| Abstract|| |
Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant inherited neurocutaneous disorder that variably affects the brain, skin, kidneys, heart, and other organs. It is characterized by skin and renal lesions in addition to central and peripheral nervous system tumors, with neurological and psychiatric findings. We report such a rare case of tuberous sclerosis in a 25-year-old female who presented with abdominal pain and hypertension. Physical examination showed dermatological signs that included hypopigmented maculae, shagreen plaque, angiofibromas on the centrofacial areas, periungual fibromas on toes, and molluscum pendulum around the neck. Abdominal ultrasonography revealed bilateral renal angiomyolipoma. Brain magnetic resonance imaging showed subependymal nodules and cortical tubers. She also presented retinal and oral lesions. Our patient has a definitive diagnosis of TSC. Hypertension was related to the renal involvement of TSC, and the patient benefitted from oral angiotensin- converting enzyme inhibitors with a favorable outcome.
|How to cite this article:|
El Aoud S, Frikha F, Snoussi M, Salah RB, Bahloul Z. Tuberous sclerosis complex (Bourneville-Pringle disease) in a 25-year- old female with bilateral renal angiomyolipoma and secondary hypertension. Saudi J Kidney Dis Transpl 2017;28:633-8
|How to cite this URL:|
El Aoud S, Frikha F, Snoussi M, Salah RB, Bahloul Z. Tuberous sclerosis complex (Bourneville-Pringle disease) in a 25-year- old female with bilateral renal angiomyolipoma and secondary hypertension. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 Feb 28];28:633-8. Available from: http://www.sjkdt.org/text.asp?2017/28/3/633/206461
| Introduction|| |
Tuberous sclerosis, also known as Bourne- ville disease or Bourneville-Pringle disease, is a hamartomatous disease with dominant auto- somal inheritance.,,,,, It is a distinct clinical entity for approximately 125 years since Desiree Magloire Bourneville described the first case in1880. It is a multisystem neuro- cutaneous syndrome that affects the skin and internal organs. The expanded phenotype is now called the tuberous sclerosis complex (TSC) to emphasize the multiorgan systemic involvement. The full classic triad including seizures, mental retardation, and cutaneous angiofibroma occurs in only 29% of the patients and 6% lack all three of the characterstics.,, The most common reported symptoms are lesions of the skin, central nervous system, heart and kidneys.
Here, we present the case of a 25-year-old female who had TSC with multiple organ involvement (cutaneous, neurological, ocular, and renal).
| Case Report|| |
A 25-year-old female with previously healthy status presented in the emergency department with abdominal pain. On physical examination, blood pressure was 160/100 mm Hg. Palpatory findings of her abdomen were normal. Echocardiography was also normal. Laboratory studies showed blood urea nitrogen, serum creatinine, and electrolytes levels within reference ranges. Complete blood count and urina- lysis also showed normal results. She was then referred to our internal medicine department for exploration. She had cutaneous lesions noted since the age of 15 years. Skin examination showed multiple hypomelanotic macules over the chest, abdomen, and extremities; angiofibromas symmetrically distributed over the centrofacial areas [Figure 1]; shagreen patch on the dorsal body, buttock, and forehead [Figure 2]; periungual fibromas and molluscum pendulum around the neck. The patient did not show any symptoms of cardiovascular, endocrine, respiratory, immune, or musculoskeletal disorders.
Abdominal ultrasonography showed bilaterally enlarged kidneys with solid, heterogenic, and echogenic masses, the bulkier measuring 11.4 cm, in the right kidney. Other abdominal organs were reported as normal. Abdominal scan confirmed the diagnosis of angio- myolipoma [Figure 3]. The association of renal angiomyolipoma (AML) and skin lesions led to the clinical diagnosis of TSC, and a search for other systemic manifestations was performed.
|Figure 3: Transaxial contrast-enhanced computed tomography image of the kidneys renal angiomyolipoma.|
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Ophthalmologic examination showed subre- tinal noncalcified hamartoma. Intraoral examination revealed fibrous proliferation in the lower vestibular face. Histological findings were compatible with angiofibroma. Chest radiograph was normal.
Brain magnetic resonance imaging (MRI) revealed subependymal nodules partially calcified in the bilateral cerebral parenchyma, subcor- tical tubers in the white matter of the frontal, occipital, and temporal lobe [Figure 4]. Echo- cardiography was normal. Based on these criteria, the diagnosis of TSC was made.
|Figure 4: Magnetic resonance image (fluid attenuation inversion recovery sequence) showing (a) multiple subependymal nodules partially calcified (yellow arrows) and (b) cortical and subcortical tubers on brain magnetic resonance image (red arrows).|
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Ambulatory blood pressure monitoring confirmed the diagnosis of hypertension. The patient did not have a family history of hypertension. The cause of secondary hypertension including renal artery stenosis, endocrine disorders (primary aldosteronism, pheochromo- cytoma, Cushing syndrome, and thyroid dysfunction), and obstructive sleep apnea was sought and was excluded in the absence of related clinical symptoms and negative laboratory and radiological results. Finally, hypertension was diagnosed as related to the TSC. The treatment was started with oral angio- tensin-converting enzyme inhibitors.
After one year of follow-up, the patient was going well; the blood pressure goal was reached. She did not have any episode of seizure. Kidney function was normal. Urine analysis did not show neither proteinuria nor hematuria.
| Discussion|| |
TSC is one of a group of related disorders known as neurocutaneous syndromes or phakomatosis, an incidence of approximately 1 in 5000–10,000 live births., It is an auto- somal dominant disease with high penetrance. However, approximately 70% of cases of TSC will be new mutations. It is caused by inactivating mutations of TSC1 and TSC2 tumor suppressor genes, located on chromosomes 9q34 and 16p13.3, respectively. The TSC1 gene is responsible for encoding a protein called hamartin and TSC2 for encoding for tuberin. The hamartin-tuberin complex is an important inhibitor of the mammalian target of rapamycin (mTOR). Its absence triggers loss of inhibition on cell proliferation and tumors growth.
TSC is a multisystem disorder with variable clinical manifestations. The wide spectrum of clinical features results from the formation of hamartomas in various organs. Hamartomas are frequently present in the skin, brain, kidneys, and heart and less frequently in lungs, retina, gingiva, bones, and gastrointestinal tract.
Cutaneous manifestations are common and represent the most frequent findings in TSC. They are typically the first clue to the diagnosis. The most prevalent of skin manifestations is the presence of hypomelanotic macules or “ash-leaf patches” occurring in 90%-98% of cases. They are often present at birth, and they may become more numerous with time. Skin hypopigmentation is also frequently noted in the “confetti lesions” seen on the anterior surface of the arms. Facial angio- fibromas (adenoma sebaceum) are patho- gnomonic for TSC and are seen in over 70% of patients. They are hamartomatous nodules of vascular and connective tissue, with a butterfly pattern over the malar eminences and nasolabial folds of the face. The forehead fibrous plaque, found in around 36% of patients, is a yellow-brown or flesh-colored patch of raised skin of variable size and shape. Another common dermatological feature of TSC is the Shagreen patch which approximately occurs in 54% of patients. Ungual fibromas, also called Koenen tumors, are generally more common on toes than on fingers. Our patient presents classical cutaneous findings including hypomelanotic macules, facial angiofibroma, shagreen patches, molluscum pendulum, and ungual fibroma.
Oral manifestations of TSC are characterized mainly by fibrous hyperplasia (angiofibromas) and dental enamel pitting., Therefore, a detailed assessment of the oral cavity is crucial, including examination of the gingiva under dentures, for the detection of these changes.
TSC has a striking variability of neurocog- nitive manifestations and psychopathological features. The most common neurological finding is seizures making epilepsy a significant cause of morbidity associated with this disease. Autistic spectrum disorders and cognitive delay are also highly prevalent among individuals with TSC. Imaging techniques, especially brain magnetic resonance, are now well established for diagnosing and following up TSC patients. They are altered in 90 to 95% of cases, with the description of cortical tubers, subependymal glial nodules, white matter hamartomas, and subependymal giant cell astrocytoma. Cortical tubers are mostly supratentorial, in the frontal lobes. In MRI, the cortical tubers have low signal on T1-weighted images and are hyperintense on T2-weighted and fluid attenuation inversion recovery images. One of the most important neurological complications is the development of brain tumors: subependymal giant cell astro- cytomas close to the foramen of Monro causing obstructive hydrocephaly., Our patient presented with extensive neurological lesions including cortical tubers and sub- ependymal nodules. However, she did not present with any symptomatic neurological disorders till now.
Renal manifestations are the second most common findings associated with TSC. They are considered as a common cause of morbidity and mortality after neurologic complications. The main manifestations are AMLs (80%) and cysts (17–47%). An association between TSC and renal malignancies has been recognized but is mostly anecdotal. The most common symptoms are abdominal pain, palpable abdominal mass, hematuria, and other consequences of intratumoral hemorrhage. Hypertension is one of the important complications of kidney involvement in TSC such as the case of our patient. It is seen in 37% of cases. It may be secondary to renal ischemia, the growth of tumors encroaching on normal renal tissue, hypersecretion of renin by the tumor, or to a progressive destruction of the parenchyma by interstitial nephritis. Both renal cystic disease and AMLs cause chronic renal disease, affecting approximately 1 million patients with TSC worldwide.
TSC is associated with both nonretinal and retinal findings. Nonretinal abnormalities such as eyelid angiofibromas, strabismus, cataracts, colobomas, and iris depigmentation have been reported. Hamartomas are the most common retinal manifestation present in about 40–50% of patients. Less common manifestations are cardiac rhabdomyoma, lung disease (lymph- angioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, and clear cell “sugar” tumor ), hepatic AMLs, splenic hamartomas, and also bony changes (sclerotic lesions).
The diagnosis and management of TSC is often challenging, requiring a broad understanding of the wide range of its manifestations. The classic Vogt’s triad (facial angiofibromas, mental retardation, and intractable epilepsy) is present in <40% of affected patients. In a consensus conference in 1998, Roach et al revised the clinical diagnostic criteria of TSC to provide a standardized approach for identification of this disease [Table 1]. The diagnosis is made when two major criteria, or one major and two minor ones, can be shown. The presence of typical imaging features of TSC may help to confirm the diagnosis in patients with suspected TSC. Our patient has a definitive diagnosis of TSC. She had seven major criteria and two minor ones.
Treatment of TSC consists in addressing the symptoms caused by hamartomas and prophylactic measures to prevent loss of function of the affected organ. Since it is a systemic disease, a multidisciplinary approach is mandatory. Inhibitors of the mTOR pathway, such as rapamycin, also known as sirolimus, have an immunosuppressive and antiproliferative action. This drug is effective in reducing the volume of tumors in patients with TSC such as renal AMLs and subependymal giant cell astrocytoma.
In the present case, the patient had been having the skin manifestations of TSC since the age of 15 years and it was unnoticed till she presented to us. She had kidney and neurological involvement:
- She had renal AML, which at the time of presentation was causing hypertension. The patient was educated about the condition and was instructed that any manifestations such as hematuria should be considered as an emergency and should be treated with utmost urgency. She was advised to have periodic ultrasound examination of the kidneys at least every three years, as these benign lesions can eventually enlarge in size.
- She had also cortical tubers and subepen- dymal nodules which were asymptomatic till now. Therefore, the patient was again educated about the importance of the clinical and radiological follow-up to diagnose neurological complications at the earliest.
| Conclusion|| |
Tuberous sclerosis is a genetic, autosomal dominant, variably expressed, multisystem disorder that can cause circumscribed, benign, noninvasive lesions in any organ. Recognition of specific radiologic features may help in early diagnosis and management and improve outcomes in TSC patients.
A multidisciplinary approach and patient’s education were essential for an early and a proper management of this disease. It is believed that, in the future, gene therapy will make it possible to treat mutations that cause TSC.
Conflict of interest: None declared.
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Sahar El Aoud
Department of Internal Medicine, Hedi Chaker Hospital, 3029 Sfax
[Figure 1], [Figure 2], [Figure 3], [Figure 4]