INTRODUCTION

Tuberous sclerosis Complex (TSC) is a neurocutaneous syndrome with multisystemic manifestations characterized by neurological symptoms and hamartomatous lesions in several organs, including brain, skin, kidney, retina, heart, lungs & gastrointestinal tract.^1,2 It presents a spectrum of signs and symptoms over a patient’s lifetime, including neurologic disorders, multisystem tumor growth, and dermatologic manifestations.¹ The classical diagnostic (Vogt’s) triad of TSC is seizures, cutaneous angiofibroma (adenoma sebaceum), and mental retardation.² The disease burden varies from intense mental retardation and debilitating seizures to normal intelligence and absence of seizures.¹

Tuberous sclerosis (also known as Bourneville disease or Epiploia) is a neurocutaneous disorder with a spectrum of phenotypic expressions.³ It is caused by a single autosomal dominant germline mutation in tumor suppressor genes TSC1 and TSC2 in about 20 – 50% of cases, with an estimated prevalence of 1:50,000 – 300,000 live births.³ Consequent to the mutation of the TSC1 or TSC2 tumor suppressor gene, the mammalian target of rapamycin (mTOR) signaling pathway becomes hyperactivated, leading to diverse derangement and abnormalities in many cell processes.⁴ The mTOR signaling pathway regulates multiple cell functions.⁵ TSC1 and TSC2 encode, respectively, for the proteins hamartin and tuberin, which serve as tumor growth suppressors that control cell proliferation and differentiation.¹

The remaining 50 – 80% of cases are due to spontaneous (sporadic) gene mutations, with a prevalence of 1:6,000 – 50,000 live births.^1,3,6 TSC affects both sexes and all ethno-racial groups.⁶

The multi-organ manfestations of TSC include cutaneous abnormalities (hypopigmented macules, facial angiofibromas, connective tissue nevi, periungual fibroma, gingival fibromas, dental enamel pits); renal abnormalities (angiomyolipomas, multiple renal cysts, renal cell carcinoma); pulmonary abnormalities (lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, clear cell tumour of the lung ); cardiac abnormalities (rhabdomyoma); ophthalmic abnormalities (retinal hamartoma, retinal hypopigmented macule, retinal achromic patches); hepatic abnormalities (liver angiomyolipomas); epilepsy; and tuberous sclerosis-associated neuropsychiatric disorders (epilepsy, cognitive impairment, autism spectrum, mental retardation, mood disturbances, subependymal giant cell astrocytomas, aggressiveness, behavior changes, anxiety, sleep disorders, depressive mood, hyperactivity, learning difficulties, attention deficit) are seen in 90%, 2 – 80%, 40%, 80%, 30-50%, 10-25%, 70-90%, and 30-75% of patients, respectively.^7–9 Other tumors (thyroid papillary adenoma, PEComa of the uterus, hamartomatous colorectal polyps) and skeletal lesions (bone cyst, scoliosis, periosteal new bone formation, hyperostosis of the inner table of the calvarium, osteoporosis) have also been documented in patients with TSC. Neurological and renal complications are the primary cause of morbidity and mortality in TSC.^7–9

The first inkling to the presence of TSC might be the detection of cardiac rhabdomyomas on obstetrics sonography or the presence of cognitive impairment, hypopigmented cutaneous macules, or seizures (especially infantile spasm) in a child.⁷

Since the traditional (Vogt’s) triad of epileptic seizures, mental retardation, and facial angiofibroma (adenoma sebaceum) is present in only 29% of patients³, the first comprehensive diagnostic criteria for tuberous sclerosis complex had to be formulated in 1998. In 2012, the revised diagnostic criteria were agreed upon at the second International Tuberous Sclerosis Complex Consensus Conference.

The new guidelines modify the previous diagnostic clinical criteria, incorporate genetic testing, and provide for a new category termed “probable diagnosis”.⁷ Identification of the pathogenic mutation (deletion, rearrangement, or inactivating mutation) in TSC1 or TSC2 gene on genetic testing is now an independent diagnostic criterion that can be used to diagnose TSC definitively. This is particularly useful in neonates in whom the usual clinical manifestations might still be latent.⁷

The modified clinical criteria are still the cornerstone of diagnosis in places where genetic testing is unavailable. The major clinical criteria are hypopigmented macules (≥ 3, with at least 5mm diameter), angiofibromas (≥ 3) or fibrous cephalic plaque, ungual fibromas (≥ 2), shagreen patch, multiple retinal hamartomas, cortical dysplasia, subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis, angiomyolipomas (≥ 2). The minor clinical criteria are: “confetti” lesion, enamel pits (> 3), intraoral fibroma (≥ 2), retinal hypopigmented macule, multiple renal cysts and nonrenal hamartomas. TSC is diagnosed when two major criteria or one major and two minor criteria are present in the patient. The detection of one major criterion or ≥ 2 minor criteria constitutes “probable diagnosis”.⁷

CASE PRESENTATION

A 24-year-old male secondary school student presented with a history of fever, an episode of seizure, poor sleep, skin lesion on the forehead since birth, and irrational behaviour. Fever occurred mainly at night and was high-grade in nature. No associated chills or rigor. The seizure was said to have been generalized, tonic-clonic, and lasted about five minutes. There was no associated foaming from the mouth or urine incontinence. Seizure episode was reportedly aborted by pouring water on him. He had been unable to sleep soundly for the past three days before presentation and was said to have taken off his clothes in public on one occasion. No history of trauma to the head, persistent headache, effortless vomiting, or fainting spells.

He started to have seizures at the age of one. There were about four episodes per day, each lasting about 3 minutes. Non-itchy skin lesions in the right forehead were noticed at birth with a gradual increase in size over time. The pregnancy, labour, and delivery were uneventful. Skull radiograph, hematologic parameters, and blood chemistry assay were normal then. He was diagnosed with a seizure disorder (epilepsy) ? neurocutaneous syndrome and managed with phenobarbitone initially, which was later combined with phenytoin. He was regular in the pediatric out-patient clinic until he was six years old when he was lost to follow-up.

He re-presented with new episodes of seizure at the age of 24. He had been seizure-free throughout the intervening period on a daily intake of phenytoin. There was no history of flank/abdominal pain, early morning facial/ feet swelling, or bone pains. There was a history of poor academic performance (frequently repeating classes).  No family history of seizure disorders.

On examination, he was conscious, kempt, and oriented in time, place, and person. The general examination was unremarkable. Chest, abdominal, and neurologic examinations were normal. Dermatological examination revealed multiple facial papules on the nose, cheeks, and jaws; left-sided sacral Shagreen’s patches; epidermal nevus (linear) on the forehead; and ash leaf macules on the back. Musculoskeletal system examination was normal. 

Hematological and clinical chemistry assays were within normal limits. A cranial Magnetic Resonance Imaging (MRI) showed a subcortical focus of increased signal intensity (cortical tuber) in the right frontal lobe (Figure. 1) and multiple subependymal hypointense foci (subependymal tubers) along the outer walls of the lateral ventricles (Figure. 2) on T2-weighted imaging. No evidence of cortical atrophy, ventricular dilatation, or a subependymal mass lesion.

Cranial CT revealed multiple hyperdense, calcific densities in the periventricular areas (Figure. 3), and in the medial portion of the right frontal lobe (Figure. 4).

Abdominal and renal sonography was normal, with no evidence of angiomyolipoma.

Electroencephalography (EEG) showed a rhythmic ictal epileptiform activity. Intelligence Quotient testing and genetic testing could not be done due to the unavailability of the relevant equipment and expertise.

He was continued on phenytoin for the seizures and has been regular on out-patient follow-up, with adequate control of seizure.