A 1-year-old girl is brought to a neurologist due to increasing seizure frequency over the past 2 months. She recently underwent a neurology evaluation which revealed hypsarrhythmia on electroencephalography (EEG) with a mix of slow waves, multifocal spikes, and asynchrony. Her parents have noticed the patient occasionally stiffens and spreads her arms at home. She was born at 38-weeks gestational age without complications. She has no other medical problems. Her medications consist of lamotrigine and valproic acid. Her temperature is 98.3°F (36.8°C), blood pressure is 90/75 mmHg, pulse is 94/min, and respirations are 22/min. Physical exam reveals innumerable hypopigmented macules on the skin and an irregularly shaped, thickened, and elevated plaque on the lower back. Which of the following is most strongly associated with this patient's condition?
Cardiac rhabdomyoma
Glaucoma
Optic glioma
Polyostotic fibrous dysplasia
Cardiac rhabdomyoma
This patient with a seizure disorder, ash-leaf spots (innumerable hypopigmented macules), Shagreen patch (elevated irregular plaque on the lower back), and West syndrome (hypsarrhythmia on EEG and movements consistent with infantile spasms) likely has tuberous sclerosis. Tuberous sclerosis is associated with cardiac rhabdomyomas.

Tuberous sclerosis is a neurocutaneous disorder that is inherited in an autosomal dominant fashion. Mutations in TSC1 and TSC2 lead to unregulated cell growth, leading to the formation of hamartomas in various locations. Manifestations of tuberous sclerosis include seizures (secondary to subependymal nodules and cortical dysplasia), mental retardation, renal angiomyolipomas, facial angiofibromas, mitral regurgitation, and hypomelanotic macules (ash-leaf spots). Cardiac rhabdomyoma is strongly associated with tuberous sclerosis and can lead to arrhythmias. West syndrome, which is characterized by infantile spasms, intellectual disability, and hypsarrhythmia (a chaotic mixture of high-amplitude slow waves, multifocal spikes, and intrahemispheric-interhemispheric asynchrony) on EEG, is also associated with tuberous sclerosis. Diagnosis of tuberous sclerosis is made with genetic testing. Advanced imaging (CT or MRI) may reveal cortical tubers and lesions in the third and fourth ventricles. Abdominal imaging may reveal renal angiomyolipomas. The management of seizures in tuberous sclerosis includes anti-seizure medications, though surgery may also be pursued in select cases.

Hinton et al. studied the cardiac manifestations of tuberous sclerosis. They found that cardiac rhabdomyomas can lead to arrhythmia later in life. They recommended that infantile spasms in tuberous sclerosis be treated with vigabatrin but other seizure types should be treated similar to other epileptic disorders.

Incorrect Answers:
Answer B: Glaucoma may occur in patients with Sturge-Weber syndrome, which is characterized by "tram-track" calcifications in the brain, port-wine stains of the face, mental retardation, and epilepsy. Diagnosis is with MRI of the brain with contrast to demonstrate leptomeningeal vascular malformations that are characteristic of the disease.

Answer C: Optic glioma is associated with neurofibromatosis type 1 (NF1), which presents with hyperpigmented macules (cafe-au-lait spots), axillary freckling, and cutaneous neurofibromas. Neurofibromas in NF1 may also grow on peripheral nerves, leading to malignant peripheral nerve sheath tumors. Lisch nodules, or benign growths of the iris, may also be seen in NF1. Diagnosis of NF1 is clinical, but can be aided by genetic testing.

Answer D: Polyostotic fibrous dysplasia is associated with McCune-Albright syndrome. Polyostotic fibrous dysplasia causes fibrous tissue in bones, leading to growth abnormalities and pathologic fractures. McCune-Albright syndrome is also associated with cafe-au-lait macules, which have irregular borders, and endocrine abnormalities such as precocious puberty and hyperthyroidism. Diagnosis is supported with endocrine tests as well as genetic testing.

Answer E: Renal cell carcinoma is associated with Von-Hippel-Lindau syndrome (VHL), which presents with tumors arising in multiple organs. Patients with VHL present with hemangioblastomas in the brain, spinal cord, cerebellum, and retina, and pheochromocytoma. Pheochromocytomas release catecholamines, leading to episodic hypertension, diaphoresis, and palpitations. Diagnosis of VHL is with genetic testing.

Bullet Summary:
Tuberous sclerosis has numerous manifestations including seizures, angiofibromas, mitral regurgitation, renal angiomyolipoma, ash-leaf spots, mental retardation, and cardiac rhabdomyoma.