Hereditary Renal Cystic Diseases: Tuberous Sclerosis Complex

Does this patient have tuberous sclerosis complex?

Tuberous sclerosis complex (TSC) is a systemic genetic disease characterized by renal cysts and skin lesions, as well as hamartomas in multiple organs. Major physical manifestations of TSC include: hypomelanotic macules, facial angiofibromas, periungual fibromas, and collagenomas (shagreen patches) as well as hamartomatous polyps of the rectum, gingival fibrosis, and enamel pits on the teeth.

The two most common renal pathologies seen in TSC patients are angiomyolipomas (AMLs) and cysts, though renal cell carcinoma, oncocytoma, focal segmental glomerulosclerosis and interstitial disease can be observed. Besides neurological and dermatological manifestations, renal complications are the next most common TSC-associated finding, with renal AMLs occurring in approximately 80% and renal cysts occurring in approximately 50% of all TSC patients.

On ultrasound (US), AMLs tend to appear as echodense, fatty masses with smooth muscle cells and thickened arterial vessels, which lack normal elastic tissue (Figure 1). Since AMLs have characteristic features on imaging modalities, they are usually diagnosed correctly.

Renal ultrasound of a patient affected with Tuberous sclerosis complex.

The second most common TSC-associated renal pathology is the presence of renal cysts. Renal cysts may occur alone or in conjunction with AMLs. Both AMLs and renal cysts occurring together are typically highly suggestive of TSC. Renal cysts will often not be detected until adulthood via computed tomography (CT) or ultrasound. When several cysts occur, renal-related signs and symptoms, such as hypertension may also become evident. A diagnosis of TSC can be made when there are at least two types of lesions found in a particular patient.

What tests to perform?

Lab testing

Management of TSC includes ordering a complete blood count (CBC) and comprehensive chemistry panels. For those with advanced renal insufficiency (chronic kidney disease [CKD] Stage 3 or 4), parathyroid hormone (PTH), Vit D 25 and Vit D 1,25 would also be included. All patients with underlying renal disease will need a lipid panel since they are at higher risk for cardiovascular disease.

Imaging

Common imaging modalities used are US, CT, and magnetic resonance imaging (MRI) scans. In general, US is sufficient to detect both renal cysts and AMLs, but may not provide enough information to accurately measure and follow the renal lesions and can also miss lesions that lack the fat component. If no cysts or AMLs are present, the kidneys should be scanned at 2-3 year intervals, preferably with MRI (avoid gadolinium if possible) or CT. If renal abnormalities are identified, then the growth of these lesions should be followed every year, unless symptoms occur. An MRI is necessary to detect exactly where the AML is located. Additionally, a prenatal ultrasound, performed by a cardiac sonographer, can detect a rhabdomyoma after 20 weeks, which can signal the presence of TSC in utero.

Overall interpretation of test results

After diagnosis, lab and imaging tests will be done to determine the severity of TSC and CKD. The results will provide practitioners a framework for treatment and management options. Renal AMLs are typically categorized as either <4cm or greater than or equal to 4cm in diameter. Most patients with AML diameters of <4cm do not report any symptoms. Patients with AML diameters of greater than or equal to 4cm can present with back or abdominal pain, nausea, fever, or vomiting.

It is recommended to monitor AMLs with a diameter of <4cm; however, if the AMLs appear to grow or cause symptoms, then medical interventions may be necessary. These may include surgical removal of the AMLs or radiological embolization of the artery contributing to its growth.

Depending on which vessel is contributing to the AML’s growth, the potential for aneurysmal formation may be increased. This may only be established by appropriate imaging, including gadolinium-enhanced magnetic resonance arteriography. One of the main concerns is hemorrhaging of the AML (usually in those AMLs greater than 4 cm in diameter).

The prognosis for patients with TSC depends on the severity of symptoms present. Patients with TSC will always be at risk for life-threatening conditions, such as brain tumors or acute rupture of renal angiomyolipomas, or poor pulmonary performance due to pulmonary lymphangiomyolipomas (LAM). Severely affected individuals can suffer from epilepsy and mental retardation; however, those with mild symptoms can lead relatively normal lives with appropriate medical care.

How should patients with tuberous sclerosis complex be managed?

Patients with TSC should be imaged every 2-3 years to survey for renal lesion development and yearly once renal lesions are indicated. A diagnosis of hypertension can also signal the presence of renal lesions. It should be noted that large AMLs might be mistaken for renal cell carcinomas, solely based on their size. An unnecessary nephrectomy may result.

In some cases, the AMLs may hemorrhage, leading to life-threatening bleeding; in these instances, surgery is necessary. In order to preserve renal function, evidence has shown that nephron-sparing surgery (NSS), selective renal artery embolization, radiofrequency ablation and cryoablation can be utilized to treat AMLs. End-stage renal failure is best treated with renal transplantation or dialysis.

What happens to patients with tuberous sclerosis complex?

TSC is an autosomal dominant disorder (Figure 2) with a birth incidence of 1 case per 6000 population and a prevalence of 1 case per 10,000 population. TSC is caused by mutations on the TSC1 gene on chromosome 9 (9q34) and TSC2 gene, which is located on chromosome 16 (16p13).

Pedigree of a family with tuberous sclerosis complex.

The TSC2 gene is also located immediately adjacent (within 50 base pairs) to the PKD1 gene, which is responsible for autosomal polycystic kidney disease (ADPKD), the most common hereditary cystic kidney disease. TSC1 encodes for the protein hamartin and TSC2 encodes for the protein tuberin. Both of these proteins form a functional complex. This results in a phenotype in TSC1 and TSC2 patients that is often indistinguishable.

TSC can be either sporadic (spontaneous mutation) or hereditary; however, approximately two-thirds of TSC cases result from sporadic genetic mutations, not inheritance. TSC2-associated disease is characterized by severe neurological complications, including epilepsy and mental retardation, as well as renal issues and physical manifestations of the disease. At least 90% of TSC patients develop visible skin lesions. Typically, AMLs tend to develop in older adolescents and continue to progress.

The main complication associated with AMLs is the potential for the lesions to bleed, due to the increased vascularity. AMLs are also likely to encroach on normal renal parenchyma, leading to kidney disease and end-stage renal failure. Among TSC patients, there is also an increased risk of cancer (renal cell carcinoma) of 1% to 2.5%, when compared to the general population. The presence of renal cysts tends to increase in prevalence as the patient ages. If the renal cysts are numerous and bilateral, then hypertension and renal failure may be observed.

In rare cases, a TSC2-PKD1 contiguous gene syndrome has been identified in patients with TSC and early-onset severe ADPKD. This syndrome is caused by chromosomal microdeletions disrupting both the TSC2 and PKD1 genes. TSC2-PKD1 contiguous gene syndrome is seen in infants fulfilling the diagnostic criteria for TSC2 and who present with grossly enlarged polycystic kidneys.

Pharmacologic considerations

Common medications for TSC management include: the immunosuppressants, rapamycin and everolimus (use has shown significant reduction in the size of the AMLs, though growth recurs on cessation of the medication. It is important to monitor for side effects of mTOR inhibitors); the antiepileptics, vigabatrin, topiramate, lamotrigine, and valproate; and either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers for hypertension. Regarding surgical options, surgery or embolization may be necessary when there is a risk for the renal lesions to hemorrhage.

How to utilize team care?

This disorder, more than any other renal cystic disease, requires interdisciplinary team care with ongoing communication by all specialists.

Specialty consultations: A clinical geneticist /genetic counselor can determine the disease and identify if it is a TSC1 or TSC2 mutation. Families of TSC patients should receive patient education on the risk for inheritance of the disease (50% in an at-risk individual) and potential progression of neurological, dermatological or renal disease for the individual if possible.
Neurologists assist in managing chronic seizures and being aware of drug interactions and toxicities of antiepileptic medications.
Dermatologists administer appropriate agents for reduction of skin lesions (mTOR inhibitors, immunosuppressants).
Nephrologic consultation is necessary for individuals with polycystic kidney disease, hypertension, CKD management, large or symptomatic AMLs, or end-stage renal disease.
Interventional radiologists must work with nephrologists to ensure that appropriate safety for patients is addressed during interventional procedures (administration of contrast for imaging of aneurysms that induces minimal nephrotoxicity).
Neurosurgeons can assist in the placement of a vagus nerve stimulator and assess the patient as a candidate for corpus callosotomy or focal resection.
Pulmonary medicine consultation is necessary for individuals with LAM, pneumothorax, chylous pleural effusions, or other types of lung involvement.
Dietitians assist in the institution and maintenance of a renal diet, which reduces the amount of phosphate, protein, sodium and acid intake.
Therapists may be necessary for children or adults who are struggling educationally, socially, or emotionally.

Are there clinical practice guidelines to inform decision making?

Since TSC can be either sporadic or hereditary, it is important for clinicians to consider the diagnostic criteria for TSC.

Other considerations

ICD-9 Codes: 759.5 (TSC); 585.1-585.5 (chronic kidney disease stages I-V); 585.6 (end stage renal disease); 403 (hypertensive chronic kidney disease); 757.32 (vascular hamartomas); 747.3 (anomalies of pulmonary artery); 345(epilepsy); 317 (mild mental retardation); 318 (moderate mental retardation); 318.1 (severe mental retardation); 318.2 (profound mental retardation); 758.33 (other microdeletions); 770.2 (interstitial emphysema and related conditions); 748.8 (other specified anomalies of respiratory system); 189.0 (malignant neoplasm of kidney except pelvis)
MIMs codes: #191100 (TSC1);#613254 (TSC2)

Currently, only one lab is allowed to test for the TSC1 and TSC2 gene.

Athena Diagnostics http://www.athenadiagnostics.com/content/index.jsp

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