Tuberous Sclerosis Complex A Review for Health Care Professionals

Transcription

1 Renal Lesions in Patients With Tuberous Sclerosis Complex A Review for Health Care Professionals

2 ONGOING SURVEILLANCE IS CRITICAL TO MONITOR THE PROGRESSION OFIntroduction KNOWN SYMPTOMS AND THE EMERGENCE OF NEW O Tuberous Sclerosis Complex The Role of Genetics in TSC Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that can cause noncancerous tumors, or hamartomas, in multiple organs particularly the brain, kidneys, lungs, eyes, skin, and heart over a patient s lifetime.1,2 Clinical manifestations vary widely, but seizures and dermatologic manifestations are the most common presenting features that lead to initial consultation.2 SC is caused by mutations in 1 of 2 genes, TSC1 (hamartin) or TSC2 (tuberin), leading to T dysregulation of the mtor (mammalian target of rapamycin) pathway.2,10 The mtor pathway controls cell growth and proliferation, angiogenesis, glucose uptake, and metabolism.11,12 TSC1 and TSC2 mutations lead primarily to the formation of nonmalignant tumors (eg, hamartomas) in multiple organ systems.11 The graphic below highlights the clinical manifestations of TSC and the age at which the various organ systems are most commonly affected. Prenatal < 1 yr 1-5 yr >5-18 yr > 18 yr Renal angiomyolipomas3 Cortical tubers4,5 SENs2 mtor Activation in TSC SEGAs2 Prevalence of TSC Dermatologic manifestations 6 SC affects an estimated 1 million people worldwide.13 But because of symptom variability T and underrecognition of less-severe phenotypes, many TSC cases remain undiagnosed.2,14 Retinal hamartomas7 TSC is more prevalent than several better-known genetic disorders Cardiac rhabdomyomas8 Number of people affected each year in the United States LAM9 LAM, lymphangioleiomyomatosis (lung); SEGAs, subependymal giant cell astrocytomas; SENs, subependymal nodules. ~50,000 TSC15 Cystic fibrosis16 30,000 ALS17 30,000 Huntington s disease18 30,000 Hemophilia19 20,000 ALS, amyotrophic lateral sclerosis

3 Diagnosis of TSC Historically, health care providers diagnosed TSC patients using Vogt s triad, which consists of epilepsy, mental retardation, and adenoma sebaceum. However, less than 30% of patients actually meet these criteria. 14 Genetic criteria are also an integral part of the diagnostic paradigm for TSC. Comprehensive and reliable screens for TSC1 and TSC2 mutations are well established, and many pathogenic mutations have been identified. Current TSC consensus guidelines have made identification of a pathogenic mutation in either TSC1 or TSC2 an independent diagnostic criterion sufficient for the diagnosis or prediction of TSC regardless of clinical findings. 20 It is important to note, however, that between 10% and 15% of TSC patients have no mutation identified by conventional genetic testing; thus, a normal result does not exclude TSC. 21 The wide range of clinical presentations in TSC patients needs to be considered. There are underrecognized groups of patients, including asymptomatic adults who are diagnosed based on physical examination and/or radiographic findings. 2 Below, 2 hypothetical patient journeys are presented: 1 with a diagnosis made early in life, and 1 made in adulthood. Genetic Testing Genetic testing is available to identify the genes associated with TSC (TSC1 and TSC2). Tests are based on gene mutations or gene deletions, and under optimal circumstances, genetic testing identifies mutations in up to 80% of affected individuals. 14 Testing may be appropriate for confirming clinical diagnosis, predicting at-risk asymptomatic family members, and for prenatal diagnosis. 14 Testing costs, which may not be covered by private insurance, range from about $250 to about $ Diagnostic Clinical Criteria The diagnostic clinical criteria include 11 major features and 6 minor features, as shown in the chart below. 20 Definitive diagnosis: 2 major features or 1 major feature with 2 minor features Possible diagnosis: Either 1 major feature or 2 minor features Major Features Infantile spasms at 6 months of age 1 Cortical tubers revealed by magnetic resonance imaging (MRI) at 3 years of age 1 Patient A Presentation in infancy/childhood Cardiac rhabdomyoma found during routine prenatal ultrasound at 26 weeks gestation 3 Patient B Presentation in adulthood Diagnosis of autism at 4 years of age 1 Development of facial angiofibromas at 5 years of age 1 Numerous angiomyolipomas identified on computed tomography (CT) scan, occurring in both kidneys at age LAM diagnosis at age Hypomelanotic macules (>3, at least 5-mm diameter) Angiofibromas (>3) or fibrous cephalic plaque Ungual fibromas (>2) Shagreen patch Multiple retinal hamartomas Cortical dysplasias a Minor Features Confetti skin lesions Dental enamel pits (>3) Intraoral fibromas (>2) Subependymal nodules (SENs) Subependymal giant cell astrocytoma (SEGAs) Cardiac rhabdomyoma Lymphangioleiomyomatosis (LAM) b Angiomyolipomas (>2) b Retinal achromic patch Multiple renal cysts Nonrenal hamartomas Development of confetti lesions on the arms at age 25 1 Numerous cysts revealed by ultrasound, occurring in both kidneys at age Many TSC cases are not diagnosed until adulthood. In one retrospective study of female patients, 59% were found to have been diagnosed as adults. 22 a Includes tubers and cerebral white matter radial migration lines. b A combination of the 2 major clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis. Although not part of the diagnostic criteria for TSC, epilepsy may be the most prevalent and challenging clinical manifestation. 2 Epilepsy occurs in more than 90% of TSC patients 24 and is a major sign that warrants further investigation of a potential TSC diagnosis. 6 7

4 Renal Imaging for TSC Renal Manifestations of TSC The initial evaluation of a patient suspected of having TSC includes renal imaging, usually by ultrasound, CT, or MRI. Follow-up is scheduled based on clinical suspicion and the results of previous imaging tests. Renal imaging should be performed every 1 to 3 years. 25 More frequent imaging is appropriate after a lesion is first detected, so that it can be monitored for stability or changes indicating progression. 25 Because of the possibility of progression or development of new lesions, renal specialists may continue to monitor a patient through adulthood even if the imaging results obtained during adolescence are normal. Imaging Technique MRI 26 Reprinted from AJR, Vol 184, Israel GM, copyright 2005 Ultrasound 30 Features At a Glance More conclusive than CT in differentiating renal angiomyolipomas from renal cell carcinoma 27 Can detect fat-poor lesions 28 Effective in detecting both the macroscopic and microscopic fat components of renal angiomyolipomas 28 Adequate for diagnosis of renal angiomyolipoma when contrast enhancement is contraindicated or CT is inconclusive 27,29 Can provide better visualization of involved areas (compared with ultrasound) when numerous lesions are involved 27 Useful during pregnancy 27 Can quickly monitor changes in renal angiomyolipomas and renal cysts 14 Preferred for use in children; does not expose patients to ionizing radiation 31 The 3 renal manifestations of TSC are renal angiomyolipomas, renal cysts, and renal cell carcinoma (table below). 33 Renal Lesions in TSC Lesion Renal Angiomyolipomas Axial noncontrast CT image through the abdomen showing enlarged kidneys with numerous angiomyolipomas. 32 Reprinted from J Clin Imaging Sci, Vol 39, Radhakrishnan R, copyright Renal Cysts MRI through the kidneys showing renal cysts occurring in both kidneys. 32 Reprinted from J Clin Imaging Sci, Vol 39, Radhakrishnan R, copyright Age of Onset and Incidence Onset: <2 years (16%); however, the majority (70%- 90%) of renal angiomyolipomas are found in adults with TSC 3 Overall Incidence: Up to 80% 8,34 Onset: Usually early childhood 2,38 Overall Incidence: 18% to 53% 33 Key Points Tend to grow more quickly than those that do not result from TSC 35 Tend to occur in both kidneys in up to 80% of patients and are often numerous 34,36 Renal angiomyolipoma cells have been shown to infiltrate normal renal tissue 28,37 Can cause serious, potentially life-threatening comorbidities 27 Retroperitoneal hemorrhage Renal insufficiency Renal failure Often numerous and occur in both kidneys 33 Usually asymptomatic 1 May cause hypertension 33 In rare cases, may present with severe early-onset renal cystic disease, progressing to end-stage renal failure by early adulthood 1 Reprinted from Eur Urol Suppl, Vol 5, Pavlica P, Renal cell carcinoma imaging, pp , copyright 2006, with permission from Elsevier. Renal Cell Carcinoma Onset: 28 to 30 years 3 Occurs at a younger age in TSC patients than in the general population 3,33 CT 32 Reprinted from J Clin Imaging Sci, Vol 39, Radhakrishnan R, copyright Can detect fat in a tumor, which is key to diagnosing renal angiomyolipoma 27 Imaging modality of choice when hemorrhage is suspected 27 Highly sensitive for identifying mass and hematomas 27 Can provide better visualization of involved areas (compared with ultrasound) when numerous lesions are involved 27 Helical CT with thin-cut sectioning has the greatest sensitivity, especially for tumors with lower fat content or with hemorrhage 27 Contrast-enhanced CT scan showing renal cell carcinoma in the left kidney. 33 Reprinted from RadioGraphics, Vol 28, Umeoka S, ppe32-e61, copyright Overall Incidence: 2% to 3% and is considered to be rare 39,40 Has a female preponderance 3 Usually occurs in both kidneys 3 Has heterogeneous pathology 33,41 May be difficult to distinguish radiologically from renal angiomyolipomas

5 Focus on Renal Angiomyolipomas Angiomyolipomas are highly vascularized tumors composed of fat and smooth-muscle cells most commonly found in the kidneys. 8 These tumors may vary in size from 1 mm to more than 20 cm in diameter. 2,29,42 Renal angiomyolipomas occur in up to 80% of TSC patients, and increase in number and size with age. 8,43 Renal Angiomyolipomas in TSC Are More Likely to Have Serious Risks Than Those Not Associated With TSC 40 Renal angiomyolipomas not related to TSC may occur in patients without the clinical features or genetic mutations characteristic of TSC, 2 and occur almost exclusively in middle-aged women. 31 Complications of TSC-Associated Renal Angiomyolipomas Renal complications are the most common cause of TSC-related death or disability and the second after neurologic complications. Renal angiomyolipomas do not spontaneously regress and are associated with serious, potentially life-threatening morbidities. 45 The Serious Risks of Renal Angiomyolipomas The estimated risk of hemorrhage from renal angiomyolipomas in patients with TSC is between 25% and 50%. 37 The risk increases with tumor size and vascularity. 37,38,40 TSC-associated renal angiomyolipomas tend to: Occur in both kidneys 8 Occur at numerous sites in the same kidney 36 Have lymph node involvement 36 Be more likely to grow 43 Once the diameter of a renal angiomyolipoma reaches 4 cm, 68% to 80% of patients may develop symptoms. 46 The risk of renal insufficiency may lead to chronic kidney disease and renal failure. 27 Occur at a younger age 36 Be larger at presentation 36 Hemorrhage 8,27 Recur 43 Comparison of TSC-Associated Renal Angiomyolipoma to Those Not TSC-Associated 44 There is a heightened risk of hypertension and renal failure if glomerular function is impaired. 25,31,33,37 Approximately 1% of individuals with TSC develop end-stage renal disease. 47,48 TSC-Associated n=14 Mean age (yr) 26 ±3.2 Mean lesion size (cm 3 ) a 19.3 ±4.8 Sporadic n=46 Mean rate of growth/year (cm) P Value 49.4 ±2 < ±0.7 <0.001 Multiple bilateral tumors (%) <0.001 Symptomatic at follow-up (%) <0.01 a Lesion size correlates to volume and was measured using orthogonal diameter technique. Data from a review of 60 patients diagnosed with renal angiomyolipomas. The differences of clinical spectrum between TSC-associated renal angiomyolipomas and sporadic renal angiomyolipomas were identified. Parameters including age, tumor size, multiplicity, symptoms, complications, association with TSC, and treatment modality were reviewed. 44 The most common presenting symptoms of patients with TSC-associated renal angiomyolipomas are flank pain, palpable masses, and hematuria. 27 Other presentations include nausea or vomiting, fever, hypertension, anemia, renal failure, and hemorrhage. 27 Angiomyolipomas Can Migrate Beyond the Kidneys In patients with TSC, renal angiomyolipoma cells have been shown to infiltrate normal renal tissue both adjacent to and distant from existing tumors. 28,37 These angiomyolipoma cells may be exhibiting an atypical migratory phenotype. 37 Renal insufficiency may occur as a result of compression and replacement of normal renal tissue with angiomyolipoma tissue. 27 One in 5 renal angiomyolipomas are related to TSC. 33,

6 Adopting a Multidisciplinary Approach to TSC Renal Lesions Brochure Update Cover Mv2.indd 11 10/13/16 10:18 AM he unpredictable nature of TSC manifestations requires a multidisciplinary approach and regular T lifelong follow-up as adopted by TSC centers of excellence nationwide. Renal specialists play a crucial role in the identification and surveillance of renal lesions and their complications. These specialists often receive referrals from other members of the multidisciplinary TSC care team to evaluate and monitor renal manifestations associated with the disease. Regular follow-up with adult TSC patients is needed to detect changes in renal structure and function as well as monitor for potentially life-threatening disease manifestations, as these may develop at any time and can cause serious complications.25,49 LAM can be associated with TSC-related renal angiomyolipomas.50 Up to 40% of adult women with TSC are affected by LAM.22 Renal specialists should refer their TSC patients to a pulmonologist, particularly their female patients who have a much higher risk. Connecting Patients With Optimal Care6,9,51,52 Pulmonologists Monitor patients for LAM Ophthalmologists Can identify retinal nodular hamartomas Nephrologists/Urologists Provide specialized care for patients with TSC-related renal manifestations and their complications Neurosurgeons Perform surgical procedures on patients with epilepsy and SEGAs Dermatologists Identify skin lesions and manifestations 12 Cardiologists Monitor cardiac rhabdomyomas Pediatricians and General Practitioners Aid in the diagnosis and care of TSC patients Neurologists Involved in diagnosis and treatment of central nervous system manifestations Geneticists Provide information on the genetics of TSC and genetic testing Psychiatrists/Psychologists Novartis Pharmaceuticals Corporation is committed to understanding and improving the lives of people with tuberous sclerosis complex through clinical research, education, and collaboration with the TSC community. Specialize in emotional and behavioral issues related to TSC 11 13

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Am J Obstet Gynecol. 2009;200(3):321.e1-321.e6. QR CODE FOR INTERNAL USE ONLY. Novartis Pharmaceuticals Corporation East Hanover, New Jersey Novartis Printed in USA 9/16 AGM