This study was approved by the Ethics Committee of Chongqing Medical University (No. 2021.138), and written informed consent was obtained from all participants. We retrospectively reviewed 14 patients diagnosed with UNC13D deficiency at our center between January 2012 and June 2024. Of these, two patients (14.29%) met criteria for hypogammaglobulinemia, defined as immunoglobulin G (IgG) levels below the age- and gender-specific reference ranges established at our institution. We collected demographic, clinical, laboratory, and genetic data for these cases. Follow-up data were obtained through medical record review and telephone interviews.

A systematic search of PubMed and Web of Science databases was conducted for articles published up to October 13, 2024, using the terms: (“familial hemophagocytic lymphohistiocytosis” OR “hemophagocytic lymphohistiocytosis” OR “HLH” OR “FHL” OR “macrophage activation syndrome” OR “hemophagocytic syndrome”) AND (“hypogammaglobulinemia” OR “antibody deficiency” OR “low IgG” OR “humoral immune deficiency”). Duplicates, animal studies, conference abstracts, and reviews were excluded. This review identified three additional UNC13D-deficient patients with hypogammaglobulinemia from the literature. Furthermore, data on patients with sporadic HLH and hypogammaglobulinemia were extracted. Sporadic HLH was defined as HLH without pathogenic gene mutations, triggered by infections. Ultimately, nine patients with sporadic HLH and hypogammaglobulinemia were identified from six publications ( Supplementary Table S1 ).

Statistical analysis was conducted by R software (version 4.4.1). The measurement data were expressed in the form of numbers and percentages. For count data, normality was first assessed using the Shapiro-Wilk test (two-sided test, α = 0.10). Data that conformed to a normal distribution were expressed as mean ± standard deviation, while data that did not follow a normal distribution were reported as median and interquartile range. To evaluate the significance of differences, we employed the unpaired t-test and Fisher’s exact test. A p-value of less than 0.05 was defined to be statistically significant.

Patient 1 (P1), initially described in a previous report (11), presented with recurrent fever and hepatosplenomegaly since 9 months of age. Between ages 1 and 9 years, she required annual hospitalizations for recurrent cough and fever episodes, attributed to suspected respiratory infections. At age 9, she was admitted to our center. Laboratory investigations revealed trilineage cytopenia, hypertriglyceridemia (3.37 mmol/L), hypofibrinogenemia (0.53 g/L), hyperferritinemia (1500 µg/L), and elevated soluble CD25 (>44,000 pg/mL), establishing an HLH diagnosis. A computed tomography (CT) scan demonstrated right lung inflammation. Hypogammaglobulinemia was observed, with IgG at 4.79 g/L (>2 SD below age- and gender-specific means), alongside markedly reduced T-, B-, and NK-cell counts despite normal B-cell proportions. No prior immunosuppressive agents affecting humoral immunity had been administered. Subsequently, without immunoglobulin replacement, her IgG levels progressively declined to a nadir of 2.52 g/L. Genetic testing identified compound heterozygous UNC13D variants, confirming FHL3. Chemotherapy per HLH-2004 protocol achieved symptom resolution. At age 13, fever recurred with findings indicative of HLH reactivation. During this episode, she developed convulsive seizures, suggesting CNS involvement. Chemotherapy was reinitiated, followed by unrelated-donor HSCT at age 14. Post-HSCT, symptoms resolved completely with normalization of immunoglobulin levels.

Patient 2 (P2) was admitted to our center at age 3 years with recurrent fever, hepatosplenomegaly, cytopenia, hypofibrinogenemia (0.99 g/L), hyperferritinemia (1965 µg/L), elevated soluble CD25 (38,971 pg/mL), and hemophagocytosis on bone marrow examination, leading to an HLH diagnosis. Genetic analysis confirmed UNC13D deficiency through compound heterozygous UNC13D variants. During the HLH episode, he developed hypogammaglobulinemia (IgG 4.98 g/L; >2 SD below age- and gender-specific means) with significantly reduced absolute B-cell counts and proportions. No prior immunosuppressive agents or steroids had been administered. The patient contracted Streptococcus pneumoniae pneumonia despite no history of recurrent respiratory infections. Immunoglobulin levels transiently decreased but normalized spontaneously after symptom resolution without intravenous immunoglobulin (IVIG) therapy. IVIG was withheld because his IgG levels were historically normal, the deficiency was transient, and values were not critically low. He subsequently developed convulsive seizures and right-sided limb weakness suggestive of hemiplegia. HLH-directed chemotherapy per HLH-94 protocol (12) (dexamethasone, etoposide, cyclosporine A) achieved initial remission but failed to prevent recurrence. The patient ultimately died of recurrent HLH at age 8 years.

Patient 3 (P3), as reported by Dr. Rohr (8), was diagnosed with hypogammaglobulinemia (IgG < 5 g/L) at the age of 32, with persistently low IgG levels thereafter. Before experiencing the first episode of HLH at 34 years of age, he suffered recurrent respiratory infections. Genetic analysis confirmed a UNC13D deficiency. Lymphocyte analysis revealed a reduction in marginal zone-like B cells and class-switched memory B cells, indicating functional impairments in the marginal zone and germinal center. Unfortunately, the patient succumbed to HLH.

Patient 4 (P4), as described by Dr. Yazdani (9), presented with fever, anemia, and hepatosplenomegaly at one month of age, along with recurrent diarrhea. At 6 months, the patient developed pneumonia, and a CT scan showed solid lung lesions. Laboratory findings revealed hypogammaglobulinemia (IgG 4.5 g/L) and a reduced proportion of B cells. Despite regular IVIG supplementation, the patient continued to experience recurrent fevers, with progressive worsening of the lung lesions. He was diagnosed with FHL3 at 8 months but tragically succumbed to respiratory failure and bradycardia at 13 months.

Patient 5 (P5), as reported by Dr. Giardino (10), presented with fever and rapidly progressive respiratory failure at the age of 6 years. A CT scan revealed extensive lesions in both lungs. Further evaluations confirmed a diagnosis of HLH accompanied by hypogammaglobulinemia, with the lowest recorded IgG level being approximately 3.15 g/L. Notably, the patient had been healthy prior to this episode, with no history of recurrent infections. Tragically, the patient succumbed to cardiopulmonary failure.

We summarized the clinical characteristics of these five patients in Table 1 . All patients experienced respiratory infections (5/5). Neurological involvement was observed in 75% (3/4) of patients in varying forms. Two patients (P1 and P3) had a history of recurrent respiratory infections prior to the diagnosis of FHL3, accounting for 40% of the cohort. However, due to incomplete patient recall, it was difficult to determine whether these infections affected the upper or lower respiratory tract. Epstein-Barr virus (EBV) infection was noted in 40% (2/5) of the patients. Immunoglobulin supplementation was administered to 75% of the patients, although only one received regular therapy. HSCT was performed in only one patient. The mortality rate for patients with UNC13D deficiency with hypogammaglobulinemia reached 80%, rising to 100% among those who did not undergo HSCT.

Compared to FHL3 data from a systematic review (13), patients with UNC13D deficiency with hypogammaglobulinemia had a higher incidence of neurological involvement (75% vs. 56%), a significantly greater frequency of respiratory infections (100% vs. 8%; p <0.01), and higher mortality rates (80% vs. 48.94%) ( Figure 1A ). In terms of HLH-related biomarkers, these patients exhibited lower median levels of white blood cells, hemoglobin, platelets, and fibrinogen ( Table 2 ).

We also summarized data on nine patients with sporadic HLH combined with antibody deficiency reported in the literature (14–19) ( Table 3 , Supplementary Table S1 ). Among these patients, four had EBV infection, three were infected with Blastocystis marneffei, and one suffered from leptospirosis. In three cases, antibody deficiency preceded the diagnosis of HLH, with two of them initially considered for common variable immunodeficiency (CVID). In comparison to sporadic HLH with hypogammaglobulinemia, UNC13D deficient patients with hypogammaglobulinemia presented with an earlier age of onset and were more likely to exhibit hepatosplenomegaly (100% vs. 44.5%, and 100% vs. 77.8%), respiratory infections (100% vs. 44.5%), neurological manifestations (75% vs. 33.3%), and a higher mortality rate (80% vs. 66.7%) ( Figure 1B ). Peripheral neuropathy was observed in two patients with HLH and antibody deficiency, but was absent in those with UNC13D deficiency with hypogammaglobulinemia. While EBV infection occurred in a similar proportion of both groups (40% vs. 44.5%), the mean IgG level was higher in patients with UNC13D deficiency with hypogammaglobulinemia, despite decreased IgG levels in all cases. Unfortunately, these clinical manifestations mentioned above did not have statistical significance, which may be due to the small quantities of cases.

All patients exhibited mildly reduced IgG levels. The immunological characteristics are summarized in Table 4 . Three out of 4 patients (75%) showed a reduced proportion of B cells, while half (2/4) demonstrated a decreased proportion of NK cells.

The details of the variants are summarized in Table 5 . Three patients carried compound heterozygous variants, while two had homozygous variants. A total of eight variant sites were identified, with 75% classified as missense variants, 12.5% as splice site variants, and 12.5% as frameshift variants. Notably, 25% (2/8) of the variants were located in exon 9, and another 25% (2/8) in exon 20. Regarding protein structure, 66.67% of the patients had variants in the region responsible for interaction with RAB27α, while 33.33% had variants within the MHD1 domain ( Figure 2B , Table 6 ).

Regarding genetic variants, patients who had UNC13D deficiency with hypogammaglobulinemia were more likely to carry missense variants (75% vs. 20.47%), have a higher frequency of mutated sites within gene exons (87.5% vs. 53.39%), and show a greater likelihood of variants affecting the domain responsible for interaction with RAB27α ( Figure 2 , Table 6 ).