A 29-year-old woman presents with multiple firm, skin-colored to reddish-brown papules and nodules on her trunk and upper extremities as shown below.
These lesions are intermittently painful, especially in response to cold or light pressure. She also reports that her mother had similar bumps and was treated for uterine fibroids in her early 30s. The patient is referred to genetics due to concern for a hereditary syndrome.
Which of the following best explains the underlying pathogenesis of this patient’s cutaneous findings?
A. Mutation in MEN1 gene
B. Post-zygotic mutation in the GNAQ gene
C. Inactivation of the fumarate hydratase gene
D. Overactivation of the mTOR pathway
E. Mutation in the CYLD gene
Rationale:
This patient’s clinical picture is consistent with Reed syndrome, also known as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). It is characterized by cutaneous leiomyomas, early-onset uterine fibroids, and an increased risk of aggressive renal cell carcinoma. Dermatologists play a critical role in identifying this syndrome through recognition of the painful, firm dermal papules and nodules.
Correct answer: C. Inactivation of the fumarate hydratase gene
This condition is caused by germline mutations in the fumarate hydratase gene which is a tumor suppressor located on chromosome 1. Loss of FH function leads to accumulation of fumarate, driving pseudohypoxic signaling and tumorigenesis, particularly in the smooth muscle and kidney epithelium.
Incorrect Answers:
A. Mutation in MEN1 gene is associated with Multiple Endocrine Neoplasia type 1, which involves tumors of the parathyroid, pancreas, and pituitary glands. It does not cause painful skin nodules or leiomyomas, and kidney cancer is not a prominent feature of MEN1.
B. Post-zygotic mutation in the GNAQ gene are found in Sturge-Weber syndrome and sporadic port-wine stains which present as capillary malformations.
D. Overactivation of the mTOR pathway can be seen in Tuberous Sclerosis Complex (TSC), which features facial angiofibromas, shagreen patches, and periungual fibromas.
E. Mutation in the CYLD gene is seen in Brooke-Spiegler syndrome, which features cylindromas, trichoepitheliomas, and spiradenomas. This does not present with painful leiomyomas and is not associated with renal malignancy.
Additional reading at Fitzpatrick's Dermatology Chapter 121: Neoplasias and Hyperplasias of Muscular and Neural Origin