Multiple cutaneous and uterine leiomyomatosis (Reed's syndrome)
Department of Dermatology, New York University School of Medicine
A 51-year-old woman with a history of uterine fibroids status post myomectomy and hysterectomy presented for evaluation and treatment of intermittently painful papules of the left shoulder. Histopathologic examination showed a proliferation of smooth muscle fascicles consistent with the diagnosis of cutaneous leiomyomas. Genetic sequencing demonstrated a novel mutation in the fumarate hydratase gene that confirmed the diagnosis of Reed's syndrome. A subset of individuals with Reed's syndrome is predisposed to develop a papillary renal-cell carcinoma, so appropriate radiologic examinations should be performed. Treatment of the pain caused by cutaneous leiomyomas includes the use of nifedipine, nitroglycerine, phenoxybenzamine, surgical excision, and carbon dioxide laser ablation.
A 51-year-old woman presented to the Charles C. Harris Skin and Cancer Pavilion for evaluation and treatment of several intermittently painful papules near her left shoulder. She states that she first noticed the growths in 1993 after starting estrogen replacement therapy following an oophorectomy for ovarian cysts. She has developed progressively more papules over the course of the past 11 years; these lesions are occasionally painful after exposure to cold or pressure. Intralesional triamcinolone acetonide injections were not beneficial. Her past medical history includes uterine fibroids with myomectomies in 1979 and 1983 and with a hysterectomy in 1984. She notes that two aunts on her father's side had hysterectomies in their 20's.
On the right posterior and anterior aspects of the shoulder in a dermatomal distribution were several firm, smooth, pink-to-brown papules that coalesced into a plaque. A mechanical stroke elicited pain but not contraction of the papules.
A novel T287P mutation (threonine to proline) was discovered in the fumarate hydratase gene following DNA sequencing. This mutation had previously not been reported in the literature but was not found in more than 55 healthy controls. Abdominal and pelvic computerized tomography scans in January 2004 demonstrated normal appearing kidneys.
Histopathology reveals a relatively well-circumscribed proliferation of spindle-shaped cells that are arranged as interlacing bundles and fascicles. The cells have abundant eosinophilic cytoplasm and elongated nuclei with blunt ends. Mitotic figures are not apparent.
Reed's syndrome is an autosomal dominant disease with incomplete penetrance that is characterized by uterine and cutaneous leiomyomas . It was initially described in 1954 in a 45-year-old woman . Subsequently, others including Reed reported multiple kindreds with similar findings . More recently, an association between Reed's syndrome and papillary renal-cell carcinoma has been elucidated .
The principal dermatologic manifestation of Reed's syndrome is cutaneous leiomyomas. They are benign tumors that are composed of smooth muscle fibers that arise from the erector pili, dartos muscle of genital skin, or smooth muscle of the vasculature. Clinically, leiomyomas appear as skin-colored or pink-brown dermal papules or nodules that range from 0.2 to 2.0 cm in diameter. Their presentation may otherwise be quite variable. They may be isolated or many in number, may develop in adolescence or late adulthood, may be variably distributed or dermatomal, and may be asymptomatic or painful in response to pressure or cold . If painful, they may be quite debilitating. On histolopathogic examination, smooth muscle fiber bundles with varying degrees of intermingled collagen can be seen in the dermis. The smooth muscle fibers are composed of eosinophilic cytoplasm with elongated blunt-ended nuclei with little or no waviness . With immunohistochemical staining, cutaneous leiomyomas, unlike uterine leiomyomas, do not demonstrate estrogen and progesterone receptors .
The predisposition gene for Reed's syndrome has been localized to chromosome 1q42.3-43 and the gene encoding fumarate hydratase. Fumarate hydratase catalyses the conversion of fumarate to malate in the Kreb's cycle but is also thought to act as a tumor suppressor gene . Several different mutations in the fumarate hydratase gene (missense, nonsense, and whole gene deletions) have been described in patients with Reed's syndrome; however, no definite association has been found between the site or type of mutation and the risk for papillary renal-cell carcinoma .
The evaluation of any individual with multiple cutaneous and uterine leiomyomatosis involves a complete history and physical examination. Currently, the National Cancer Institute recommends evaluating all patients with leiomyomatosis for the presence of an occult renal malignancy. Families may also be referred to the National Institute of Health for DNA analysis.
The treatment of cutaneous leiomyomas is dictated by the degree of discomfort or the cosmetic concerns. Camouflage with cosmetics and avoidance of cold may be the only treatment required. Individual lesions, if few in number, may be excised with the possibility of recurrence . Otherwise, medications that block smooth muscle contraction, such as nifedipine, phenoxybenzamine, nitroglycerine, and doxazosin, and medications that target the activity of nerves, such as gabapentin and topical analgesics, have been efficacious in small studies and case reports [9, 10, 11]. A report of pain relief after carbon dioxide laser ablation also has been published .
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