Tuberous Sclerosis Complex: Diagnostic Role of Magnetic Resonance Imaging.

Tuberous sclerosis complex (TSC) is a well-known clinical entity, characterized by facial angio-fibroma, shagreen patch, and hypo-melanotic, and confetti-like skin lesions. An exquisite fresh case is being narrated, emphasizing its microscopic pathology. The role of magnetic resonance imaging of the brain, in particular, is highlighted to define the large variety of neurological abrasions for determining its future progression.

What was known?

Tuberous sclerosis complex is a rare entity, the cutaneous manifestations of which are extraordinary and have been well illustrated along with its neurological undertones.

Introduction

Tuberous sclerosis is a genetic disorder, where cellular differentiation and proliferation result in hamartoma formation in the skin, brain, eye, kidney, and heart.[12] The credit of its initial description, in the year 1862, goes to Von Recklinghausen,[3] while Désiré-Magloire Bourneville[4] coined the term sclerose tubereuse; the current name is its derivative. The clinical triad of epilepsy, low intelligence, and adenoma sebaceum, the epiloia, was invented by Sherlock.[5] The term tuberous sclerosis complex (TSC)[1] is now widely acclaimed, emphasizing the variegated nature of its attribute.

Case Report

An 11-year-old girl of class 6th standard, of average IQ, presented with insidiously evolving reddish-brown, small hard bumps occupying the mid-face since early childhood. She also had couple of small white spots over the trunk. There was neither history of neurological (seizures), visual deficit nor burning on exposure to sunlight. She was born by normal delivery from non-consanguineous parents. Her younger brother is normal. No history indicative of the disease could be elicited either in maternal or fraternal family members. Skin surface examination of the face was marked by the presence of reddish-brown papules of 2-4 mm size (millet seed). These papules were numerous, occupied the nose, nasolabial folds and cheeks and were bilateral and symmetrical [Figure 1a]. In addition, a plaque of 3 to 4 cm size was recognized in the lumbo-sacral region. It had uneven surface, resembling an “orange peel,” the shagreen patch [Figure 1b]. Hypomelanotic, ivory-white macule (s) of 5 to 10 mm size was located. The macules were 2 in number and were well defined with irregular margins [Figure 1c]. The mucous membrane of the oral cavity and nails were normal. Neurological examination too was normal. Indirect ophthalmoscopic and slit-lamp examinations of the eye were normal. Complete hemogram, including total and differential leukocyte count, and cardiac- and kidney functions tests were normal. Ultrasonography of the abdomen was normal too. Kidneys and liver, in particular, did not reveal any focal lesion. The radiograph of the chest and electrocardiogram (ECG) were normal.

Figure 1

(a) Angio-fibroma on the face. (b) Shagreen patch on the lumbo-sacral region. (c) Hypomelanotic, confetti-like macules

Histopathology

Hematoxylin-eosin (H and E)-stained sections prepared from the face, revealed a normal looking epidermis, small pilo-sebaceous units, and an evidence of increased dermal collagen [Figure 2a]. At higher magnification, “onion-peel”- like concentric bands of collagen surrounding abortive hair follicles [Figure 2b] were seen. Concentric bands of fibrosis were also seen around some of the eccrine ducts [Figure 2c], appearing to constrict their lumina. Likewise, the small sebaceous glands in the dermis were surrounded by dense collagen bands.

Figure 2

(a) Section, exhibiting a normal epidermis and small pilosebaceoous units (H and E, ×40). (b) “Onion-peel”-like concentric bands of collagen surrounding a hair follicle (H and E, ×200). (c) An eccrine duct surrounded by concentric fibrosis (H and E, ×400)

The sections from the plaque on the back showed a dome-shaped elevation of the epidermis by dense fibrous tissue, a paucity of dermal appendages, and vasculature. Concentric bands of collagen, surrounding small, congested blood vessels were also seen in the dermis.

Magnetic resonance imaging

MRI of the brain performed on a 1.5 TMR (Signa HDxt, GE Medical Systems, Milwaukee, Wisconsin, USA), using turbo spin-echo (TSE) T1-weighted, T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences in axial planes, showed sub-ependymal nodules (SENs) along the wall of both the lateral ventricles, appearing hyper-intense on T1-and T2-weighted MRI [Figure 3a and b], small focal lesions in the left frontal lobe cortex [Figure 4a and b] and in left cerebellum [Figure 5a and b] appearing hyper-intense on T2-weighted, and FLAIR and iso-intense to hypo-intense on T1-weighted images [Figure 5a and b]. In addition, band like hyper-intense bilateral lesions were seen in deep white matter on FLAIR images. An extra-axial cystic lesion was also seen in the left temporal region, appearing hypo-intense on FLAIR and hyper-intense on T2-weighted images. Both the orbits were unremarkable.

Figure 3

(a) Axial T2-weighted image demonstrating hyper-intense subependymal nodules (white arrow) along bilateral lateral ventricles. (b) On axial T1-weighted image the nodules appeared hyperintense with central hypo-intensity (white arrow)

Figure 4

(a and b) Axial FLAIR image demonstrating hyper-intense linear radial band in bilateral deep white matter (white arrow) and focal hyper-intense lesion in the left parietal cortex (black arrow)

Figure 5

(a) Axial T2-weighted image showing a focal hyper-intense lesion in the left cerebellum (white arrow) and an extra-axial hyper-intense lesion in the left temporal region (thick arrow). On axial FLAIR images (b) the left cerebellar lesion appeared hyper-intense (white arrow) and the extra-axial left temporal lesion appeared hypo-intense (thick arrow)

The ultrasound of abdomen including kidneys and liver was normal.

Discussion

It is a rare entity and has sparingly been reported.[67] Nonetheless, it continues to be in reckoning, ever since its inception, because of its overwhelming clinical ramifications. Accordingly, a consensus conference was sponsored by the Tuberous Sclerosis Alliance and the National Institute of Health, the deliberations of which took cognizance of its wide ranging clinical manifestations to evolve criteria for its diagnosis [Table 1].[8]

Table 1

Tuberous sclerosis complex: Criteria for diagnosis

The present case had facial angio-fibroma, shagreen patch, and hypo-melanotic, confetti-like[910] skin lesions, a few of its salient cutaneous manifestations, adequate to consider the diagnosis of TSC, conforming to the major features (vide supra).

The exquisite exposition of microscopic pathology[111] was fascinating and is required to be taken cognizance of as an essential adjunct for confirming the clinical diagnosis. Virtually, it should form a part component of already enlisted major and/or minor features of TSC. It is, therefore, recommended to undertake a biopsy of accessible cutaneous lesions before proceeding to perform MRI. The narrative account of TSC was accomplished in the present case by performing MRI of the brain to identify the presence of lesions involving the cerebral cortex. Multiple high-signal MRI lesions are characteristic of TSC[12] corresponding to the hamartomas and gliotic area seen pathologically. Furthermore, MRI may be useful in predicting the eventual clinical severity of younger children with newly diagnosed TSC.

Cortical tubers, SENs and white matter lesions are commonly encountered in TSC. Its less common manifestations include cerebellar atrophy, dys-genesis of corpus callosum, Chiari malformation, arachnoid cyst, and infarctions due to occlusive vascular disorders. MRI is the most sensitive modality for their detection.[1314] Cortical tubers, SENs, white matter lesions and left temporal arachnoid cysts were seen in the present case. The cortical tubers had increased signal intensity on T2- and decreased signal intensity on T1-weighted sequence. On MRI, SENs are iso-intense/hyper-intense on T2-weighted images and hyper-intense on T1-weighted images, and may also demonstrate central low T2 signal with surrounding hyper-intense rim. SENs typically measure less than 1 cm, but may grow over time, giving rise to subependymal giant cell astrocytomas (SEGAs), which are commonly located at the foramen of Monro and can cause acute obstructive hydrocephalus. They are of heterogeneous appearance on MRI, contain calcification and show intense inhomogeneous enhancement. Superficial white matter abnormalities and radial white matter bands, which are lines of arrested neuronal migration, appear as radiating bright lines on T2-weighted and FLAIR images. White matter cystic lesions may also occur. Hence, MRI plays an important role in the correct diagnosis of TSC, especially in asymptomatic patients to determine the presence and extent of organ involvement. Follow-up MRI must be done for evolution of lesions and early detection of associated complications. Thus, it may play a crucial role in its management. Moreover, it is worthwhile to highlight the limitations of conventional MRI to match micro-structural changes, for which diffusion tensor imaging (DTI) and related noninvasive techniques[15] are being practiced to define the well-known pathological changes. In addition, DTI has a putative role in identifying potential disease biomarkers, as DTI abnormalities of the white matter are associated with neurocognitive morbidity including autism. If indeed DTI changes parallel phenol-typical changes related to the investigational treatment of epilepsy, cognition and behavior with mTOR inhibitors, it will facilitate future clinical trials.

Conclusions

Although tuberous sclerosis complex is a well-known genetic disorder, its reporting is sporadic. Slowly evolving angio-fibroma affecting the mid face, shagreen patch, and hypo-melanotic, confetti-like lesions should arouse suspicion. Nevertheless, its diagnosis needs to be supplemented by histopathology. Magnetic resonance imaging is imperative to define its neurological undertones, in addition to slit-lamp examination of the eye.

Noninvasive MRI measures of microstructural may be handy.

What is new?

The imperatives of magnetic resonance imaging (MRI) for evaluating the variety of associated neurological abnormalities are focused attention for diagnosis of tuberous sclerosis complex, and to predict the future course of the disease.