X-linked Agammaglobulinemia First Diagnosed in Adulthood with Recurrent Pneumonia and Multiple Warty Skin Nodules

Abstract

A 21-year-old man with a history of recurrent pneumonia and aggregated skin nodules on both legs was admitted to our hospital. His family history revealed an early death from unknown causes, which led us to suspect immune abnormalities. Laboratory tests showed markedly low B cell counts and serum IgG, IgA, and IgM levels, while his T-cell system appeared normal. Genetic testing revealed a Bruton Tyrosine Kinase gene variant, and the patient was diagnosed with X-linked agammaglobulinemia. The patient has recovered from all illnesses since receiving immunoglobulin replacement therapy and is currently doing well without any further infections.

Introduction

X-linked agammaglobulinemia (XLA) is a congenital humoral immunodeficiency disorder that was first reported by Bruton in 1952 (1). XLA is characterized by B-cell maturation insufficiency associated with Bruton Tyrosine Kinase (BTK) gene deletions or mutations, decreased immunoglobulin levels, and recurrent bacterial infections (2). XLA is usually diagnosed during childhood and is rarely diagnosed in adulthood (3).

We herein report a case of XLA diagnosed in adulthood due to recurrent infectious diseases in various organs, including warty skin nodules.

Case Report

The patient was a 21-year-old Japanese man who had experienced recurrent bacterial pneumonia and other infectious neutrophilic diseases, such as sinusitis and otitis media, since childhood. He became aware of nodules on both legs when he was approximately 18 years old and received treatment with traditional Chinese medicine, but these lesions gradually spread. He had been suffering from a prolonged fever and productive cough with pneumonia resistant to treatment with ceftriaxone sodium (CTRX) and Lascufloxacin and was referred to our institution by his family doctor. He was a college student with no history of smoking, dust inhalation, or overseas travel. He had never kept pets and had moved several times because of his parents' job transfers. His home at the time was a newly built wooden house, but he had lived there for only a short time.

His medical history of recurrent infections since childhood, along with a family history of early death of his maternal grandfather and his brother of unknown causes, led us to suspect genetic immune abnormalities (Fig. 1). On a physical examination, coarse crackles were audible in the lower right lung. His skin was hard and multiple aggregates of small nodules of varying sizes were present on both lower legs, with itching mainly on the left leg (Fig. 2). The pathological findings of the biopsied tissues obtained from the nodule showed deep intrafollicular neutrophilic accumulation with colonies of round yeasts, follicular rupture, abscess formation, and granulomatous reaction in the perifollicular dermis (Fig. 3a, b). Grocott stain confirmed the presence of yeasts, the morphology of which was compatible with that of Malassezia (formerly Pityrosporum; Fig. 3c). Although skin scrapings in potassium hydroxide (KOH) preparation and exudate culture on the skin surface failed to identify any fungi, Malassezia folliculitis was suspected. Blood test results showed a decreased white blood cell count (2,800 cells/μL; neutrophils, 1,954 cells/μL) and an increased serum C-reactive protein (10.06 mg/dL) level, indicating an inflammatory response. β-lactamase-negative ampicillin-resistant Haemophilus influenzae were isolated from both sputum and blood cultures. Chest radiography and computed tomography (CT) showed an infiltrative shadow in the right lower lung field (Fig. 4). He was diagnosed with bacterial pneumonia and bacteremia and treated with CTRX again.

Figure 1.

Family tree showing that the patient’s maternal grandfather died of liver cirrhosis caused by hepatitis B, and his brothers died of gastric cancer and tuberculous meningitis in childhood. However, the details are unclear.

Figure 2.

Multiple small nodules with papulopustular appearance varying in size are observed in the both legs. Note that some of them are impetiginized.

Figure 3.

Histologic sections reveal a) marked infiltration of inflammatory cells within a hair follicle at the level of lower infundibulum. The follicle at lower segment has ruptured and is surrounded by abscess. The overlying skin surface is covered by crust [Hematoxylin and Eosin (H&E) staining, ×4]. b) There is a collection of neutrophils and numerous yeast within the follicular space (H&E staining, ×100). c) Many yeast forms are depicted here as black rings in groups (Grocott, ×100).

Figure 4.

Chest X-ray (left) and CT (right) showing infitration in the right lower field.

The B-cell count was significantly decreased (B cells, 1%; CD19⁺ cells, 0.1%), which led us to suspect B-cell genetic immunodeficiency with severely low peripheral immunoglobulin levels (IgG 3 mg/dL, IgA ＜7 mg/dL, IgM 7 mg/dL). He had been vaccinated against measles and rubella; however, his antibodies against these diseases were negative. In the innate immune system, his blood complement levels, neutrophil count with normal phagocytic or bactericidal functions, and T cell and CD4 cell counts with normal lymphocyte blastogenesis test were within normal ranges (T cells 96%, CD3⁺ cells 85.3%, CD4⁺ cells 42.3%, CD8⁺ cells 52.5%).

Tests for human immunodeficiency virus (HIV) antibodies were negative. Genetic testing revealed a mutation in BTK (c.1760T＞C; p. Met587Thr), and the patient was diagnosed with XLA. He was treated with immunoglobulin replacement therapy, and his respiratory symptoms and general condition improved remarkably; otherwise, the skin lesions gradually improved without antifungal agents, but the skin remained hard. Blood culture results were negative. The patient was discharged from the hospital and continued on outpatient immunoglobulin replacement therapy.

Discussion

XLA is a congenital disease caused by mutations in the BTK gene, which impairs the differentiation of B cells and reduces immunoglobulin production, resulting in immunodeficiency. XLA is treated with immunoglobulin replacement therapy, and the prognosis is good if treated appropriately (4). XLA is often diagnosed based on a family history and, most commonly, increased susceptibility to infections (3). Agammaglobulinemia is usually diagnosed during early childhood. In a large study, the first symptoms occurred at an average age of 2 years old, and the diagnosis of agammaglobulinemia was made at an average of 3.5 years old (5). Kanegane et al. (6) reported that, in most cases where XLA is diagnosed in adults, the IgG level is ＞300 mg/dL, and it is rare for the patient to remain undiagnosed until adulthood with almost no immunoglobulin, as in our case. Twenty-five of 80 families had a family history, and over 60% of cases showed a decrease in IgG, IgA, and IgM. It is speculated that early administration of antibiotics and prompt treatment of infections prevented severe infections during childhood in our patient, and since he did not develop a serious condition after receiving the live vaccine, it is possible that his immunoglobulin level gradually decreased from an early age. These factors may have contributed to the delayed diagnosis of XLA in this study.

Bacterial pneumonia is the most common XLA infection and has been reported to occur in 62% of patients with XLA (3,5). Pulmonary diseases observed in XLA, such as bacterial pneumonia and bronchiectasis, may sometimes be asymptomatic and only discovered on high-resolution CT (7). XLA is often accompanied by respiratory infections caused by encapsulated bacteria. Haemophilus influenzae is the most common bacterium detected in the lower respiratory tract of patients with hypogammaglobulinemia (8,9).

The symptoms of Malassezia folliculitis are classically similar to those of acneiform dermatitis, characterized by erythematous dome-shaped papules with a central pore and pruritic follicular pustules, although they may sometimes be asymptomatic. In severe cases, nodules and cysts may be observed in areas with many sebaceous glands, such as the scalp, face, trunk, and proximal upper extremity (10). Malassezia folliculitis is typically associated with T-cell immunodeficiency (such as HIV/acquired immune deficiency syndrome), although it rarely but occasionally occurs in patients with XLA or other forms of hypogammaglobulinaemia (11). While XLA is primarily a B-cell (antibody) deficiency, some patients may exhibit subtle T-cell functional abnormalities, such as impaired cytokine signaling or reduced helper T-cell activity. The absence of antibodies may indirectly affect antigen presentation and immune regulation, leading to dysregulation of the skin microbiota, including overgrowth of Malassezia species. However, our patient also presented with atypical folliculitis. We suspect that the various sizes of the nodules on the lower legs with hardened skin were due to prolonged untreated infection. This highlights the importance of considering agammaglobulinemia when severe Malassezia folliculitis is encountered.

Through a detailed medical history, we knew that the patient had suffered from repeated episodes of otitis media, sinusitis, enteritis, and bacterial pneumonia since childhood, which led us to suspect underlying immunodeficiency. A blood test revealed almost no immunoglobulins, and a genetic test detected a BTK variant, leading to a diagnosis of XLA. The c.1760T＞C (p.Met587Thr) is listed in the ClinVar database as a single nucleotide variant and is classified as likely pathogenic, suggesting a potential contribution to disease (12). In the present case, the reason that XLA was diagnosed in adulthood was thought to be that the patient had moved frequently since childhood, did not have a regular family doctor, and had not been treated at the same facility for a long period. In cases of repeated bacterial and/or fungal infections, it is necessary to consider the possibility of underlying immunodeficiency disease. In particular, bacterial pneumonia is frequent, and atypical folliculitis is observed in immunodeficient patients.

The authors state that they have no Conflict of Interest (COI).