History
The most common feature in patients with multiple piloleiomyomas is pain. Pain can be spontaneous or induced by cold or tactile (eg, pressure) stimuli. The pain or tenderness may be secondary to pressure on nerve fibers within the tumor; however, some authors believe it may be solely due to contraction of muscle fibers. [1]
Many solitary piloleiomyomas are similarly symptomatic.
About 60% of angioleiomyomas are symptomatic. [14] Pain in angioleiomyomas may be due to nerve fibers in the stroma or wall of the tumors or perhaps due to the contraction of blood vessels with local ischemia. [1]
In addition to the previously described trigger factors (ie, temperature and pressure), symptoms are also reported to occur with menses or pregnancy.
Genital leiomyomas are usually asymptomatic solitary lesions arising from the dartoic, vulvar, or mammillary muscles in the genital region or on the nipple. [2]
Physical Examination
Individual piloleiomyomas are smooth, firm papules or nodules, usually smaller than 2 cm in diameter, and reddish brown. Many are tender to palpation. Multiple piloleiomyomas can occur on the face, trunk, or extremities. Various distribution patterns are reported, including bilaterally symmetric, grouped, dermatomal, and linear patterns. [16] A solitary piloleiomyoma is usually found on a lower extremity. Because piloleiomyomas develop in the superficial dermis, they are fixed in the skin. However, they can be easily moved over the deeper subcutaneous tissues.
Upon closer inspection, one can appreciate that these piloleiomyomas are superficial dermal nodules.
Angioleiomyomas are usually well-defined, fairly deep dermal nodules that are smaller than 4 cm. Pain to palpation is not uncommon. Angioleiomyomas are generally solitary and occur predominantly on the lower extremities, less commonly on the head or trunk, and rarely on the hands or in the mouth. [3, 4, 5] The most common clinical presentation of an angioleiomyoma is that of a solitary skin-colored nodule.
Leiomyomas of the vulva or scrotum may be larger than those already described above. Leiomyomas of the nipple and piloleiomyomas are generally similar in size.
Causes
As yet, no mutations have been discovered in association with sporadic piloleiomyomas; however, associated mutations have been discovered for sporadic genital and angioleiomyomas. According to a study in which comparative genomic hybridization was performed in 33 angioleiomyomas, [17] the most recurrent loss of chromosome for angioleiomyoma is found in 22q11.2.
Genital leiomyoma are associated with the following mutations [18, 19] :
-
OCM gene - Codes for a calcium-binding oncoprotein
-
MOS gene - Codes for a proto-oncogene serine/threonine protein kinase
-
RB1CC1 gene - Codes for a key regulator of the tumor suppressor gene RB1, with inv(12) (p12q13–q14), with a rearranged and consequently active HMGA2 gene
Research has revealed the location of the gene for transmission of dominantly inherited, multiple cutaneous piloleiomyomas associated with uterine leiomyomas in female family members. The gene was linked to band 1q42.3-q43. Haplotype construction and recombination analysis narrowed the locus to an approximately 14-centromere interval located between D1S517 on the centromeric side and D1S2842 on the telomeric side. As reported by Alam et al, [20] the locus is termed MCUL1 for multiple cutaneous and uterine leiomyomata (MCUL)‒1.
Studies of an extended family narrowed the locus further to a region of the 4.55-7.17 centromere on chromosome 1. This gene encodes for fumarate hydratase (FH gene), an enzyme of the tricarboxylic acid cycle that acts as a tumor suppressor. In families with multiple cutaneous and uterine leiomyomata (MCUL) and hereditary leiomyomatosis and renal cell cancer (HLRCC), FH missense mutations often occur in fully conserved residues and in residues functioning in the substrate binding A-site, substrate-binding B-site, or subunit-interacting region. All missense mutations in these families are associated with decreased enzyme activity, suggesting that the tumor suppressor role of fumarate hydratase is related to its enzymatic activity. [21]
A study of 108 affected individuals, including 46 probands and 62 affected relatives, revealed that highly penetrant FH mutations underlie MCUL. Of women with FH mutations, 69% had both skin and uterine leiomyomas, 15% had only skin leiomyomas, and 7% had only uterine leiomyomas. [22] Uterine leiomyomas not associated with skin leiomyomas were associated with the G354R FH mutation. Wei et al [23] have so far identified 31 different germline FH mutations in 56 families with HLRCC. Six additional FH mutations have been described among Dutch and Spanish families with MCUL. [24]
Complications
Cosmetic disfigurement can occur in association with the presence of multiple piloleiomyomas.
Pain is present in most cases.
-
These multiple hyperpigmented nodules are piloleiomyomas on an upper extremity.
-
Upon closer inspection, one can appreciate that these piloleiomyomas are superficial dermal nodules.
