Varied manifestations of tuberous sclerosis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0975-2870.150504
Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease. The prevalence of TSC is estimated to be 1 in 95,136 in general population and in those <6 years of age, it is 1 in 14,608. It is an autosomal dominant neurocutaenous disease and in about 80% of cases it is caused by a de novo mutation. The relationship between cardiac rhabdomyomas and TSC is well established. The cardiac rhabdomyomas may arise anywhere in the myocardium but are more commonly seen in the left ventricle. However, in our case an interventricular septal rhabdomyoma was seen. Angiomyolipomas (AMLs) occur in up to 80% of patients with TSC. Bilateral renal AMLs were seen in our case. There was evidence of systemic involvement in form of lymphangiomyomatosis and subependymal hamartomas. Keywords: Angiomyolipoma, cardiac intra ventricular septal rhabdomyoma, tuberous sclerosis
Tuberous sclerosis complex (TSC) also called Bourneville's disease. The prevalence of TSC is estimated to be 1:95,136 and those <6 years of age is 1:14,608. [1] It is an autosomal dominant neurocutaenous disease and about 80% is caused by de novo mutation. [2] Cardiac involvement in TSC is characterised by presence of rhabdomyomas. They may present as arrythmias, heart failure or ventricular inflow or outflow tract obstruction. The cardiac rhabdomyomas may arise anywhere in the myocardium but are more commonly seen in the left ventricle. However, in our case an interventricular septal rhabdomyoma was seen. Angiomyolipomas (AMLs) occur in up to 80% of patients with TSC. [3] Thus, this case reveals an important but rare site for cardiac rhabdomyoma.
A 35-year-old female, presented to us with the complaint of 1 episode of seizure which were generalized tonic clonic in semiology. She was a diagnosed case of epilepsy since the age of 1½ months and had been on anti-epileptic medication (valproate) in past and it was self-discontinued around 10 years ago. The fits were associated with urinary incontinence, frothing, and up rolling of eyeballs. There was no history of tongue bite. There was history of mental retardation. Although her milestones were not delayed, she was able to speak only in small sentences. She had acute visual loss at the age of 10 years. On physical examination, she was restless, with a Glasgow coma scale of 7/15. Her vitals were stable. Physical signs revealed facial angiofibromas, hypomelanotic macules in lower abdomen and periungal fibromas in the left thumb. A shagreen patch was present in the right lower lumbar region. Patient was put on valproate. Patient became conscious and oriented over a span of 1 h. Investigations showed a normal complete blood count. Besides routine tests, her serum levels of calcium, sodium, potassium phosphorus, and magnesium were within normal limits. Fundus examination was normal. Electrocardiographic and pulmonary function test were normal. Patient underwent contrast enhanced computed tomography (CT) of abdomen which showed presence of well-marginated, cortical-based, heterogeneously enhancing tumor, predominantly of fat density (<−20 HU) in bilateral kidneys s/o renal AMLs [Figure 1]. Patient was further subjected to contrast enhanced CT thorax that revealed multiple variable sized cysts distributed randomly in bilateral lung fields with intervening normal lung parenchyma in between the cysts suggestive of lymphangiomyomatosis (LAM) like changes in bilateral lung fields [Figure 2]. A hypodense non enhancing lesion was noted in the interventricular septum, likely a septal rhabdomyoma [Figure 2] and rest of the cardiac chambers were normal. To further evaluate, noncontrast CT cranium was also done that showed the presence of multiple calcified periventricular subependymal nodules with basal ganglia calcification [Figure 1]. A gene analysis was done and patient was found to have a mutation in gene TSC 2. Patient refused treatment with Rapamycin. Laser therapy reduced the size of facial angiomas. Patient is under a regular follow up from psychiatric clinic. Her brother was screened for mutation of TSC gene and was found to have a TSC 2 gene mutation as well. He had various clinical manifestations of TSC including left ventricle cardiac rhabdomyoma. Rest of the relatives of the patient had died in an accident 8 years ago.
Summarizing her history, extensive physical signs and investigations, the final diagnosis of TSC was made.
Tuberous sclerosis is a autosominal dominant neurocutaneous syndrome with benign hamartomatous lesions involving multiple organ systems of the body. There appears to be a chronological pattern of organ involvement; cardiac rhabdomyomas occur in antenatal and neonatal period, renal AMLs become more frequent with increasing age. [4] Though, the gender predilection has not been reported, except LAM that affects only females. Tuberous sclerosis is also characterized by angiofibromas formation on the face which leads to cosmetic issues to the patient. Diagnosis can be delayed due to late manifestations of some symptoms. Some patients may present with only renal and pulmonary manifestations while in some skin or neurological manifestations might be absent. However, in our case, the patient had skin and neurological features as the presenting complaints. Cardiac rhabdomyomas mostly present in neonatal period. Often multiple lesions are seen in one or both ventricles (more commonly left ventricle), [5] rhabdomyomas have also been rarely reported in interventricular septum. Our patient had an incidentally discovered interventricular septum rhabdomyoma. These lesions are seen as smooth, round, intraventricular masses with characteristics similar to normal heart. Intracranial involvement can be complex involving cortical, subcortical, subependymal and cerebellar tissue. Periventricular subependymal hamartomas are seen which may show calcification in 90% cases. [6] When at foramen of monro these hamartomas may rarely transform into giant cell astrocytoma. Cortical and subcortical tubers are seen as hypodense lesions on CT. Rarely, they may appear hyperdense. Magnetic resonance imaging (MRI) is superior in identifying cortical tubers. Our patient too was found to have subependymal hamartomas with calcification. Renal involvement is seen in 60% of cases of TSC with AMLs being the most common lesion. [5] TSC accounts for 20% of all AMLs that tend to be multiple, large, bilateral. On ultrasonography, they are seen as heterogenous masses with predominantly hyperechoic fat content. [6] In few cases multiple simple cysts are also seen in combination with AML. On CT, they are seen as hypodense lesions due to fat content which makes them hyper intense on T1-weighted MRI with complete loss of signal on fat suppressed sequences. Intrarenal haemorrhage has been reported as a complication. [7] Our patient was found to have an asymptomatic bilateral AML on work up. High resolution computed tomography thorax may show multiple, variable sized cysts distributed in bilateral lung fields with normal intervening lung parenchyma suggestive of LAM. Hamartomatous proliferation of pneumocytes may also be seen in addition to LAM. Renal AML may be observed in 50% of patients affected with TSC. [8] LAM co-exists with TSC and a possible relationship between LAM and TSC is under investigation. [8] Webb, in his study, found skin signs to be present in 96% of patients with TSC. [9] However, in another study, dermatologic features were found to be presenting signs in only 6% of patients with TSC. [10] In addition, hamartomatous polyps may occur anywhere from oesophagus to rectum, most commonly involving large bowel. Musculoskeletal involvement is seen as a patchy increase in bone density. As has been reported in the literature, multisystem involvement is also noted in our case with an uncommon location of cardiac rhabdomyoma seen in the interventricular septum with bilateral large renal AMLs, with lung changes suggestive of LAM, along with skin manifestations and intracranial periventricular subependymal hamartomas with calcification. Our case was diagnosed using criteria adopted from Roach and Sparagana. [11] Our patient fulfilled more than 2 major criteria which include cardiac rhabdomyoma, renal angiomyolioma, shagreen patch, facial angioma's, hypomelanotic macules and periungal fibromas.
The cardiac rhabdomyomas may arise anywhere in the myocardium but are more commonly seen in the left ventricle. However, in our case an interventricular septal rhabdomyoma was seen. Thus, our case demonstrates a rare location of cardiac rhabdomyomas in TSC patients.
[Figure 1], [Figure 2]
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