Tuberous sclerosis complex is characterized by a wide phenotypic spectrum, occurring in approximately 1 in 6000 to 10,000 individuals (Sampson et al 1989; Osborne et al 1991). The diagnosis of tuberous sclerosis complex is based on the lesions found on clinical examination, imaging, and pathologic studies.
Revised diagnostic criteria of tuberous sclerosis complex include major and minor features (Roach et al 1999; Roach and Sparagana 2004; Northrup et al 2013). Fundamental to the first revision was consensus that there are no truly pathognomonic clinical signs for tuberous sclerosis complex; the signs that were once regarded as specific sometimes occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Major features are signs with a high degree of specificity for tuberous sclerosis complex, whereas minor features are less specific. Although the skin is the most commonly involved organ, the brain, kidneys, retina, heart, lungs, and the large arteries are all frequently involved. The most recent revision in June 2012 includes genetic criteria for diagnosis and eliminates probable disease as a diagnostic class (Northrup et al 2013). It is anticipated that use of the genetic criteria will allow presymptomatic diagnosis of tuberous sclerosis complex in some individuals, allowing earlier implementation of surveillance and treatment with potential for better clinical outcomes.
Genetic diagnostic criteria. The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of tuberous sclerosis complex (TSC). A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (eg, frameshift or nonsense mutation), prevents protein synthesis (eg, large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment.
Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria, and are not sufficient to make a definite diagnosis of tuberous sclerosis complex. Ten percent to 25% of tuberous sclerosis complex patients have no mutation identified by conventional genetic testing, and a normal result does not exclude tuberous sclerosis complex, or have any effect on the use of clinical diagnostic criteria to diagnose tuberous sclerosis complex.
Molecular testing of the TSC1 and TSC2 genes yields a positive mutation result for 75% to 90% of tuberous sclerosis complex-affected individuals categorized as “definite” by the 1998 Consensus Conference Clinical Diagnostic Criteria.
Clinical diagnostic criteria.
Definite tuberous sclerosis complex
Possible tuberous sclerosis complex
If both renal angiomyolipoma and lymphangioleiomyomatosis are present, other features of tuberous sclerosis complex should be present for a definite diagnosis.
Clinical manifestations according to organ systems. The type, size, number, and sometimes the location of involved lesions and organ systems dictate the clinical presentation.
Skin lesions are found in 96% of patients with tuberous sclerosis complex, who usually seek medical attention because of seizures, making it a prototypical neurocutaneous disorder. There exist 2 types of skin lesions: hamartomas (including facial angiofibromas, fibrous cephalic plaques, shagreen patches, and ungual fibromas) and hamartias (such as white spots or hypomelanotic macule) (Moolten 1944; Gomez 1988a; Rogers 1988). Hamartomas present in infancy to adulthood, whereas hamartias predominantly present in infancy to childhood. Of all patients with tuberous sclerosis complex, 87% have hypomelanotic macules, 75% have facial angiofibromas, 21% have ungual fibromas, 50% have shagreen patches, and 4% have no skin lesions at all. The most common skin manifestation, the hypomelanotic macule, is best seen with a Wood's lamp and is often noted over the buttocks and trunk. The facial angiofibromata are usually bilateral, in a butterfly distribution over the naso-labial folds and malar area. Fibrous cephalic plaques may be the most specific dermatological finding in tuberous sclerosis complex. In addition, dental pits have been noted in 90% of the patients with tuberous sclerosis complex, approximately 10 times more often than in the general population (Flanagan et al 1997).
The CNS manifestations of tuberous sclerosis complex, noted in about 85% of afflicted children, include seizures, cortical dysplasia, tumors, mental retardation, autism, ADHD, and sleep disorders.
Seizures are by far the most common presenting complaint (in 84% of patients and in greater than 95% of all infants). All types of seizures can occur, but the predilection is to present with infantile spasms when they occur in early infancy. A third of all children with tuberous sclerosis complex develop infantile spasms. The absence of seizures during infancy foreshadows better cognitive development. Patients with infantile spasms may progress to develop Lennox-Gastaut syndrome. Earlier onset portends a worse prognosis for developmental delays and subsequent intractable partial epilepsy. Improved development has been proven to occur when infantile spasms and partial seizures are controlled.
The cortical tuber is the CNS lesion that is most frequently symptomatic, and often is associated with simple partial or complex partial seizures in infancy. It is a form of cortical dysplasia, and may be associated with radial migration lines, which are formed by a similar pathology. These tubers can be detected prenatally (Khanna et al 2005) and are composed of abnormally configured dysplastic neurons and molecularly altered glutamate and GABA receptors (White et al 2001) with defective inhibition (Calcagnotto et al 2005). Tubers are not the only determinant of epilepsy.
CNS tumors are found in 5% to 15% of individuals afflicted with tuberous sclerosis complex. These tumors differ in their location, radiological characteristics, and biological behavior (Torres et al 1998). Subependymal nodules are present in almost 80% of patients and can be identified prenatally or at birth. They are commonly low-grade dysplasias, which share histology with subependymal giant cell astrocytomas, whose presentation may vary from totally asymptomatic to obstructive hydrocephalus and death. Subependymal giant cell astrocytomas are hamartomas that are located near the foramen of Monro, are greater than 0.5 cm in size, and grow and enhance with gadolinium on MRI. Less commonly, there are aggressive tumors like pineal giant cell astrocytomas, glioblastoma multiforme, or spongioblastoma. Ependymoma, neurinoma, acoustic neuroma, hemangioma, and neuroblastoma have also been reported.
Sleep disorders such as night waking, early waking, seizure-related sleep problems, and excessive daytime sleepiness are among the most frequent behavioral features of tuberous sclerosis complex (Hunt and Stores 1994).
Tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) is new terminology proposed to describe the interrelated functional and clinical manifestations of brain dysfunction seen in tuberous sclerosis complex, including aggressive behaviors, autism spectrum disorders, intellectual disabilities, psychiatric disorders, and neuropsychological deficits, as well school and occupational difficulties (de Vries 2010). Autism and ADHD occur in 40% of patients with tuberous sclerosis complex (Jones et al 1999). Tubers account for the arrest in motor and language development and, therefore, mental retardation or autism (Gomez 1988a; 1988b). Patients with tuberous sclerosis complex and early-onset seizures or mental retardation tend to have large numbers or sizes of cortical tubers on MRI (Shepherd et al 1995).
Astrocytic retinal hamartomas are found in about 50% of patients with tuberous sclerosis complex on indirect ophthalmoscopy (Robertson 1991). They are histopathologically similar to subependymal nodules and subependymal giant cell astrocytomas. They may continue to grow past adolescence, but they are seldom symptomatic. There have been only a handful of reported incidents of symptomatic change in the past few decades (Mennel et al 2007). Pigmentary changes and punched out lesions may also be found on retinoscopy. An increased incidence of association with subependymal giant cell astrocytomas, angiofibrolipoma, cognitive impairment, and epilepsy has been noted in the presence of retinal findings (Aronow et al 2012).
Renal lesions occur in more than half of children at the time of initial evaluation. Eighty percent are affected by 10 years of age (Ewalt et al 1998). Simple epithelial cysts may appear or disappear at any time and commonly present with severe hypertension. Angiomyolipomas, which account for 75% of renal abnormalities, increase in size with age and may become symptomatic causing lumbar pain and hematuria. This is especially so in females by the third decade of life. Even when numerous, angiomyolipomas seldom cause renal failure or arterial hypertension. They, however, predispose to aneurysms and massive bleeding (Wunderlich syndrome), especially when the angiomyolipomas are greater than 4 cm in diameter and the aneurysms are greater than 5 mm in size (Yamakado et al 2002). Renal cell carcinoma occurs at an earlier age in tuberous sclerosis complex and is more frequent (approximately 2% to 3%) than in comparable cohorts (Bjornsson et al 1996; Cook et al 1996). Intriguingly, all histological types of renal cell carcinoma (clear cell, chromophobe, papillary, or oncocytic) have been reported in tuberous sclerosis complex. Patients may manifest with autosomal polycystic kidney disease phenotype, as the polycystic kidney disease gene, PKD1, is located in close proximity to the gene TSC2, on chromosome 16, accounting for the occurrence of both conditions in families with large rearrangements (contiguous gene syndromes) (Brook-Carter et al 1994).
Cardiac involvement is common in tuberous sclerosis complex and is found in up to 80% of patients (Quek et al 1998). Rhabdomyomas are common in infants, occurring in approximately half who undergo echocardiography and can be diagnosed by fetal ultrasound. The majority of afflicted patients are asymptomatic and their tumors regress spontaneously, often completely disappearing (Watson 1991; Tworetzky et al 2003). Prenatal identification of rhabdomyomas by fetal ultrasound appears to be sensitive in identifying tuberous sclerosis complex postnatally (Bader et al 2003), with a 75% to 80% risk for tuberous sclerosis complex. Arrhythmias and symptoms due to mechanical effects of the rhabdomyomas on the heart can occur at any time as an initial presentation. Wolff-Parkinson-White syndrome can occur in the absence of rhabdomyomas (Van der Hauwaert 1971). Giant intracranial aneurysms involving the internal carotid artery have also been reported (Jurkiewicz and Jozwiak 2006).
The incidence of pulmonary involvement in tuberous sclerosis complex is estimated to be from 0.1% to 2.3%. An ominous hamartoma – pulmonary lymphangioleiomyomatosis – is the third leading cause of mortality after CNS and renal phenotypes (Shepherd et al 1991). The prevalence of lymphangioleiomyomatosis in tuberous sclerosis complex has been reported to be as high as 39% (McCormack et al 2002). However, not all individuals with lymphangioleiomyomatosis have tuberous sclerosis complex. It usually presents in women in their third or fourth decade with recurrent spontaneous pneumothorax, hemoptysis, chylothorax, and respiratory failure. Female patients with tuberous sclerosis complex and lymphangioleiomyomatosis are also highly likely to manifest renal angiomyolipomas. However, sporadic lymphangioleiomyomatosis is also associated with renal angiomyolipomas about a third of the time. This has led to the consensus that the presence of both constitutes a single major criterion. Clear cell tumors of the lung and multifocal micronodular pneumocyte hyperplasia are other lesions that can occur (Popper et al 1991; Chuah and Tan 1998).
The vascular lesions of tuberous sclerosis complex are secondary to a defect in the arterial walls of large and midsize arteries, resulting in aneurysms. Other findings include angiomyolipomas in various organs, thyroid and parathyroid adenomas, liver, colon and rectal polyps, gingival fibromas, and bone cysts.
Clinical manifestations by age. The clinical findings vary according to age. The fetal period may be punctuated by seizures and arrhythmias, whereas the neonate may present with Wolff-Parkinson-White syndrome, hydrops fetalis, and ultrasound evidence of multiple renal cysts or rhabdomyomas. Infantile spasms, retinal hamartomas, and the pathognomonic hypomelanotic macules mark infancy. Developmental retardation may also present during this period. Early childhood features include autism, seizures, and hypomelanotic macules, whereas subependymal giant cell astrocytomas, angiofibromas, and ungual fibromas present in late childhood. Adolescents develop shagreen patches, and adults manifest with pulmonary lymphangioleiomyomatosis and renal angiomyolipomas (Gomez 1999).