Tuberous Sclerosis 1

A number sign (#) is used with this entry because tuberous sclerosis-1 (TSC1) is caused by heterozygous mutation in the TSC1 gene (605284) on chromosome 9q34. The product of the TSC1 gene is known as 'hamartin.'

Description

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems, including the brain, skin, heart, kidneys, and lung. Central nervous system manifestations include epilepsy, learning difficulties, behavioral problems, and autism. Renal lesions, usually angiomyolipomas, can cause clinical problems secondary to hemorrhage or by compression and replacement of healthy renal tissue, which can cause renal failure. Patients can also develop renal cysts and renal-cell carcinomas. Pulmonary lymphangioleiomyomatosis can develop in the lungs. Skin lesions include melanotic macules, facial angiofibromas, and patches of connective tissue nevi. There is a wide clinical spectrum, and some patients may have minimal symptoms with no neurologic disability (reviews by Crino et al., 2006 and Curatolo et al., 2008).

Genetic Heterogeneity of Tuberous Sclerosis

See also tuberous sclerosis-2 (613254), which is caused by mutation in the TSC2 gene (191092) on chromosome 16p13.

Approximately 10 to 30% of cases of tuberous sclerosis are due to mutations in the TSC1 gene: the frequency of cases due to mutations in the TSC2 gene is consistently higher. TSC2 mutations are associated with more severe disease (Crino et al., 2006) (see GENOTYPE/PHENOTYPE CORRELATIONS section).

Clinical Features

Skin Manifestations

Fitzpatrick et al. (1968) described white macules shaped like the leaf of a mountain ash in patients with tuberous sclerosis. The white macules, which may be evident only under Wood light, are present at birth in most cases, thus permitting early diagnosis.

Teplick (1969) stated that 'adenoma sebaceum,' better referred to as facial angiofibroma (Gorlin, 1981), are present in about half of patients with tuberous sclerosis. Teplick (1969) described a 53-year-old woman of normal intelligence with bone and pulmonary lesions misinterpreted as those of sarcoid. Bundey et al. (1970) described a father and 3 children with tuberous sclerosis without adenoma sebaceum.

Webb et al. (1996) found skin abnormalities in 126 of 131 English patients with tuberous sclerosis. Hypomelanotic macules were found in 80 patients; 32 of these had more than 5 such macules. Most macules were evident from birth, but some regressed in adulthood. Shagreen patches and facial angiofibromas appeared before 14 years of age, and their frequency remained constant in postpubertal patients (54 to 55% for shagreen patches and 81 to 88% for angiofibromas). The frequency of ungual fibromas increased with age: ungual fibromas were not found in children younger than 5 years, were found in 23% of children between 5 and 14 years, and were evident in 88% of patients older than 30 years.

McGrae and Hashimoto (1996) described a patient with segmental expression of tuberous sclerosis in the form of unilateral facial angiofibromas and suggested that this resulted from a postzygotic mutation.

Renal Manifestations

Anderson and Tannen (1969) noted that the kidney lesions in tuberous sclerosis are angiomyolipomas, which can be confused with polycystic kidney disease (PKD; 173900).

Norio (1981) observed enormous cystic kidneys in infants with tuberous sclerosis. Severe hypertension was present in some. Surgical marsupialization of large cysts appeared to be beneficial. The epithelium lining the cysts 'looked active' in a humoral or secretory way.

Grether et al. (1987) described Wilms tumor (194070) in a 20-month-old child with tuberous sclerosis. However, Wilms tumor in this disorder appears to be rare, whereas angiomyolipomas and renal cysts are frequent.

Van Baal et al. (1989) found renal angiomyolipomas in 23 of 38 patients with proven tuberous sclerosis. Multiplicity and bilateral localization were important differences between the tuberous sclerosis cases and the isolated, usually solitary, angiomyolipomas. One of the parents of a patient with tuberous sclerosis had small renal angiomyolipomas without signs of tuberous sclerosis, suggesting that renal angiomyolipomas may be a 'forme fruste' of tuberous sclerosis.

Sampson et al. (1995) described multifocal renal cell carcinomas (RCCs) together with angiomyolipomas and renal cysts in 2 sisters with tuberous sclerosis. One sister was a 35-year-old mother of 3 whose tuberous sclerosis had been diagnosed at the age of 27 years, when the family was investigated in connection with the diagnosis of TSC in a cousin who developed epilepsy. Linkage studies provided evidence for linkage to chromosome 9 (TSC1). The authors noted that in the animal model, the Eker rat, germline mutations affecting the chromosome 16 TSC2 gene (191092) are associated with transmission of multifocal RCC as an autosomal dominant trait. However, the family reported by Sampson et al. (1995) appeared to be the first instance of a similar role for the TSC1 gene.

Cook et al. (1996) reviewed 139 patients with TSC who had presented without renal symptoms but had been investigated by renal ultrasound. Renal lesions were found in 85 of the patients (61%). Forty patients had only angiomyolipomas and 17 had only cysts; 28 had both angiomyolipomas and cysts. Angiomyolipomas were multiple in 91% and bilateral in 84% of patients. The incidence of angiomyolipomas increased with age, but the incidence of renal cysts did not appear to be age-related. In children under the age of 5 years, cysts were a more common lesion. Renal carcinomas were found in 3 patients.

Central Nervous System Manifestations

Marshall et al. (1959) described brain tumors in 2 affected families with tuberous sclerosis. In 1 family, ependymoma of the third ventricle was found, and in the second a mother and her 16-year-old son had astrocytoma of the third ventricle. Harvey Cushing had removed the mother's brain tumor in 1932. In 1959 the patient was still alive without evidence of recurrence.

De Leon et al. (1988) described olfactory hamartomas in 3 infants with tuberous sclerosis, 2 of whom were newborns. They suggested that cardiac and olfactory hamartomas may be particularly characteristic of tuberous sclerosis in infants; olfactory involvement was not surprising because the hamartomas appeared to arise from the subependymal germinal layer.

The incidence of childhood brain tumors in patients with tuberous sclerosis varies between 5 and 14% (Pascual-Castroviejo et al., 1995). More than 90% of these tumors are subependymal giant cell astrocytomas. The most common location of giant cell astrocytomas are the retina and the borders of the lateral ventricles, particularly the region of the foramen of Monro. Pascual-Castroviejo et al. (1995) reported a 23-year-old patient with giant cell astrocytomas in both the retina and the region of the foramen of Monro.

Rott et al. (2002) described 3 children with TS, aged 16 months to 6 years, in whom MRI showed cyst-like brain lesions as large as 2 cm. Smaller cyst-like lesions had been found in the white matter of patients with TS by van Tassel et al. (1997) and Griffiths et al. (1998).

Shields et al. (2005) reported the clinical course and histopathologic findings in 4 patients with tuberous sclerosis complex, each of whom developed progressive growth of a juxtapapillary astrocytic hamartoma that caused secondary retinal detachment and neovascular glaucoma, necessitating enucleation of the affected eye.

Cardiac Manifestations

Freycon et al. (1971) reported death due to rupture of an aortic aneurysm in a 3-year-old boy, and Larbre et al. (1971) described rupture of the ascending thoracic aorta in a 2.5-year-old boy.

Harding and Pagon (1990) concluded that between 51% and 86% of cardiac rhabdomyomas are associated with tuberous sclerosis. Cerebral and probable renal embolization from cardiac rhabdomyoma was reported by Kandt et al. (1985). Sugita et al. (1985) showed that intracranial calcification may be evident by computer-assisted cranial tomography within 1 week after birth.

Journel et al. (1986) recorded the curious experience of making the diagnosis of familial tuberous sclerosis by finding cardiac tumors (rhabdomyomas) by routine ultrasonography. There was no evidence of TS in either of the parents, in the earlier-born sister, or in the maternal grandmother, but a maternal aunt was mentally deficient with seizures, numerous depigmented spots, and a shagreen patch on the back. The mother's grandmother died at age 67, following removal of a cerebral tumor of astrocytoma type. There were no signs of renal tumor in the fetus. The usual experience is that whereas rhabdomyomas are congenital, renal tumors develop only later in life and are never found on ultrasonography in the prenatal or neonatal period.

Smith et al. (1989) concluded from an echocardiographic study that cardiac rhabdomyomas in tuberous sclerosis tend to regress in early infancy, remain the same size through childhood, and then again regress in adolescence. They stated that the 'prevalence of tumours in young infants with tuberous sclerosis is likely to be considerably above 50%.' As other signs of tuberous sclerosis are usually absent at this age, echocardiography may afford the most useful single diagnostic test in early infancy.

Bosi et al. (1996) reported results from a retrospective study of 33 children with cardiac rhabdomyoma collected from 3 pediatric cardiology centers. Tuberous sclerosis was associated in 30 of the 33 patients. In 21 of 23 cases cardiac rhabdomyoma was detected before the age of 1 year, and in 11 of the total series of 33 the diagnosis was made before 1 month of age. Cardiac manifestations were present in 19 patients. Cardiac rhythm disturbances were found in 13. Wolff-Parkinson-White syndrome (WPW; 194200) was documented in 6, 4 of whom presented paroxysmal arrhythmias. Obstructive or regurgitative phenomena were present in 5, and in 2 patients surgical removal proved necessary. With the exception of 1 mass in the right atrium, all 77 tumors were located somewhere in the ventricles, including at the atrioventricular valve level. Because of spontaneous regression of most of the tumoral masses, treatment should at first be symptomatic, while surgical removal is required in life-threatening conditions, as documented in 2 of the 33 patients.

Ruggieri et al. (1997) pictured cardiac rhabdomyoma, which they presumed was the cause of the early death in the 3 sibs with a severe form of tuberous sclerosis. They pointed out that the mortality rates among patients with cardiac rhabdomyomas as part of TSC differs from that of cardiac masses without TSC. In more than 80% of TSC patients demonstrated at birth to have cardiac rhabdomyomas, there were no symptoms and the tumors regressed during infancy, whereas in the absence of other TSC signs, the rhabdomyomas often presented as large intracavity tumors and had a worse prognosis. Hepatic and splenic involvement was demonstrated in the autopsied case and, as in rhabdomyomas, a few of the hepatocytes looked like 'spider cells.' Bizarre hepatocytes were reminiscent of the lesions of the brain, heart, and spleen (Grasso et al., 1982).

O'Callaghan et al. (1998) identified 10 patients with concurrent diagnoses of WPW syndrome and tuberous sclerosis. WPW presented early in life, 9 cases being diagnosed in the first year. Eight of 10 cases were male. In 8 cases, the syndrome was associated with supraventricular tachycardias, and in 9 with cardiac rhabdomyomas. One child died from cardiac failure secondary to obstruction of the left ventricular outflow tract by a rhabdomyoma. Five of 9 survivors showed resolution of WPW on follow-up. The accessory pathway was localized in 9 patients by surface electrocardiograms: 6 children had left-sided pathways and 3 had right-sided pathways.

Dental Manifestations

Lygidakis and Lindenbaum (1987) observed multiple enamel pits (pitted enamel hypoplasia) in 71% of persons with typical TS and in 1 of 10 'atypical' cases. One parent and one half sib of persons with typical TS were found to have multiple enamel pits but no other sign of TS.

Sampson et al. (1992) reported that of 23 patients with permanent teeth, 11 (48%) showed multiple enamel pits (mean 4.6 pits, range 3-9), but none was seen in 6 patients with deciduous teeth. Similar pitted enamel hypoplasia was found in 5 of 563 controls (0.88%). Webb et al. (1994) suggested that children with mental handicap due to causes other than tuberous sclerosis have a higher occurrence of dental pits than the normal controls reported by Sampson et al. (1992).

Flanagan et al. (1997) studied 10 probands with tuberous sclerosis, 20 first-degree relatives, and 25 controls for evidence of pitted enamel hypoplasia. They found that 100% of TS patients, 65% of relatives, and 72% of controls had pits. While 70% of TS patients had more than 14 pits per person, only 5% of relatives and 4% of controls had a similar number. Eighty-five percent of relatives and 84% of controls had fewer than 6 pits per person. Flanagan et al. (1997) concluded that examination for the presence or absence of dental enamel pits is not a useful screening test for first-degree relatives to detect otherwise unsuspected tuberous sclerosis.

Chordoma

In a retrospective review, McMaster et al. (2011) identified 10 cases of chordoma associated with tuberous sclerosis complex, although only 3 patients had documented mutations: 2 in the TSC1 gene and 1 in the TSC2 gene. The median age at onset in TSC-associated chordoma was 6.2 months (range 0 to 16 years), with only 1 patient diagnosed with chordoma after age 5. Chordomas were skull-based in 50% and sacral-based in 40%; the 16-year-old had a spinal-based tumor. The 5-year survival was 83%. Molecular and immunohistochemical studies of the chordomas from 2 patients with identified mutations in the TSC1 and TSC2 genes, respectively, demonstrated that 1 tumor had loss of heterozygosity (LOH) for the wildtype TSC1 allele, while the other tumor had LOH for the wildtype TSC2 allele, suggesting a pathogenetic role for the TSC1/TSC2 genes in these chordomas. Comparison with 65 cases of non-TSC-associated pediatric chordoma (215400) showed important clinical differences. The latter patients had onset between ages 0 and 18 years (median age at diagnosis was 12 years). Most (64.1%) were intracranial, 26.6% were spinal, and 9.4% were sacral. Chordomas were exclusively skull-based in the youngest age tertile, while sacral chordomas were confined to patients in the oldest tertile. Survival was poorer, at 68.2% at 5 years and 53.1% at 20 years. The findings suggested that TSC-associated chordoma has an unusually early onset and/or rapid growth, and that chordoma can be a rare pediatric manifestation of TSC.

Cognitive and Psychiatric Manifestations

O'Callaghan et al. (2000) reported a statistically significant association between renal angiomyolipomas and learning difficulties in a study of 22 patients with tuberous sclerosis. Of 9 of the individuals who had learning difficulties, all had renal angiomyolipomas; of the 13 with normal intellect, 5 had angiomyolipomas (p = 0.006). O'Callaghan et al. (2000) suggested that this observed correlation might be due to a generalized increased propensity to form hamartomas in some individuals, resulting both in renal lesions and cerebral tubers causing learning difficulties.

Humphrey et al. (2004) reported monozygotic male twins with tuberous sclerosis who showed developmental differences. Specifically, twin A had mild to moderate mental retardation and met criteria for autism, whereas twin B had low average to borderline mental retardation and did not meet criteria for autism, although he had some social and communication difficulties. Although both twins had seizures, twin A had earlier onset (3 months) than twin B (7 months). Brain imaging showed that twin A had larger tubers with more extensive brain involvement than twin B. Humphrey et al. (2004) suggested that tuber volume, location, and seizure history play a role in developmental deficits in tuberous sclerosis. They noted that Gomez et al. (1982) had reported 2 sets of twins discordant for tuberous sclerosis. One twin in each set had normal intelligence whereas the other was mentally 'subnormal.' One twin in each set had either no seizures or short-lived seizures whereas the other twin had frequent generalized seizures from early life. Gomez et al. (1982) suggested that early onset of severe seizures may underlie some of the dementing processes in tuberous sclerosis.

De Vries et al. (2009) performed detailed neuropsychologic testing of 20 children with TSC and 17 sibs without TSC from 23 families. The average age was 11 years. Seventeen of the 20 children with TSC had lifetime histories of epilepsy and 13 were on anti-seizure medication. Five of the 20 children with TSC had mild mental retardation (IQ, 50-70), 4 had borderline IQ (IQ, 70-80), and 11 had normal IQ (IQ greater than 80). Overall, the TSC patients had significantly lower scores than their unaffected sibs on a range of neuropsychologic attentional tasks, independent of age, gender, IQ, and seizures. Eighteen (90%) of the 20 patients had deficits in attentional tasks, mostly difficulties with dual task performance (85%). The patients were not segregated by genotype. Overall, the findings suggested that patients with TSC may have attentional deficits even with normal intellectual ability.

Other Features

Bender and Yunis (1981) reported 3 cases in neonates. Each had focal, frequently perivascular, collections of large cells in the spleen. These cells resembled those found in brain lesions of TS but did not stain for acidic protein.

Scappaticci et al. (1988) described increased frequency of premature centromere disjunction (PCD) in cultured fibroblasts. Chromosome 3 appeared to be involved preferentially with both PCD and dicentric formation.

Diagnosis

Fryer et al. (1990) concluded that the routine use of cranial CT scan, renal ultrasound, and skeletal survey is not indicated in the investigation of possibly affected parents and sibs of patients with tuberous sclerosis. They noted that the diagnosis of tuberous sclerosis has been made in adults exclusively on the basis of a CT scan but thought that renal ultrasound or skeletal x-rays were not indicated in parents who had normal clinical examinations.

Webb et al. (1992) used echocardiography in the search for signs of rhabdomyoma in 60 parents of children with tuberous sclerosis (thought to represent new mutations) and 60 age- and sex-matched controls. Bright echodense areas interpreted as possible rhabdomyomas were observed in 2 parents and 3 controls. The technique appears to have little usefulness for detection of the gene for tuberous sclerosis.

The tuberous sclerosis complex consensus conference (Roach et al., 1998) proposed major and minor diagnostic criteria. Since no single feature is diagnostic, an evaluation that includes consideration of all clinical features is necessary to make a correct diagnosis. The clinical manifestations of TSC appear at distinct developmental points, which may further complicate the clinical diagnosis. Major criteria include retinal hamartomas, renal angiomyolipomas, facial angiofibromas, and cortical tubers, among other features. Minor criteria include dental pits, bone cysts, and cerebral white matter radial migration lines, among other features.

Pathogenesis

Liang et al. (2014) generated a mosaic Tsc1-knockout mouse model in which mutant mice developed renal mesenchymal lesions that recapitulated perivascular epithelioid cell tumors (PEComas) found in patients with TSC. The authors found that YAP (YAP1; 606608) was upregulated by MTOR (601231) in mouse and human PEComas. Genetic or pharmacologic inhibition of Yap blunted abnormal proliferation and induced apoptosis of mouse Tsc1/Tsc2-deficient cells in culture and in mosaic Tsc1-knockout mice. Yap accumulated in cells lacking Tsc1/Tsc2 due to impaired degradation of Yap by autophagy in an Mtor-dependent manner. Liang et al. (2014) proposed that YAP is a potential therapeutic target for TSC and other disease with dysregulated MTOR activity.

Inheritance

Many pedigrees support autosomal dominant inheritance of tuberous sclerosis (Sampson et al. (1988, 1989)). However, up to 86% of cases of tuberous sclerosis can result from de novo heterozygous mutations (Bundey and Evans, 1969). Contrary to the findings with other dominant disorders such as achondroplasia (ACH; 100800), Apert syndrome (101200), and fibrodysplasia ossificans (FOP; 135100), no increase in parental age has been found in sporadic (presumably new mutation) cases of tuberous sclerosis (Gunther and Penrose, 1935; Borberg, 1951; Nevin and Pearce, 1968; Bundey and Evans, 1969).

Rushton and Shaywitz (1979) reported a family in which 3 males, related as proband, maternal uncle, and maternal great-uncle, had tuberous sclerosis, but their mothers were unaffected. They postulated an independent dominant gene that modified expression of the gene for tuberous sclerosis. However, Sybert and Hall (1979) pointed out that expression is highly variable and involvement may be missed in a mildly affected individual. Cassidy et al. (1983) studied the 26 presumably unaffected parents of 13 patients with TS. Three fathers and 1 mother were found in fact to have signs of being affected; 3 had skin changes, 3 had intracranial calcification by computerized tomography, and 1 had renal cysts.

Baraitser and Patton (1985) described tuberous sclerosis in 2 first cousins; the brother and sister who were the 'intervening' parents of the cousins showed no signs of the disorder and presumably the grandparents were unaffected. The authors postulated reduced penetrance.

Sampson et al. (1988, 1989) attempted complete ascertainment of tuberous sclerosis in the west of Scotland. Both parents of 84 of the ascertained cases were assessed for signs of tuberous sclerosis; in 51 pairs of parents no evidence of the condition was seen, indicating that up to 60% of the cases were new mutations. The mutation rate was calculated as 2.5 mutations per 100,000 gametes. No significant parental age effect was observed in this study. In 13 families 35 patients were observed in an autosomal dominant pedigree pattern. In 1 sibship, nonpenetrance or gonadal mosaicism resulted in affected sibs with normal parents.

Webb and Osborne (1991) reported an instance of apparent nonpenetrance in 2 successive generations: between a great-grandfather and his great-grandson. The great-grandfather developed a single fleshy ungual fibroma on 1 little toe as the only clinical sign; on echocardiography, he showed 2 probable rhabdomyomas in the right ventricular wall and right ventricular outflow tract. Cranial magnetic resonance imaging was normal. His daughter had no discernible feature of the disorder.

Somatic or Gonadal Mosaicism

Wilson and Carter (1978) described a family in which a son and daughter had full-blown tuberous sclerosis. However, the nonconsanguineous parents were unaffected and were normal by clinical examination and by computerized brain tomography. Gonadal mosaicism of 1 parent might explain these findings.

Hall and Byers (1987) suggested that gonadal mosaicism may be responsible for recurrence of tuberous sclerosis in sibs in the same manner as has been reported for osteogenesis imperfecta congenita, pseudoachondroplasia, achondroplasia, and Apert syndrome.

Rott and Fahsold (1991) described affected brother and sister whose parents were normal by extensive examinations that included x-ray computerized tomography of brain, liver, and kidneys, echocardiography, and MR imaging of the brain. Germinal mosaicism in one of the parents was considered likely.

Ruggieri et al. (1997) described a family in which all 4 sibs, born to consanguineous, healthy, asymptomatic parents, had a severe form of tuberous sclerosis. Three of these infants had a course that was rapidly fatal in the neonatal period; death was attributed to congestive heart failure, with radiographic evidence of cardiomegaly in all of them. Necropsy, done in only 1 of them, showed the typical findings of tuberous sclerosis in the central nervous system, kidneys, heart, and liver. The last-born sib, 2 years old at the time of the report, also had typical signs of TSC, namely hypomelanotic skin macules and calcified subependymal nodules. Both parents and a living maternal grandmother showed no signs of the disorder after appropriate examination, and there was no family history suggestive of TSC. Loss of heterozygosity (LOH) investigations on a variety of lesions obtained from postmortem and tissue or blood specimens from all available family members studied failed to identify microdeletion in the chromosomal region where TSC genes are located. Ruggieri et al. (1997) found no previous reports of TSC families with more than 1 affected sib, unusually severe manifestations of the disease, and completely normal, consanguineous parents. At the TSC1 locus, the 2 sibs in whom DNA was available shared a haplotype, inherited from the father; at the TSC2 locus, the 2 sibs also shared a haplotype, inherited from the mother. Ruggieri et al. (1997) also knew of no instances of demonstrated gonadal mosaicism in this disorder but considered that the most likely explanation.

Verhoef et al. (1999) identified 6 families with mosaicism in a series of 62 unrelated families with a mutation in either the TSC1 or the TSC2 gene. In 5 families, somatic mosaicism was present in the mildly affected parent of an index patient. In 1 family with clinically unaffected parents, gonadal mosaicism was detected after tuberous sclerosis was found in 3 children. The detection of mosaicism has obvious consequences for genetic counseling. Clinical investigation of the parents of patients with seemingly sporadic mutations is essential to determine their residual chance of gonadal and/or somatic mosaicism, unless a mosaic pattern is detected in the index patient, proving a de novo event. In the dataset of Verhoef et al. (1999), the exclusion of signs of tuberous sclerosis in the parents of a patient with tuberous sclerosis reduced the chance of one of the parents to be a mosaic mutation carrier from 10% to 2%. In the 5 families with somatic mosaicism, the parent was given the diagnosis after the diagnosis was made in the child.

Mapping

In a study of 5 families with tuberous sclerosis, Connor et al. (1987) found a maximum lod score of 1.46 at zero recombination with the ABO blood group (616093) on chromosome 9q34. Connor et al. (1987) found further evidence of linkage to 9q34 in 6 families with tuberous sclerosis: a maximum lod score of 3.18 was found at ABL1 (189980) in 13 informative meioses (4 phase known).

Fryer et al. (1987) found a maximum lod score of 3.85 for linkage of ABO and TSC at zero recombination.

Renwick (1987) presented data on the TSC/ABO linkage derived from the data published from Copenhagen on pedigrees of Borberg (1951). Combined data yielded a maximum lod score of 1.94 at theta = 0.16. Renwick (1987) pointed out that Fryer et al. (1987) found no recombinants out of 4 opportunities for the TSC/AK1 (103000) linkage.

In 3 informative families, Northrup et al. (1987) found negative lod scores with ABO. They pointed out the usefulness of multiple RFLPs at the ASS1 locus (603470), which maps to 9q34, in the study of these families.

Povey et al. (1988) reported recombinants between TSC and ABL in 2 of 3 families informative for the linkage; none of these was informative for ABO or AK1. All affected individuals fulfilled their criteria and all at-risk individuals classified as unaffected were rigorously investigated. Combined with the data of Connor et al. (1987), the new data made the maximum lod score 2.36 at theta = 0.1. Povey et al. (1988) suggested that it is impossible to distinguish between 2 possibilities: that TSC is loosely linked to ABL in all families, or that in some families the mutation for TSC is not in the 9q linkage group at all. They urged that ABL not be used as a marker for prenatal diagnosis of TSC because of these uncertainties.

From study of 8 families, Kandt et al. (1988) concluded that they could exclude linkage of TS to ABO (lod equal to or less than -2.00) for 14 cM on the centromeric side and 18 cM telomeric to the ABO locus. From multipoint analysis in 8 families, Sampson et al. (1989) found a lod score of 3.77 at 6 cM for the location of TS proximal to the ABL locus.

Sampson et al. (1992) collated data on 1,622 members of 128 TS families. They estimated that the locus on 9q34 accounts for approximately 50% of families.

Janssen et al. (1992) pointed out that on average TSC families are very small; in most cases there are fewer than 2 meioses informative for linkage. The size distribution of chromosome 9-linked families was similar to that of unlinked families.

Au et al. (1996) studied a large family with tuberous sclerosis in which linkage with the TSC2 gene had been excluded. The authors analyzed the haplotypes of several genes and polymorphic markers from the 9q34 region, including the highly polymorphic marker A6. A6 is located 100 kb proximal to D9S114 and 200 kb distal to D9S66. The study of haplotypes showed a crossover event at the A6 locus in 1 affected patient, eliminating the terminal segment of DNA (approximately 100 kb) as a possible location of the TSC1 gene. The COL5A1 gene (120215) was eliminated as a candidate gene.

Genetic Heterogeneity

Haines et al. (1991) presented data on 22 families of which 21 were previously unreported. The results strongly supported the TSC1 locus in the 9q32-q34 region for approximately one-third of families and provided significant evidence for genetic heterogeneity. The use of highly polymorphic dinucleotide repeat marker loci enhanced the informativeness of the pedigrees and were vital to the detection of heterogeneity.

Povey et al. (1994) did linkage studies in 32 families of tuberous sclerosis, using genetic markers on chromosomes 9, 11, 12, and 16. Approximately half the families appeared to be linked to TSC1 on chromosome 9 between ASS and D9S298 and half to TSC2 on chromosome 16 close to D16S291. There was no definite support for a third locus, although in many families this could not be excluded.

Molecular Genetics

Approximately 10 to 30% of tuberous sclerosis cases are due to TSC1 mutations, whereas the frequency of TSC2 mutations is consistently higher. TSC1 mutations account for 15 to 30% of familial cases and 10 to 15% of sporadic cases. The frequency of TSC2 mutations in sporadic cases ranges from 75 to 80%. About 15 to 20% of patients have no identifiable mutations; in these patients, tuberous sclerosis may be due to mosaicism (Crino et al., 2006; Curatolo et al., 2008).

In patients with tuberous sclerosis, Van Slegtenhorst et al. (1997) identified 32 distinct heterozygous mutations in the TSC1 gene (see, e.g., 605284.0001-605284.0003). There were 30 truncating mutations. One mutation (2105delAAAG; 605284.0001) was seen in 6 apparently unrelated patients. In 1 of these 6, a somatic mutation in the wildtype allele was found in a tuberous sclerosis-associated renal carcinoma, suggesting that hamartin acts as a tumor suppressor.

Kwiatkowska et al. (1998) performed a comprehensive analysis for mutations in the TSC1 gene using Southern blot analysis, and SSCP and heteroduplex analysis of amplified exons in 13 families with genetic linkage to the TSC1 region, 22 small families without linkage information, and 126 sporadic patients. Seventeen unique mutations were identified in 21 patients. Mutations were found in 7 of 13 (54%) tuberous sclerosis-1-linked families, in 1 of 22 (5%) small families without linkage, and in 13 of 126 (10%) sporadic cases. The mutations were all chain-terminating, with 14 small deletions, 1 small insertion, and 6 nonsense mutations. Twelve of the 21 mutations were previously reported by van Slegtenhorst et al. (1997), and 9 were new. In families with mutations, all individuals carrying a mutation met formal diagnostic criteria for tuberous sclerosis, apart from a 3-year-old girl who had inherited a deletion mutation and who had no seizures, normal intelligence, normal abdominal ultrasound, and hypomelanotic macules only on physical examination. Her 7-year-old sister with the same TSC1 mutation had severe mental retardation. They found no significant difference in the incidence and severity of mental retardation in the 13 sporadic patients with TSC1 mutations versus the entire sporadic cohort. The observation indicated that TSC1 mutations are all inactivating, suggested that tuberous sclerosis-1 occurs in only 15 to 20% of the sporadic tuberous sclerosis population, and demonstrated that presymptomatic tuberous sclerosis occurs.

Ali et al. (1998) screened 83 unrelated individuals with tuberous sclerosis for mutations in TSC1. Mutations were found in 16 of the 83 cases (19%). The mutations comprised base substitutions, small insertions, or small deletions giving rise to 6 nonsense mutations, 8 frameshifts, and 2 splice site mutations, all of which would be expected to result in a truncated or absent protein. In 8 of 10 cases showing linkage to the TSC1 locus, mutations were found. In the remaining 73 unassigned cases, only 8 mutations were found (11%). From these data, Ali et al. (1998) estimated that TSC1 mutations account for 22% of tuberous sclerosis cases.

See also TSC1 (605284) for a detailed discussion of the molecular genetics of tuberous sclerosis-1.

Genotype/Phenotype Correlations

Lewis et al. (2004) used validated tools measuring intellectual function, depression, anxiety, and autistic and behavioral disorders to study the relationships between genotype, seizures, mental retardation, and behaviors in a cohort of 92 patients with mutations in the TSC1 or TSC2 genes. TSC2 but not TSC1 mutations were associated with autistic disorder (p = 0.001), infantile spasms (p = 0.001), and higher risk of low IQ (p = 0.0004) even after adjustment for a history of infantile spasms using logistical regression (OR, 3.50; 95% CI, 1.03-11.95). Previously unrecognized anxiety was frequently diagnosed in patients with mutations in either gene.

Au et al. (2007) performed mutation analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. The authors identified mutations in 72% (199 of 257) of de novo and 77% (53 of 68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in 2 previous large studies. Au et al. (2007) showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. The authors also observed results consistent with 2 similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing metaanalyses of their data and the other 2 large studies in the literature (Dabora et al., 2001; Sancak et al., 2005), Au et al. (2007) found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas.

Jansen et al. (2008) compared the clinical features of 17 TS patients with mutations in the TSC1 gene and 31 patients with mutations in the TSC2 gene. Patients with TSC2 mutations tended to have an earlier onset of seizures, a higher incidence of infantile spasms, and lower cognition scores compared to those with TSC1 mutations. Patients with TSC2 mutations had more tubers and more tubers per brain proportion than those with TSC1 mutations, but the ranges overlapped. Patients with a mutation deleting or inactivating the GTPase-activating protein domain had more tubers than those with intact GTPase-activating domains. Despite some of these small differences, Jansen et al. (2008) concluded that there was considerable overlap between the groups and that prediction of the phenotype in patients with tuberous sclerosis should not be based on their particular TSC1 or TSC2 mutation.

Some patients with tuberous sclerosis develop pulmonary lymphangioleiomyomatosis (LAM; 606690), also known as pulmonary lymphangiomyomatosis, which has been reported in 34 to 39% of asymptomatic women and in some men with tuberous sclerosis. In a retrospective review of the chest CT scans of 45 female and 20 male patients with tuberous sclerosis, Muzykewicz et al. (2009) found cysts consistent with LAM in 22 (49%) women and 2 (10%) men. Among the women, changes consistent with LAM were observed in 6 (40%) of 15 with TSC1 mutations, 11 (48%) of 23 with TSC2 mutations, and 5 (71%) of 7 with no mutation identified. While the predominant size of cysts did not differ across these 3 groups, LAM women with TSC2 mutations had a significantly greater number of cysts than did women with TSC1 mutations. Some of the same mutations were identified in patients with LAM and in those without LAM. These findings suggested a higher rate of LAM in patients with TSC1 than previously recognized, as well as a fundamental difference in CT presentation between individuals with TSC1 and TSC2.

In a retrospective chart review of brain MRI scans of 173 patients with TSC, Chu-Shore et al. (2009) found that 46% of patients had at least 1 cyst-like cortical tuber. The tubers are called cyst-like because they presumably lack the inner endothelial lining seen in true cysts. Patients with TSC2 mutations were more likely to have a cyst-like tuber than patients with TSC1 mutation (p = 0.002) or patients with no mutation identified (p = 0.039). Patients with at least 1 cyst-like cortical tuber were more likely to have a history of infantile spasms (p = 0.00005; relative risk, 2.18), epilepsy (p = 0.0038; relative risk, 1.22), and refractory epilepsy (p = 0.0007; relative risk, 1.47) than patients without a cyst-like cortical tuber. Chu-Shore et al. (2009) concluded that cyst-like cortical tubers are strongly associated with TSC2 gene mutation and a more aggressive seizure phenotype in patients with tuberous sclerosis complex.

Population Genetics

The reported birth rate of tuberous sclerosis is 1 in 6,000. Frequency estimates for the disorder in children under 10 range from 1 in 12,000 to 1 in 14,000 (Curatolo et al., 2008).

Hunt and Lindenbaum (1984) attempted complete ascertainment of cases in the Oxford (UK) region. They estimated that the frequency is 1 in 29,900 for persons under 65 years of age and 1 in 15,400 for children under age 5.

Sampson et al. (1988, 1989) attempted complete ascertainment of tuberous sclerosis in the west of Scotland. An overall minimum prevalence of 1 in 27,000 was calculated, with a minimum prevalence in children under 10 years of 1 in 12,000.

Nomenclature

Tuberous sclerosis, the preferred designation for this disorder, refers to the changes observed in the brain. 'Adenoma sebaceum,' a synonym that refers to the cutaneous features, is a misnomer; 'facial angiofibroma' more accurately describes the lesions. Another synonym, epiloia, stands for 'epilepsy plus anoia'; anoia is a synonym for mental retardation. Gorlin (1981) suggested that epiloia is a useful acronym and mnemonic for 'epilepsy, low intelligence, and adenoma sebaceum.'

History

Gomez (1979) reviewed the experiences with tuberous sclerosis at the Mayo Clinic from 1935 to 1979. Commenting on the monograph, Comings (1980) suggested that future studies may show that hamartomas in TSC have a homozygous mutation of a cell surface protein, with heterozygosity in normal surrounding tissue.

Exclusion of Tuberous Sclerosis Loci TSC3 and TSC4

Some studies suggested a locus for TSC (designated TSC4) on chromosome 11q (Clark et al., 1989; Flodman et al., 1989; Smith et al., 1989; Haines et al., 1989). Janssen et al. (1990) reported results that supported, in their view, a model with 2 different loci independently causing tuberous sclerosis. One locus (TSC1) mapped in the vicinity of the Abelson oncogene at 9q34, and a second locus (TSC4) mapped in the region of the dopamine D2 receptor gene (126450) at 11q23. Analyses by an international group of collaborators (Haines, 1990) suggested that 2 TSC loci exist, one residing near the ABL oncogene on chromosome 9q and the other near the locus D11S48 on 11q. In all, 111 families were examined. Tests of heterogeneity were highly significant (to the 0.0001 level). However, Haines et al. (1991) found no clear evidence of linkage to chromosome 11q22 markers in 22 families. Kandt et al. (1992) and Short et al. (1992) found little or no evidence for a tuberous sclerosis gene on 11q.

Fahsold et al. (1991) reported the association of tuberous sclerosis with a translocation t(3;12)(p26.3;q23.3). The parents were both healthy and had normal karyotypes. The finding suggested the existence of a tuberous sclerosis locus, designated TSC3, at 12q23. Little or no evidence of linkage to 11q, 12q, or 14q was found by Short et al. (1992). Sampson et al. (1992) collated data on 1,622 members of 128 TS families. They estimated that the locus on 9q34 accounts for approximately 50% of families and concluded that there was no evidence of major loci on 11q or 12q.

Kwiatkowski (2005) also concluded that there is no evidence for additional TSC genes besides TSC1 and TSC2, and suggested that the lack of mutations in some 15% of patients may be due to mosaicism or to failure of technology to detect mutations.

Animal Model

Uhlmann et al. (2002) demonstrated that heterozygous Tsc1 and Tsc2 mice exhibit increased numbers of astrocytes, suggesting that hamartin and tuberin are important growth regulators for astrocytes. To study the consequence of hamartin loss on astrocyte function, Uhlmann et al. (2002) generated mice in which the Tsc1 gene was specifically inactivated in astrocytes