Chapter 578. Phakomatoses

The phakomatoses refer to a variety of neurocutaneous syndromes.1 Almost all are multisystem disorders that are embryonal in origin. Neurofibromatosis type 1 and tuberous sclerosis complex are the most common phakomatoses. These disorders are also discussed in Chapter 182.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, with an estimated incidence of approximately 1 in 3000 live births. It has diverse manifestations in tissues that are primarily, although not exclusively, of neural crest origin. Clinical findings form the basis of the National Institutes of Health Consensus Statement of diagnostic criteria for neurofibromatosis type 1 (Table 578-1).2 The diagnostic criteria are met in an individual if 2 or more of the features listed are present. Clinical, molecular and management aspects of neurofibromatosis 1 are discussed in Chapter 182.

Optic pathway gliomas are the main central nervous system tumor with a marked increased frequency in neurofibromatosis type 1. Because of their growth, it is recommended that all children age 10 years or younger with neurofibromatosis type 1 undergo annual ophthalmologic examinations. When they progress, visual symptoms are produced because the tumors enlarge and put pressure on the optic nerves-chiasm resulting in impaired visual acuity and visual fields. Extension into the hypothalamus can lead to endocrine deficiencies or failure to thrive.

Although more than 50% of individuals with neurofibromatosis type 1 will have only cutaneous neurofibromas, café au lait spots, or Lisch nodules, an estimated 30% to 40% will develop 1 or more of the serious complications in their lifetime. The major categories of these complications are malignancy, learning disability, cerebrovascular disease, hypertension, and scoliosis. Because of the diverse and unpredictable complications associated with neurofibromatosis type 1, close multidisciplinary follow-up is necessary. Patients with neurofibromatosis type 1 should have regular clinical assessment at least yearly, focusing the history and examination on the potential problems for which they are at increased risk. Laboratory tests and imaging studies should be reserved for investigating specific clinical symptoms and signs. Some of the routine follow-up recommended includes yearly clinical assessment with blood pressure monitoring and yearly ophthalmologic examination.

Tuberous sclerosis complex is an autosomal dominant multisystem disease. It usually presents with seizures, mental retardation, and autism. Tuberous sclerosis complex affects the brain, eye, skin, kidneys, and heart. It is estimated to affect 1 in 6000 to 10,000 newborns. The diagnosis of tuberous sclerosis complex is still based on clinical criteria. To make the definite diagnosis of tuberous sclerosis complex an individual must have 2 major features or 1 major feature plus 2 minor features. (See Tables 578-2 and 578-3 for major and minor features.) The non-neurologic clinical manifestations, molecular aspects and management of tuberous sclerosis complex patients is discussed in Chapter 182.

Neurologic Clinical Presentation

The hallmark of tuberous sclerosis complex is the involvement of the brain. This occurs in 95% of affected individuals. The findings in the brain usually take the form of (1) cortical tubers, (2) subependymal nodules, and (3) subependymal giant cell astrocytomas. It is from the cortical tubers that the origin of the name tuberous sclerosis comes. Tubers are made up of a collection of abnormally large neurons and glia. Tubers are most commonly found in the cerebral cortex. The number, size, and location of the tubers vary tremendously among patients with tuberous sclerosis complex. Brain MRI is the best way of identifying cortical tubers. Based on fetal MRI studies, we know that cortical tubers are formed while in utero in the second trimester.3 Subependymal nodules are lesions found along the wall of the lateral ventricles in the brain. In the past they were referred to as “candle guttering” to convey that their appearance is similar to drippings of wax from a candle. These lesions do not cause any problems; however, in 5% to 10% of cases, these benign lesions can grow into subependymal giant cell astrocytomas. Subependymal giant cell astrocytomas can grow and block the circulation of cerebrospinal fluid around the brain and cause hydrocephalus. Median age of ventricular obstruction due to subependymal giant cell astrocytomas is 9 years. Hydrocephalus requires immediate neurosurgical intervention.

Epilepsy is by far the most common medical condition in tuberous sclerosis complex, occurring in 80% to 90% of patients. In about one third of patients, epilepsy starts out as infantile spasms. Infantile spasms are characterized by brief, but often repetitive, muscle contractions, usually involving the head, trunk, and extremities. The spasms often occur in clusters, and there is usually crying associated with these spells. Often, the children may look like they have colic or abdominal discomfort. The EEG often shows “hypsarrhythmia” (high-voltage, that is, 300–400 mV, chaotic disorganized background with multifocal spikes, and slow waves). However, it is important to remember that one can have hypsarrhythmia without infantile spasms and infantile spasms without hypsarrhythmia, especially in tuberous sclerosis complex patients.

Patients with tuberous sclerosis complex can develop partial or generalized seizures. Depending on the seizure type, there are multiple antiepileptic medications available. If the seizures are intractable despite the use of antiepileptic medications, epilepsy surgery can be an option. Individuals with tuberous sclerosis complex have an increased risk of having neurodevelopmental and behavioral impairment. Although approximately 50% of people with tuberous sclerosis complex have normal intelligence, developmental delay and learning disabilities are commonly found in children with tuberous sclerosis complex. Therefore, early intervention with physical, occupational, and speech therapy is highly recommended.

Some of the behavioral disorders that are common in tuberous sclerosis complex include attention deficit hyperactivity disorder (40–60%), autism spectrum disorder (20–58%), oppositional defiant disorder (25%), and sleep disturbance. Autism is a developmental disability that presents with repetitive behaviors and difficulty with communication and social interactions. The relationship between autism and tuberous sclerosis complex has been an intense area of investigation; however, the underlying cause of autism in patients with tuberous sclerosis complex remains unclear. Autism is associated with temporal lobe epileptiform discharges, seizure onset within the first 3 years of life, and history of infantile spasms.4 An American Academy of Neurology practice5 recommends searching for cutaneous abnormalities associated with tuberous sclerosis complex as a part of the diagnostic evaluation for autism.

von Hippel-Lindau disease is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma; and endolymphatic sac tumors. Patients present with headache, vomiting, and gait disturbances or ataxia or vision loss. Its incidence is around 1:36,000. It results from an autosomal dominant mutation affecting a tumor suppressor gene, VHL. Around 80% of individuals with von Hippel-Lindau disease syndrome have an affected parent, and around 20% have a de novo gene mutation. Molecular testing is available and detects mutations in almost 100% of probands.6

Incontinentia pigmenti is a disorder that affects the skin, hair, teeth, nails, eyes, and the CNS. Characteristic skin lesions evolve through several stages, from vesicular to hyperpigmented to hypopigmented. Alopecia, hypodontia, abnormal tooth shape, dystrophic nails, and neovascularization of the retina can be seen. The syndrome is inherited as an X-linked dominant disorder with male lethality and can occur due to mutations in NEMO gene, the only gene known to be associated with incontinentia pigmenti. Clinical molecular testing is available, and in 80% of the affected patients a deletion that removes exons 4 through 10 of NEMO can be detected.7 Differential diagnosis includes hypomelanosis of Ito, which presents with similar skin manifestations.

Sturge-Weber syndrome is thought to be a congenital sporadic condition characterized by a vascular birthmark and neurologic abnormalities. The classic symptom of the disease is a port wine stain, often in the distribution of the first division of the trigeminal nerve. Other symptoms can include angiomas on the surface of the brain leading to seizures and hemiparesis on the side of the body opposite the port wine stain and glaucoma on the side of the port wine stain. Although rare, it is possible for a child to have Sturge-Weber syndrome without a facial port wine stain. It is important to note that if a child does have a facial port wine stain, it doesn’t necessarily mean he or she will have neurologic abnormalities. In fact, only 8% of children with a facial port wine stain have neurologic problems. The disorder is diagnosed from the physical and radiographic findings. Therapy is symptomatic, although early surgical excision (lobectomy or hemispherectomy) is sometimes done in the hopes of preventing intellectual decline associated with intractable epilepsy.

Please see Table 578-4 for a list of other neurocutaneous diseases. These are discussed in other sections of this text.