Tuberous sclerosis complex: A case report.

Tuberous sclerosis complex is an unusual autosomal dominant neurocutaneous syndrome characterized by the development of benign tumors affecting different body systems affecting the brain, skin, retina, and viscera. It is characterized by cutaneous changes, neurologic conditions, and the formation of hamartomas in multiple organs leading to morbidity and mortality. The most common oral manifestations are fibromas, gingival hyperplasia, and enamel hypoplasia. The management of these patients is often multidisciplinary involving specialists from various fields. Here, we present a case report of a 26-old-year male patient with characteristic clinical, radiological, and histological features of tuberous sclerosis complex.

Introduction

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder first described by von Recklinghausen in 1862. In 1880, Bourneville coined the term “sclerose tubereuse” based on the pathologic features of the sclerotic tubers found in the postmortem investigation of patients with epilepsy and mental retardation, henceforth known as Bourneville's disease.[1] TSC is classified as a phakomatosis (neurocutaneous disorder) and which is characterized by the presence of glial cell tumors arising in the cerebral hemispheres and retina.[2] It is clinically characterized by the triad of epilepsy (EPI), intellectual disability (LOI), and adenoma sebaceum (A), therefore, encompassing these features Sherlock coined the term EPILOIA.[3]

The frequency of TSC has been estimated to be 1 in 10,000 live births and is about a third as common as neurofibromatosis type 1.[4] It is a multisystemic disorder which becomes perceptible only in late childhood, limiting the expediency for early diagnosis in infancy.[5] Here, we present a case report of a 26-year-old male patient with distinctive clinical, radiological, and histological features of TSC.

Case Report

A 26-year-old male patient presented with multiple growths in the upper and lower gums since 5 years. The patient noticed the growth for the past 5 years, which gradually increased in size to attain the present size. There was no history of pain or blood/purulent discharge associated with the growth. The patient was a known epileptic and hysteric since the age of 10 and under anticonvulsant and antidepressants. He had been dropped out from school at the age of 12 years. He also gave a history of slurred speech and difficulty in understanding. Past dental history and family history were insignificant.

On general physical examination, multiple well-defined, reddish-brown sessile nodular growths were noted on the forehead, nose, and cheeks in a characteristic “butterfly pattern” and front and back trunk region-angiofibromas. Similar sessile and firm nodular growths were noted in the upper and lower extremities of varying sizes, suggestive of periungual fibromas or Köenen tumors. A well-defined roughened hypermelanotic patch was noted in the left shoulder girdle and the right lumbosacral region showing an orange peel appearance indicative of shagreen patch [Figure 1]. Vital signs were found to be within satisfactory limits.

Figure 1

Clinical photograph of the patient showing multiple well-defined, reddish-brown sessile nodular growths on the forehead, nose, and cheeks in a characteristic “butterfly pattern,” Shagreen patch, and periungual fibromas

On intraoral examination, similar well-defined, sessile, firm, and nodular growths were seen in the marginal and attached gingiva in the upper and lower anterior region of varying sizes. Marginal and papillary gingival enlargement was also observed in the lower anteriors. Multiple hypoplastic enamel pits were noted in the occlusal aspect of posterior teeth [Figure 2]. Based on the history and clinical findings, a provisional diagnosis of drug-induced gingival enlargement was considered. Differential diagnosis of gingival fibromas and neurofibromas were well thought out.

Figure 2

Multiple gingival growths and hypoplastic enamel pits

The patient was subjected to various radiological, hematological, and histopathological investigations. Orthopantomogram revealed no evidence of bony involvement. A radiopaque mass resembling tooth such as structure involving enamel, dentin, and pulp was seen in the periapical region of 21, 22 regions suggestive of compound odontome. Chest radiograph revealed inferior displacement of the left border of ventricle suggestive of left ventricular hypertrophy. Axial computed tomographic sections of the brain showed hypodense areas measuring approximately 5 mm × 5 mm in the subependymal regions of both ventricles indicating multiple calcified tuberous lesions (subependymal nodules) [Figure 3]. Ultrasound of the whole abdomen showed no abnormality.

Figure 3

Orthopantomogram, intraoral periapical radiographic view, chest radiograph, and axial computed tomography view

Hematological investigations were found to be satisfactory except for erythrocyte sedimentation rate which was found to be raised to 32 mm. Henceforth, excisional biopsy of the gingival growth in 23, 24 regions and cutaneous punch biopsy was performed. Microscopically, hematoxylin and eosin-stained section of the intraoral tissue specimen showed a stretched out, hypoplastic stratified squamous epithelium overlying connective tissue stroma. The underlying connective stroma consisted of dense, thick collagenous bundles with hypocellularity comprising of few fibroblasts, mesenchymal cells, constricted blood vessels, and inflammatory cells. The extraoral biopsy specimen showed orthokeratinized stratified epithelium overlying the connective tissue stroma. The epithelium appeared to be flattened and thinned out with the basal cells exhibiting an abundance of deeply stained melanocytes. Underlying connective tissue was dense with collagen bundles, mesenchymal cells, and few nerve fiber bundles. There was no evidence of sebaceous glands or hair follicles [Figure 4a–c].

Figure 4

Histopathological view (a and b, × 10; c, × 40)

Based on all the clinical findings and investigations, a final diagnosis of tuberous sclerosis was confirmed.

Discussion

TSC is characterized by the development of unusual tumor-like growths (hamartomas) in brain, skin, retina, and viscera. The term “tuberous sclerosis” refers specifically to the presence of multiple sclerotic masses scattered throughout the cerebrum. The diagnosis of TSC is based on the identification of hamartomas in more than one organ system.[6]

TSC is an autosomal dominant disorder with nearly complete penetrance but variable expressivity. The abnormal genes have been localized to one of two sites, the long arm of chromosome 9 (9q34), designated as TSC 1 (encoding hamartin), and the short arm of chromosome 16 (16p 13.3) designated as TSC 2 (encoding tuberin). These gene products form a tumor suppressor complex which drives Rheb (Ras homolog enriched in brain) a member of Ras superfamily into the inactive guanosine diphosphate-bound state. When Rheb is in the guanosine triphosphate-bound active state, it stimulates the mammalian target of rapamycin (mTOR), an evolutionarily conserved protein kinase and a major effector of cell growth. The mutations in these genes result in constitutive mTOR activation leading to the formation of various growths and hamartomas in various organs of the body.[7] In a study conducted on 325 TSC individuals, 17% of the mutations were found in the TSC1gene, 50% in the TSC2gene, 4% unclassified variants, and 29% with no identifiable mutations.[8]

At the Tuberous Sclerosis Consensus Conference of 1998, the clinical diagnostic criteria of TSC were revised and a new classification system based on major and minor findings was established. The presence of two major features or one major and two minor features was considered sufficient for a definitive diagnosis. The major features include (a) hypomelanotic macules (≥3, at least 5-mm diameter), (b) angiofibromas (≥3) orfibrous cephalic plaque, (c) ungual fibromas (≥2), and (d) shagreen patch. The minor features include (1) “confetti” skin lesions, (2) dental enamel pits (≥3), and (3) intraoralfibromas (≥2).[9] The most common oral manifestations of TSC are fibromas, gingival hyperplasia, and enamel hypoplasia (in almost 100% of these patients and is associated with an increased risk of caries). The other features include hamartomatous rectal polyps, nonrenal hamartomas, multiple renal and bone cysts, high arched palate, bifid uvula, cleft palate, delayed dental eruption, and presence of diastemas. Our case presented with three major features – facial angiofibromas, Köenen tumors and subependymal nodules and two minor features – gingival fibromas and enamel hypoplasia.[1011]

The management of these patients is often multidisciplinary involving the neurosurgeon, neurologist, nephrologist, pulmonologist, cardiologist, ophthalmologist, and the genetic counselor. Surgery including dermabrasion and laser treatment may be useful for the treatment of skin lesions. Intervention programs including special schooling and occupational therapy may benefit individuals with special needs and developmental concern.[46]

Drug therapy for some of the manifestations of TSC is currently in the developmental stage. Recent trials have shown the use of topical 0.1% rapamycin on facial angiofibromas. The use of inhibitors of mTOR in regression of various hamartomatous growths is a newer modality in the management of TSC.[47]

These patients must adopt measures for careful oral and dental hygiene with regular visits to the dentist in order to eliminate potential irritative factors and ensure the early diagnosis of any possible lesions.[10] In the present case, the patient was advised to take his physician consultation for modification of the antiepileptic drug. At present, the daily dose of phenytoin is reduced from 400 to 300 mg as maintenance protocol. Application of fluoride varnish in hypoplastic enamel pits was also performed and kept under periodic recall.

The prognosis of TSC depends on the severity or multiplicity of organ involvement. About a quarter of severely affected infants is thought to die before the age of 10% and 75% before 25 years. However, in the case of individuals diagnosed late in life with few cutaneous signs, prognosis depends on the associated internal tumors and cerebral calcifications.[6]

The present case unambiguously exemplifies the systemic manifestations of TSC and its specific expression in the oral cavity. Hence, in turn to establish an appropriate diagnosis, oral manifestations of the disorder must not be overlooked which implies the necessity for the level of awareness of TSC among oral practitioners.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.