Tuberous Sclerosis

TSC is a multisystemic disorder involving the eyes, heart, lung, kidney, brain, and skin (Figure 76-1). The prevalence of TSC is one in 6000 to 10,000 live births. TSC is caused by an autosomal dominant mutation in TSC 1 on chromosome 9q34 or TSC 2 gene on chromosome 16p13. TSC can result from inherited or de novo mutations. TSC 1 and 2 code for hamartin and tuberin, respectively, which form a protein complex involved in the regulation of cell growth. In TSC, there is loss of inhibition of Rheb (a rapamycin) by TSC 1–TSC 2 complex leading to uncontrolled cell growth of hamartomas in multiple organ systems. The diagnosis of TSC is based on clinical findings, and genetic testing is corroborative. The TSC Consensus Conference in 1998 revised the diagnostic criteria (Table 76-1); a patient must have two major features, or one major and two minor features. A patient with one major and one minor feature is diagnosed with probable TSC.

Figure 76-1 Tuberous sclerosis and Sturge-Weber disease.

Table 76-1 Criteria for Tuberous Sclerosis Complex

From Roach ES, DiMario FJ, Kandt RS, et al. Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. J Child Neurol 14:401-407, 1999.

The skin lesions of TSC include hypopigmented macules (“ash leaf spots”), facial angiofibromas (adenoma sebaceum), shagreen patches, and ungual fibromas. Ash leaf spots, which are best seen with a Wood’s lamp, occur in 90% of patients and appear during infancy. Facial angiofibromas first present in preschoolers on the nose and checks and become more prominent in adolescents extending down the nasolabial folds. These skin lesions may be treated with laser therapy. The shagreen patch is a fleshy, raised lesion often located on the lower back in teenagers. Ungual fibromas, a nodular lesion underneath the nail at the cuticle, also appear in teenagers.

Cardiac rhabdomyomas occur in 50% to 70% of infants with TSC. Fetal ultrasound often detects these benign tumors. The tumors may cause dysrhythmias, such as Wolff–Parkinson-White syndrome. Rhabdomyomas are often not treated and may remit spontaneously. However, an arrhythmia may require medical management, or cardiac outlet obstruction may require surgery.

Renal manifestations of TSC include renal cysts, angiolipomas, and renal cell carcinoma (RCC). The renal cysts are detected in infants and children. They may be asymptomatic or cause hypertension or renal failure. Angiolipomas occur in approximately 75% of TSC patients older than 10 years of age. They have abnormal vasculature that is at risk for bleeding, especially if the angiolipoma is larger than 3 or 4 cm. RCC is rare in TSC patients but may occur at a younger age than the general population. Renal disease remains a significant cause of mortality in patients with TSC.

The neurologic manifestations of TSC include tubers, subependymal nodules, and giant cell tumors. Tubers are dysplastic cortical lesions resulting from disrupted proliferation, migration, and differentiation in early fetal life. Tubers are associated with the clinical triad of TSC—seizures, mental retardation, and behavior difficulties. Our appreciation of the significance of tuber count and its use in predicting prognosis has changed. It was once thought that increased tuber count correlated with a worse prognosis. However, the medical data supporting this correlation are quite limited. Current research suggests that the surrounding tissue of the tuber is epileptogenic and not the tuber itself. Subependymal nodules are hamartomas protruding from the ventricle walls. As they grow and calcify, they can obstruct the foramen of Monro, causing hydrocephalus. The symptoms and signs of hydrocephalus include lethargy, change in behavior, emesis, limited upgaze, headaches, and increased seizures. If a subependymal nodules grows to be larger than 1 cm, then it is considered a subependymal giant cell tumor. These are benign, but malignant transformation may occur. Subependymal giant cell tumors obstructing cerebrospinal fluid are surgically removed.

A total of 87% of TSC patients have retinal hamartomas, which are commonly asymptomatic. However, they may cause visual impairments, retinal detachment, or vitreous hemorrhage. The lungs in only adult-aged women may also be affected by TSC. Lymphangiomyomatosis cause shortness of breath, hemoptysis, or a pneumothorax.

Table 76-2 shows the tests and surveillance recommended for TSC.

Table 76-2 Tests and Surveillance Recommended for Tuberous Sclerosis Complex

CT, computed tomography; ECG, electrocardiography; ECHO, echocardiography; EEG, electroencephalography.

The neurologic symptoms of TSC include epilepsy, behavior disturbances, and cognitive difficulties. Approximately 80% to 90% of patients have epilepsy. Infants with TSC are at risk for infantile spasms. The antiepileptic drug of choice for infantile spasms is vigabatrin. The goal of antiepileptic treatment is early seizure control to improve cognitive outcomes. Cognitive impairments range from mild learning disability to mental retardation. The neurobehavioral disturbances include autism and attention-deficit hyperactivity disorder.

Von Hippel–Lindau Disease

VHL disease is a neurocutaneous disorder with benign and malignant tumors of the central nervous system (CNS), retina, ear, and pancreas. The prevalence is one in 39,000 live births. The inheritance pattern is autosomal dominant involving the VHL gene on chromosome 3p25, which codes for a tumor suppressor protein. The disease may also result from de novo mutations. According to the Massachusetts General Hospital Center for Cancer Risk Analysis and VHL Center, patients should be screened for VHL disease if they have a blood relative with VHL disease, have a VHL disease–associated tumor and a family history of VHL disease–associated tumors, or have two or more VHL disease–associated lesions. VHL disease–associated lesions include hemangioblastoma, clear cell renal carcinoma, pheochromocytoma, middle ear endolymphatic sac tumor, epididymal papillary cystadenoma, pancreatic serous cystadenoma, and pancreatic neuroendocrine tumors (Figure 76-2). Individuals with clinical features listed in Box 76-1 should be screened for VHL.

Figure 76-2 von Hippel–Lindau disease.

Hemangioblastomas of the CNS are benign tumors with a rich capillary blood supply that develop most commonly in the second decade. They are the most common lesions in VHL disease. The CNS hemangioblastomas are located most commonly in the brainstem, spinal cord, and cerebellum. They do not metastasize but can apply pressure to adjacent structures and bleed. Treatment is observational, but surgical intervention is necessary with accelerated growth or symptomatic lesions.

Retinal angiomas are hemangioblastomas of the retina or optic nerve that develop during childhood. Complications include hemorrhage leading to glaucoma, vision loss, or retinal detachment. Ophthalmic treatment for retinal lesions includes laser photocoagulation and cryotherapy.

There are many different tumors seen with VHL disease. Table 76-3 shows tests and screening recommended for VHL disease. RCC (clear cell type) is the highest mortality risk factor associated with VHL disease. It rarely develops before 20 years of age. Renal tumors greater than 3 cm are surgically excised. Patients present with hematuria, flank pain, or a palpable mass. Pheochromocytomas are associated with VHL in childhood. They are often asymptomatic with no clinical evidence of increased blood pressure. Endolymphatic sac tumors are papillary cystadenomas located within the posterior temporal bone. These lesions have an extensive vascular supply. Children present with hearing loss, vertigo, nystagmus, and facial muscle weakness. Treatment is surgical. Pancreatic lesions include cysts and serous cystadenomas, which are surgically excised when larger than 3 cm. VHL disease is also associated with asymptomatic papillary cystadenomas of the epididymis and broad ligament.

Table 76-3 Tests and Screening Recommended for von Hippel–Lindau Disease

CT, computed tomography; ENT, ear, nose, and throat; MRI, magnetic resonance imaging; US, ultrasound.

From Maher ER, Neumann HPH, Richard S. Hippel-Lindau disease: A clinical and scientific review. Eur J Human Genetics Mar 9, 2011, 1-7.

Neurofibromatosis Type 1 and 2

The inheritance pattern of neurofibromatosis type 1 (NF-1) is autosomal dominant. The disease is caused by a mutation in a tumor suppressor gene on chromosome 17, which encodes for neurofibromin. It is the most common neurocutaneous disorder (incidence of one per 3000 individuals). To make the diagnosis of NF-1, the patient must have at least two of the criteria shown in Table 76-4.

Table 76-4 Diagnostic Criteria of Neurofibromatosis-1

NF, neurofibromatosis.

Neurofibromas are benign Schwann cell tumors of the peripheral nervous system. The subcutaneous and cutaneous neurofibromas may be asymptomatic, cause cosmetic deformity, or cause pruritus or pain (Figure 76-3). Spinal neurofibromas cause sensory and motor deficits. Plexiform neurofibromas involve multiple nerve fascicles and grow along the length of the nerve. They may invade surrounding tissue (muscle, bone, and internal organs). Plexiform neurofibromas cause pain and neurologic deficits. They may transform into spindle cell sarcomas or malignant peripheral nerve sheath tumors, which have a poor prognosis. Optic gliomas occur in approximately 15% to 25% of patients with NF-1 during childhood. Patients present with visual acuity impairment, visual field loss, optic disc swelling, strabismus, or proptosis. NF-1 is also associated with moyamoya disease (vascular abnormality within the brain), cardiac malformations, and renal arterial stenosis. NF-1 patients may have mild behavior and cognitive difficulties. Treatment management involves analgesics for the pain associated with neurofibromas, symptomatic neurofibroma resections by soft tissue surgeons and neurosurgeons, yearly evaluations for scoliosis, annual ophthalmologic examinations for optic pathway gliomas, magnetic resonance imaging (MRI) surveillance scans for diagnosed gliomas, hypertension management, and orthopedic surgery for bone deformities.

Figure 76-3 Neurofibromatosis type 1.

The inheritance pattern of neurofibromatosis type 2 (NF-2) is autosomal dominant. It results from a mutation in a tumor suppressor gene on chromosome 22, which codes for neurofibromin-2. NF-2 is diagnosed if a patient has at least one of the following:

Patients often present with deafness or tinnitus. Others have facial numbness, facial weakness, headaches, vertigo, or ataxia. They may also have café-au-lait lesions similar to NF-1. A workup for NF-2 involves an MRI with contrast of the internal auditory canal and brain. Genetic testing is available. A hearing test should also be performed.

Sturge-Weber Syndrome

SWS is a congenital disorder with an unknown cause. It is characterized by skin angiomas known as port-wine stains and leptomeningeal angiomas. The port-wine stain often involves the V1 and V2 distribution of the trigeminal nerve. The majority of children with facial port-wine stains do not have SWS, especially if they are limited to the midline of the forehead (“stork bite” birth mark). However, involvement of the upper and lower eyelid has a greater association with leptomeningeal angiomas than involvement of the upper eyelid alone. Port-wine stains may also involve the trunk and extremities. These lesions are present at birth and become hyperpigmented and larger with age. Leptomeningeal angiomas occur ipsilateral to the facial angiomas. Venous angiomas form in the pia mater and cause venous congestion leading to parenchymal hypoxia, hemispheric atrophy, and parenchymal calcifications. MRI of the brain is the study of choice to diagnose leptomeningeal angiomas. However, it should be noted that MRI findings may not be apparent at birth, so if a child is stable, the MRI should be done after 1 year of age. However, an MRI in infancy is recommended if seizures, ocular findings, or hemiparesis is present.

The clinical presentation of SWS involves seizures (mostly symptomatic partial seizures), port-wine stains, vision loss caused by glaucoma or other vascular abnormalities of the eye, a visual field cut caused by leptomeningeal angiomas and parenchymal calcifications, and mental retardation. Children may also have strokelike episodes secondary to thrombosis within the leptomeningeal angioma or hypoxia. Hemiparesis and limb atrophy on the contralateral side of the leptomeningeal angioma often develop with the onset of seizures. Patients are also at risk for hydrocephalus secondary to venous congestion. Treatment involves laser therapy of the port-wine stains, antiepileptics for seizures, ophthalmic surgery or medical management of glaucoma, physical therapy for hemiparesis, and special educational programs for mental retardation. Occasionally, surgical treatment of refractory epilepsy is necessary. Management of recurrent strokes is problematic and no clear consensus has been reached.