18q Deletion Syndrome Presenting with Late-Onset Combined Immunodeficiency

Patient 1 was a 29-year-old male with no family history of immunodeficiency or congenital anomalies. The patient was identified as having a complex chromosomal abnormality (46, XY, 10p+, 18q−, 20p−, 21q+), and was accordingly diagnosed with chromosome 18q deletion syndrome. Subsequently, the patient developed psychomotor developmental delays, epilepsy, and scoliosis. He was admitted to the Yamabiko Medical Welfare Center, Kagoshima, Japan with severe psychomotor developmental delays at 3 years of age. After admission, the patient did not experience infections. The measles–rubella combined vaccine, Bacillus Calmette–Guérin vaccine, and other vaccines were administered, and the patient presented no severe adverse reactions. At 27 years of age, he presented with a persistent fever and cough and was diagnosed with pneumonia following chest radiography and computed tomography (CT). Although various intravenous antibiotics and micafungin were administered, they were ineffective. Three months later, his β-D-glucan was found to be high (122 pg/mL; normal, ≤ 20 pg/mL), and he was diagnosed with Pneumocystis pneumonia (PCP) based on a Pneumocystis jirovecii PCR examination of his sputum. A combination of sulfamethoxazole and trimethoprim (ST) was administered and his symptoms improved rapidly. Six months after the resolution of the first episode of pneumonia, he developed a fever and cough, his percutaneous oxygen saturation decreased, and his chest X-ray and chest CT scans showed atelectasis in the right upper lobe and a granular shadow in all the lung fields (Fig. 1A and B). The patient was diagnosed with acute pneumonia. Although his β-D-glucan, aspergillus antigen, and candida antigen levels were normal (10 pg/mL, < 0.1 UA/mL, and < 0.1 UA/mL, respectively), the patient was suspected to have fungal pneumonia. Other opportunistic infections, such as herpes zoster, persistent intestinal viral infections, and herpes viral infections, were clinically ruled out. Micafungin was administered intravenously, and the drug combination ST was administered orally, which relieved his fever and symptoms. However, owing to the recurrent opportunistic infections, we decided to evaluate the patient’s immune status. His white blood cell count was 14,700/µL, with 70% granulocytes and 22% lymphocytes (3,263/µL). His serum IgG, IgA, and IgM levels were low (188, 105, and 26 mg/dL, respectively; normal ranges: 870–1,700, 110–410, and 33–190 mg/dL, respectively). His serum IgE level was < 5 IU/mL (normal value: \(\le\)232 IU/mL). Human immunodeficiency virus (HIV) antibody test results were negative. In the analysis of lymphocyte subpopulations (Table 1), CD3⁺ T cells comprised 71.3% of the total lymphocytes, NK cells comprised 18.1%, and CD19⁺ B cells decreased to 0.72%. Although CD4⁺ T cells were within the normal range, naïve CD4⁺ T cells were depleted, accounting for only 3.58% of the CD3⁺CD4⁺ cell population. The naïve CD8⁺T cells were within normal ranges. T-cell receptor (TCR)Vβ repertoire analysis revealed prominent skewing to Vβ16 for the CD4⁺ T cells (Fig. 2A). In the lymphocyte stimulation test, proliferation in response to both phytohemagglutinin (PHA) stimulation and concanavalin A was low (8,226 cpm; normal value: 20,500–56,800 cpm and 8,053 cpm; normal value: 20,300–65,700 cpm, respectively). The level of T-cell receptor recombination excision circles (TREC) was extremely low (25.27 copies/10⁵ cells, normal > 565 copies/10⁵ cells). Additionally, the Ig κ-deleting recombination excision circle (KREC) level was extremely low (93.36 copies/10⁵ cells; normal, ≥ 456 copies/10⁵ cells). The carboxyfluorescein diacetate succinimidyl ester (CFSE) cell proliferation test showed that the CD4⁺ and CD8⁺ T cells failed to divide in response to PHA (Fig. 3). T-cell proliferation studies were performed when the patient was not experiencing acute illness. Based on these findings, the patient was diagnosed with LOCID, a combination of humoral and cell-mediated immunodeficiencies. 18q deletion was confirmed through array-based comparative genomic hybridization (CGH) analysis, and presented with a loss of 18q21.32–q22.3 in the patient (Fig. 4A and Supplementary Table 1). The patient exhibited no morbid variants in his normal alleles without deletion of 18q in the whole-exome analyses. Subsequently, immunoglobulins were substituted periodically, and ST was administered prophylactically. However, the patient died of fungal pneumonia 2 years after the first episode.

Patient 2 was a 48-year-old female who was referred to the Tokyo Medical and Dental University Hospital, Tokyo, Japan with abnormal bilateral lung shadows, found during chest radiography at a routine annual checkup (Fig. 1C). She experienced intellectual disability, bilateral foot deformities, and bilateral third finger morphological abnormalities. She had been attending Tokyo Medical and Dental University Hospital because of hearing loss, congenital stenosis of the external auditory canal, and cleft lip and palate. Regarding her family history, no immune deficiencies or congenital anomalies were found. Chest CT revealed mottled frosted shadows and irregular nodular shadows in both lungs (Fig. 1D), as well as enlarged left supraclavicular fossa, bilateral axillae, mediastinum, abdominal cavity, and inguinal lymph nodes. A left inguinal lymph node biopsy was performed to differentiate lymphoproliferative diseases such as lymphoma. Consequently, the patient was diagnosed with granulomatous lymphadenitis and was followed up without treatment. G-banding of the biopsied lymph nodes revealed a chromosome 18 long-arm defect. The deletion was located at q21 on chromosome 18. Therefore, the patient was diagnosed with chromosome 18q deletion syndrome. Her white blood cell count was 5,100/µL, with 69% granulocytes and 21% lymphocytes (1,071 /µL). Her serum IgG, IgA, and IgM levels were low (8, 9, and 131 mg/dL, respectively). Her serum IgE level was 0.3 IU/mL, and her human immunodeficiency virus antibody test results were negative. Analysis of the lymphocyte subpopulations (Table 1) indicated that CD3⁺ T, NK, and CD19⁺ B cells comprised 61.5, 22.6, and 9.22% of the total lymphocytes, respectively. CD4⁺ T-cell levels were decreased to 396/µL. Furthermore, the naïve CD4⁺ T cells were depleted, accounting for only 5.97% of the CD3⁺CD4⁺ cell population. CD8⁺ T-cell levels were decreased to 217/µL, and naïve CD8⁺ T cells were depleted to 15.0% of the CD3⁺CD8⁺ cell population. Among the CD19⁺B cells, the proportion of IgD⁻CD27⁺ (class-switched memory) B cells was extremely low (1.17% of CD19⁺ cells). TCRVβ repertoire analysis showed prominent skewing to Vβ13.2 for the CD8⁺ T cells (Fig. 2B). The levels of TREC were extremely low (0 copies/10⁵ cells). Additionally, the KREC level was extremely low (11.4 copies/10⁵ cells). The CFSE T-cell proliferation assay performed after the acute phase indicated that the CD4⁺ and CD8⁺ T cells did not divide in response to PHA stimulation (Fig. 3). Based on these findings, patient 2 was diagnosed with LOCID. 18q deletion was confirmed by array-based CGH analysis, and presented with a loss of 18q21.33–qter in the patient (Fig. 4B and Supplementary Table 2). Analysis of the targeted panel sequence for 400 genes related to inborn errors of immunity (IEI) using DNA from peripheral blood mononuclear cells indicated that the patient did not exhibit any morbid variants in her normal alleles (without deletion of 18q). Immunoglobulin replacement therapy and prophylactic ST were subsequently initiated.