A 2-year-old girl was brought to her pediatrician for her well child visit. On exam, she was noted to have several hypomelanotic lesions over her trunk (Figures 205-1 to 205-3). Based on the presence of these lesions, the pediatrician orders an MRI of the brain, which revealed subependymal tubers, which also projected into the ventricles. She was diagnosed with Tuberous sclerosis, and a renal ultrasound and cardiac echocardiogram were obtained, which did not reveal any abnormalities. A multidisciplinary approach to her care was planned and included a pediatric neurologist, developmental pediatrician, and dermatologist.
FIGURE 205-1
Hypomelanotic, or “ash leaf” lesion on the abdomen of a 2-year-old girl found to have tuberous sclerosis. She presented with over five hypomelanotic lesions on exam. This prompted the physician to order an MRI of the brain. Tubers were found to confirm the diagnosis. (Used with permission from Richard P. Usatine, MD.)
FIGURE 205-2
Hypomelanotic, or “ash leaf” lesion on the back of the same child as in Figure 205-1. (Used with permission from Richard P. Usatine, MD.)
FIGURE 205-3
Hypomelanotic or “ash leaf” lesion in axilla of the child in Figure 205-1. (Used with permission from Richard P. Usatine, MD.)
Tuberous sclerosis (also called Tuberous sclerosis complex-TSC) is an inherited neurocutaneous and multisystemic disorder characterized by hamartomas (sclerotic tubers), which most notably affect the skin, brain, kidneys, heart and eyes.1,2 TSC results in a wide spectrum of clinical manifestations and neurologic sequelae.
TSC affects both sexes equally and all ethnic groups.
The prevalence is estimated to be one per 6,000 to 10,000 individuals.3
With one affected parent, the recurrence risk is 50 percent. When both parents appear to be unaffected, the recurrence risk is 1 in 22 after one affected offspring and 1 in 3 after two affected offspring.
Only 7 to 37 percent of newly diagnosed cases have a family history of TSC.
TSC is caused by mutations on two genes, named TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present.
TSC has an autosomal dominant mode of inheritance with almost complete penetrance, but a variable expressivity range in terms of the age of onset, severity of disease, and different signs and symptoms that result from a specific genotype.
The variability is due to multiple causes. These include somatic mosaicism, differences between TSC1 and TSC2 genes, a variety of mutation types found in each gene, and the requirement for a secondary somatic mutation in the wild-type copy of the gene for the development of many pathologic features of TSC.
Approximately 65 percent of cases are caused by a spontaneous mutation.
Molecular genetic studies have identified two loci for TSC—TSC1 is located on the long arm of chromosome 9 (9q34) and TSC2 is located on the short arm of chromosome 16 (16p13.3). These loci encode for hamartin and tuberin, respectively. Hamartin and tuberin are thought to function together as a protein complex or as adjacent steps within the same intracellular pathway, which may explain why the phenotypic expression of either mutation leads to almost identical disease.2,4
Both TSC1 and TSC2 have tumor suppressor activity, which, when not activated, leads to uncontrolled cell cycle progression and the proliferation of hamartomas throughout the body.
Dermatologic manifestations:
Hypomelanotic macules or “ash leaf” spots are found in more than 90 percent of patients with TSC, are evident within the first 2 years of life, and become more evident with age (Figures 205-1 to 205-3). In newborn infants and in fair-skinned individuals, these lesions often are difficult to visualize without the aid of an ultraviolet light (Wood’s lamp).
Facial angiofibromas (adenoma sebaceum) are comprised of vascular and connective tissue elements and are found in approximately 75 percent of patients with TSC. The lesions typically appear during the preschool years in the malar area as small pink to red dome-shaped papules in a “butterfly distribution” (Figures 205-4 to 205-6).
A shagreen or “leather” patch is identified in 20 to 30 percent of patients with TSC. They result from accumulation of collagen, and are typically is found in the lumbosacral area. The lesion presents as an irregularly shaped, grayish-green, or light brown, unevenly thickened plaque with a cobblestone or orange-peel appearance (Figure 205-7).
Periungual and ungual fibromas are smooth, firm, nodular, or fleshy lesions that are adjacent to or underneath the nails. These usually appear later in life and are not typically apparent in the pediatric age-group (Figures 205-8 to 205-10).
Café au lait spots are seen in up to 30 percent of patients with TSC. Most patients have fewer than six lesions whereas patients with neurofibromatosis usually have at least six (see Chapter 206, Neurofibromatosis).
Neurologic manifestations:
There is a wide spectrum of neurological manifestations.
About half of persons with TSC will have normal intellect.
Neurologic complications, when present, are the most common causes of mortality and morbidity, and the most likely to affect the quality of life.
Seizures are the most common neurologic complication and are reported to occur in 75 to 90 percent of patients. These most commonly present as infantile spasms, partial motor seizures, and generalized tonic clonic seizures.3,4
Autism, attention deficit, hyperactivity, and sleep problems are the most frequent behavioral disorders.
Intracranial abnormalities include tubers, subependymal nodules, and subependymal giant cell astrocytomas (Figure 205-11).5
Patients with numerous cortical tubers tend to have more cognitive impairment and more difficulty with seizure control.
Subependymal giant cell astrocytomas develop in about 5 percent of patients and may lead to obstructive hydrocephalus.
Renal manifestations:
Renal complications are the second most common cause of mortality.
The most common renal lesion is an angiomyolipoma, which occurs in approximately 75 to 80 percent of affected children and is usually present in older children and adults. These are benign vascular, smooth muscle, and adipose tissue tumors. The lesions are often multiple and bilateral, and increase in size and number with age.6
Renal cysts are the second most frequent renal manifestation (Figure 205-12). Cysts greater than 4 cm in diameter are more likely to be symptomatic. Presenting features may include flank pain, gross hematuria, or a tender mass.
Cardiac manifestations:
Cardiac rhabdomyomas are usually asymptomatic but can result in outflow obstruction, valvular dysfunction, arrhythmias (especially Wolff-Parkinson-White syndrome), and cerebral thromboembolism.
The most common presentation of cardiac dysfunction is heart failure soon after birth. The lesions often regress over the first few years of life.
Ophthalmologic manifestations:
Retinal hamartomas occur in 40 to 50 percent of patients with TSC and are bilateral in a third of cases. While these are mostly asymptomatic, visual impairment as a result of a large macular lesion do occur in some patients.
Respiratory manifestations:
Pulmonary involvement, as lymphangioleiomyomatosis, occurs in only approximately 1 percent of patients with TSC. This can manifest as spontaneous pneumothorax and progressive lung disease seen mainly in adult females.
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