Syndrome Synopsis: Tuberous Sclerosis
by Beth A. Pletcher, MD, November 1999

Tuberous sclerosis (TS) is an autosomal dominant disorder that can affect a variety of organs and tissues including the brain, skin, kidneys and heart. As with many dominant conditions, there is wide variability in expression with many relatively asymptomatic individuals identified only when they have a more severely affected child. Furthermore, approximately 2/3 of affected individuals have TS as the result of a new mutation and are therefore the first person in their family with the condition. At least two different genes have been identified that cause TS with one localized to the long arm of chromosome 9 and one on the short arm of chromosome 16. Diagnosis of TS depends, for the most part, on detection of a number of clinical signs and clinicians in 1998 set forth diagnostic guidelines to categorize patients into one of three groups, either definite, probable or possible TS. (For more information see the TS consensus report as referenced below). Clinical findings associated with TS will be outlined below by organ system.

  • Skin: Almost every patient with TS will exhibit some type of cutaneous lesion and therefore this system requires great attention in the diagnostic exam. Frequency of occurrence in TS from most common to least common are: hypomelanotic macules (so called "ash leaf" spots), facial angiofibromas, shagreen patches, fibrous facial plaques and ungual fibromas. Although not technically skin findings, depigmented tufts of hair, tumors of the eyelid, conjunctival nodules and pit-like enamel defects of the teeth are also reported.

  • CNS: The most serious consequences of TS generally result from CNS tumors and include subependymal glial nodules as well as cortical or subcortical tubers. Heterotopias are also frequent incidental findings in individuals with TS. The greater the number of CNS lesions, the greater the likelihood of mental retardation or seizures to occur. A subset of TS patients go on to develop subependymal giant cell astrocytomas which may cause obstructive hydrocephalus and brain damage if not treated. Because of frequent calcification of the cortical and subcortical lesions, CT scan is preferable to MRI in the evaluation of a patient where TS is suspected.

  • Kidneys: Benign renal lesions that may appear during childhood into adulthood include: angiomyolipomas, epithelial cysts and adenomatous hamartomas. Since renal disease is the second leading cause of death in TS patients following CNS abnormalities, it is essential to monitor kidney function in affected individuals throughout their lifetime. A subset of TS patients actually develop full blown polycystic kidney disease with all the morbidity and mortality this entails. Rarely patients with TS develop malignant angiomyolipomas or renal cell carcinoma which requires aggressive therapy.

  • Heart: Although many patients with TS are incidentally found to have cardiac rhabdomyomas, the peak time of diagnosis for these is during early infancy. These lesions may be quite large at birth and in some cases lead to CHF and neonatal death. If one or more rhabdomyomas are present at birth and cause no obstruction of blood flow, they tend to regress with time and would rarely be of any consequence down the line.

  • Eye: Retinal hamartomas (mulberry lesions) are the classic eye lesions of TS, but achromic patches similar to ash leaf spots may also be found on fundoscopic exam.

  • Lungs: Between 1 and 6% of patients with TS develop pulmonary lymphangiomyomatosis, leading to hemoptysis and/or shortness of breath. This occurs most often in women between the ages of 20 and 40 and can lead in some cases to respiratory failure. CXR would usually show a diffuses reticular pattern whereas chest CT would clarify the diffuse cystic changes and interstitial infiltrates.

Minimal work-up for a patient suspected to have TS because of a single initial clinical finding such as ash leaf spots or first degree relative with known TS should include:

  1. Focused medical history looking for TS findings

  2. Focused family history as above

  3. Careful cutaneous exam using a Woods lamp if possible to identify specific skin lesions

  4. Cranial CT

  5. Renal ultrasound

  6. Dilated eye exam by an experienced ophthalmologist who is aware of the diagnostic concerns

  7. Echocardiogram if a murmur is heard or there are cardiac symptoms

  8. Neurodevelopmental assessment

REFERENCE

Roach ES, Gomez MR, Northrup H (1998) Tuberous sclerosis complex consensus conference : Revised clinical diagnostic criteria. J Child Neurology 13:624-628.