This chapter discusses neurocutaneous disorders, or phakomatoses, with an emphasis on neurologic symptoms as a presenting factor. These symptoms may include seizures, weakness, ataxia, or intellectual disabilities.
The tuberous sclerosis complex (TSC) was first described by Désire-Maloire Bourneville in 1880. It is an autosomal dominant multisystemic disease that results in a disruption of cell growth regulation in the brain, heart, kidneys, eyes, skin, and blood vessels. More recent studies estimate an incidence of 1 in 5800 live births. Recent guidelines have updated the clinical diagnostic criteria to include a known pathogenic variant (mutation) in 1 of 2 genes: TSC1 (Online Mendelian Inheritance in Man [OMIM] no. 191100) or TSC2 (OMIM no. 613254). The molecular pathogenesis of TSC is described below.
Table 567-1 summarizes the major and minor clinical diagnostic criteria and additional genetic diagnostic criteria. Most commonly, a diagnosis of TSC is first suspected either prenatally, due to cardiac rhabdomyomas and/or subependymal nodules detected on fetal ultrasound, or in infancy with the onset of seizures or infantile spasms. In 2012, the Tuberous Sclerosis Complex Consensus Group convened to finalize diagnostic criteria and surveillance recommendations and summarized the known incidence of each clinical finding.
TABLE 567-1CLINICAL DIAGNOSTIC CRITERIA FOR TUBEROUS SCLEROSIS COMPLEX (TSC) ||Download (.pdf) TABLE 567-1CLINICAL DIAGNOSTIC CRITERIA FOR TUBEROUS SCLEROSIS COMPLEX (TSC)
|Major Features |
|Angiofibromas (at least 3) or fibrous cephalic plaque |
|Cardiac rhabdomyoma |
|Cortical dysplasias (includes tubers and cerebral white matter radial migration lines) |
|Hypomelanotic macules (at least 3, at least 5 mm in diameter) |
|Multiple retinal hamartomas |
|Pulmonary lymphangioleiomyomatosis (LAM)a |
|Renal angiomyolipoma (at least 2)a |
|Shagreen patch |
|Subependymal giant cell astrocytoma |
|Subependymal nodule |
|Ungual fibroma (at least 2) |
|Minor Features |
|Confetti skin lesions |
|Dental enamel pits (> 3) |
|Intraoral fibromas (at least 2) |
|Multiple renal cysts |
|Nonrenal hamartomas |
|Retinal achromatic patch |
|Genetic Diagnostic Criteria |
|Pathogenic variants in TSC1 or TSC2: nonsense, frameshift, deletion, or missense mutations that result in TSC1 or TSC2 protein inactivation are sufficient to make a definite diagnosis |
|Variants of uncertain significance in TSC1 or TSC2 are not sufficient to make a definite diagnosis |
|10–25% of patients with clinically definite TSC may have negative genetic testing |
Dermatologic findings comprise the most frequent and visible manifestation, with nearly all patients affected by TSC having at least 1 finding. Ninety percent of individuals with TSC have been reported to have 3 or more hypomelanotic macules (“ash leaf spots”) greater than 5 mm in diameter (Fig. 567-1) These typically occur at birth or infancy and, in pale skin, may be seen more clearly with a Wood’s lamp or ultraviolet A (UVA) lighting. It has also been suggested that an ...