Tuberous sclerosis complex with multisystem involvement: A case report

Abstract

Tuberous sclerosis complex is a rare, autosomal dominant disorder caused by pathogenic variants in the tuberous sclerosis complex 1 or tuberous sclerosis complex 2 genes, leading to constitutive activation of the mammalian target of rapamycin pathway and abnormal cell growth. Tuberous sclerosis complex is characterized by benign hamartomas affecting multiple organs, most commonly the brain, skin, kidneys, heart, and lungs. Clinical manifestations vary depending on the organs involved and disease severity. We report the case of a Chinese woman in her mid-30s who presented with progressive dyspnea. Her medical history included hypertension, intellectual disability, seizures, left nephron-sparing enucleation for renal angiomyolipoma, and hysterectomy for uterine smooth muscle tumors. Physical examination revealed classic features of tuberous sclerosis complex, including facial angiofibromas and periungual fibromas. Imaging demonstrated a right-sided pleural effusion. Thoracoabdominal imaging showed pulmonary lymphangioleiomyomatosis and bilateral renal angiomyolipomas with hemorrhage. Genetic testing identified three pathogenic variants in the tuberous sclerosis complex 2 gene. A multidisciplinary team confirmed the diagnosis of tuberous sclerosis complex with multisystem involvement. This case highlights the multisystem heterogeneity of tuberous sclerosis complex and underscores the importance of an interdisciplinary approach to diagnosis and management.

Introduction

Tuberous sclerosis complex (TSC), also known as Bourneville–Pringle disease, is a rare autosomal dominant disorder caused by pathogenic variants in the TSC1 or TSC2 gene. TSC affects both sexes and all ethnic groups, with an estimated incidence of 1 per 6000 to 1 per 10,000 individuals. ¹ Lymphangioleiomyomatosis (LAM) is an uncommon systemic disease that occurs almost exclusively in women and may be sporadic or associated with TSC. It is characterized radiologically by numerous thin-walled pulmonary cysts distributed throughout the lung parenchyma on computed tomography (CT). In patients with TSC, these cystic changes may be accompanied by multifocal micronodular pneumocyte hyperplasia (MMPH), which presents as randomly distributed small nodules. Other typical manifestations of TSC include epilepsy, intellectual disability, renal angiomyolipoma (AML), and characteristic cutaneous lesions. We describe a woman in her mid-30s who presented with a right-sided chylous pleural effusion and was ultimately diagnosed with TSC with multisystem involvement.

Case presentation

The reporting of this study conforms to the Case Report (CARE) guidelines. ² This study protocol was approved by the Ethics Committee of The Second Affiliated Hospital of Soochow University, Suzhou, China. Written informed consent for publication was obtained from the patient, and all identifying details have been removed. The patient was admitted to our hospital in mid-2024.

A woman in her mid-30s presented to the Respiratory Department with a 2-week history of progressive dyspnea and chest tightness, accompanied by intermittent right flank pain. Her medical history included hypertension, intellectual disability, and seizures. She had not undergone a formal neuropsychiatric evaluation for TSC-associated neuropsychiatric disorders (TAND). She denied smoking, alcohol consumption, and long-term medication use. During this admission, she denied fever, hemoptysis, or chest pain. On admission, her oxygen saturation was 88% on room air. Vital signs showed a blood pressure of 139/97 mmHg, heart rate of 115 beats/min, and respiratory rate of 24 breaths/min. Physical examination revealed crackles in the lung fields, with decreased breath sounds over the right lung.

The patient’s diagnostic timeline at our hospital extended over more than a decade. In 2012, she was admitted to the Urology Department with a 5-year history of bilateral renal space-occupying lesions. Abdominal examination revealed flat renal regions without costovertebral angle tenderness. Abdominal CT showed marked enlargement of both kidneys, which were largely replaced by fat-containing masses with vascular components, consistent with renal AML (Figure 1). After ruling out contraindications, the patient underwent selective renal artery embolization and left nephron-sparing tumor enucleation in the Urology Department.

Figure 1.

(a, b) Abdominal CT scans from 2013 showing multiple renal masses with fat and soft-tissue densities, consistent with AML and (c, d) abdominal CT scans from 2024 revealing an enlarging right renal lesion with hemorrhage. CT: computed tomography; AML: angiomyolipoma.

In February 2023, the patient was admitted to the Gynecology Department because of irregular vaginal bleeding lasting more than 3 months. A comprehensive evaluation was performed to exclude other causes of abnormal uterine bleeding. Magnetic resonance imaging (MRI) showed marked uterine enlargement with multiple masses replacing the uterine body and cervix, with features suggestive of cystic degeneration with hemorrhage (Figure 2). The patient underwent laparoscopic hysterectomy and bilateral salpingectomy. On gross examination, two myomatous nodules measuring 0.5–5 cm in diameter were identified. Microscopically, spindle cell proliferation was observed. On immunohistochemical analysis, the tumor was positive for α-smooth muscle actin (α-SMA) and high-molecular-weight caldesmon (H-caldesmon), with partial positivity for desmin (Figure 3).

Figure 2.

(a, b) T1-weighted magnetic resonance imaging showing multiple isointense lesions in the cervix and uterine body, with the primary lesion on the anterior wall and (c, d) T2-weighted imaging demonstrating a hyperintense anterior wall myoma with cystic degeneration and possible hemorrhage.

Figure 3.

Uterine spindle cell tumor with infiltrative borders, moderate cytologic atypia, and low mitotic activity (<5/10 HPF), consistent with atypical leiomyoma (low-risk variant). (a) Uterine spindle cell tumor. (b) Hematoxylin and eosin staining. (c) Positive for α-smooth muscle actin and (d) Ki-67 immunostaining. HPF: high-power field.

During the mid-2024 admission, diagnostic evaluation proceeded systematically. Chest CT revealed a large right pleural effusion along with numerous bilateral thin-walled pulmonary cysts and nodules, highly suggestive of pulmonary LAM (Figure 4). Thoracentesis was performed, yielding a hemorrhagic exudative effusion; cytological examination showed no tumor cells. Pleural effusion examination revealed a total nucleated cell count of 2164/µL, red blood cell count of 220,000/µL, total protein level of 45.6 g/L (serum protein, 70.4 g/L), lactate dehydrogenase (LDH) level of 516 mmol/L (serum LDH, 645 units/L), glucose level of 5.54 mmol/L, and adenosine deaminase (ADA) level of 8 units/L. A lung biopsy was not performed because the patient declined the procedure. Dermatological examination revealed reddish, shiny, papular, and plaque-like lesions on the nose, consistent with adenoma sebaceum. Ungual fibromas were observed on the fingers and toes (Figure 5). Brain CT revealed patchy hypodense lesions in the left frontal and parietal lobes, along with multiple calcified densities along the bilateral lateral ventricles (Figure 6). Abdominal CT demonstrated bilateral renal AML with hemorrhage and hematoma formation in the right renal lesion (Figure 1). Genetic testing confirmed the diagnosis by identifying three pathogenic variants in the TSC2 gene: two splice-site changes (c.2742 + 1G>A and c.774 + 2T>C) and one frameshift mutation (p.L1394Afs*19), all predicted to impair TSC2 protein function.

Figure 4.

(a, b, c) Chest CT from 2023 showing numerous small, thin-walled pulmonary cysts in both lungs and (d) right pleural effusion. CT: computed tomography.

Figure 5.

(a) Facial fibromas and hypopigmented macules and (b, c) Periungual fibromas on the fingers and toes.

Figure 6.

Brain CT showing patchy hypodense areas in the left frontal and parietal lobes and multiple calcified densities along the bilateral lateral ventricles. CT: computed tomography.

The presence of bilateral pulmonary cysts on CT initially suggested LAM. A comprehensive evaluation of other TSC features was performed. Multiple major features—such as facial angiofibromas, periungual fibromas, renal AML, cortical tubers, subependymal nodules, and pulmonary LAM—supported the clinical diagnosis of TSC. The identification of pathogenic TSC2 variants further confirmed this diagnosis.

Following extensive counseling, the potential benefits of mammalian target of rapamycin (mTOR) inhibitor therapy were carefully discussed with the patient’s family. After consideration, the patient declined pharmacological treatment and opted for conservative, symptom-focused management. She was discharged with plans for outpatient supportive care. Unfortunately, telephone follow-up revealed that the patient died approximately 6 months after discharge.

Discussion

This case illustrates a severe phenotype of TSC with multisystem involvement. The diagnosis was firmly established based on multiple major clinical features and confirmed by genetic testing. Classic dermatological signs of TSC, including facial angiofibromas and periungual fibromas, were instrumental in guiding the diagnosis toward TSC once pulmonary LAM was suspected.

The patient’s pulmonary presentation, including dyspnea, pleural effusion, and characteristic bilateral thin-walled cysts on CT, is typical of LAM. ³ LAM occurs predominantly in women and is a recognized manifestation of TSC. ⁴ The radiographic appearance of bilateral, diffuse thin-walled pulmonary cysts is characteristic of the disease. ⁵ Cystic lung destruction results from proliferation of abnormal smooth muscle-like cells, which can lead to chylous effusions. ⁶ Although the patient’s hemorrhagic effusion was less typical than chylous effusion, such presentations have been reported in LAM and may result from vascular rupture or inflammation. ⁷ The biochemical profile of the pleural fluid, including elevated LDH with normal ADA and absence of malignant cells, was consistent with that of LAM-related effusions. ⁸ Hypoxemia and respiratory distress were likely caused by cystic lung disease and the pleural effusion.

Renal AML, which occur in 70%–80% of patients with TSC, represent a major source of morbidity. ⁹ These benign tumors may hemorrhage, leading to anemia, shock, or renal impairment. ⁵ In this case, abdominal CT demonstrated bilateral AML with active bleeding, highlighting this serious risk and likely contributing to the patient’s anemia.

Beyond structural brain lesions, TSC is commonly associated with TAND, including intellectual disability, autism spectrum disorder (ASD), and behavioral issues.^9,10 Although our patient had no formal diagnosis of ASD, her intellectual disability highlights the neurodevelopmental impact of TSC. Early identification of these neuropsychiatric features allows timely intervention, which can improve quality of life.^10,11 Therefore, a comprehensive evaluation of TSC should include neuropsychiatric assessment within a multidisciplinary framework.

The presence of three pathogenic TSC2 variants correlates with the severe phenotype observed in this patient. Mutations in TSC2 are generally associated with a more severe disease burden than those in TSC1, including more frequent intellectual disability, larger renal AML, and a higher risk of LAM.^4,12 Multiple disruptive mutations likely account for the extensive multisystem involvement observed in this case.

The differential diagnosis included sporadic LAM. Both sporadic and TSC-associated LAM (TSC–LAM) share the hallmark radiological feature of diffuse thin-walled pulmonary cysts and occur almost exclusively in women. Sporadic LAM is typically caused by somatic TSC2 mutations confined to affected tissue, ¹³ whereas TSC–LAM results from a germline mutation in TSC1 or TSC2, predisposing patients to multisystem involvement beyond the lungs. ¹⁴ Radiologically, the presence of MMPH nodules alongside cystic changes strongly suggests TSC–LAM, a feature absent in the sporadic form. ¹⁵ Uterine involvement in TSC can present as perivascular epithelioid cell tumors (PEComa) or smooth muscle tumors, with reported prevalence in female patients.^16,17 These lesions often show hemorrhagic and cystic degeneration, which can manifest clinically as menorrhagia, anemia, or compressive symptoms. ¹⁸ Although the immunohistochemical profile in this case was more consistent with a smooth muscle tumor, the significant morphological and immunophenotypic overlap with PEComa warrants consideration of both entities when evaluating uterine masses in patients with TSC.

Management of TSC focuses on symptom control, prevention of complications, and mTOR pathway inhibition. mTOR inhibitors are effective for multiple manifestations of TSC. For example, everolimus has been shown to reduce subependymal giant cell astrocytoma volume, with 32% of patients achieving ≥50% reduction and 75% achieving ≥30% reduction after 6 months of treatment. ¹⁹ Sirolimus effectively stabilizes the growth of renal AML and preserves kidney function. ²⁰ The Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial demonstrated that sirolimus stabilizes lung function in most patients with pulmonary LAM. ⁶ Beyond mTOR inhibition, comprehensive management requires a multidisciplinary approach, such as rehabilitation therapy or surgical interventions for space-occupying lesions. For renal AML, mTOR inhibitors are the preferred treatment for progressively growing lesions, while selective arterial embolization is essential for acute hemorrhage. ²⁰ Further research is needed to optimize early intervention and develop personalized therapeutic strategies.

This report is limited by its single-case nature and the fragmented medical history. Longitudinal follow-up would have provided a clearer characterization of disease progression, and genetic counseling for family members is recommended due to the autosomal dominant inheritance of TSC.

Conclusion

This case highlights the multisystem nature of TSC and underscores the importance of multidisciplinary management. International consensus guidelines recommend regular surveillance, including annual brain MRI, renal imaging, and pulmonary function tests, with treatment decisions individualized according to organ involvement and disease progression. ¹⁴ Early genetic testing and imaging facilitate timely care, and therapies such as mTOR inhibitors can help slow disease progression. Further research is needed to clarify genotype–phenotype correlations and optimize treatment strategies for rare manifestations, including uterine involvement.