Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare autosomal dominant primary immunodeficiency disorder caused by heterozygous gain-of-function mutations in the PIK3CD gene, which encodes the p110δ catalytic subunit of the class IA phosphoinositide 3-kinase (PI3Kδ) (1). PI3Kδ is primarily expressed in leukocytes and plays a critical role in lymphocyte development, survival, activation, and migration (2). Dysregulation of this signaling pathway leads to excessive immune activation and impaired immune responses, manifesting clinically as recurrent respiratory tract infections, bronchiectasis, lymphadenopathy, and increased risk of lymphoma and other malignancies (1, 2).

APDS typically presents in childhood or adolescence, although milder cases may remain undiagnosed until adulthood. Frequent complications include persistent viral infections especially Epstein-Barr virus, lymphoproliferation, autoimmune cytopenias, and gastrointestinal involvement. Diagnosis is often delayed due to its phenotypic overlap with common variable immunodeficiency (CVID) and other primary immunodeficiencies. Genetic testing for PIK3CD mutations is required for definitive diagnosis (2, 3).

Recent advances in understanding APDS pathogenesis have led to the development of targeted therapies, including mTOR inhibitors (e.g., sirolimus) and PI3Kδ-specific inhibitors, offering new hope for effective and personalized treatment. Early identification and intervention are critical to prevent long-term complications such as structural lung damage, severe infections, and malignancies. This report describes a pediatric case of APDS with prominent cervical lymphadenopathy and splenomegaly, initially mimicking lymphoma, ultimately diagnosed through genetic analysis and successfully managed with sirolimus (3, 4).

A 12-year-old girl was admitted to our pediatric hematology and oncology department approximately 10 days after noticing a progressively enlarging mass on the right side of her neck. The mass was initially quail-egg sized, mildly tender to palpation, and was not accompanied by systemic symptoms such as fever, fatigue, night sweats, or weight loss. Her past medical history was notable for the surgical excision of a right breast mass at a local hospital approximately eight months prior, histological documentation was unavailable.

Of particular relevance, the patient experienced significant respiratory illness earlier that year. About three months before presentation, she was reportedly diagnosed with severe pneumonia, fungal infection, and bronchiectasis at a local hospital following a prolonged cough. Although detailed records were not available, her caregivers confirmed that she responded to treatment and was discharged on oral voriconazole. About one month prior to the current admission, she was hospitalized at Jinan Children’s Hospital with a three-day history of hemoptysis. Bronchial artery computed tomography angiography (CTA) revealed bilateral bronchial artery tortuosity, bronchiectasis with active infection, and tracheal diverticulum. She underwent systemic-to-pulmonary collateral embolization and bronchial artery embolization. Concurrent antimicrobial therapy with linezolid and voriconazole led to clinical improvement.

On physical examination, she appeared well-nourished with stable vital signs. Local examination revealed a firm, moderately mobile mass in the right submandibular region, approximately 3.5 × 3.5 cm in size, with mild tenderness and no overlying skin changes. The oral cavity and oropharynx appeared normal. Cardiopulmonary examination was unremarkable. Abdominal palpation revealed splenomegaly, with the spleen tip extending 5 cm below the left costal margin. There was no hepatomegaly or ascites. Additionally, the patient had no history of vaccine side effects.

Activated PI3K-δ Syndrome (APDS) presents considerable diagnostic and therapeutic challenges due to its overlapping clinical features with other primary immunodeficiencies and lymphoproliferative disorders (2). APDS is caused by gain-of-function mutations in the PIK3CD gene, resulting in constitutive activation of the PI3K-AKT-mTOR signaling pathway. This dysregulation disrupts immune homeostasis, leading to a paradoxical state of immunodeficiency coupled with immune hyperactivation, manifesting as recurrent infections, chronic lymphadenopathy, autoimmunity, and an increased risk of malignancies (5, 6).

Our patient exhibited persistent cervical lymphadenopathy and splenomegaly, clinical features that initially raised suspicion for lymphoma—particularly Hodgkin lymphoma or EBV-associated B-cell lymphoma—both recognized complications in APDS (2, 7). The detection of EBV latent infection Type III in lymphoid tissue, commonly seen in post-transplant lymphoproliferative disorders and immunodeficiency-associated cancers, further complicated the clinical assessment and underscored the necessity of precise molecular diagnosis.

This case underscores the critical importance of genetic testing in pediatric patients presenting with atypical or persistent lymphoproliferative disease. Identification of the PIK3CD c.3061G>A (p.Glu1021Lys) mutation confirmed the diagnosis of APDS1, obviating empiric cytotoxic chemotherapy and facilitating timely initiation of targeted therapy (2, 8, 9).

Sirolimus, an mTOR inhibitor, has become a cornerstone in APDS management due to its ability to counteract downstream effects of PI3Kδ hyperactivation (7, 10). In our patient, sirolimus treatment resulted in rapid and sustained regression of lymphadenopathy and splenomegaly, alongside normalization of hematologic parameters. The drug was well tolerated, with no significant adverse events reported during follow-up. These findings are consistent with prior studies demonstrating that sirolimus effectively reduces lymphoproliferation, improves immune function, and decreases infection frequency in APDS patients.

Effective management of APDS necessitates a multidisciplinary approach involving pediatric immunologists, hematologists/oncologists, infectious disease specialists, and genetic counselors to address immune dysfunction, monitor for malignancy, and prevent infectious complications (11, 12). Regular monitoring of sirolimus trough levels is vital to optimize therapeutic efficacy while minimizing toxicity.

This case also highlights the need to consider APDS in the differential diagnosis of children presenting with EBV-driven lymphoproliferation or bronchiectasis accompanied by systemic lymphadenopathy (13). APDS may mimic conditions such as common variable immunodeficiency (CVID), EBV-related lymphadenitis, or malignancies. Delayed diagnosis risks unnecessary cytotoxic treatments, heightened infection susceptibility, and poorer long-term outcomes.

This case provides several unique clinical and diagnostic insights that advance the understanding and management of APDS. Notably, the presence of EBV latent infection Type III within lymphoid tissue posed a significant diagnostic challenge, as this form of EBV latency is typically associated with post-transplant lymphoproliferative disorders and immunodeficiency-related malignancies, yet it is less commonly reported in APDS patients. This highlights the complexity of distinguishing benign lymphoproliferation from malignant transformation in the context of EBV-driven disease, underscoring the indispensability of comprehensive molecular and genetic evaluation to avoid misdiagnosis and overtreatment.

Therapeutically, the successful use of sirolimus in controlling both lymphoproliferation and EBV-associated immune dysregulation emphasizes its dual role - not only as an immunomodulatory agent but also as a targeted inhibitor that can mitigate viral-driven lymphoid expansion. The case underscores the challenges in balancing immunosuppression to control lymphoproliferation while preserving sufficient immune competence to prevent EBV reactivation or other opportunistic infections.

Moreover, this report underscores the importance of vigilant longitudinal monitoring for EBV viral load and immune parameters during sirolimus therapy, as viral dynamics in APDS may differ from other immunodeficiencies, potentially necessitating tailored antiviral or adjunctive immunotherapies. These insights collectively enrich the existing literature by illustrating the nuanced interplay between genetic immune dysregulation, viral oncogenesis, and targeted molecular treatment in APDS.

With the increasing accessibility of next-generation sequencing, early and accurate diagnosis of primary immunodeficiencies like APDS is increasingly attainable. Emerging therapies such as PI3Kδ-specific inhibitors (e.g., leniolisib) offer promise for more precise targeted treatment and are currently under clinical investigation (14, 15).

The patient’s early-onset bronchiectasis aligns with previous reports describing recurrent severe pulmonary infections in APDS, which can cause progressive airway damage. Although objective documentation was limited, the history of multiple serious pulmonary infections and requirement for interventional therapies emphasize the importance of considering underlying immunodeficiency in children with early structural lung disease. This case reinforces the diagnostic relevance of APDS in pediatric bronchiectasis of unclear etiology, especially when systemic features or recurrent infections are present.

This case highlights the importance of early genetic testing in pediatric patients with persistent lymphadenopathy and recurrent infections. Genetic confirmation of APDS allowed for targeted therapy with sirolimus, leading to significant clinical improvement without the need for cytotoxic treatments. Sirolimus effectively managed the patient’s symptoms, supporting its role as a cornerstone in APDS treatment. Early diagnosis and personalized therapy are crucial to avoid overtreatment and improve long-term outcomes. This case also underscores the need for a multidisciplinary approach and raises awareness of APDS as a differential diagnosis in similar clinical presentations.