Clinical Presentations Of Tuberous Sclerosis Complex

Vogt's classic triad of seizures, mental retardation, and adenoma sebaceum is present in less than 50% of all cases of TSC. Moreover, a wide variety of clinical manifestations and their variable expressions make the diagnosis more difficult. So in 1992 the National Tuberous Sclerosis Association formulated the diagnostic criteria for TSC.46 For a definitive diagnosis the presence of one primary criterion, two secondary criteria, or one secondary and three tertiary criteria are required (Table 22-1). When one secondary and one tertiary or three tertiary criteria are present, the disease is a possibility. If only one secondary or two tertiary criteria are detected, the disease is suspected.

Seizures and mental retardation are the most common symptoms, but they are not included in the diagnostic criteria because of lack of specificity. Seizures are initially flexion

Table 22-1

Diagnostic Criteria of Tuberous Sclerosis Complex

Primary Criteria

Facial angiofibroma Multiple subungual fibroma Multiple retinal astroblastoma Cortical tuber (histologically confirmed) Subependymal giant cell astrocytoma (SGCA) Multiple calcified subependymal nodules protruding into the ventricles

Secondary Criteria

Cortical tuber (radiologically confirmed) Noncalcified subependymal nodule (radiologically confirmed) Forehead plaque Shagreen patch

Other retinal hamartoma or achromic patch Cardiac rhabdomyoma

Pulmonary lymphangiomyomatosis (histologically confirmed)

Renal angiolipoma

Renal cyst (histologically confirmed)

Affected first-degree relative

Tertiary Criteria

Hypomelanotic macules Confetti skin lesions Gingival fibroma

Enamel pits in deciduous or permanent teeth Cerebral white matter migration tracts or heterotopias Pulmonary lymphangiomyomatosis (radiologic evidence) Renal cysts (radiologic evidence) Hamartomatous rectal polyps (histologically confirmed) Bone cyst (radiologically confirmed) Hamartoma of other organs (histologically confirmed) Infantile spasm myoclonus with hypsarrhythmia but may gradually evolve into grand mal or psychomotor epilepsy. Many of these patients have features of autism; rarely, there may be chorea and atheto-sis. With time higher mental function deteriorates. Approximately two thirds of patients with normal mental function have seizures. On the other hand, all patients with mental retardation suffer seizure disorders.19 A loose correlation exists between a large number of cortical lesions, developmental delay, and poor seizure control.

In TSC the brain is the most common organ to be affected. Spinal cord and peripheral nerves are always spared. The cerebral manifestations include cortical tubers, cerebral white matter migration tracts, subependymal nodules, and SGCA. Ophthalmic manifestations include retinal astrocytomas, retinal hamartomas, and achromic patches. Retinal astrocytomas are detected in approximately 50% of patients with TSC. They are usually bilateral and multiple. In children they must be differentiated from retinoblastomas.

Adenoma sebaceum (facial angiofibroma) is the most distinctive dermal manifestation (Figure 22-1). These reddish

Tuberous Sclerosis

Facial rash of a 32-year-old woman with tuberous sclerosis complex (TSC) who underwent resection of a subependymal giant cell astrocytoma (SGCA) 9 years previously and remains well in follow-up. Her 10-year-old daughter also has TSC. (Photo used by permission of patient.)

Figure 22-1

Facial rash of a 32-year-old woman with tuberous sclerosis complex (TSC) who underwent resection of a subependymal giant cell astrocytoma (SGCA) 9 years previously and remains well in follow-up. Her 10-year-old daughter also has TSC. (Photo used by permission of patient.)

tecture of the cerebral gray matter is lost. Rarely the cerebellum may be affected.

Magnetic resonance imaging (MRI) is the best diagnostic investigation. It can detect cortical tubers in 95% of patients with TSC. The inner core is usually hypointense to isointense to gray matter on Tl-weighted images and hyperintense on T2-weighted images. The peripheral part is isointense to mildly hyperintense on both Tl- and T2-weighted images.11 Less than 5% of tubers are enhanced with gadolinium (Gd-diethyl tri-amine penta-acetic acid [DTPA]).28 Associated expansion and thickening of cortical gyri and blurring of gray-white matter junctions are important findings. In neonates and in small children normal white matter contains more water and less myeli-nation, so the inner core appears hyperintense in Tl-weighted and hypointense in T2-weighted images.16 Small cortical tubers may be obscured by the partial-volume effect caused by cere-brospinal fluid in hemispheric cisterns. In that situation fluid attenuation inversion recovery (FLAIR) image or magnetic transfer imaging is a better alternative.

Computed tomography (CT) is less sensitive in detecting these lesions. They appear hypodense on CT; calcification may be detected in 54% of cases,3 and occasionally calcification may be gyriform mimicking Sturge-Weber syndrome.63

Figure 22-1

papules appear on the nose, cheeks, and chin in 70% of the affected population. They usually develop between 5 years of age and puberty. Polygonal or ash-leaf shaped hypomelanotic macules are better seen by Wood's lamp (ultraviolet light) and may have been present since birth. Pitting in the teeth is found in 90% of adults with TSC as opposed to 9% of the general population.

Renal cysts occur in children. These may occasionally lead to hypertension and end-stage renal disease. Renal angiolipoma is more often seen in adults. This may give rise to retroperi-toneal hemorrhage19 or renal cell carcinoma.2 Multiple cardiac rhabdomyomas are present at birth and usually regress over time. They may even be diagnosed antenatally by ultrasonog-raphy. Rarely, they cause ventricular outflow obstruction leading to heart failure. Pulmonary lymphangiomyomatosis is a very rare manifestation characterized by the patient's slow decline to end-stage lung disease. There are several case reports of TSC associated with cerebral aneurysm,812 fibrillary astrocytoma,17 and glioblastoma multiforme.16 It is not yet established whether these are incidental findings or there is any causal relationship with TSC.

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