INTRODUCTION — Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder that is characterized by pleomorphic features involving many organ systems, including multiple benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin [1-3]. The expression of the disease varies substantially. The diagnosis of TSC can be made clinically or through genetic testing, but genetic testing is recommended, where available, to support a clinical diagnosis.
The genetics, clinical features, and diagnosis of TSC will be reviewed here. Other aspects of TSC are discussed elsewhere. (See "Tuberous sclerosis complex: Management and prognosis" and "Renal manifestations of tuberous sclerosis complex" and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)
GENETICS — Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 to 10,000 live births [3-7]. It is caused by pathogenic variants in either the TSC1 or the TSC2 genes, which results in overactivation of the mTOR pathway and benign tumor formation in multiple organs [8]. (See 'TSC1 and TSC2 genes' below and 'Mechanism of tumor formation' below.)
De novo versus inherited TSC — De novo pathogenic variants account for approximately 80 percent of TSC cases, with TSC2 pathogenic variants being approximately four times as common as TSC1 pathogenic variants among de novo cases, while the prevalence of TSC1 and TSC2 pathogenic variants is approximately equal among familial TSC cases [9]. There are several different explanations for the apparently nonfamilial cases. Most often, such cases result from a de novo pathogenic variant in the egg or sperm prior to fertilization. In addition, the parent may be a somatic mosaic where a subset of somatic and germ cells carry the pathogenic variant, or a gonadal mosaic in which mosaicism is confined to the parental germline [10-12]. In germline mosaicism, there may be more than one egg or sperm that contains the pathogenic variant, which can result in more than one sibling affected with the disease (ie, there is an appreciable recurrence risk). Finally, in a child with no affected parents or siblings, TSC may be the result of somatic mosaicism where the pathogenic variant occurred after fertilization during one of the early cell divisions [10]. Once a "de novo" germline pathogenic variant occurs in an individual, their offspring will have a 50 percent chance of inheriting TSC, which then follows an autosomal dominant pattern of inheritance in subsequent generations. (See 'Genetic testing' below.)
TSC is highly variable in its expression, that is, in the range of phenotypic changes such as age of onset, severity of disease, and different signs and symptoms that result from a specific genotype. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)
Thus, the severity of disease in TSC can vary substantially among affected individuals within the same family, and particularly from one family to another [13,14]. The variability is due to multiple causes. These include somatic mosaicism (individuals who have low-level mosaicism for a TSC-associated pathogenic variant may be very mildly affected) [12], differences between TSC1 and TSC2 genes, a variety of pathogenic variants found in each gene, and the requirement for a secondary somatic pathogenic variant in the wild-type copy of the gene for the development of many pathologic features of TSC [15,16]. The latter feature is consistent with the two-hit hypothesis of Knudson, in which one pathogenic variant is inherited and the second is acquired in somatic tissues [17]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Pathogenesis'.)
TSC1 and TSC2 genes — Pathogenic variants in two separate genes, TSC1 and TSC2, were first identified in genetic linkage analysis of families with TSC [18,19]. Both genes were subsequently cloned and the spectrum of pathogenic variants in TSC patients described [9,20,21].
A disease-causing pathogenic variant can be identified by conventional molecular genetic testing (eg, gene-targeted sequence analysis and deletion/duplication analysis) in 85 to 90 percent of patients who meet the diagnostic criteria for TSC [22-25]. Mosaicism and noncoding pathogenic variants probably account for most of those with no pathogenic variant identified. In one report of 53 individuals with TSC who had no pathogenic variant identified after conventional genetic assessment, next-generation sequencing of tissue samples, including blood, saliva, and skin tumor biopsies, identified pathogenic variants in 45 (85 percent) [24]. Among these 45 subjects, mosaicism was present in 28 individuals, and intronic pathogenic variants were found in 18. These data suggest that next-generation sequencing with full gene analysis and testing of TSC-related tumors can increase the detection rate of pathogenic variants.
●The TSC1 gene – Pathogenic variants in TSC1 account for approximately 25 percent of TSC cases with identified pathogenic variants [23,24,26,27]. The TSC1 gene, which maps to chromosome 9q34, spans 50 kb of genomic DNA and contains 23 exons [20]. It encodes a protein termed hamartin, which is widely expressed in normal tissues [28]. Hamartin forms a complex with the tuberin protein that is encoded by the TSC2 gene [29,30]. The functions of these proteins are described below. (See 'Mechanism of tumor formation' below.)
Several different types of TSC1 pathogenic variants have been identified, most of which result in a truncated protein with loss of function [31]. Pathogenic variants include small deletions and insertions (58 percent), nonsense variants (23 percent), splicing variants (11 percent), missense variants (6 percent), and large deletions and rearrangements (3 percent) [23].
●The TSC2 gene – Pathogenic variants in TSC2 account for 75 percent of TSC cases with identified pathogenic variant [23,24,26,27]. The TSC2 gene, which maps to chromosome 16p13.3, spans 45 kB of genomic DNA and contains 42 exons [21]. The gene is ubiquitously expressed in all normal adult tissues, and encodes the tuberin protein [32]. Tuberin forms a complex with the hamartin protein, the product of the TSC1 gene [29,30].
TSC2 functions in normal brain development [33] and in withdrawal of the normal cardiomyocyte from the cell cycle during terminal differentiation [34]. This latter finding is intriguing in view of the benign cardiac tumors (rhabdomyomas) that are observed in TSC. (See 'Cardiovascular manifestations' below.)
As with TSC1, the majority of pathogenic variants identified in TSC2 are loss of function variants [26,27,35]. These include small deletions and insertions (38 percent); missense (26 percent), nonsense (15 percent), and splice variants (17 percent); and large deletions and rearrangements (5 percent) [23].
In some cases, the pathogenic tuberin protein is made but inhibits tuberin phosphorylation, preventing the formation of the tuberin-hamartin complex [36]. Other pathogenic variants in both TSC1 and TSC2 also disrupt the interaction between these two proteins [37].
Mechanism of tumor formation — Several lines of evidence support the view that the TSC genes function as tumor suppressor genes:
●Inactivating variants or complete loss of TSC genes are found in patients with TSC, and loss of heterozygosity at these gene loci characterize TSC-associated tumors (eg, hamartomas, angiofibromas, and lymphangioleiomyomas) [15,38-42].
●In animal models, germline variants that disrupt either TSC2 or TSC1 predispose to hereditary clear cell renal cell carcinoma as well as multiple subependymal and extrarenal tumors such as subcortical hamartomas, similar to those encountered in patients with TSC [43-45].
●Reintroduction of wild-type, but not mutant, TSC protein suppresses tumor formation [46].
Role of tuberin and hamartin — Insights concerning the function of tuberin were first provided by the observation that its C-terminal end has extensive sequence homology with the catalytic domain of the GTPase activating protein 3 (GAP3), which stimulates the intrinsic activity of GTPases. These enzymes cleave a phosphate group from GTP to form GDP, thus inactivating GTP-binding proteins such as ras, and the ras-like proteins Rap-1A and rab5a [47]. The ras superfamily of proteins is central to a wide range of cellular processes, including control of the cell cycle. Tuberin stimulates the GTPase activity of Rap-1A but not ras or other ras-like proteins [32].
It is hypothesized that lack of tuberin (or a functional tuberin-hamartin complex) results in loss of GTPase activity, and inappropriate or constitutive activation of these proteins, thereby releasing an inhibitory influence on the cell cycle [29,32,48]. The net result is that cells spend less time in G1, the resting phase of the cell cycle, and quiescent cells are induced to enter the cell cycle [49,50]. As an example, cardiomyocytes from whole embryo cultures derived from rats with pathogenic germline TSC2 gene variants show sustained DNA synthesis along with an inability to undergo terminal differentiation and exit from the cell cycle [34].
There appears to be a direct interaction of polycystin 1, the protein product of the PKD1 gene, with tuberin in kidney epithelial cells [51]. The implications of this finding remain undefined. However, interactions of polycystin 1 with tuberin could provide another area of cell cycle modulation and possibly contribute to the development of renal angiomyolipomas commonly seen in patients with TSC.
The contribution of hamartin to the molecular pathogenesis of tumors in TSC is predominately related to the stabilization of the tuberin protein, thereby allowing the protein complex to function normally [29,52].
Role of mTOR — The most important advancement in our understanding of TSC is the delineation of the role of the hamartin-tuberin complex (figure 1) through inhibition of cellular signaling mediated by the mechanistic target of rapamycin (mTOR) [3,29,53,54]. The mTOR pathway is important for regulating protein translation (in response to nutrition), cell cycle progression, and response to hypoxia. As an example, in vitro studies suggest that angiomyolipomas in TSC are associated with intracellular phosphorylation of targets known to be the result of activation of mTOR [55].
Both protein kinase B and extracellular signal-regulated kinase (ERK) are modulators of the mTOR pathway [56,57]. These protein kinases, particularly ERK, may be involved in the development of TSC-associated tumors [57,58]. The role of hamartin-tuberin complex in mTOR signaling led to the development of the mTOR inhibitor everolimus, the first agent for treatment of patients with TSC. (See "Tuberous sclerosis complex: Management and prognosis", section on 'Everolimus'.)
CLINICAL FEATURES — TSC is characterized by the development of a variety of benign tumors in multiple organs, including the brain, heart, skin, eyes, kidney, lung, and liver [3,59]. In addition, there is an increased risk of malignancy in TSC. Nearly all patients with TSC have one or more of the skin lesions that are characteristic of the disorder. Most patients with TSC have epilepsy, and one-half or more have cognitive deficits and learning disabilities; other common manifestations include autism, behavioral problems, and psychosocial difficulties [60]. Collectively, these are termed TSC-associated neuropsychiatric disorders (TAND) [61]. These problems are usually associated with brain lesions including glioneuronal hamartomas (also called tubers), periventricular giant cell astrocytomas, and abnormalities of cerebral white matter detected on neuroimaging studies [1,62] (see 'Brain lesions' below). However, there is a wide variety of phenotypes between and within families regarding the number and severity of TSC manifestations [13,63].
Other possible manifestations of TSC reported in occasional patients include vascular anomalies, limb overgrowth (hemihypertrophy), and segmental lymphedema [64-67].
Dermatologic features — In population-based studies, 81 to 95 percent of patients with TSC have one of the characteristic skin lesions [68,69]. The most common lesions are:
●Hypopigmented macules, also known as ash-leaf spots, which are usually elliptic in shape and may require evaluation with a Woods light (ultraviolet [UV]) to visualize (picture 1 and picture 2)
●Angiofibromas (sometimes called fibroadenomas; previously called adenoma sebaceum), which typically involve the malar regions of the face (picture 3)
●Shagreen patches, seen most commonly over the lower back (picture 4)
●A distinctive brown fibrous plaque on the forehead, which may be the first and most readily recognized feature of TSC to be appreciated on physical examination of affected neonates and infants (picture 5) [68]
Hypomelanotic macules and fibrous forehead plaques typically appear earlier than facial angiofibromas or ungual fibromas [68]. Periungual and subungual fibromas may develop during adolescence or adulthood (picture 6), and occur more commonly on the toenails than on the fingernails [68,70,71]. Given the variable age of onset, it is important for the clinician to inspect the nails of both the patient and the parents when first doing an evaluation for TSC. Longitudinal nail grooves without visible fibromas are also commonly seen [70]. Less frequent acral lesions include subungual red comets (red longitudinal streaks with a larger distal head and a narrowing proximal tail), splinter hemorrhages, and longitudinal leukonychia (white streaks extending from the nail matrix to the end of the nail).
A solitary ungual fibroma as a result of trauma is not a diagnostic feature of TSC [25,72]. On the other hand, a history of trauma in a patient presenting with an ungual fibroma should not be used to discount the possibility of TSC [70].
There is no significant risk of malignant transformation of skin lesions, which tend to increase in size and number through puberty and then tend to be stable over time.
Brain lesions — Central nervous system lesions characteristic of TSC include [73,74]:
●Glioneuronal hamartomas, also called cortical tubers (image 1)
●Subependymal nodules (image 2)
●Subependymal giant cell tumors (SGCTs), also known as subependymal giant cell astrocytomas (SEGAs) (image 3 and picture 7)
●White matter heterotopia (dysplastic and dysmyelinated white matter lesions)
Hamartomas — Both cortical glioneuronal hamartomas and subependymal nodules are regarded as hamartomas. Cortical glioneuronal hamartomas are composed histologically of enlarged atypical and disorganized neuronal and glial elements with astrocytosis. In keeping with their hamartomatous nature, "glioneuronal hamartoma" is preferred in place of the outdated term "tuber" when describing a finding in patients. Subependymal nodules are also composed of atypical enlarged glial and neuronal cells. These nodules (image 2) are indistinguishable histologically from SGCT (image 3) except for their small size.
Cortical glioneuronal hamartomas and subependymal nodules are present on brain magnetic resonance imaging (MRI) in approximately 90 percent of children with TSC [69,75,76]. The detection rate of these lesions is moderately lower on computed tomography (CT). Cortical glioneuronal hamartomas may be calcified on CT scan in approximately one-half of patients, and subependymal nodules are usually calcified on CT except in the early years of life [75,77,78]. In order to minimize radiation exposure, the use of CT monitoring for children with TSC should be limited. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'CT safety considerations'.)
The extent of cerebral dysfunction (ie, seizure status and cognitive function) in TSC is only loosely related to the burden of glioneuronal hamartomas as demonstrated on cranial imaging.
●In a meta-analysis of five studies, the number of MRI-detected glioneuronal hamartomas in patients with TSC and severe cerebral dysfunction (ie, poor seizure control and/or moderate to severe intellectual disability) was six times more likely to be above the median compared with mildly affected patients [79]. Because glioneuronal hamartomas form during embryogenesis, disruption of normal cortical development and function occurs early in gestation.
●In a later study of 61 patients with TSC, the proportion of brain volume occupied by glioneuronal hamartomas was inversely related both to age at seizure onset and to cognitive function [80]. However, the relationship was not invariant, as some patients with a large glioneuronal hamartoma volume had normal intelligence.
Subependymal giant cell tumors — The characteristic brain tumor in TSC is the SGCT (image 3), which is a benign, slow-growing tumor that usually arises in the periventricular area [74,81-83]. Although most often called "subependymal giant cell astrocytomas" (SEGAs), they are of mixed glioneuronal lineage; thus "subependymal giant cell tumors" (SGCTs) is a more accurate description. The prevalence of SGCTs in TSC ranges from 5 to 20 percent in different studies [5]. As noted, the distinction between subependymal nodules and SGCTs may be largely semantic. Immunohistochemistry studies in mouse model of TSC suggest that both glioneuronal hamartomas and SGCTs share a functionally related neuroglial progenitor cell of origin, and that both result from aberrant neuroglial differentiation [84]. It is not clear why neoplastic transformation to SGCTs may occur in subependymal nodules and not in cortical glioneuronal hamartomas. In addition, growing evidence from radiologic studies supports the hypothesis that SGCTs can arise from the growth of preexisting subependymal nodules, the latter occurring in 88 to 95 percent of children with TSC [85-87]. However, the apparent absence of subependymal nodules on neuroimaging does not eliminate the risk of developing a SGCT.
Symptomatic SGCTs occur in 6 to 9 percent of individuals with TSC [74,88,89]. The tumors usually become symptomatic between the ages of 10 and 30, although they can occur as early as 1.5 years [82,90]. Affected children typically present subacutely with signs and symptoms of obstructive hydrocephalus, such as headaches and vomiting, or with focal neurologic deficits, including vision loss [74,81,82,88,91]. In addition, children may present with nonspecific symptoms such as fatigue, depression, decreased appetite, and increased seizure frequency [74].
The distinction between subependymal nodules (image 2) and SGCTs (image 3) is often not possible on radiographic criteria alone [74].
Diagnostic features associated with increased morbidity are likely to have the most clinical utility for decision making regarding subependymal lesions; these include [74]:
●New symptoms or papilledema
●Hydrocephalus
●Growth of the lesion on serial imaging
In most cases, the presence of these criteria should define the lesion as a SGCT rather than a nodule, independent of tumor size, location, signal characteristics, or contrast enhancement [74]. In the absence of better data, however, size ≥10 mm may still be a useful criterion for identifying SGCTs. Radiologic hydrocephalus may not be prominent on neuroimaging studies in patients with TSC even when increased intracranial pressure due to SGCT is present; in such cases new symptoms or papilledema may be present.
Others — White matter lesions are common in patients with TSC [92]. These include nodules, cysts, and areas of gliosis and hypomyelination. Linear white matter lesions may be visualized by MRI in about 15 percent of children with TSC [92]. These linear lesions are hyperintense on T2 weighted MRI and are either isointense or hypointense on T1 images. They typically extend from the ventricle to the cortex, with a subependymal nodule or subcortical lesion on each end; they are thought to represent demyelination, dysmyelination, or hypomyelination from a migration disorder [93]. Microscopic white matter lesions are characteristically present in patients with TSC [73], and normal appearing white matter may show pathologically increased water diffusivity (ie, an increased apparent diffusion coefficient) by diffusion weighed MRI [94].
In a retrospective review of brain MRIs from 220 patients with TSC, asymptomatic arachnoid cysts were noted in approximately 5 percent; this compares with an estimated prevalence in the general population of 0.5 to 1 percent [95]. Thus, arachnoid cysts may be part of the clinical spectrum of TSC.
Epilepsy — Epilepsy is one of the most frequent and significant causes of morbidity in TSC, affecting 79 to 90 percent of patients in population-based studies [69,96]. Seizures begin in the first year of life in just over 60 percent of cases; however, patients with TS remain at risk for new-onset seizures into adult life [69,97,98]. In a natural history study that included 248 patients with TSC who had a single seizure, epilepsy subsequently developed in 246 (99 percent) [98]. Risk factors for the development of epilepsy include the presence of tubers (ie, cortical glioneuronal hamartomas) and pathogenic TSC2 variants [99].
Seizures are the most frequent presenting feature of TSC; infantile spasms are the most common type at initial diagnosis, occurring in 36 to 69 percent of patients [100]. Conversely, up to 25 percent of children with infantile spasms may have TSC [101]. Other seizure types that occur in TSC include focal onset seizures with and without impaired awareness, focal onset to bilateral tonic clonic seizures (previously termed secondarily generalized), subclinical seizures, and, less commonly, generalized onset seizures [98,102].
Approximately 75 percent of patients with TSC have epileptiform abnormalities on routine electroencephalography (EEG). These include focal or multifocal discharges, hypsarhythmia, and generalized spike-wave abnormalities in 48, 19, and 8 percent, respectively [101]. Not all cortical glioneuronal hamartomas are epileptogenic and patients with TSC and epilepsy may have normal brain MRI studies, raising significant questions about the role of glioneuronal hamartomas in producing seizures [103]. Furthermore, epileptic foci can shift over time.
Cortical glioneuronal hamartomas with central low signal on fluid-attenuated inversion recovery (FLAIR) MRI may predict a higher risk of epilepsy in TSC [104]. The majority of cortical glioneuronal hamartomas show homogeneous high signal on FLAIR MRI images. However, some cortical glioneuronal hamartomas, sometimes called "cyst-like" though they are not true cysts, show central low signal intensity on FLAIR and T1-weighted sequences and increased signal on T2-weighted sequences. In a retrospective study of 173 patients with TSC, epilepsy was significantly more frequent in patients with compared with those without at least one cortical glioneuronal hamartoma of low FLAIR and T1 signal intensity (92 versus 76 percent, relative risk [RR] 1.22, 95% CI 1.07-1.40) [104]. Similarly, refractory epilepsy was significantly more common in patients with at least one cortical glioneuronal hamartoma of low FLAIR and T1 signal intensity (80 versus 54 percent, RR 1.47, 95% CI 1.18-1.83).
Despite the frequency of seizures in TSC, epilepsy is not one of the diagnostic criteria because of the large number of disorders that are associated with seizures, including infantile spasms. (See 'Diagnostic criteria' below.)
Cognitive deficits — Cognitive disability is a primary feature of TSC, affecting 44 to 65 percent of patients in population-based reports [69,96]. It is associated with a history of infantile spasms [96,98,105,106], refractory seizures [98,107,108], and, to a lesser extent, number of glioneuronal hamartomas [109,110]. In a cohort of over 1600 patients from a TSC database, epilepsy onset before the age of two years was associated with a higher frequency and severity of intellectual disability [111]. Epilepsy was also associated with autism and attention-deficit-hyperactivity disorder. (See "Specific learning disabilities in children: Clinical features", section on 'Risk factors'.)
There are conflicting data as to whether intellectual disability is less frequent with pathogenic variants involving TSC1 compared with those involving TSC2, a question that is further complicated by a potential association between TSC2 and an increased risk for epilepsy, including infantile spasms [98,108]. (See 'Genotype-phenotype correlations' below.)
Similar to other features of TSC, the range of intelligence in affected patients is highly variable. This was illustrated in a study of standardized testing in 108 patients with TSC, in which intelligence quotient (IQ) scores had a bimodal distribution [96]. In 55 percent of patients, IQ was in the normal range, while 14 percent had mild to severe impairment, and 30 percent had profound disability (IQ <21). Even among the children with a normal range IQ, scores were 10 points lower on average than their unaffected siblings. All of the children with learning disabilities had a history of seizures, usually infantile spasms, which began before one year of age.
A history of immunization for diphtheria, tetanus, and pertussis was not a risk factor for poor cognitive development in a review of 106 patients with TSC [105].
Autism and behavioral problems — Autism and autistic behaviors, including hyperactivity, inattention, and self-injurious behavior, are common in children with TSC and can be a significant source of stress for parents and caregivers [112-117]. In different case series, the prevalence of significant behavioral problems among children with TSC ranges from 40 to 90 percent. While behavioral problems can occur in the setting of either normal intelligence or cognitive dysfunction, at least one case series found that low intellectual functioning and higher seizure frequency were risk factors for behavioral disorders [115].
Whether autism is associated with a specific location of glioneuronal hamartomas is uncertain. In one study, development of an autism spectrum disorder was associated with the presence of temporal lobe glioneuronal hamartomas, temporal lobe epileptiform discharges, and early onset of persistent infantile spasms [118]. However, others have shown that the frequency of glioneuronal hamartomas in the subcortical or cortical regions was similar in TSC patients with and without autism [60,119].
The clinical features and diagnosis of autism are discussed separately. (See "Autism spectrum disorder: Clinical features" and "Autism spectrum disorder: Evaluation and diagnosis", section on 'Diagnosis'.)
Cardiovascular manifestations — The characteristic cardiac feature of TSC is a rhabdomyoma, a benign tumor that often presents as multiple lesions. Cardiac rhabdomyomas are one of the most common pediatric cardiac tumors. (See "Cardiac tumors", section on 'Rhabdomyomas'.)
Most infants and children who have cardiac rhabdomyomas have TSC [120]. However, rhabdomyomas are not a universal finding in children with TSC. In one longitudinal series of 125 patients with TSC, rhabdomyomas were found overall in 58 percent, including 61 percent of children ages 0 to 4, and 36 percent of children ages 5 to 18 [69]. Rhabdomyomas associated with TSC are typically multifocal. Occasionally, cardiac rhabdomyomas appear as an isolated finding in TSC [121].
Cardiac rhabdomyomas characteristically develop in utero and are often detected on prenatal ultrasound. In the longitudinal series of 125 patients with TSC, the finding of one or more rhabdomyomas before or soon after birth was the initial sign of TSC in 18 percent [69]. Although many rhabdomyomas are asymptomatic, patients with TSC and cardiac rhabdomyomas are most likely to be symptomatic in the newborn and early infancy period [122,123]. Thereafter, cardiac rhabdomyomas usually undergo spontaneous regression. The morbidity and mortality associated with these tumors reflect the potential for flow abnormalities if they grow to sufficient size to restrict blood flow. In one report that included 15 children with symptomatic cardiac rhabdomyoma (12 with TSC), the clinical presentation was heart failure or a cardiac murmur in 6 patients each and arrhythmia in 3 patients [123].
There is no evidence that cardiac rhabdomyomas undergo malignant transformation, and no treatment is necessary for asymptomatic tumors, particularly when first noted in an older child or adult with TSC.
Coarctation of the aorta and constriction of major arteries (such as renal artery stenosis), are sometimes associated with TSC [122]. Aortic aneurysm may also occur [64].
Renal manifestations — Renal lesions are common among patients with TSC, and their prevalence increases with age. Angiomyolipomas are the most frequent renal manifestation of TSC. Less often, benign cysts, lymphangiomas, and renal cell carcinoma occur. Progressive enlargement of angiomyolipomas and hemorrhage into the lesion can result in pain and interfere with renal function. The risk of hemorrhage increases with size. Patients with tuberous sclerosis and renal lesions may have renin-dependent hypertension and are at risk of developing chronic kidney disease due to replacement and compression of the renal parenchyma. These issues are discussed in detail separately. (See "Renal manifestations of tuberous sclerosis complex".)
Pulmonary manifestations — Some adults with TSC develop pulmonary disease that is indistinguishable from the diffuse interstitial fibrosis known as lymphangioleiomyomatosis (LAM). This condition represents a cystic lung disease that can result in significant limitation in pulmonary function. The most common presenting features of LAM are dyspnea and pneumothorax. Among adults with TSC, the prevalence of LAM is higher for women than for men. The condition may worsen during pregnancy and can be a life-limiting complication of TSC.
LAM can occur as an isolated finding or can be associated with renal angiomyolipomas. As mentioned above, some women appear to have this combination as an isolated finding with no other features of TSC and no identifiable germline pathogenic variant in the TSC1 or TSC2 genes except in the LAM cells or angiomyolipoma.
The pulmonary manifestations of TSC and LAM are discussed in greater detail elsewhere. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults" and "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis".)
Ophthalmic manifestations — Ophthalmic findings in TSC include both retinal and non-retinal abnormalities and are useful in making the diagnosis. These lesions rarely affect vision, and do not require specific treatment [122].
The prevalence of ophthalmic features was described in a report of 100 TSC patients (median age 27, range 2 to 76 years) [124]. The following findings were noted:
●Retinal hamartomas were seen in 44 patients. These included a flat, translucent lesion, the most common type, in 31 (70 percent), a multilobular mulberry lesion (picture 8) in 24 (55 percent), and a transitional lesion with features of the two other types in four (9 percent). Calcification of the multilobular lesions results in the classic mulberry appearance.
●Punched-out areas of chorioretinal depigmentation (ie, retinal achromic patches) in the midperiphery of the retina were seen in 39 patients compared with only 6 of 100 controls.
●Non-retinal lesions included angiofibromas of the eyelids (in 39 of 100 patients), nonparalytic strabismus (in 5), colobomas (in 3), and sector iris depigmentation (in 2).
●Among the refractive errors noted were myopia, hyperopia, and astigmatism >0.75 D in 27, 22, and 27 percent of eyes, respectively; these values are similar to those expected for the general population.
Risk of invasive malignancy — TSC is associated with a variety of benign hamartomatous tumors such as angiofibromas, rhabdomyomas, and angiomyolipomas. However, both children and adults with TSC are at risk for malignant tumors, primarily in the kidneys, brain, and soft tissues. In a report that analyzed 16,564 cases of childhood cancer, 509 cases were diagnosed in patients with genetic diseases, and of those, children with TSC accounted for 20 cases (4 percent) [125]. Based upon an estimated prevalence of TSC of 1 in 15,000 children in the United Kingdom, the relative risk of malignancy in children with TSC was 18-fold higher than for those without TSC. This was almost entirely due to the increased incidence of brain tumors and rhabdomyosarcoma. It has been suggested that the risk of invasive cancer is higher in patients with pathogenic variants involving TSC2 compared with those in TSC1 [126].
Specific observations regarding malignancy are as follows:
●Spontaneous malignant transformation of subependymal giant cell tumors has been described [126].
●Adults with TSC are at increased risk for the development of renal cell carcinoma. (See "Renal manifestations of tuberous sclerosis complex", section on 'Renal cell carcinoma' and "Renal manifestations of tuberous sclerosis complex".)
●Some angiomyolipomas can become malignant and these are usually of the epithelioid type.
●Although rare, there is an increased risk for rhabdomyosarcoma in both children and adults with TSC [125,127]. Since they are not localized to one organ system, there is no specific surveillance for these tumors.
The periodic surveillance that is recommended for all patients with TSC is predominantly focused on monitoring the development of benign and malignant tumors. (See "Tuberous sclerosis complex: Management and prognosis".)
Genotype-phenotype correlations — Most studies have found that TSC1 pathogenic variants tend to have a milder neurologic phenotype than TSC2 pathogenic variants, but the relationship is not strict [9,27,128-130]. As examples, one report analyzed 120 pathogenic variants (22 involving TSC1 and 98 involving TSC2) in 150 patients with TSC and found that mental disability was significantly more frequent in patients with pathogenic variants involving TSC2 compared with TSC1 (67 versus 31 percent) [27]. A similar difference was noted in another report of 252 patients with pathogenic variants in TSC1 or TSC2 [9]. In addition, the same report found that hypomelanotic macules were more common in patients with TSC2 pathogenic variants [9]. However, some studies have found that patients with pathogenic variants involving TSC1 and TSC2 could not be distinguished on the basis of their clinical features [26]. Further confounding this type of analysis is the fact that mosaicism for a TSC-associated "severe" pathogenic variant can result in a patient demonstrating mild features.
In a later series, glioneuronal hamartomas with low FLAIR and T1-weighted signal intensity ("cyst-like") on brain MRI were found in all groups of patients but were significantly more frequent in patients with TSC2 pathogenic variants than in those with TSC1 pathogenic variants (RR 2.7, 95% CI 1.28-5.62) [104]. Furthermore, these glioneuronal hamartomas were correlated with a history of infantile spasms, epilepsy, and severe refractory epilepsy. (See 'Epilepsy' above.)
While TSC2 pathogenic variants may generally have a more severe phenotype, mild forms of familial TSC2 have been reported [128,129,131]. In a study that identified 19 families with pathogenic variants at codon 905 of the TSC2 gene, individuals with the R905Q pathogenic variant had unusually mild features of TSC, and many did not meet standard diagnostic criteria for TSC [131]. In contrast, other missense changes at this same amino acid (R905W and R905G) were associated with more severe disease phenotype. These clinical findings also correlated with the results of in vitro functional analysis of the three pathogenic proteins.
As mentioned above, TSC1 pathogenic variants are underrepresented in patients presenting with de novo disease [26,27,128,132]. These differences may be due in part to ascertainment bias created by the possibility that TSC1 pathogenic variants result in a less severe disease phenotype (particularly mental disability). This less severe phenotype, in the absence of a family history of TSC, may lead to delayed identification of de novo cases [128,132].
A small number of patients have deletions that inactivate both the TSC2 gene and the polycystic kidney disease 1 gene (PKD1) that is located nearby, a disorder that is called the TSC2/PKD1 contiguous gene syndrome. Affected patients have the clinical features of both TSC and polycystic kidney disease, and typically present with early-onset renal cystic disease. (See "Renal manifestations of tuberous sclerosis complex", section on 'TSC2/PKD1 contiguous gene syndrome'.)
EVALUATION AND DIAGNOSIS — The diagnosis of TSC is based upon clinical criteria and/or genetic testing (see 'Diagnostic criteria' below). Genetic testing is not required to make a diagnosis in patients who fulfill clinical criteria for definite TSC, but it is helpful for family studies (eg, defining disease status and reproductive risks for relatives) and particularly for patients with probable or possible TSC, due to the age-dependent penetrance of some features of TSC and the possibility of somatic mosaicism. Therefore, we suggest molecular genetic testing for disease-causing pathogenic variants in the TSC1 and TSC2 genes for all individuals with suspected TSC (see 'Genetic testing' below).
Suspicion for TSC — Certain clinical scenarios should raise suspicion for the diagnosis of TSC [59]:
●The prenatal detection of cardiac rhabdomyomas (see 'Cardiovascular manifestations' above)
●The detection of hypopigmented skin macules (see 'Dermatologic features' above)
●The onset of seizures, particularly infantile spasms (see 'Epilepsy' above)
●An evaluation for autism with or without cognitive disability (see 'Autism and behavioral problems' above)
The classic TSC diagnostic triad of seizures, intellectual disability, and facial angiofibromas (Vogt triad) occurs in less than one-third of patients with TSC [2]. Thus, clinicians must be familiar with the full spectrum of TSC-associated diagnostic features and not rely on this outdated concept. Furthermore, there is a range of phenotypes between and within families that includes patients with normal to severely impaired neurologic function [13,63]. In particular, a parent who is a somatic mosaic for a pathogenic variant may have mild features. However, an offspring who inherits this pathogenic variant will not be mosaic and may have much earlier onset of symptoms and more severe symptoms than the parent.
Diagnostic criteria — Diagnostic criteria from the International Tuberous Sclerosis Complex Consensus Conference allow for the diagnosis of TSC based upon genetic testing results and/or clinical findings (table 1) [25].
Genetic criteria — The identification of either a TSC1 or TSC2 pathogenic variant from non-lesional tissue is sufficient to make a definite diagnosis of TSC, regardless of clinical findings [25]. A pathogenic variant is defined as a variant that clearly inactivates the function of the TSC1 or TSC2 proteins (eg, nonsense variant), prevents protein synthesis (eg, large deletion), or is a missense variant whose effect on protein function has been established by functional assessment and clinical correlation.
Clinical criteria — The clinical diagnostic criteria for TSC include 11 major and 7 minor features [25].
The following are major clinical features of TSC [25]:
●Hypomelanotic macules (≥3, at least 5 mm diameter)
●Angiofibromas (≥3) or fibrous cephalic plaque
●Ungual fibromas (≥2)
●Shagreen patch
●Multiple retinal hamartomas
●Multiple cortical tubers and/or radial migration lines
●Subependymal nodules (≥2)
●Subependymal giant cell astrocytoma
●Cardiac rhabdomyoma
●Lymphangioleiomyomatosis (LAM)*
●Angiomyolipomas (≥2)*
*A combination of LAM and angiomyolipomas without other features does not meet criteria for a definite diagnosis
The following are minor features of TSC [25]:
●"Confetti" skin lesions (1 to 2 mm hypomelanotic macules)
●Dental enamel pits (≥3)
●Intraoral fibromas (≥2)
●Retinal achromic patch
●Multiple renal cysts
●Nonrenal hamartomas
●Sclerotic bone lesions
The diagnostic certainty of TSC depends upon the number of major and minor features [25]:
●Definite TSC requires two major features or one major and two or more minor features.
●Possible TSC requires either one major feature or two or more minor features.
Some women have angiomyolipomas of the kidney associated with pulmonary lymphangioleiomyomatosis but no other TSC-related features [133]. These patients do not have an increased risk of having an affected child. Therefore, they are not considered to have TSC. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)
Genetic testing — A positive test for a pathogenic TSC1 or TSC2 variant in non-lesional tissue is sufficient to make a definite diagnosis of TSC independent of clinical findings [25]. Genetic testing is most helpful in confirming the diagnosis in any individual with possible TSC who does not meet the criteria for definite TSC by clinical evaluation [69]. It is also useful for preimplantation or prenatal diagnosis, and to identify whether other at-risk relatives (eg, parents or siblings) carry the pathogenic variant. Genetic testing may confirm suspected TSC when a clinical diagnosis is not made. Genetic testing is also useful in definite TSC given differences in phenotypic presentation.
Disease-causing pathogenic variants in the TSC1 or TSC2 genes can be detected in 85 to 90 percent of patients who meet the diagnostic criteria (see 'Genetics' above). Because of the wide spectrum of mechanisms leading to pathogenic variants, full sequencing plus analysis for small- and large-scale deletions of both TSC1 and TSC2 is necessary for a comprehensive molecular diagnosis of patients with suspected TSC [9].
Since 10 to 15 percent of individuals with TSC have no pathogenic variant identified by genetic testing, a negative genetic test does not exclude the diagnosis of TSC in an apparently affected individual [25]. Furthermore, a positive test does not predict either the severity or nature of the disease complications. One cause of a negative genetic test is the presence of somatic mosaicism, which is estimated to occur in 2 to 10 percent of de novo cases of TSC [12]. In somatic mosaicism, the pathogenic variant in the TSC1 or TSC2 gene is not present in all cells. This occurs when the pathogenic variant is present in the developing embryo and results in a variable mixture of normal and affected cells in different tissues. In individuals with mosaicism, genetic testing performed on DNA from blood leukocytes may be normal, depending upon the degree of mosaicism in the blood [12].
Also, parents who are negative on genetic testing for the TSC pathogenic variant found in their affected child may still carry this variant as either a low level somatic or germline mosaic. Thus, they may be at risk for having future children affected with TSC. It is very important to make this point clear to parents. Other causes of a negative genetic test may include splice-region variants or other variants that may not be tested for in routine sequencing analyses.
Initial evaluation — The initial screening evaluation should confirm the diagnosis by identifying clinical features of TSC. History should be obtained regarding symptoms associated with the disorder. (See 'Clinical features' above and 'Diagnostic criteria' above.)
The parents should be questioned specifically about the presence or absence of seizures or developmental delay, which are frequently associated with TSC, but are not diagnostic criteria for the disorder. A detailed family history also should be obtained to detect possible symptoms of TSC. International TSC guidelines recommend obtaining a three-generation family history to assess for additional family members at risk for TSC [61]. When possible, parents and siblings should be examined for characteristic signs.
Physical examination should focus on the skin and neurologic systems:
●The skin should be thoroughly examined for the characteristic dermatologic features of TSC, including hypopigmented macules, fibroadenomas, shagreen patches, and the distinctive brown fibrous plaque often present on the forehead. The skin manifestations are most apparent on the face. Use of a Wood's lamp may facilitate the identification of hypopigmented macules. The presence or absence of each of the major dermatologic features should be specifically recorded in the medical record. Parents of a child suspected of having TSC should undergo a similar examination. (See 'Dermatologic features' above.)
●A careful neurologic examination should be performed.
●Ophthalmic evaluation may identify the characteristic TSC lesions, which include retinal hamartomas, hypopigmented choroidal lesions, and lid angiofibromas.
●Cranial MRI should be performed to detect cortical glioneuronal hamartomas, subependymal nodules, subependymal giant cell tumors, or cerebral white matter abnormalities.
●Imaging with MRI of the abdomen or renal ultrasound is indicated to evaluate for the presence of renal angiomyolipomas or renal cysts.
Other studies depend upon the history and physical findings. An electroencephalogram should be obtained in children with a history of seizures or spells suspicious for seizures.
Natural history — TSC is a progressive disorder, but the individual features have different natural histories. In addition, because the expression of TSC varies significantly among patients and within families, it is difficult to predict the extent to which a child with newly diagnosed disease is affected. (See 'Clinical features' above.)
Infancy — All of the clinical features of TSC may not be apparent in the first year of life. Thus, a child is often diagnosed initially with possible or probable TSC and later diagnosed with definite TSC after additional features are identified. Rather than waiting for additional features to emerge, the diagnosis of definite TSC can be confirmed in this setting by molecular genetic testing, which reveals a disease-causing TSC1 or TSC2 pathogenic variant in 85 to 90 percent of individuals who eventually meet clinical diagnostic criteria for TSC. (See 'Genetic criteria' above and 'Genetic testing' above.)
●In a longitudinal study of 125 patients with TSC, the median age at presentation was seven months [69]. Seizures were the most common presentation of TSC in infancy or early childhood, accounting for 62 percent of cases. An abnormality on prenatal ultrasound, mainly cardiac rhabdomyoma, was the second most common presentation, accounting for 14 percent of cases. Presentation before the onset of seizures was not uncommon, occurring in 24 percent.
●In a retrospective review that included 101 infants with TSC diagnosed within the first week to 12 months of life, most presented with new onset seizures, infantile spasms, or hypopigmented macules [134]. In another 22 infants diagnosed within the first week of life, most had asymptomatic cardiac rhabdomyomas first detected by prenatal ultrasound, and 17 showed signs of TSC in utero.
●In another series of 41 infants diagnosed with TSC complex before age one year, the initial presentation of TSC was related to cardiac rhabdomyoma, seizures, and hypomelanotic macules in 56, 34, and 15 percent of infants, respectively [135]. Neuroimaging revealed cortical glioneuronal hamartomas and subependymal nodules in 88 and 93 percent, respectively.
Childhood — Many of the dermatologic features of TSC become apparent during childhood. Thus, the diagnosis of TSC is often first made once the hypopigmented macules, forehead plaque, or angiofibromas of the face become visible. (See 'Dermatologic features' above.)
In addition, certain neurologic problems including learning disabilities first become apparent during childhood. The risk of developmental delay may be increased for those with a TSC2 pathogenic variant, as suggested by a prospective study of 92 children with TSC who had genetic testing and evaluation of cognition, language, and motor development [136]. Significant developmental delays at age 24 months were present in approximately three-quarters of those with a TSC2 pathogenic variant and only one-quarter of patients with a TSC1 pathogenic variant. (See 'Genetics' above.)
Complications caused by subependymal giant cell tumor growth are most likely to occur during childhood, with these lesions stabilizing in the teens to twenties. (See 'Brain lesions' above.)
In the retrospective review cited above, there were 74 children with TSC diagnosed from age 1 to 10 years, and most presented with new onset seizures or a history of seizures [134]. In addition, a family history of TSC and dermatologic features were common presenting features. Among 16 patients diagnosed from ages 11 to 20 years, the most common presenting features were new onset seizures and angiofibromas.
Adulthood — The diagnosis of TSC is sometimes made in adults after the diagnosis is made in an affected child, particularly if the parent is mosaic for a TSC1/TSC2 pathogenic variant and is mildly affected. In a retrospective review that included 23 patients diagnosed with TSC as adults, most presented because of a new diagnosis in a family member or a known family history of TSC [134]. (See 'Parental evaluation' below.)
Features of TSC that are likely to first present in adulthood as significant problems include renal angiomyolipoma, periungual fibroma, and lymphangioleiomyomatosis. (See 'Dermatologic features' above and 'Renal manifestations' above and 'Pulmonary manifestations' above.)
Parental evaluation — Although TSC is an autosomal dominant condition, only a minority of patients have a known family history of TSC. The remaining cases represent new pathogenic variants or mosaicism in the affected parent (see 'Genetics' above). In such cases, the parents are often surprised and distressed when the diagnosis of TSC is made in a child. Furthermore, because of the variable clinical features, making a diagnosis of TSC in a parent after the diagnosis is made in his or her child is not unusual [12]. Normal intelligence and the absence of a history of seizures in the parents do not exclude the diagnosis of TSC.
When the diagnosis is made in a child with no family history of the disorder, both parents should be evaluated. This evaluation should include:
●Testing for the familial TSC pathogenic variant if a TSC1 or TSC2 pathogenic variant has been identified in the child
●A thorough examination of the skin (in normal light and with a Wood's lamp)
●Ophthalmic examination
●Cranial MRI (preferably) or CT scan
●Imaging (eg, MRI of the abdomen or renal ultrasound) to evaluate for the presence of renal angiomyolipomas or renal cysts
The importance of determining whether a parent is affected lies in providing appropriate follow-up for the parent (eg, screening for renal disease) and in providing an appropriate risk estimate of having a subsequent child with TSC. Because TSC is inherited in an autosomal dominant pattern, the risk of this disorder in each offspring of an affected parent is 50 percent. However, if neither parent meets the clinical criteria for TSC, the risk of the parents having another child with TSC is approximately 2 percent [12]. This risk is due to gonadal or gonosomal mosaicism, which occurs when either parent carries the pathogenic variant in more than one egg or sperm cell [10,12]. As mentioned previously, an adult who is mosaic for a severe pathogenic variant (eg, a truncating variant in TSC2) may be mildly affected. However, any offspring who inherit this variant will not be mosaic; they will carry the pathogenic variant in every cell of the body and may be severely affected. (See 'Genetics' above.)
Preimplantation and prenatal testing — Reproductive decisions by couples are facilitated by appropriate genetic counseling. Prospective parents should be aware that TSC exhibits wide clinical variability within families and that establishing the diagnosis prenatally cannot predict the severity or outcome. The couple should also understand that their risk of having an affected child could be substantially lowered by use of reproductive technologies, including preimplantation genetic diagnosis if the pathogenic variant is known, or sperm or oocyte donation depending upon which parent is affected.
Preimplantation or prenatal genetic testing with DNA analysis can be performed in families in which a specific pathogenic variant in the TSC1 or TSC2 gene has been identified in an affected family member.
For families where a specific TSC pathogenic variant is identified, the couple may elect to use preimplantation genetic diagnosis. This involves single cell analysis after biopsy of an embryo obtained through in vitro fertilization and subsequent implantation of embryos at low risk of carrying the pathogenic variant [137]. Prenatal testing for TSC1 or TSC2 pathogenic variants of specimens obtained during pregnancy through either chorionic villus sampling or amniocentesis is also available to couples and should be offered to all parents where a pathogenic variant has been identified in their child, even those with apparently "de novo" pathogenic variants in their offspring, in view of the high rate of gonadal mosaicism in this condition.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tuberous sclerosis" and "Society guideline links: Lymphangioleiomyomatosis".)
SUMMARY AND RECOMMENDATIONS
●Genetics – Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 to 10,000 live births. It is caused by pathogenic variants in two separate genes, TSC1 and TSC2. (See 'Genetics' above.)
●Clinical features – TSC is characterized by the development of variety of benign tumors in multiple organs, including the brain, heart, skin, eyes, kidney, lung, and liver. In addition, there is an increased risk of malignancy in TSC. (See 'Clinical features' above.)
•Skin lesions – Nearly all patients with TSC have one or more of the skin lesions that are characteristic of the disorder. The most common skin lesions in TSC are hypopigmented macules (picture 1), angiofibromas (picture 3), shagreen patches (picture 4), and fibrous plaques (picture 5). (See 'Dermatologic features' above.)
•Brain lesions – Brain lesions characteristic of TSC include glioneuronal hamartomas, also called cortical tubers, (image 1), white matter heterotopia, subependymal nodules (image 2), and subependymal giant cell tumors (SGCT), which are also known as subependymal giant cell astrocytomas (SEGAs) (image 3). (See 'Brain lesions' above.)
•Epilepsy – Most patients with TSC have epilepsy, and one-half or more have cognitive deficits and learning disabilities. Autism and autistic behaviors are common in children with TSC. (See 'Epilepsy' above and 'Cognitive deficits' above and 'Autism and behavioral problems' above.)
•Ophthalmic, cardiac, pulmonary, and renal manifestations – The characteristic cardiac feature of TSC is a rhabdomyoma. Angiomyolipomas are the most common renal manifestation of TSC. Benign cysts and lymphangiomas also can occur. Some adults with TSC develop pulmonary disease that is indistinguishable from the diffuse interstitial fibrosis known as lymphangioleiomyomatosis. Ophthalmic findings in TSC include both retinal and non-retinal abnormalities, although they rarely impact vision. (See 'Cardiovascular manifestations' above and 'Renal manifestations' above and 'Pulmonary manifestations' above and 'Ophthalmic manifestations' above.)
●Evaluation and diagnosis – The diagnosis of TSC is based upon genetic testing and clinical features. (See 'Evaluation and diagnosis' above.)
•Suspicion for TSC – The diagnosis may be suspected in certain clinical scenarios, including prenatal detection of cardiac rhabdomyomas, the presence of hypopigmented skin macules, the onset of seizures, particularly infantile spasms, and suspicion for autism.
•Diagnostic criteria – The diagnostic criteria for TSC are outlined above. (See 'Diagnostic criteria' above.)
•Genetic testing – For all individuals with suspected TSC, we suggest molecular genetic testing for pathogenic variants in the TSC1 and TSC2 genes. The identification of a pathogenic variant in either TSC1 or TSC2 is sufficient to make a definite diagnosis of TSC. Genetic testing is useful for confirming the diagnosis in individuals with possible TSC, for reproductive planning, and for identifying at-risk family members. However, a negative genetic test does not exclude the diagnosis of TSC in an apparently affected child, particularly due to the possibility of mosaicism. Although there is some association of phenotype with the pathogenic variant type and gene involved, the pathogenic variant result does not completely predict either the severity or nature of the disease complications. (See 'Genetic testing' above.)
•Parental evaluation – When the diagnosis is made in a child with no family history of the disorder, both parents should be carefully evaluated for features of TSC and offered genetic testing if a causative variant has been identified. (See 'Parental evaluation' above.)
●Management – The management of TSC is reviewed separately. (See "Tuberous sclerosis complex: Management and prognosis".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sharon Plon, MD, PhD, James Owens, MD, PhD, and John B Bodensteiner, MD, who contributed to earlier versions of this topic review.
