Gaucher disease (GD, OMIM #230800) is a rare autosomal recessive disorder caused by mutations in the glucocerebrosidase1 (GBA1) gene, leading to decreased β-glucocerebrosidase (GCase) activity and consequent issues with lysosomal storage (1). The consequences of this deficiency are generally attributed to the accumulation of the GCase substrate, GlcCer, in macrophages, inducing their transformation into Gaucher cells (2). Gaucher cells subsequently infiltrate the bone marrow, spleen, liver, and multiple systemic organs, eliciting corresponding pathological changes. GD can be categorized into three subtypes based on the presence of neuronopathy and the rate of disease progression. Type 1 GD is non-neuronopathic and the most prevalent form worldwide. Type 2 GD, the acute neuronopathic form, manifests in infancy and patients with this form of GD have a life expectancy of less than 2 years. Type 3 GD is an adolescent onset form with subacute neuronopathy. However, this traditional classification is increasingly being challenged by a growing body of evidence indicating a correlation between Type 1 GD and neurological impairments, such as Parkinson's disease and peripheral neuropathies (3, 4). GD diagnosis relies on detecting reduced GCase activity or direct sequencing of the GBA1 gene. Despite the importance of timely diagnosis and treatment, GD is often missed or misdiagnosed, due to its rarity and heterogeneous symptoms. The incidence of GD is low, with an estimated rate of 1/40,000–1/60,000 births in the general population (2, 5). Clinicians, especially generalists, are often unfamiliar with the early clinical features of GD. Additionally, the signs and symptoms of GD are highly variable, making it challenging to differentiate the disease from other conditions. In a survey by Mistry et al., when patients presented with typical features, only 20% of hematologists or oncologists considered GD in their differential diagnosis (6). Another study by Mehta et al. found that almost one in six patients remained undiagnosed for 7 years or more after initial consultation (7). Hematologists, hepatologists, and pediatricians are the main specialists to whom patients first present (8, 9). Gaucher disease patients in China experience elevated misdiagnosis incidence, substantial diagnostic delays, and financially burdensome treatment expenses (10). Although timely diagnosis can minimize the impact of misdiagnoses and avoid unnecessary invasive diagnostic procedures, as well as being crucial for optimal therapy and patient management, particularly since enzyme replacement and substrate reduction therapies have proven effective in treating certain types of GD. Due to prolonged diagnostic delays coupled with restricted access and prohibitive costs of therapies, Chinese patients often lose confidence in future treatment prospects (10).

Gaucher disease patients may exhibit functional immunodeficiency, clinically manifesting as impaired antimicrobial host defense, delayed resolution of infections, increased infection susceptibility, and increased risk of autoimmune disorders (11–13). Additionally, they demonstrate predisposition to recurrent infections (14). Zahran et al. reported that children with GD1 exhibit a significant expansion of activated T cells in peripheral blood, correlating with heightened infection risks (15). However, systematic data on infection susceptibility in Gaucher disease remain limited, and no study has yet compared infection risk across the different GD subtypes. Therefore, we analyzed Chinese pediatric patients to enhance awareness among hematologists, pediatricians, and other clinicians regarding the distinctive clinical and immunological profile of this rare disorder, with the aim of informing timely diagnosis, treatment selection, and long-term management.

Our study presents a comprehensive characterization of Chinese children with GD, detailing their clinical manifestations, biochemical markers, immunophenotypes, genotypes, and systemic organ involvement, together with systematic longitudinal follow-up of disease progression and prognosis. Type 1 GD patients exhibited pronounced hematologic impairment, whereas type 2 patients showed marked hepatic injury. For the first time, we demonstrate subtype-specific differences in infection risk among Chinese pediatric cohorts, revealing a significantly higher susceptibility and risk in type 2 patients. These findings underscore the importance of tailored infection surveillance and management strategies, particularly for individuals with type 2 GD.

The hematological manifestations of GD include splenomegaly, thrombocytopenia, anemia, and cytopenia; these disorders are attributable to hypersplenism, bone marrow infiltration by Gaucher cells, or intrinsic hematopoietic cell deficiencies (16–18). Occasionally, the phenomenon of erythrophagocytosis has been reported in GD (19, 20), suggesting immune dysfunction in the context of hematological abnormalities. Kaplan et al. found that anemia and severe hepatosplenomegaly were more common in young children, while thrombocytopenia was prevalent in patients up to 18 years old. Type 1 GD is associated with more severe hematological impairment than that detected in other GD types (21). Patients with Type 2 GD exhibit similar findings, with anemia and thrombocytopenia appearing later and/or with moderate severity (22). In the current study, patients in the Type 1 GD group exhibited worse hematological impairment than those in the other groups. In one case, Type 1 GD was comorbid with beta-thalassemia, and the patient presented with severe anemia, which could have interfered with appropriate interpretation of anemia in Type 1 GD. Almost half of patients in this study exhibited leukopenia, which is generally an uncommon hematological impairment. Long-term monitoring of a larger patient cohort is necessary to better evaluate the hematological characteristics of patients with GD.

Neurological impairment is common in Types 2 and 3 GD and can include brainstem degeneration, fine motor dysfunction, hypertonia, rigidity, and seizures (23, 24). Ophthalmological abnormalities, such as horizontal saccade and strabismus, are among the earliest central nervous system features in patients with GD, followed by hypertonia, rigidity, opisthotonus, swallowing impairment, and seizures (25, 26). Apnea caused by laryngeal spasms is a symptom of late stage of Type 2 GD and contributes to shortened life expectancy (27). In our study, neuronopathy was more severe in patients with Type 2 GD than in the Type 3 GD group. Symptoms including psychomotor retardation, seizures, and strabismus were observed in both groups, while hypertonia/hypotonia, opisthotonos, and laryngeal spasms were characteristic signs in the Type 2 GD group (data not shown).

Recent research has confirmed that neuronopathy also occurs in the non-neuronopathic form of GD (i.e., Type 1 GD); In a study, microstructural alterations of brain white matter were discovered in children with Type 1 GD using diffusion tensor magnetic resonance imaging (28), and the researchers compared the topological properties of the brain network in patients with Type 1 GD with those of healthy controls. Children with GD showed abnormal small-world topology and altered distribution of motor- and sensory-related regions throughout the course of the disease (29). These findings support the notion that GD should be considered a continuum, rather than as a set of discrete categories (8).

Bone impairment in GD includes osteopenia, osteonecrosis, bone crises, chronic bone pain, pathological fractures, lytic lesions, and skeletal deformities, which are prevalent symptoms of Types 1 and 3 GD (30–32). Kaplan et al. reported that approximately 80% of pediatric patients had at least one radiological skeletal abnormality at diagnosis (21). Erlenmeyer flask deformity (49%) and bone marrow infiltration (38%) were the two most common radiological manifestations, with older children more prone to severe skeletal problems. In another report, 63% of patients with GD aged <10 years presented with Erlenmeyer flask deformity (33). Importantly, children with GD who manifest bone pain are often incorrectly characterized as having growing pains (34).

In our cohort, the cytological findings from bone marrow examinations exhibited significant differences across the various subtypes of GD. Patients with type 1 consistently demonstrated a uniformly low myeloid-to-erythroid (M/E) ratio, while all type 2 patients presented with an elevated M/E ratio. Additionally, type 3 patients consistently displayed abnormal erythrocyte morphology. The potential correlation between these cellular aberrations and distinct skeletal manifestations warrants further investigation.

Hepatic involvement in GD includes hepatomegaly, liver fibrosis, and hepatocellular carcinoma. In this study, we found that liver dysfunction severity correlated with GD type, with significant abnormalities detected in patients with Type 2 GD (35–37). Patlas et al. analyzed the clinical features of 103 children with GD and found that all exhibited hepatomegaly (38). Serai et al. evaluated liver stiffness in patients with Type 1 GD using magnetic resonance elastography and discovered a significant correlation between liver stiffness and disease severity (39). Starosta et al. investigated hepatic impairment in 42 patients with GD, finding that the rates of liver enzyme abnormalities, hepatomegaly, and steatosis were 68%, 67%, and 8%, respectively; six patients underwent liver biopsy, among which three had liver fibrosis and two had steatohepatitis; one patient developed hepatocellular carcinoma (40). Several studies have observed prolongation of PT and APTT in both adults and children (41–43). In the current study, the severity of liver dysfunction was related to disease type. Patients with Type 2 GD exhibited elevated AST and GGT, but a decrease in ALB. Further, both PT and APTT were prolonged in all three groups, with significantly elevated APTT in the Type 2 GD group, indicating inferior liver function. Our data indicate that liver dysfunction severity correlates with GD type, with Type 2 GD associated with significant abnormalities.

In GD, lung lesions are caused either by Gaucher cell infiltration, leading to interstitial lung disease, including pulmonary fibrosis, pulmonary arterial hypertension, restrictive ventilatory impairment, and intrapulmonary arterial-venous shunts, or by repetitive aspiration pneumopathies, which lead to chronic lung disease (22, 44). Pulmonary involvement is severe in patients with Type 2 GD, often presenting as recurrent respiratory infections. Similarly, most patients with Type 2 GD in our study reported bacterial respiratory infections. These findings align with current evidence indicating that GD can confer increased susceptibility to infection and a propensity for recurrent infectious episodes (14). The heightened infection risk in GD may be attributable to dysfunction of immune cells, including monocytes, macrophages, dendritic cells, T cells, and B cells, as well involvement of cytokines, such as MCP1/CCL2, CXCL8/IL8, CXCL1, IL-1β, IFNγ, and TNFα, are implicated in GD progression (45–50). Gene-knockout mice exhibit impaired thymic maturation (51, 52) and a loss of macrophage function (53). An Egyptian pediatric study reported an increased in CD8⁺ T lymphocytes alongside a reduction in NK cells in GD patients (54). Although these alterations in immune cells and mediators may contribute to heightened susceptibility, the relationship between subtype-specific immunological profiles and differential infection risk in GD remains to be elucidated.

Patients with GD may present with hypergammaglobulinemia. Studies have reported elevated IgG, IgM, and IgA levels in GD patients, with IgG elevation being the most persistent and pronounced. Following enzyme replacement therapy, IgG levels typically rise further, whereas IgA and IgM usually normalize or decrease (55–58). Regrettably, no patients in our cohort received ERT and no significant immunoglobulin elevation was observed. These findings suggest that immunoglobulin dysregulation may be uncommon among Chinese pediatric GD patients. However, given the limited sample size, larger prospective studies with systematic immunoglobulin profiling are warranted to clarify the true prevalence of immunoglobulin abnormalities in this population.

GD may exhibit autoimmune lymphoproliferative syndrome (ALPS)-like characteristics and defects in FAS-mediated apoptosis. Although double-negative T cells are generally considered specific to ALPS, elevated levels of double-negative T cells have also been observed in patients with GD. In our study, lymphocyte subset analysis was performed on samples from four patients, of which 2 (50%) had elevated levels of double-negative T cells, consistent with a report by Maurizio Miano and colleagues (59). This finding also suggests an immunophenotypic overlap between GD and ALPS, indicating that genetic diagnosis is the gold standard for differentiation between these conditions. Over 400 GBA1 mutations have been identified, with some linked to specific phenotypes and ethnic groups (60, 61). The N370S mutation is highly prevalent in the Ashkenazi Jewish and Caucasian populations and is considered “neuroprotective,” as patients with this mutation, in both homozygous and heterozygous states, are less likely to develop neurological impairment (34, 62). The L444P mutation is common in Asian countries and associated with neurological impairment (63–66). Further, patients with Type 3 GD homozygous for the D409H mutation present with characteristic heart valve damage (67–69). Overall, although GD diagnosis depends on GBA1 mutation, the relationships between genotypes and phenotypes appear to be weak.

ERT has significantly improved most manifestations of GD1 and has enhanced the quality of life for patients (70). Additionally, it may provide benefits for patients with GD3 who experience chronic visceral involvement (8). However, pediatric Gaucher disease remains under-recognized in China, with only a small percentage of affected children receiving ERT. Therefore, systematic collection and analysis of long-term clinical data from a larger cohort is essential to facilitate early recognition and accurate diagnosis, enabling timely initiation of ERT and ultimately improving patient outcomes.

In Chinese children with Gaucher disease, Type 1 GD may be associated with more pronounced hematological impairment, whereas Type 2 GD is potentially characterized by significant liver damage and heightened susceptibility to infections. Timely diagnosis and appropriate management are crucial for improving the quality of life in pediatric patients with GD in China. Given the clinical and immunophenotypic overlap between GD and IEI, genetic diagnosis is the gold standard.