Abstract
Introduction: Tuberous sclerosis complex (TSC) is a rare, multisystem genetic disorder caused by mutations in the TSC1 or TSC2 genes, resulting in dysregulation of the mTOR pathway. Clinical manifestations include epilepsy, cutaneous lesions, and hamartomas in various organs, presenting diagnostic challenges, especially in resource-limited settings. In low- and middle-income countries (LMICs), barriers such as lack of access to genetic testing, advanced imaging, and targeted therapies contribute to underdiagnosis and delayed care. Case Presentation: We present a 22-year-old male from rural Tanzania with a 20-year history of intractable, treatment-refractory epilepsy. He also exhibited cutaneous findings, including facial angiofibromas, ash-leaf macules, and a shagreen patch. Brain imaging revealed subependymal nodules, and renal imaging identified angiomyolipomas. Despite the absence of genetic testing, a clinical diagnosis of TSC was made. The patient’s condition was further complicated by aspiration pneumonia. Management included anticonvulsant therapy, antibiotics, and supportive care. Multisystem evaluation revealed cystic lung disease and renal involvement, underscoring the need for comprehensive follow-up. This case highlights the diagnostic reliance on clinical expertise and basic imaging in resource-limited settings. Conclusion: This report emphasizes the importance of clinical recognition and multidisciplinary management of TSC in resource-constrained settings. Strengthening healthcare infrastructure, raising awareness, and fostering collaborations to enhance access to genetic testing and mTOR-targeted therapies are critical to improving outcomes for TSC patients in LMICs. The lessons from this case underscore the global relevance of addressing healthcare disparities in rare genetic disorders.
Introduction
Tuberous sclerosis complex (TSC) is a rare, multisystem genetic disorder characterized by the growth of benign tumors, known as hamartomas, in various organs, including the brain, skin, kidneys, heart, and lungs [1]. Mutations in the TSC1 or TSC2 genes (located on the long arm of chromosome 9 and the short arm of chromosome 16, respectively), which regulate cell growth through the mechanistic target of rapamycin (mTOR) pathway, underlie this condition [2]. These are tumor suppressor genes; therefore, loss-of-function mutations result tumor growth [1]. The clinical manifestations of TSC are diverse, ranging from mild dermatological findings to severe complications such as epilepsy, renal dysfunction, and neuropsychiatric disorders [1, 3]. This broad spectrum poses significant challenges in diagnosis and management, particularly in resource-limited settings.
Globally, advances in the diagnosis and management of TSC, including genetic testing and mTOR inhibitors, have significantly improved outcomes [3‒5]. However, the condition remains underdiagnosed and undertreated in low- and middle-income countries (LMICs) such as Tanzania. Limited access to genetic testing, advanced imaging, and specialized care in these settings contributes to delayed diagnosis and suboptimal treatment. This gap underscores the importance of raising awareness among healthcare providers, promoting early recognition of TSC manifestations and developing locally applicable management strategies.
The diagnostic and therapeutic challenges faced by clinicians in resource-limited settings highlight the critical role of clinical diagnosis especially in environments where advanced tools are unavailable, the need for multidisciplinary care [5, 6], and the importance of addressing healthcare disparities to improve outcomes for TSC patients. Furthermore, this discussion provides insight into how lessons learned in Tanzania can inform the management of similar conditions in other LMICs, underscoring the global relevance of these challenges.
The report aims to emphasize actionable strategies, including early clinical recognition, the development of tailored management protocols, and fostering collaborations with international institutions to enhance access to diagnostic and therapeutic resources. Addressing these barriers has the potential to improve the quality of life for individuals with TSC in Tanzania and similar contexts worldwide.
Case Presentation
We present the case of a 22-year-old male from Mpwapwa, Tanzania, with a 20-year history of epilepsy. He was first diagnosed with epilepsy at age 2 years and has been on long-term phenobarbitone treatment with incomplete seizure control. He was referred to our hospital following an 8-day episode of recurrent generalized tonic-clonic seizures, accompanied by low-grade fever and difficulty breathing during the preceding 2 days. There were no associated symptoms of headache, vomiting, or visual disturbances.
The patient’s past medical history included multiple hospital admissions due to recurrent seizures, as well as progressive cutaneous lesions on his face and trunk that started in childhood and were refractory to topical treatments. His family history was notable for epilepsy in first-degree relatives, including his aunt and sister, raising suspicion of a hereditary condition.
Upon examination, the patient was febrile (temperature 38.8°C), tachycardic (heart rate 104 beats per minute), and tachypneic (respiratory rate 28 breaths per minute). Blood pressure measured 119/78 mm Hg. Oxygen saturation was 78% on room air, improving to 96% with supplemental oxygen via a non-rebreather mask at 4 L per minute. His eyes opened to pain; the pupils were 4 mm, symmetric, and reactive to light. He had no verbal response. Corneal and gag reflexes were present. He withdrew his arms and legs to pain. His Glasgow Coma Scale score was 7 (on a scale of 3–15, with lower scores indicating greater alteration of consciousness). The neck was supple. He had brisk biceps, supinator, triceps, patellar, and ankle reflexes, as well as bilateral Babinski signs.
Dermatological examination identified multiple lesions, including facial angiofibromas and a forehead plaque (shown in Fig. 1), hypopigmented ash-leaf macules, a shagreen patch on the lower back (shown in Fig. 2), and no ungual fibromas on the fingernails or toenails. Ophthalmologic evaluation, including fundoscopy, revealed no retinal hamartomas or other ophthalmic abnormalities. Oral examination showed dental enamel pitting. Pulmonary examination was consistent with consolidation in the right lower lobe.
Facial angiofibromas appear as multiple small, raised, reddish-brown to flesh-colored papules distributed predominantly over the cheeks, nose, and nasolabial folds. Additionally, a prominent fibrous plaque is visible on the forehead, characterized by a larger, firm, thickened, and elevated lesion. Fibrous plaques of variable sizes are visible on the forehead and scalp.
Facial angiofibromas appear as multiple small, raised, reddish-brown to flesh-colored papules distributed predominantly over the cheeks, nose, and nasolabial folds. Additionally, a prominent fibrous plaque is visible on the forehead, characterized by a larger, firm, thickened, and elevated lesion. Fibrous plaques of variable sizes are visible on the forehead and scalp.
Hypomelanotic macules are visible as faint, lighter-colored patches on the sides of the back. A shagreen patch is present on the lower back, characterized by a slightly raised, thickened, and rough-textured area.
Hypomelanotic macules are visible as faint, lighter-colored patches on the sides of the back. A shagreen patch is present on the lower back, characterized by a slightly raised, thickened, and rough-textured area.
A brain CT scan revealed subependymal nodules along the ventricles (shown in Fig. 3). Additional investigations, including cerebrospinal fluid (CSF) analysis, electroencephalography (EEG), renal function tests, abdominal ultrasonography, electrocardiography (ECG), echocardiography, malaria rapid diagnostic test (mRDT), HIV ELISA, random blood glucose (RBG), and a chest X-ray, were performed. The CSF analysis results were normal, and the chest X-ray showed alveolar infiltrates in the superior segment of the right lower lobe, confirming the aspiration pneumonia. Abdominal ultrasound revealed mildly enlarged kidneys with bilateral heterogeneous masses. An ECG showed normal sinus rhythm without significant abnormalities, and the echocardiogram was normal. The EEG indicated slow background activity, indicating diffuse cortical dysfunction. Multifocal epileptiform discharges were predominantly observed over the bilateral frontotemporal and parietal regions, manifesting as high-amplitude sharp waves and spike-wave complexes interspersed with periods of focal slowing. Other laboratory test results are shown in Table 1.
Head CT scan demonstrating multiple calcified SENs lining the lateral ventricles.
Head CT scan demonstrating multiple calcified SENs lining the lateral ventricles.
Laboratory data
| Investigation | Result | Reference range |
|---|---|---|
| CSF analysis | ||
| Appearance | Clear CSF | Clear CSF |
| Opening pressure | 17 cm H2O | Normal: 10–25 cm H2O |
| CSF glucose | 4.1 mmol/L | ≥60% of serum glucosea |
| CSF protein | 0.2 g/L | 0.15–0.45 g/L |
| CSF Gram stain | No organisms detected | No organisms |
| Biochemical investigations | ||
| Serum creatinine | 101 µmol/L | 61–115 µmol/L |
| BUN | 3.4 mmol/L | 2.5–7.1 mmol/L |
| Uric acid | 374 µmol/L | 120–420 µmol/L |
| RBG | 6.2 mmol/L | ≤7.8 mmol/L |
| Infectious disease markers | ||
| mRDT | Negative | Negative |
| HIV ELISA | Negative | Negative |
| CBC | ||
| Leukocytes | 12.5 × 109/L | 4–11 × 109/L |
| Basophils | 0.1 × 109/L | 0.01–0.1 × 109/L |
| Eosinophils | 0.1 × 109/L | 0.04–0.4 × 109/L |
| Lymphocytes | 2.5 × 109/L | 1.5–4.0 × 109/L |
| Monocytes | 0.8 × 109/L | 0.2–0.8 × 109/L |
| Neutrophils | 9.0 × 109/L | 2.0–7.0 × 109/L |
| Erythrocytes | 5.41 × 1012/L | 4.5–6.5 × 1012/L |
| Hb | 14.1 g/dL | 13–18 g/dL |
| HCT | 46.7% | 40–54% |
| MCV | 86.3 fL | 80–100 fL |
| MCH | 28.0 pg | 27–33 pg |
| MCHC | 32.8 g/dL | 32–36 g/dL |
| RDW | 12.0% | 11.5–14.5% |
| Platelet count | 152 × 109/L | 150–400 × 109/L |
| MPV | 9.78 fL | 7.5–11.5 fL |
| Investigation | Result | Reference range |
|---|---|---|
| CSF analysis | ||
| Appearance | Clear CSF | Clear CSF |
| Opening pressure | 17 cm H2O | Normal: 10–25 cm H2O |
| CSF glucose | 4.1 mmol/L | ≥60% of serum glucosea |
| CSF protein | 0.2 g/L | 0.15–0.45 g/L |
| CSF Gram stain | No organisms detected | No organisms |
| Biochemical investigations | ||
| Serum creatinine | 101 µmol/L | 61–115 µmol/L |
| BUN | 3.4 mmol/L | 2.5–7.1 mmol/L |
| Uric acid | 374 µmol/L | 120–420 µmol/L |
| RBG | 6.2 mmol/L | ≤7.8 mmol/L |
| Infectious disease markers | ||
| mRDT | Negative | Negative |
| HIV ELISA | Negative | Negative |
| CBC | ||
| Leukocytes | 12.5 × 109/L | 4–11 × 109/L |
| Basophils | 0.1 × 109/L | 0.01–0.1 × 109/L |
| Eosinophils | 0.1 × 109/L | 0.04–0.4 × 109/L |
| Lymphocytes | 2.5 × 109/L | 1.5–4.0 × 109/L |
| Monocytes | 0.8 × 109/L | 0.2–0.8 × 109/L |
| Neutrophils | 9.0 × 109/L | 2.0–7.0 × 109/L |
| Erythrocytes | 5.41 × 1012/L | 4.5–6.5 × 1012/L |
| Hb | 14.1 g/dL | 13–18 g/dL |
| HCT | 46.7% | 40–54% |
| MCV | 86.3 fL | 80–100 fL |
| MCH | 28.0 pg | 27–33 pg |
| MCHC | 32.8 g/dL | 32–36 g/dL |
| RDW | 12.0% | 11.5–14.5% |
| Platelet count | 152 × 109/L | 150–400 × 109/L |
| MPV | 9.78 fL | 7.5–11.5 fL |
CBC shows mild leukocytosis, predominantly neutrophilia. BUN, blood urea nitrogen; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; Hb, hemoglobin; HCT, hematocrit; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MPV, mean platelet volume; mRDT, malaria rapid diagnostic test; RBG, random blood glucose; RDW, red cell distribution width. aSee the RBG.
The patient was diagnosed with TSC, complicated by intractable epilepsy and aspiration pneumonia. Initial management included intravenous ceftriaxone 1 g twice daily and metronidazole 500 mg three times daily for 3 days to treat the aspiration pneumonia. Seizures were controlled using intravenous diazepam 10 mg as needed and intravenous phenytoin 100 mg 3 times daily. Supportive measures included paracetamol for fever, urinary catheterization, nasogastric tube feeding, four-hourly repositioning to prevent pressure sores, and oxygen therapy, which was tapered and discontinued on day 3. On the first postadmission day, tendon reflexes were normal and the plantar response was flexor bilaterally. On the fourth day, he was transitioned to oral therapy with amoxicillin-clavulanate 500/125 mg twice daily, oral metronidazole 400 mg 3 times daily, sodium valproate 500 mg orally twice daily, and paracetamol as needed. Upon discharge, he continued with sodium valproate 500 mg orally twice daily.
Despite the lack of genetic testing due to resource constraints, the clinical presentation was sufficient for a definitive diagnosis of TSC, although it had not been previously diagnosed. His condition improved, and he was discharged after 10 days of hospitalization, with follow-up planned in the outpatient clinic.
During a follow-up examination 1 month after discharge, the patient reported no complaints, and a subsequent chest X-ray showed normal results. A detailed TSC-associated neuropsychiatric disorders (TAND) evaluation was performed using the TAND checklist [7]. The patient’s TAND profile (see online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000546098) revealed significant neuropsychiatric challenges associated with TSC. Behavioral concerns included anxiety, mood swings, and difficulties with attention and concentration. Intellectual assessment indicated a moderate intellectual disability, alongside reported memory difficulties. Additionally, family dynamics were affected by heightened stress levels, and the patient experienced low self-esteem. These findings underscore the complex neuropsychiatric burden of TSC, necessitating multidisciplinary management to address both medical and psychological needs.
Subsequently, a chest and abdominal CT scan was performed to evaluate for other potential manifestations of TSC. The chest CT revealed numerous thin-walled, round cystic spaces throughout both lungs (shown in Fig. 4), indicating cystic lung disease. Furthermore, the abdominal CT scan indicated multiple heterogeneous masses in both kidneys, likely renal angiomyolipomas (AMLs) (shown in Fig. 5). These findings underscored the multisystem involvement of TSC and the need for continued multidisciplinary care. The patient was managed by a multidisciplinary team comprising specialists in neurology, dermatology, pulmonology, psychiatry, psychology, and nephrology. This team worked collaboratively to address the various neurological, dermatological, pulmonary, and neuropsychiatric manifestations, ensuring comprehensive evaluation and treatment.
Chest CT scan demonstrates numerous thin-walled, round cystic spaces scattered throughout both lungs, consistent with cystic lung disease.
Chest CT scan demonstrates numerous thin-walled, round cystic spaces scattered throughout both lungs, consistent with cystic lung disease.
Abdominal CT scans show multiple renal angiomyolipomas (AMLs). The AMLs appear as heterogeneous masses involving both kidneys.
Abdominal CT scans show multiple renal angiomyolipomas (AMLs). The AMLs appear as heterogeneous masses involving both kidneys.
This case highlights the diagnostic challenges in resource-limited settings, where reliance on clinical findings is essential in the absence of advanced diagnostics. It underscores the importance of early recognition of TSC manifestations and the role of a multidisciplinary approach in managing this complex condition. Additionally, it illustrates the need for collaborative efforts to improve access to genetic testing and targeted therapies in low-resource environments.
The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material.
Discussion
TSC is a genetic disorder with wide-ranging clinical manifestations due to mutations in the TSC1 or TSC2 genes, leading to dysregulation of the mTOR pathway [1, 3]. This case illustrates the multifaceted challenges of diagnosing and managing TSC in resource-limited settings, particularly in rural Tanzania, where access to advanced diagnostic tools and targeted therapies is restricted.
The patient presented with hallmark clinical features of TSC, including intractable epilepsy, facial angiofibromas, and subependymal nodules [1, 3]. Despite the absence of genetic testing, these findings were sufficient to confirm the diagnosis [8], highlighting the critical role of clinical expertise in such settings. This aligns with previous studies emphasizing the importance of clinical diagnostic criteria in environments where advanced resources are unavailable [9]. Early recognition of TSC features, such as hypopigmented macules and renal AMLs, is crucial to initiating timely interventions and improving outcomes.
The prolonged, 20-year diagnostic delay in this patient underscores the pressing need for increased awareness of TSC among healthcare providers in LMICs [10]. A lack of familiarity with its clinical manifestations often leads to underdiagnosis and mismanagement, as seen in this case. Incorporating TSC diagnostic criteria into medical training programs and developing locally applicable management guidelines are essential steps to address this gap.
Management of TSC in resource-limited settings often focuses on symptomatic relief due to the unavailability of advanced therapies, such as everolimus [3]. These inhibitors have demonstrated significant efficacy in reducing tumor burden and improving seizure control in TSC patients [4, 6, 11]. However, in LMICs, logistical and financial barriers frequently limit access to such therapies. Strengthened collaborations with international institutions could facilitate access to these critical treatments through subsidized programs or research partnerships.
The identification of cystic lung disease and renal AMLs during follow-up highlights the multisystemic nature of TSC and the necessity for ongoing, multidisciplinary care. Coordination between specialties such as neurology, dermatology, pulmonology, psychiatry, psychology, and nephrology is essential for comprehensive management. Establishing multidisciplinary clinics dedicated to TSC patients could enhance outcomes in resource-limited settings.
This case also reinforces the importance of leveraging locally available resources. For example, detailed clinical evaluations and basic imaging tools, such as ultrasound and CT scans, remain invaluable in settings where advanced diagnostics are unavailable. Strengthening infrastructure to support such tools while exploring affordable genetic testing options could significantly improve diagnostic accuracy.
Therefore, this case underscores the critical challenges of diagnosing and managing TSC in resource-limited settings, while highlighting actionable strategies to improve care. Increasing awareness among healthcare providers, fostering international collaborations, and investing in healthcare infrastructure are pivotal steps toward better outcomes for TSC patients in LMICs. Addressing these barriers, the lessons from this case can inform efforts to improve the care of rare genetic disorders globally.
Conclusion
This case highlights the critical role of clinical expertise in diagnosing TSC in resource-limited settings, where access to genetic testing and advanced therapies is limited. The prolonged diagnostic delay underscores the need for heightened awareness among healthcare providers, the integration of TSC diagnostic criteria into medical training, and development of resource-appropriate management protocols.
Leveraging basic diagnostic tools and fostering multidisciplinary care can improve outcomes for TSC patients, even in constrained settings. International collaborations to enhance access to genetic testing and targeted therapies, combined with investments in healthcare infrastructure, are essential for addressing the challenges of managing rare genetic disorders in LMICs.
Acknowledgments
We sincerely thank the patient and his family for their cooperation in sharing their medical journey. We acknowledge the Department of Internal Medicine at Dodoma General Referral Hospital for its institutional support and the multidisciplinary team for their contributions to patient care. We also appreciate the healthcare professionals at Mpwapwa District Hospital for their initial management and referral.
Statement of Ethics
This case report was reviewed and approved by the Dodoma General Referral Hospital Research Ethics Committee (approval reference No. EB.229/254/01D/114). Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the consent form is available for review by the editor upon request.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
B.T., J.C., and E.I. wrote the main manuscript. B.T. formatted the tables, figures and main text. All authors reviewed the manuscript and approved its publication.
Additional Information
Basil Tumaini and John Calori share first authorship on this work.
Data Availability Statement
All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.
References
