Four-month-old Hispanic boy brought for evaluation because of hypopigmented patches on his skin and a history of seizures. Infant was the product of an uncomplicated pregnancy; born at 40 weeks' gestation to a 16-year-old gravida 1, para 1 mother who received appropriate prenatal care. At birth, he had multiple hypopigmented patches on his face, torso, and extremities. At age 2 months, he was hospitalized for new-onset seizures.
Four-month-old Hispanic boy brought for evaluation because of hypopigmented patches on his skin and a history of seizures. Infant was the product of an uncomplicated pregnancy; born at 40 weeks' gestation to a 16-year-old gravida 1, para 1 mother who received appropriate prenatal care. At birth, he had multiple hypopigmented patches on his face, torso, and extremities. At age 2 months, he was hospitalized for new-onset seizures. Brain MRI scan revealed multiple subependymal and subcortical hamartomas; phenobarbital was prescribed. Echocardiogram and renal ultrasonography both normal. His developmental milestones within normal age ranges. No significant family history reported.
Infant appeared well, robust, and happy. Weight, 7.9 kg (17.4 lb) (90th percentile); height, 62 cm (24.4 in) (25th percentile). Occipitofrontal (head) circumference, 42 cm (16.5 in) (50th percentile). No dysmorphic features. Results of a physical examination unremarkable except for 11 elliptical hypopigmented macules on his face, torso, and extremities.
This patient's neurocutaneous findings suggest tuberous sclerosis, also called tuberous sclerosis complex (TSC). Hypomelanotic macules and brain hamartomas are considered to be among the salient features of this genetic syndrome.
TSC is a rare multisystem genetic disorder characterized by the growth of hamartomatous lesions in different organ systems. Neoplastic growth occurs primarily in the CNS, eyes, kidneys, and skin. The incidence of TSC is estimated to be 1 in 5000 to 10,000 live births.1 The syndrome occurs with equal frequency in girls and boys, and the number of cases does not vary among ethnic groups.2
TSC is inherited as a mendelian autosomal dominant disorder with complete penetrance and a wide spectrum of phenotypic expressions.2 Mutations involving 2 different genes (TSC1 and TSC2) can each produce the phenotype of TSC. Patients with a TSC2 mutation tend to have more severe phenotypic and neurological involvement than do patients with a TSC1 mutation.1 One-third of cases of TSC are familial. Two-thirds of cases are the result of a new dominant mutation in the affected patient.1-3 Prenatal molecular genetic testing using sequence analysis is available to identify a mutation in the fetus if the TSC-causing allele has been identified in an affected family member.2 Prenatal ultrasonography during the third trimester (after 24 weeks' gestation) can also assist in making the diagnosis by identifying cardiac tumors associated with TSC, known as cardiac rhabdomyomas.2
A wide variability in phenotype is seen among patients with TSC and even within families with affected members. The skin is involved in close to 100% of patients with TSC,3 and cutaneous findings and seizure activity in a newborn can be diagnostic clues. However, any organ system can be involved.1,2 For a summary of the primary manifestations in various organ systems, see the Table.
TSC is a clinical diagnosis. The salient features of the disease have been divided into major and minor features. A definite diagnosis of TSC requires the presence of 2 major features or 1 major feature plus 2 minor features. Probable TSC is defined as the presence of 1 major feature plus 1 minor feature, and possible TSC is defined as 1 major feature or 2 or more minor features.4
The major features are:
The minor features include:
Initial evaluation. In a patient in whom TSC is suspected, the initial evaluation requires multidisciplinary assessments from specialists in a variety of fields, including genetics, neurology, ophthalmology, nephrology, and dermatology; specialists in neurosurgery, plastic surgery, and dentistry may also be needed.1 In addition, because patients are at increased risk for endocrine disorders such as hypothyroidism and precocious puberty, evaluation by an endocrinologist may also be required.1,3
It is recommended that the initial evaluation of a patient in whom TSC is suspected include the following:
This patient's brain MRI scan revealed multiple subependymal and subcortical hamartomas. An MRI image from another patient shows typical intracranial hamartomas seen in TSC (Figure).
This MRI scan from another patient shows typical intracranial hamartomas seen in tuberous sclerosis.
Guidelines for ongoing care. At present, there is no cure for TSC. The goal of management is the prevention and treatment of complications associated with TSC. Surveillance guidelines for primary care providers have been established to ensure the optimal ongoing care and treatment of patients with TSC. These consist of the following:
A number of resources are available that can help patients, parents, and health care providers with management issues. These are listed in the Box.
Parental assessment. Thorough evaluation of the biological parents of an affected child with an apparently negative family history of TSC is also recommended. An assessment should include some, if not all, of the following:
Obtaining this information allows for the ascertainment of recurrence risks if the parents have another child.
Most patients with TSC have a normal life expectancy. Prognosis is dependent on the severity of symptoms, degree of organ involvement, and access to proper medical care.5 The increased risk of CNS, pulmonary, and renal neoplasias can shorten the lives of affected patients. Other leading causes of premature death include complications associated with severe mental impairment.2
Tuberous sclerosis is identifiable at birth or shortly thereafter on the basis of the characteristic cutaneous findings and possible development of seizure activity early in life. It is important that this neurocutaneous complex be recognized so that pertinent medical concerns can be promptly addressed.
Resources for Patients With Tuberous Sclerosis
The following national and international support groups and organizations are invaluable resources that can help patients with tuberous sclerosis and their caregivers as well as educate medical personnel about neurocutaneous disorders:
Tuberous sclerosis. UpToDate.
. Accessed July 11, 2008.
Northrop H, Au K. GeneReviews Database. University of Washington, Seattle.
. Updated December 5, 2005. Accessed November 12, 2008.
OMIM. Tuberous sclerosis; TS (#191100).
. Accessed November 12, 2008.
Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex.
J Child Neurol
National Institute of Neurological Disorders and Stroke. NINDS Tuberous Sclerosis Information Page.
. Updated September 9, 2008. Accessed November 12, 2008.
Jones KL, Smith DW.
Smith's Recognizable Patterns of Human Malformation
. 5th ed. Philadelphia: WB Saunders; 1997.