IgA (84 mg/dL; normal: 70-400 mg/dL), IgG (922 mg/dL; normal: 700–1600 mg/dL) and reduced IgM (26 mg/dL; normal: 40–230 mg/dL) levels. The patient was responsive to Mumps, Measles, Rubella, and Diphtheria vaccinations among others, consistent with SIGMD diagnoses. Antibody responses to polysaccharide antigens were absent. The leukocyte counts were within normal limits. His parents are connexin-26 deficient carriers, and his older brother was diagnosed with SIGMD. Connexin-26 has been identified with multiple immunological mechanisms. Although mutations of this gene have no direct tie to antibody formation in relation to IgM, the presence of these 2 pathologies in 1 patient is intriguing and may suggest a pathophysiologic connection. We describe the first case of connexin mutation with an IgM deficiency in an 18-year-old male.

IgM deficiency is characterized by recurrent infections, atopy, autoimmune disorders, and malignancies. IgM deficiency is defined by IgM levels greater than 2 standard deviations below normal, with normal IgA, IgG, and T-cell function. ¹ Despite normal levels, immune dysregulation can occur due to impaired IgG antibody response. ¹ Several mechanisms have been proposed to explain the IgM secretion deficiency with normal IgG, IgA, and the presence of IgM⁺ B-cells, but the pathophysiology remains unknown. ¹ IgM deficient patients tend to have a normal response to vaccinations. ² The connexin gene encodes a gap junctional protein, which has functions of autoimmune signaling, paracrine signaling, and immune activation. ³ The connexin-26 protein channel is specifically important within the cochlea, playing a role in intercellular signaling. ⁴ Therefore, deficiency or mutation commonly leads to deafness. Current data shows that deafness is the leading sensory deficit in humans and has a genetic component in 70% of cases. ⁵ We present a unique case of an IgM deficiency with poor polysaccharide response and a connexin-26 deficiency.

We report an 18-year-old male with chronic sinusitis, Marfanoid joint hypermobility syndrome, and sensorineural hearing loss due to connexin-26 deficiency with bilateral cochlear implants (the patient gave verbal and written consent to include the details about his diagnoses in this case report). This patient's mutation is a GJB2 deletion located on chromosome 13 which encodes for the connexin-26 protein. The patient experienced recurrent infections, and serum immunoglobulins showed a normal IgA (84 mg/dL; normal: 70-400 mg/dL), IgG (922 mg/dL; normal: 700-1600 mg/dL) and reduced IgM (26 mg/dL; normal: 40-230 mg/dL) levels. The patient was responsive to Mumps, Measles, Rubella, and Diphtheria vaccinations among others, consistent with an IgM deficiency diagnoses. Antibody responses to polysaccharide antigens were absent. Follow-up laboratory results on the polysaccharide antigen response showed a lack of response to 7 of the 14 serotypes. The leukocyte counts were within normal limits. The patient's serum antibodies were repeated once a year from 2015 to 2021 and remained deficient. His parents are connexin-26 deficient carriers, and his older brother was previously diagnosed with selective IgM deficiency.

The clinical presentation of IgM deficiency is characterized by recurrent infections, atopy as well as autoimmune disorders and malignancies.^1,6 A variety of mechanisms have been proposed to explain the deficiency of IgM secretion with a normal concentration of other immunoglobulins including increased activity of suppressor T-cells, abnormal activity of T_reg cells, and innate B-cell defects such as an inability to produce functional µ heavy chain mRNA transcripts. ¹ IgM is also known to reduce the risk of developing infections because of its recognition of molecules on bacterial cell walls. ² Thus, a deficiency may lead to increased infections with common organisms.

A recent review reported a role for connexins in B-cell migration, cytoskeletal structure, as well as T-cell responses. ³ Due to the many proposed functions of connexin-26 there are multiple mechanisms that may be resulting in deafness. ⁴ The mutations of connexin-26 can vary from complete lack of protein synthesis to decreased functional ability. ⁷ The attenuation of K + or cell signaling molecule transfer through cells of the developing cochlea in connexin-26 deficiency is proposed to cause hair cell degeneration, spiral ganglion neuron degeneration, and other abnormalities. The lack of a functional gap junction protein results in many hereditary diseases outside of deafness due to the ability of gap junctional proteins to transport larger molecules such as immune cells.

The laboratory and clinical findings described in our case demonstrate a concern for immunodeficiency in patients diagnosed with a connexin-26 deficiency that presents clinically with recurrent respiratory tract infections. We describe the first case of IgM deficiency, poor polysaccharide response, and a connexin-26 deficiency.