Review Question - QID 220797

This patient who presents with seizures and developmental delay as well as ash leaf spots on his skin most likely has tuberous sclerosis, which is associated with the development of cardiac rhabdomyomas.

Tuberous sclerosis is an autosomal dominant neurocutaneous disorder that can be caused by mutations in the genes on chromosome 9 that produce hamartin or chromosome 16 that produce tuberin. This disease leads to the formation of hamartomas in many tissues and may lead to developmental delay and failure to thrive. Notable hamartomas include cortical "tubers” that are associated with hard-to-control seizures, as well as benign cardiac rhabdomyomas that can lead to flow obstruction. Other tumors include retinal glial hamartomas, renal angiomyolipomas, cutaneous angiofibromas, and periungual fibromas. Characteristic physical exam findings in this disease include hypopigmented macules known as ash leaf spots and patches of localized thickenings called Shagreen patches. This disease is also associated with West syndrome, which presents with early-onset seizures in children.

Curatolo et al. review the evidence regarding the diagnosis and treatment of tuberous sclerosis. They discuss how many of the manifestations of this disease do not present until after 3 years of age. They recommend having a high index of suspicion for these cases with unusual findings.

Figure/Illustration A is a clinical photograph that shows hypopigmented macules (black circles) on the skin known as ash leaf spots. These lesions are characteristically seen in patients with tuberous sclerosis.

Incorrect Answers:
Answer 1: Acoustic neuromas would be seen in neurofibromatosis type 2, which is caused by a mutation in the gene that encodes for the protein merlin on chromosome 22. This disease presents with bilateral vestibular schwannomas, meningiomas, ependymomas, and juvenile cataracts.

Answer 3: Hemangioblastomas would be seen in von Hippel-Lindau disease, which is caused by a mutation in the VHL gene on chromosome 3. This disease also presents with clear cell renal carcinomas, pheochromocytomas, endolymphatic sac tumors, and pancreatic tumors.

Answer 4: Leptomeningeal angiomas would be seen in Sturge-Weber syndrome, which is caused by a mutation in GNAQ signaling that is not inherited. This disease also presents with a nevus flammeus "port-wine stain" and capillary-venous malformation that may occur in the brain and is associated with intellectual disability.

Answer 5: Optic gliomas would be seen in neurofibromatosis type 1, which is caused by a mutation in the gene that encodes the protein neurofibromin on chromosome 17. This disease would also present with café-au-lait macules, neurofibromas, iris hamartomas, and axillary or inguinal freckling.

Bullet Summary:
Tuberous sclerosis can be identified by hypopigmented "ash leaf" macules on the skin and is associated with the development of hamartomas.