September 2014 Dermatology CME/CE
An 8-year-old Hispanic female presented to the dermatology clinic with her mother for evaluation of lesions that had been on her face for years. The patient reported that the lesions were asymptomatic.
A review of systems was negative for fever, chills, and weight loss. Her personal and family history was negative for spontaneous pneumothorax, seizures, and cancers of the breast, thyroid, colon, and kidneys.
Physical examination was notable for multiple firm, skin-colored papules on the face, especially on the malar cheeks and nasal dorsum. No lesions were noted on the scalp. Similar papules were found on the mother’s skin.
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Multiple familial trichoepithelioma (MFT) is considered to be a clinical variant of Brooke-Spiegler syndrome (BSS).1 MFT differs from BSS in that it presents only with smooth, round neoplasms, called trichoepitheliomas, whereas BSS is characterized by the presence of trichoepitheliomas in addition to other neoplasms of the cutaneous adnexa, including cylindromas and spiradenomas. Many authors prefer to group MFT and BSS under the unifying term of BSS.
Because MFT and BSS are so rare, the incidence and prevalence are unknown. Grossman et al followed the largest cohort of 67 patients with MFT and BSS.1 Since these conditions are inherited in an autosomal-dominant fashion, males and females are presumably affected equally. These syndromes have been reported most frequently in whites (United States and Europe), but cases have also been observed in Asian and Latino patients.1,2
Both MFT and BSS are caused by mutations of the CYLD gene, a tumor suppressor located on chromosome 16.1 CYLD encodes a deubiquinating enzyme that negatively regulates nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). NF-κB is a transcription factor with anti-apoptotic properties.3
In the presence of a functional CYLD gene that is negatively regulating NF-κB, apoptosis is promoted, thereby preventing uncontrolled cell proliferation.
When the CYLD gene is not functioning properly, NF-κB prevents apoptosis, allowing for the development of adnexal neoplasms. In BSS, CYLD mutations are seen in 80% to 85% of patients, whereas in MFT, this mutation is only seen in 40% to 45% of patients.
Missense mutations leading to amino acid substitutions within the ubiquitin (Ub)-specific protease (USP) domain of the CYLD protein have been reported.4
In the absence of syndromes such as MFT and BSS, trichoepithelioma usually presents as a solitary, skin-colored papule or nodule located most commonly on the nose.4
Other common locations for solitary trichoepitheliomas are the face and upper trunk.4 In the setting of MFT, multiple trichoepitheliomas develop with a predilection for the central face, including the upper lip, nasolabial fold, and eyelids.4,5 Rarely, lesions may develop on the scalp, neck, and trunk.5
The individual papules are round, smooth, firm, and 2 mm to 4 mm on average.5 At times, the center of the papule may be slightly depressed.5 Lesions are often grouped and can become disfiguring. Trichoepitheliomas in the setting of MFT and BSS develop in childhood or around puberty, earlier than seen in solitary trichoepitheliomas.5 Basal cell carcinoma (BCC) has been reported to rarely develop in patients with BSS and MFT.1,4
In contrast to MFT, BSS is characterized by the presence of multiple cylindromas, spiradenomas, trichoblastomas, follicular cysts, and milia, in addition to trichoepitheliomas.
Cylindromas are usually pink, firm, rubber-like tumors seen most commonly on the scalp. In the setting of BSS, cylindromas are often numerous and can sometimes cover the entire scalp, leading them to be referred to as “turban tumors.”5
Cylindromas may also be seen on the face and neck. Spiradenomas and trichoblastomas are clinically nondistinct neoplasms (firm nodules that vary from skin-colored to pink or red); they often require biopsy for diagnosis.
A diagnosis of MFT can be suspected clinically; however, because of its nonspecific clinical features, a biopsy should be performed for confirmation. Histopathologic examination shows trichoepitheliomas to be dermal tumors with multiple nests of basaloid cells.5
These nests tend to show abortive follicular differentiation, with clusters of plump nuclei resembling the cells of the follicular papilla, known as papillary mesenchymal bodies, which is a helpful feature that distinguishes this condition from BCC.5
The stroma tend to resemble the fibrous sheath of a normal hair follicle with concentrically arranged fine collagen fibers and fibroblasts.5 There is usually no stromal retraction as seen in BCC. Keratinous cysts, calcifications, and amyloids may also be seen.5
A few other diagnoses that should be considered when encountering a patient with numerous papules on the face that are skin-colored to pink or red include Birt-Hogg-Dubé (BHD) syndrome, Cowden syndrome, and tuberous sclerosis (TS).
BHD is characterized by trichodiscomas and fibrofolliculomas. Cowden syndrome presents with numerous trichilemmomas of the face, acral keratoses, and mucosal lesions.5 In TS, the pathognomonic adenoma sebaceum are also multiple papules on the face, but these are typically more red-brown in color, and patients often concomitantly present with ash-leaf hypomelanotic macules, periungual fibromas, and collagenomas.
Most patients with TS are usually diagnosed at a young age, as 40% to 60% show signs of mental deficiency and 80% to 90% have seizures or abnormal electroencephalogram findings in early life.5 Patients with TS also often have numerous other extracutaneous findings, including retinal tumors, renal angiomyolipomas, cardiac rhabdomyomas, pulmonary lymphangioleiomyomatoses, and bony abnormalities.5
Although adenoma sebaceum are classically associated with TS, they may rarely be associated with multiple endocrine neoplasia type I (MENI). Because appendageal neoplasms can be difficult to distinguish clinically, a skin biopsy is highly recommended to differentiate between trichoepitheliomas and fibrofolliculomas, trichodiscomas, and adenoma sebaceum.
Depending on the results of histopathologic examination, patients can be referred to the appropriate specialists for monitoring.
There is no medical necessity for treating trichoepitheliomas in the setting of MFT and BSS; however, the lesions can be cosmetically disfiguring, and patients often inquire about treatment options, which are unfortunately limited.
Solitary trichoepitheliomas are often treated by surgical excision, but this is not recommended for MFT and BSS because of the number of lesions seen.
Reports suggest that ablative methods, such as laser or electrosurgical destruction, are occasionally effective, but the procedures usually need to be repeated because lesions tend to recur.5Some authors recommend routine skin examination to monitor for the possible development of secondary BCC.4
Because our patient had relatively few lesions, treatment was not pursued. She and her mother were educated regarding the rare development of BCC, and her mother opted for follow-up as needed.
Audrey Chan, MD, is a pediatric dermatology fellow at Texas Children’s Hospital in Houston.
- Grossmann P, Vanecek T, Steiner P, et al. Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens. Am J Dermatopathol. 2013;35(1):34-44.
- Zhao XY, Huang YJ, Liang YH, et al. Multiple familial trichoepithelioma: report of a Chinese family not associated with a mutation in the CYLD gene and CYLD protein expression in the trichoepithelioma tumor tissue. Int J Dermatol. 2014;53(4):e279-e281.
- Kirshenbaum LA. Bcl-2 intersects the NFκB signaling pathway and suppresses apoptosis in ventricular myoctes. Clin Invest Med. 2000;23(5):322-330.
- Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, Pa.: Elsevier Saunders; 2012:chap 111.
- James WD, Berger T, Elston D. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders Elsevier; 2011:682.