Tuberous sclerosis complex (TSC) is a genetic disorder characterized by autosomal dominant (dominant) mutations in the tumor suppressor genes TSC1 and TSC2. Also called Bourneville-Pringle disease, its classic triad includes facial angiofibromas (adenoma sebaceum), epilepsy, and intellectual disability.
In 1880, Bourneville named tuberous sclerosis a disease presenting with epilepsy and intellectual disability in autopsy cases with multiple cerebral sclerotic lesions. In 1890, Pringle added adenoma sebaceum to establish the disease concept. However, all three features are present in only about 29% of patients.
The incidence of TSC is estimated at 1 in 5,000 to 10,000 births2). It affects males and females equally across all ethnicities. About 60% of cases are due to sporadic mutations, and 40% are familial autosomal dominant inheritance. The number of patients in Japan is estimated at 4,000 to 12,000.
The most representative ophthalmic sign is retinal astrocytic hamartoma. It is found in about 50% of TSC patients and is bilateral in 25%. It is usually non-progressive and follows a benign course.
About 60% of cases are due to sporadic mutations (de novo mutations) and are not necessarily inherited from parents. The remaining 40% are familial autosomal dominant inheritance, but there is wide variability in phenotype even within the same family.
Retinal astrocytic hamartoma is often asymptomatic. It is usually discovered incidentally during pediatric or neuropsychiatric referrals, or on routine fundus examination.
Rarely, the following symptoms may appear:
If obstructive hydrocephalus due to SEGA occurs, worsening headache, nausea/vomiting, and transient visual disturbances may appear.
Retinal hamartomas in TSC are mainly classified into three types.
Flat Type
Most common type: Most frequently seen in TSC patients.
Appearance: Pale gray to yellow, translucent, with well-defined borders. Lacks calcification.
Predilection site: Located at the temporal end of the vascular arcade; blood vessels becoming indistinct is a clue.
Complications: The covered blood vessels are fragile and prone to vitreous hemorrhage.
Multinodular type
Mulberry-like lesion: Presents as a white nodular elevation with calcification.
Predilection sites: Commonly in the posterior pole, peripapillary area, and on the optic disc.
Size: 0.5 to 4 disc diameters.
Note: May be mistaken for optic disc drusen.
Transitional type
Frequency: Seen in 9–12% of TSC patients.
Features: Combines characteristics of both flat and multinodular types.
Appearance: The base is flat and translucent, with a nodular and calcified center.
Usually, it does not cause vision loss. However, lesions on the optic disc may cause exudative changes or dissemination, requiring attention. Invasive types are extremely rare, but if they enlarge, they can lead to blindness.
TSC is caused by loss-of-function mutations in the TSC1 gene (9q34) or the TSC2 gene (16p13).
Sporadic cases are mostly due to TSC2 abnormalities. TSC2 mutations are more strongly associated with epilepsy, renal angiomyolipoma, SEGA, and significant cognitive impairment than TSC1 mutations. Ophthalmologically, TSC2 mutations also correlate with more severe retinal findings.
Retinal hamartomas arise from disordered proliferation of glial astrocytes and blood vessels. In cases with central nervous system lesions, fundus lesions also tend to be multiple.
The diagnostic criteria established by the International Tuberous Sclerosis Complex Consensus Group in 2012 are shown below.
A definite diagnosis requires meeting one of the following:
The main major and minor criteria are as follows:
| Major criteria | Minor criteria |
|---|---|
| Multiple retinal hamartomas | Retinal depigmented spots |
| Three or more facial angiofibromas | Confetti skin lesions |
| Subependymal nodules or SEGA | More than three dental enamel pits |
| Cardiac rhabdomyoma | Multiple renal cysts |
Multiple retinal hamartomas are one of the major diagnostic criteria for TSC, and ophthalmic examination plays an important role in diagnosis.
Identification of a pathogenic variant in TSC1 or TSC2 can confirm the diagnosis 2). Multi-gene panel analysis using next-generation sequencing (NGS) is performed. However, since mutations are not detected by conventional genetic analysis in 10–25% of patients, clinical criteria remain important.
The differential diagnosis of retinal astrocytic hamartoma includes the following:
When TSC is diagnosed, regular fundus examinations are recommended. Retinal hamartomas usually progress slowly, but lesions on the optic disc and aggressive types rarely enlarge, so longitudinal evaluation is important. In patients with SEGA, attention to neuro-ophthalmologic complications is also necessary.
Retinal hamartomas usually have little tendency to grow and do not require treatment. Observation is the standard approach.
Indications for treatment of ocular findings are limited to the following cases:
Systemic treatment of TSC is performed through multidisciplinary collaboration.
The core pathology of TSC is dysfunction of the hamartin-tuberin complex, the products of the TSC1/TSC2 genes.
This complex functions as a negative regulator of the mTOR (mechanistic target of rapamycin) signaling pathway. Normally, hamartin stabilizes tuberin, and tuberin acts as a GTPase-activating protein for Rheb-GTPase, suppressing mTORC1 (mTOR complex 1) 2).
When a loss-of-function mutation occurs in TSC1 or TSC2, the following cascade occurs:
Retinal hamartomas are formed by a network of glial astrocytes and blood vessels in the nerve fiber layer. As the lesion develops, calcification occurs to varying degrees.
Knudson’s “two-hit hypothesis” explains the phenotypic diversity. The first hit is a preexisting mutation in TSC1/TSC2, and when a second hit occurs within the same gene causing loss of heterozygosity, a tumor develops.
Kamel et al. (2024) reported a case of a 40-year-old woman with bilateral SEGA who underwent fractionated stereotactic radiotherapy (60 Gy in 30 fractions), achieving a 72–82% reduction in tumor volume over approximately 8 years 1). Subsequently, everolimus (2.5 mg/day) was initiated for the treatment of renal angiomyolipomas, leading to further shrinkage of the residual SEGA tumor, ultimately to less than 10% of the original volume. An additive effect of radiotherapy and mTOR inhibitors was suggested.
Radiotherapy for SEGA has historically been considered ineffective, but this report suggests the efficacy of fractionated stereotactic radiotherapy. Radiotherapy after tumor shrinkage with everolimus is expected to reduce side effects due to a smaller irradiation volume, and a combination strategy to prevent regrowth after drug discontinuation has been proposed 1).
Jurca et al. (2023), in a case report of a 33-year-old female patient with a TSC1 gene mutation (exon 13, c.1270A>T), suggested that metformin, a type 2 diabetes drug, may have beneficial effects on TSC-related tumor progression and epileptic seizures by inhibiting the mTOR pathway 2).
The association between TSC and the PI3K/AKT/mTOR signaling pathway is an important research topic in the search for new therapeutic targets 2). The mTOR pathway is also involved in the regulation of insulin sensitivity and glucose metabolism, and its relationship with metabolic diseases is attracting attention.
