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Abstract
On chromosome 10q23 is found the PTEN gene, which encodes a phosphate and tension homologue. The protein dephosphorylates phosphatidylinositol-(3,4,5)-trisphosphate at the plasma membrane to produce inorganic phosphatidylinositol-(4,5)-bisphosphate. This enzymatic activity inhibits the phosphatidylinositol-3-kinase, protein kinase B and mammalian target of the rapamycin signalling cascade. Consequently, essential cellular functions, including metabolic regulation, cellular growth, proliferation and viability, are affected. A mutation in this gene gives rise to hamartoma tumour syndrome, which exhibits a range of phenotypes, including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome and proteus-like disease. A man in his late 20s with a PTEN tumour-like arteriovenous malformation in the right thigh was recently diagnosed with lupus nephritis. The patient’s nephritic symptoms, pleural effusion, dyslipidaemia and splenomegaly demonstrate systemic lupus erythematosus (SLE) multisystem involvement. The case report identifies an association between a PTEN mutation and a new diagnosis of SLE that might have been triggered by PTEN-associated immune dysregulation.
- genetics
- renal medicine
- rheumatology
- systemic lupus erythematosus
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Background
A mutation or malfunction of the phosphatase and tensin homolog (PTEN) protein can result in the dysregulation of cell division, which in turn leads to uncontrolled cell proliferation and subsequent tumour growth (as shown in figure 1). This phenomenon is particularly observed in the thyroid gland, breast and uterus. The clinical diagnosis is confirmed by molecular genetics.1 2
Created by Wiktoria Drozdz with the BioRender.com. A schematic depiction of the PI3K-AKT-mTOR pathway mechanism. The PTEN gene, located on chromosome 10q23, functions as a tumour suppressor gene. Its main role involves the dephosphorylation of PIP3 to produce inorganic PIP2 at the plasma membrane. This action results in the suppression of the PI3K-AKT-mTOR signalling cascade, thereby impeding multiple cellular processes, including metabolic regulation, growth, proliferation, motility and survival. AKT, protein kinase B, mTOR, mammalian target of rapamycin; PIK3, phosphatidylinositol-3-kinase; PIP2, phosphatidylinositol-(4,5)-bisphosphate; PIP3, phosphatidylinositol-(3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; PDK1, phosphoinositide-dependent kinase-1.
Systemic lupus erythematosus (SLE) is a chronic immune-mediated multisystem disease that impacts the kidney in about 40% of patients. The pathophysiology of lupus nephritis is heterogeneous; various environmental, hormonal and genetic factors contribute to its pathogenesis.3
There is an increasing quantity of scientific evidence indicating that the dysregulation of PTEN is a crucial factor in the development of immune-mediated polygenic diseases, including SLE.4 5
Case presentation
A man in his late 20s was admitted to the hospital with a 6-week history of progressive exertional dyspnoea, diffuse pleuritic chest pain that waxed and waned and a general functional decline after prolonged pneumococcal sepsis due to pneumonia 1 month earlier. The patient was known to have the heterozygous variant of PTEN gene QC.1O7delG (p. (Gly36Aspfs-18)) mutation, which manifested itself with an arteriovenous malformation type II C in the right thigh and macrocephaly.
On admission, the patient appeared distressed. Blood pressure was 173/79 mm Hg, pulse rate was 99 beats per minute, and oxygen saturation was 96% breathing ambient air; other vital signs were unremarkable. The patient had a body mass index of 34.8 kg/m2. There was no history of illicit drug abuse, skin changes or joint pain. The patient had recently been using over-the-counter non-steroidal anti-inflammatory drugs as needed for pleuritic chest pain. There is no family history associated with autoimmune disease and no prior serious infections.
The physical examination revealed a significant swelling of the right lower extremity. Breath sounds were absent at the right base, with dullness on percussion. Cardiac examination was unremarkable, and the abdomen was soft and non-tender. Blood results and urinalysis showed acute, oliguric renal failure acute kidney injury network stage 3 accompanied by hypoalbuminaemia, dyslipidaemia, proteinuria in the nephrotic range and glomerular microhaematuria consistent with rapidly progressive glomerulonephritis. Furthermore, new onset of normocytic normochromic anaemia, leucopenia with overt lymphopenia and thrombocytopenia were observed.
The patient underwent extensive workup to rule out infectious and autoimmune diseases: SARS-CoV-2 swab PCR testing and serological screening for HIV were negative. Autoimmune serologies revealed highly elevated antinuclear antibodies (ANA), anti-DNA antibodies and low complement C3 and C4 levels. Key laboratory values from admission to 6-month follow-up are compared in table 1, while table 2 delves into immunological parameters and serum immunoglobulin levels upon admission.
Comparison of the most important laboratory values: admission versus 6-month follow- up
Immunological parameters and serum immunoglobulin levels at admission
Despite elevated D-dimer levels and a high pretest probability for pulmonary embolism, pulmonary scintigraphy did not reveal a thromboembolic event. A parallel CT scan of the chest and abdomen showed significant splenomegaly and extensive pulmonary infiltrates in the upper posterior and lower basal lobes on the right side. Microbiological analyses yielded a negative legionella and a pneumococcal antigen in the urine. Bronchoscopy with bronchoalveolar lavage and examination of the bronchial secretion revealed a bacterial settlement with Staphylococcus aureus and Rothia mucilaginosa. To reduce the potential risk of infection, a 10-day course of antibiotic medication with amoxicillin and clavulanic acid was administered.
A chest X-ray confirmed a right pleural effusion. Diagnostic and therapeutic thoracocentesis was performed. Based on light criteria, the fluid was interpreted as transudate. The cytology did not reveal malignancy.
For further evaluation of rapid progressive glomerulonephritis, a kidney biopsy was performed 6 days after admission. The diagnosis of combined diffuse proliferative and membranous lupus nephritis with strong activity is shown by numerous crescents in light microscopy, ruptured capillary loops and endocapillary proliferation of neutrophilic granulocytes. Immunofluorescence revealed significant positivity for IgA, IgG and IgM, as well as complement proteins C3 and C1q, which is typical for lupus nephritis. Electron microscopy displayed reticular aggregates in the cytoplasm of endothelial cells as frequently observed in lupus nephritis (International Society of Nephrology/Renal Pathology Society class IV (A) and V).
The concluding review of the patient’s findings revealed typical features of lupus erythematosus with kidney and haematological involvement (pancytopenia).
Treatment
Immediately after diagnosis and sperm preservation, treatment for lupus nephritis was initiated. As induction therapy, the Euro-Lupus regimen was applied (pulse cyclophosphamide 500 mg every 2 weeks for a total of six doses) accompanied by steroid pulse therapy (500 mg methylprednisolone) over 3 days followed by peroral steroid maintenance therapy (starting dose prednisone 50 mg followed by gradual steroid taper). Additionally, hydroxychloroquine 200 mg was started. Observing a slowed clinical response to immunosuppressive therapy (though pancytopenia improved significantly, no renal remission could be reached), the regimen was switched to the higher-dosed National Institutes of Health regimen (cyclophosphamide 1 g/m2 per month for a total of 6 months). Moreover, infection prophylaxis against Pneumocystis jiroveci with co-trimoxazole was initiated. The patient was supported by physiotherapy, particularly with breathing exercises. The respiratory condition improved in the course of the treatment, and the patient gradually gained a greater degree of mobility.
Outcome and follow-up
The patient was discharged to a rehabilitation facility after 14 days to regain physical stability. The administration of cyclophosphamide was performed according to the schedule in our outpatient clinic, leading to remission of lupus nephritis after 6 months of treatment. In detail, complete remission concerning kidney function (normalisation of serum creatinine), partial remission concerning proteinuria (from a maximum of 6.7 g per day to 2.2 g per day) and significant reduction of glomerular haematuria could be achieved. Pancytopenia resolved completely, as did humoral disease activity (C reactive protein and complement consumption). Anti-double-stranded DNA remained persistently increased. After 6 months of induction therapy, maintenance immunosuppression with mycophenolate mofetil (1 g two times a day) and 7.5 mg of prednisolone daily was started.
Discussion
SLE is a disorder characterised by hyperactive immune response and heterogeneity. It causes T-cell-driven B-cell activation and the subsequent production of autoantibodies, which tend to compromise immune regulation and result in organ damage.6
The gene encoding the PTEN is located on chromosome 10q23. Verily, it does serve as a tumour suppressor by assuming the role of an inhibitor for the prosurvival and progrowth pathways known as phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) pathways, as well as the signalling pathways of the mammalian target of rapamycin, known as mTOR. Even minor alterations in PTEN expression have a significant impact on proper cellular function. It is important to acknowledge that there have been observations suggesting that dysregulation of PTEN is linked to the disturbance of cellular homeostasis and may have implications for the development of immune-mediated diseases.1 5
Knockout mouse models have been used to investigate the relationship between PTEN and immune system alterations. The pioneering study by Di Cristofano et al revealed that mice with reduced PTEN expression developed autoimmune features, such as elevated ANA, urinary protein and glomerulopathy characterised by focal thickening of the capillary wall and the deposition of immune complexes.7 Subsequent investigations by Suzuki et al further elucidated that PTEN deficiency in mice disrupts B cell development and impairs immunoglobulin isotype switching, underscoring the importance of PTEN in maintaining immune homeostasis.8 Xiang-ni Wu et al observed reduced PTEN expression in all subsets of B cells in SLE compared with healthy controls, correlating with disease severity.9 Furthermore, research by Katsuyama et al showed that mice lacking T cell-specific serine/arginine splicing factor 1 (SRSF1) exhibited SLE-like symptoms due to hyperactive T cells, which downregulated PTEN expression and increased mTOR activity. This study underscores the intricate interplay between PTEN, SRSF1 and immune dysregulation in SLE pathogenesis. Collectively, these findings suggest that targeting PTEN-related pathways could offer promising therapeutic avenues for managing autoimmune disorders like SLE.5
Kidney biopsy is the gold standard to assess and categorise kidney disease in patients with SLE and is usually essential to make therapeutic recommendations and prognostic statements. Indications for kidney biopsy include albuminuria greater than 500–1000 mg/24 hours, especially in the setting of haematuria or impaired kidney function.10 Based on current knowledge, a limited number of published cases provide strong evidence supporting the association between PTEN mutation and the development of SLE. The first case was documented in 2013, detailing the presentation of a 13-year-old girl with a PTEN mutation. This genetic alteration was observed to manifest as macrocephaly and lymphangioma in the left ovary, along with predominantly cutaneous symptoms of SLE.11 The second patient was a boy who was 14 years old and had a phenotype of macrocephaly along with simultaneous seizures and developmental delay. He also had a PTEN mutant variation that was underlying the condition. He was diagnosed with SLE after exhibiting symptoms including urticarial rash, arthritis and nephritis.12 The most recent case describes the occurrence of early onset of SLE in a 6-year-old girl. This condition was primarily characterised by mucocutaneous and haematological manifestations.4
Based on the current findings in the literature, it appears that the disease tends to present itself during early childhood. Our case represents a unique instance of the late onset of severe lupus nephritis in a patient with a PTEN mutation. This case highlights the growing hypothesis surrounding a potential connection between PTEN and SLE. Additional investigation into PTEN dysfunction is necessary to further explore the specific regulators involved in this pathway. This has the potential to enhance understanding of the underlying pathophysiology of SLE and potentially discover new targets for treatment.
Patient’s perspective
I am a male patient in my 30s, enjoying a fulfilling marriage. Since my formative years, I have grappled with a rare genetic condition associated with the PTEN gene. Subsequently, a few years later I received a diagnosis of a severe lupus flare, particularly impacting my renal function. The diagnosis of lupus, a chronic autoimmune disorder characterised by persistent immune system dysfunction, with available therapeutic modalities but regrettably no definitive cure, marked a pivotal moment. I resolved to assume command over my life, acknowledging the manifold challenges intrinsic to this condition. It is my conviction that individuals confronting lupus must exhibit unwavering resilience and unyielding determination to maintain their vitality.
Learning points
The phosphatase and tensin homolog (PTEN) gene product acts as a tumour suppressor and plays an essential role in regulating the immune system mainly through B cells, T cells, serine/arginine splicing factor 1 levels and microRNA.
Systemic lupus erythematosus (SLE) can present in individuals with PTEN mutations during the later stages of life.
SLE should be considered a differential diagnosis when the European Alliance of Associations for Rheumatology disease-defining criteria are met. Additionally, those patients should undergo an investigation of kidney function and urinalysis screening, that is, microscopic urinalysis and quantification of albuminuria in a random urine sample.
The potential association between PTEN and SLE represents a promising avenue for further research, offering insights into novel molecular pathways and potential therapeutic targets.
Ethics statements
Patient consent for publication
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms and critical revision for important intellectual content. WD contributed to the conception and design of the case report, data acquisition, analysis, drawing, interpretation, sourcing and editing of clinical images and drafted the initial manuscript. DJ participated in data collection and provided critical revisions and intellectual contributions to the manuscript. PG was involved in the clinical management of the patient and provided important insights and revisions to the case report. TF participated in literature reviews and manuscript revisions, ensuring the accuracy and completeness of the report. The following authors gave final approval of the manuscript: DJ, PG and TF.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.