Tuberous sclerosis complex: “When Genes Go Off Script

Tuberous sclerosis complex: “When Genes Go Off Script “

Yashaswini.K¹, Kiran Araballi², Pavan Satyam³, Soniya Tambe⁴, Sudhindra Kulkarni⁵

¹Lead Consultant PICU, Kauvery Hospital, Banglore

²Junior Consultant PICU, Kauvery Hospital, Banglore

³Pediatric Neurologist, Synapse Neurocentre, Bangalor

⁴Consultant – Neurology, Kauvery Hospital, Banglore

⁵HOD Radiology, Kauvery Hospital, Banglore

Case Presentation

11 months old male infant born of a non-consanguineous marriage, developmentally normal with uneventful birth history, vaccinated up to age, presented with Febrile status epilepticus. On examination child was noticed to have Cafe-au lait spots, hypomelanotic macules cardiovascular system examination revealed a short systolic murmur in the left parasternal area. Seizures was managed with anti-epileptics, Child remained encephalopathic for more than 24 hr with high grade fever spikes.

Hence neuro imaging and CSF analysis was done. CSF analysis was within normal limits. MRI brain with spine showed multiple hyper-intensities bilaterally, opined as demyelination. Differentials of neuro- cutaneous syndrome versus autoimmune disorder were considered. 2D ECHO was suggestive of echogenecity noted on pulmonary valve leaflet measuring 5×4mm towards the ventricular surface, muscle bundle, suspected vegetation with good biventricular function.

MRI brain with spine was suggestive of multifocal asymmetrically distributed cortical, subcortical white matter T2 /FLAIR hyperintense lesion with subtle post contrast enhancement and no restricted diffusion in bilateral frontal temporal lobes, parieto- occipital lobes – probable demyelination/probable tubers, multiple enhancing subependymal nodules in bilateral lateral ventricle, spine screening was normal.

Pediatric neurologist reviewed the child, child’s sensorium improved, steroids were deferred. EEG was suggestive of bifronto central inter ictal epileptiform discharges, no features of hypsarrhythmia. USG KUB, fundus examination and autoimmune report were normal. Genetic counselling and development assessment was done. Elder sibling also had similar hypomelanotic macules (asymptomatic), advised for evaluation. Child was discharged on Levetiracetam and counselling done with multidisciplinary team. Genetic work up – Whole exome sequencing was positive for pathogenic variant for Tuberous sclerosis. Child was started on Vigabatrin on follow up.

Discussion

Tuberous sclerosis complex (TSC) is a rare genetic disorder inherited in an autosomal dominant pattern, characterized by multisystem involvement. The incidence of TSC ranges from 1 in 6,000 to 1 in 10,000 live births. Spontaneous pathogenic variants occur in 65% of the cases. Molecular genetic studies have identified two foci for TSC: the TSC1 gene (located on chromosome 9q34) and the TSC2 gene (located on chromosome 16p13).

TSC is primarily marked by the development of hamartomatous tumors across multiple organ systems, including the brain, skin, heart, kidneys, and eyes. In addition to epilepsy, about 90% of individuals with TSC have a spectrum of cognitive, behavioural, psychiatric and academic impairments termed tuberous sclerosis–associated neuropsychiatric disorders (TANDs), which include intellectual disability, autism spectrum dis order, attention- deficit/hyperactivity disorder, anxiety and depression. About 45% of individuals with TSC have intellectual disability and up to 25–50% have autism spectrum disorder. Subependymal nodules in 5–10% of cases, these benign lesions can grow into subependymal giant cell astrocytomas(SEGAs). Approximately 50% of children with TSC have cardiac rhabdomyomas, which may be detected in the fetus by an echocardiogram, usually by 20 – 30 weeks of gestation. They can cause congestive heart failure and arrhythmias in a minority of patients; they tend to slowly resolve spontaneously. In 75–80% of patients older than 10 years of age, the kidneys display angiomyolipomas that are usually benign tumors.

The following are recommended for routine follow- up of individuals with TSC in addition to physical examination: brain MRI every 1–3 years, abdominal MRI to evaluate the kidneys every 1–3 years; echocardiogram every 1–3 years in patients with cardiac rhabdomyomas until there is regression of the rhabdomyomas; electrocardiogram every 3–5 years; high- resolution chest CT every 5–10 years in females older than 18 years; dental examination twice a year; skin examinations once a year; detailed ophthalmic examination once a year in patients with vision concerns or retinal lesions (sooner if they are receiving treatment with vigabatrin); neurodevelopmental testing at the beginning of first grade or sooner based on concerns; and screening for TAND at each clinic visit.

S. No	Major Features of Tuberous Sclerosis Complex	Index case
1	Cortical dysplasias (including tubers and cerebral white matter migration lines)	✓
2	Subependymal nodules	✓
3	Subependymal giant cell astrocytoma
4	Facial angiofibromas (≥3) or forehead plaque
5	Ungual fibromas (≥2)
6	Hypomelanotic macules (≥3, ≥5 mm in diameter)	✓
7	Shagreen patch
8	Multiple retinal nodular hamartomas
9	Cardiac rhabdomyoma	✓
10	Renal angiomyolipoma
11	Pulmonary lymphangioleiomyomatosis

S. No	Minor Features of Tuberous Sclerosis Complex	Index case
1	Dental enamel pits (>3)
2	Intraoral fibromas (≥2)
3	Retinal achromic patch
4	Confetti skin lesions
5	Nonrenal hamartomas
6	Multiple renal cysts

Diagnosis

Definite TSC is diagnosed when at least two major or one major plus two minor features are present. In addition, carrying a pathogenic variant in TSC1 or TSC2 is sufficient for the diagnosis of TSC.

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Tuberous sclerosis complex: “When Genes Go Off Script