REVIEW Pediatric Dermatology 1–7, 2015
Pediatric Lichen Sclerosus: A Review of the Epidemiology and Treatment Options Lana X. Tong, B.A.,*,† Grace S. Sun, M.D.,‡ and Joyce M.C. Teng, M.D., Ph.D‡ *David Geﬀen School of Medicine at the University of California, Los Angeles, Los Angeles, California, †Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts, ‡Department of Dermatology, Stanford University, Palo Alto, California
Abstract: Lichen sclerosus (LS) is a rare, chronic, inflammatory disease of the skin that primarily affects postmenopausal women but may occur in men and children as well. Approximately 7% to 15% of cases are believed to occur in children. The epidemiologic data for LS have been limited and treatment options are not well studied, particularly in children. We reviewed new developments available in the current literature on the epidemiology and management of LS for children.
Lichen sclerosus (LS), also known as lichen sclerosus et atrophicus, is a rare, chronic, inﬂammatory disease that primarily aﬀects the anogenital region. It is a complex skin condition, with many genetic, physiologic, and environmental factors contributing to its pathogenesis. First described by Hallopeau in 1887 (1), LS is considered to be an autoimmune disease, although its etiology is controversial and remains unclear (2). LS is known to be associated with other autoimmune conditions, such as alopecia areata, autoimmune thyroiditis, vitiligo, and pernicious anemia (3). LS is more common in women than men, usually presenting in the ﬁfth or sixth decade of life. Approximately 7% to 15% of cases occur in children (4,5). It usually presents with atrophic or ivory-white patches, ecchymoses, and sclerosis. Chronic pruritus and subsequent excoriation lead to superﬁcial erosions and hyperkeratosis. As the disease progresses, ﬁssures, superinfection, and symmetric hypermelanosis may also occur (2). Because of scarring in severe disease, labial resorption, burying of the clitoris, and
introitus narrowing can be observed in girls and women and urethral strictures in boys and men. Scarring of the vaginal introitus results in adhesions, and the vagina becomes susceptible to tearing because of a lack of elasticity (6). Sexual activity may become diﬃcult or cause signiﬁcant distress. LS has also been associated with the development of squamous cell carcinoma (SCC). Extragenital symptoms have been observed in 11% of patients (7). Therefore accurate diagnosis and appropriate treatment are crucial. Epidemiologic data are diﬃcult to gather because patients tend to present to many diﬀerent specialists, such as dermatologists, pediatricians, gynecologists, and urologists. There are also a wide variety of treatment options available, which can lead to improper treatment regimens, particularly in children. METHODS We searched PubMed for published studies from 1970 to August 2014 on the epidemiology and treatment
Address correspondence to Joyce M.C. Teng, M.D., Ph.D., 700 Welch Road, 301 G, Palo Alto, CA 94304, or e-mail: [email protected]
© 2015 Wiley Periodicals, Inc.
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options available for LS using the search strings “lichen sclerosus,” “lichen sclerosus et atrophicus,” “children,” “pediatric,” “treatment,” “epidemiology,” “management,” and “therapy.” These categories included the subterms “lichen,” “sclerosus,” “atrophicus,” “therapeutic,” “therapeutics,” “child,” and “pediatrics.” Only articles written in English were included. Bibliographies were examined for additional articles meeting inclusion criteria. Sixty-six articles were reviewed for this article. Grades of evidence used to evaluate the existing data for each treatment option for LS (Table 1) were based on the criteria determined by the Institute for Clinical Systems Improvement (8). Level Ia refers to evidence from meta-analyses of randomized controlled trials (RCTs); Ib refers to evidence from at least one RCT; IIa refers to evidence from at least one non-RCT; IIb refers to at least one experimental study; III refers to evidence from case, correlation, or comparative studies; and IV refers to evidence from expert opinions.
Epidemiology and Etiology LS has an estimated prevalence of 1:60 to 1:1,000 in adults and children in the United States (2,9). Its true prevalence is diﬃcult to estimate because many patients are asymptomatic and may also be hesitant to report their condition, in addition to a frequent incidence of misdiagnosis (10). The etiology of LS is complex and probably multifactorial. Because of its association with other autoimmune diseases, such as alopecia areata and thyroid disease, and a family history of autoimmune conditions, it is thought that the pathogenesis of LS is possibly autoimmune with underlying genetic predisposition, which recent studies have supported (11,12). Thyroid disease has been shown to have a prevalence in LS patients 5 to 30 times greater than in the general population. LS has been shown to run in families, and human leukocyte antigen DR and DQ haplotypes are thought to play a role in pathogenesis (13).
TABLE 1. Summary of Treatment Options for Pediatric Lichen Sclerosus (LS) Treatment option
Anti-inﬂammatory Vasoconstrictive Occlusive
Topical immune modulators
Burning sensation Black box warning of skin
Chi et al (37) Focseneanu et al (38) Kiss et al (43) Fischer and Rogers (39) Garzon and Paller (40) Vincent and Mackinnon (41) Jørgensen and Svensson (42) Smith and Quint (44) Chi et al (37) Goldstein et al (46) Hengge et al (47) Matsumoto et al (49)
Antiinﬂammatory Antiproliferative Normalization
cancer and lymphomas
of epithelial keratinocyte diﬀerentiation
Topical androgens, estrogen, progesterone
Skin atrophy Hypopigmentation Burning sensation Irritation Adrenal suppression
Tissue strengthening Increased capillary
Dry skin Arthralgias, back pain Hyperglycemia,
dyslipidemia Tinnitus Visual disturbance Increased intracranial pressure Inﬂammatory bowel disease Teratogenicity Depression, suicidal ideation
Acne Clitoromegaly Hirsutism Irregular menstruation
Level of evidence in children and adults* Ib; Ia (supportive)
IIa; Ia (supportive)
Bousema et al (50) Ioannides et al (51) Niinimaki et al (52) Virgili et al (53)
III; Ib (supportive) (adults)
Val and Almeida (34) Chi et al (37) Friedrich (54)
III; Ia (nonsupportive) (adults)
ﬁbroblast proliferation *Grades of evidence used to evaluate the existing data for each treatment option for LS were based on the criteria determined by the Institute for Clinical Systems Improvement (6). Level Ia refers to evidence from meta-analysis of randomized controlled trials (RCTs); Ib refers to evidence from at least one RCT; IIa refers to evidence from at least one non-RCT; IIb refers to at least one experimental study; III refers to evidence from case, correlation, or comparative studies; and IV refers to evidence from expert opinions.
Tong et al: Treatment and Epidemiology of Pediatric Lichen Sclerosus
Furthermore, LS has been associated with high levels of basement membrane zone immunoglobulin G antibodies in children and adults (14). Lesions have also been shown to overexpress tumor suppressor proteins such as p53 and proliferation markers (Ki67, minichromosome maintenance protein 3), which may reﬂect a greater risk of malignant transformation (15). As with other autoimmune conditions, LS presents more commonly in women. Approximately 7% to 15% of LS cases are thought to occur in children (5), presenting as early as the ﬁrst few years of life. The bimodal distribution of incidence in postmenopausal women and young children are thought to be correlated with low estrogen states in individuals of these ages (2). A higher incidence of Turner’s syndrome and kidney disease have also been noted, suggesting that low estrogen states might be a contributing factor in the etiology of LS (16), although more in-depth studies are needed. Some vulvar LS lesions have also been found to have low levels of androgen receptors (17), with another study suggesting low 5-a reductase levels (18). It is unclear whether there is an association between LS and infectious etiologies such as hepatitis C virus and Borrelia burgdorferi (19). Other possible triggers include trauma, enhanced oxidative stress, and immunocytologic changes such as extracellular matrix protein 1 autoantibodies (20). Clinical Characteristics The presentation of LS may vary between children and adults. In children, LS tends to present with vulvar purpura or ecchymosis with petechia and erosions, which can be mistaken for sexual abuse. Patients typically complain of irritation and soreness. Urinary symptoms, constipation, and behavioral problems are especially common in children (10). There are also diﬀerences between the sexes in terms of clinical features. In girls, the anogenital region is frequently aﬀected. In boys, the glans, foreskin, and urethra are usually involved, but the perianal area is often spared (21,22). LS may also be associated with phimosis in boys, with one prospective study by Kiss et al (23) demonstrating LS in 40% of phimosis cases, most frequently in boys ages 9 to 11 years old. Risk of SCC Girls with LS are also at risk of vulvar SCC if LS persists past puberty. LS does not carry a risk of SCC during childhood. The incidence of vulvar SCC for women in Western countries is 1.5 per 100,000 (24). In
girls and women with LS, the risk is thought to be approximately 4% to 5%, with some studies reporting an incidence of up to 7% (4,25). Approximately 60% of vulvar SCC appears to be associated with LS, particularly in individuals without human papillomavirus (HPV) infections. Penile and pseudohyperplastic SCC is also associated with LS in boys, mostly in uncircumcised patients (26,27). There is wide variation in the incidence of penile SCC in boys with LS, ranging from 2% to 50%; the exact incidence is unclear because fewer cases are reported (21). Association with Morphea LS sometimes coexists with linear scleroderma or morphea, another autoimmune connective tissue disease, which is also more common in women and girls (28). Both diseases have been strongly associated with other autoimmune conditions and have similar histopathologic ﬁndings (29). It is thought that LS occurs more frequently in people with morphea than the general population (30). One study demonstrated an incidence of 5.7% of LS in adults and children with morphea (odds ratio 18.1; 95% conﬁdence interval 2.6, 134.2; p < 0.001) (31). Extragenital LS occurs more frequently with morphea and is often detected after initial diagnosis with morphea. Furthermore, 25.9% of patients developed extragenital LS at the same site of a previous morphea lesion, suggesting that Koebner’s phenomenon may play a role as a trigger of LS . The two conditions can also be difﬁcult to distinguish diagnostically (32). Furthermore, the familial coexistence of LS and morphea has been shown, supporting the hypothesis of a possible shared genetic predisposition to these conditions (33), although the association between the entities remains unclear. Nonetheless, a complete skin examination is warranted when one of the two disorders is diagnosed. Treatment The management of LS is primarily medical and focuses on symptomatic relief and reduction in atrophy, scarring, strictures, and prevention of malignant transformation. It remains controversial whether treating asymptomatic patients will prevent the development of SCC (34). First-line therapies consist of topical corticosteroids and immune modulators (35), but few large-scale studies or RCTs of LS treatment have been performed in children. The primary therapies of LS are summarized in Table 1. Treatment failure occurs frequently in children and is usually secondary to behavioral problems or parental anxiety
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(2). Extensive counseling and reassurance for patients and parents are critical when treating children. Other symptoms associated with LS include pruritus, pain, and discomfort. Antihistamines, such as diphenhydramine and hydroxyzine, should be used for any pruritus (35). Persistent pain can be managed using tricyclic antidepressants (amitriptyline, desipramine), gabapentin, or serotonin reuptake inhibitors (ﬂuoxetine) (35). It is also important to implement strict moisturizing practices to reduce irritation. If symptoms do not improve, biopsy may be considered to conﬁrm the diagnosis. Generally, precautions such as using hypoallergenic soap, avoiding scratching, and wearing loose cotton underclothing are recommended. Topical Corticosteroids High-potency topical corticosteroids are typically used in the treatment of LS because of their antiinﬂammatory eﬀects. The most commonly used agents include clobetasol propionate and betamethasone valerate (35). LS is generally responsive to ultrapotent topical steroids, and steroids have been shown to reverse some histologic changes seen in LS (2,4,36). Ointments are the preferred vehicle because they have a low rate of contact dermatitis and good penetrance (35). Dosing ranges from weekly application to twice daily, and various regimens are recommended (34). A 2011 Cochrane Review by Chi et al (37) examined seven RCTs investigating the eﬃcacy of common treatments for LS in adults but was unable to draw conclusions in children. They found that clobetasol propionate cream 0.05% was signiﬁcantly more eﬀective than placebo in reducing symptoms and inducing remission. In children, clobetasol ointment 0.05% was eﬃcacious in the treatment of pediatric LS in a study of 36 girls, with 75% achieving complete response and 25% achieving partial response (38). Clobetasol cream and ointment have been shown to be eﬀective in several other case series as well (39–42). An RCT examining the eﬃcacy of mometasone furoate ointment 0.05% in 40 boys with LS found clinical improvement in 40% (43). Because of the recalcitrant nature of the condition, topical treatments are often administered using a tapering regimen. In a case series by Smith and Quint (44), clobetasol ointment was initiated twice daily for 2 weeks, then once daily for 2 weeks, followed by midpotency triamcinolone ointment 0.1% twice daily for 2 weeks, then daily for 2 weeks, and subsequent hydrocortisone ointment use as needed. The schedule
was found to be eﬀective in 93% of the children treated. Other regimens from a separate study recommended clobetasol propionate or mometasone furoate ointment once daily for 1 month, then the treatment was reduced to three times weekly the second month and twice weekly the third month. Maintenance treatment is often needed weekly for years to prevent ﬂares (34). Side eﬀects of corticosteroids include skin atrophy, risk of superinfection, xerosis, hypopigmentation, burning, irritation, and rarely, suppression of the hypothalamic–pituitary axis (44). Although there have been theoretical concerns of greater risk of side eﬀects in children because of the potential risk of greater absorption through their thinner skin, the use of topical steroids has been shown to be safe in children. LS typically does not occur on the hairbearing skin of the vulva; mucosal skin is particularly resistant to atrophy and can tolerate the application of ultrapotent topical steroids. Symptoms may recur upon cessation of corticosteroid application, so maintenance therapy is frequently recommended, which may vary by patient. Topical Immune Modulators Topical calcineurin inhibitors (TCIs) such as tacrolimus and pimecrolimus can also be used in the management of LS. They are antiinﬂammatory and immunomodulating, selectively inhibiting cytokine secretion such as interferon-c and interleukins 2, 4, and 10. Their advantage is thought to lie in less immunosuppression and risk of dermal atrophy than with corticosteroids. Although several case reports have demonstrated their eﬃcacy (41,45), larger-scale clinical trials and data are limited. The primary side eﬀect of TCIs is a burning sensation during application when ﬁrst initiating treatment that tends to resolve with continued use (34). The ideal dosage and duration of treatment is unknown. In the 2011 Cochrane Review, although pimecrolimus was shown to be as eﬀective as clobetasol propionate in reducing pruritus, it was signiﬁcantly less eﬀective at improving overall symptoms (37,46). A phase II trial using topical tacrolimus in 85 patients ranging in age from 5 to 85 years found complete remission in 43% and partial remission in 34% (47). TCIs are not approved for patients younger than 2 years of age. Furthermore, the black box warning of a possible causal association with lymphoma and skin cancer can be a deterrent to parents (48). The use of TCIs in the treatment of LS is oﬀlabel and is signiﬁcantly more expensive than topical
Tong et al: Treatment and Epidemiology of Pediatric Lichen Sclerosus
corticosteroids. This may present a problem in terms of insurance coverage if the results are not superior to that of topical steroids, but a case report by Matsumoto et al (49) describes a 5-year-old girl who responded to tacrolimus ointment 0.03% after failing treatment with topical steroids. Other Treatments Oral retinoids (etretinate, isotretinoin, acitretin) have been demonstrated to have eﬃcacy in treating recalcitrant cases of LS in adults (50–53). By activating nuclear retinoic acid receptors, retinoids are thought to work through subsequent inhibition of interleukin 6, interferon-c, and migration inhibitory factor–related protein 8, which reduces inﬂammation and cell proliferation. Because of an extensive side eﬀect proﬁle, including teratogenicity, the use of systemic retinoids should be limited to recalcitrant cases in adults. Topical androgens, estrogen, and progesterone have also been used for their ability to strengthen tissue, increase capillary perfusion, and stimulate ﬁbroblast proliferation (34,54), but the 2011 Cochrane Review found that they were not eﬀective in treating LS and the authors did not recommend their use in children (37). Associated side eﬀects include acne, clitoromegaly, irregular menstruation, hirsutism, and other signs of virilization. Other treatments that have been mentioned in the literature but do not have signiﬁcant supporting data include antimalarials (hydroxychloroquine, chloroquine) (55,56), stanazolol (57), calcitriol (58), potassium para-aminobenzoate (59), narrowband ultraviolet B therapy (60), cryotherapy, cyclosporine, oxatomide, psoralen plus ultraviolet A therapy, antibiotics, and other types of phototherapy, such as photodynamic therapy in conjunction with topical 5aminolevulinic acid solution 20% (61). Surgical Treatment Surgical intervention may be necessary in cases with signiﬁcant disease progression, particularly if anatomic distortion is observed (62). Vulvectomy in adults is not indicated unless malignancy is observed. Surgery typically plays a more signiﬁcant role in penile LS, in which circumcision may be helpful in managing early LS in boys (63). Surveillance After resolution of acute symptoms, long-term followup is recommended because the clinical course in
children is often unpredictable (16,64–66). LS does not usually resolve after puberty but oftentimes will improve (10). If the disease persists past puberty, patients should be closely monitored because they are at greater risk of SCC. Follow-up with a dermatologist is suggested annually until the patient is 18 years old, after which he or she may follow up yearly in primary or secondary care, such as gynecology, if the condition is no longer active (2). If the patient begins to reexperience symptoms, he or she should be referred back to dermatology. Patients should also be counseled regarding self-examination and educated regarding their risk of malignancy. Although LS often remits after treatment, any scarring acquired during periods of activity is permanent. CONCLUSION LS is a chronic, debilitating disease that may have tremendous ramiﬁcations for health and quality of life. Prompt diagnosis and aggressive therapy is warranted to reduce the morbidity and mortality associated with the disease. Further investigation regarding the prevalence of the condition in children and large-scale clinical studies examining the risks and beneﬁts of diﬀerent treatments in children are greatly needed. The possibility of recurrence should be kept in mind even after remission, and regular follow-up is strongly encouraged. REFERENCES 1. Klaber R. Lichen Sclerosus et Atrophicans (Hallopeau). Proc R Soc Med 1937;30:977–979. 2. Murphy R. Lichen sclerosus. Dermatol Clin 2010;28:707–715. 3. Harrington CI, Dunsmore IR. An investigation into the incidence of auto-immune disorders in patients with lichen sclerosus and atrophicus. Br J Dermatol 1981;104:563–566. 4. Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet 1999;22:1777–1783. 5. Sahn EE, Bluestein EL, Oliva S. Familial lichen sclerosus et atrophicus in childhood. Pediatr Dermatol 1994;11:160–163. 6. Neill SM, Tatnall FM, Cox NH. Guidelines for the management of lichen sclerosus. Br J Dermatol 2002;147:640–649. 7. Thomas RH, Ridley CM, McGibbon DH et al. Anogenital lichen sclerosus in women. J R Soc Med 1996;89:694–698. 8. Greer N, Mosser G, Logan G et al. A practical approach to evidence grading. Jt Comm J Qual Improv 2000;26:700–712. 9. Nelson DM, Peterson AC. Lichen sclerosus: epidemiological distribution in an equal access health care system. J Urol 2011;185:522–525.
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10. Powell J, Wojnarowska F. Childhood vulvar lichen sclerosus: an increasingly common problem. J Am Acad Dermatol 2001;44:803–806. 11. Sherman V, McPherson T, Baldo M et al. The high rate of familial lichen sclerosus suggests a genetic contribution: an observational cohort study. J Eur Acad Dermatol Venereol 2010;24:1031–1034. 12. Dendrinos ML, Quint EH. Lichen sclerosus in children and adolescents. Curr Opin Obstet Gynecol 2013;25:370–374. 13. Gao XH, Barnardo MC, Winsey S et al. The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated DRB10301/04/ DQB10201/02/03 haplotype protects from vulval lichen sclerosus. J Invest Dermatol 2005;125:895–899. 14. Baldo M, Bhogal B, Groves RW et al. Childhood vulval lichen sclerosus: autoimmunity to the basement membrane zone protein BP180 and its relationship to autoimmunity. Clin Exp Dermatol 2010;35:543–545. 15. Gambichler T, Kammann S, Tigges C et al. Cell cycle regulation and proliferation in lichen sclerosus. Regul Pept 2011;167:209–214. 16. Lagerstedt M, Karvinen K, Joki-Erkkila M et al. Childhood lichen sclerosus—a challenge for clinicians. Pediatr Dermatol 2013;30:444–450. 17. Taylor AH, Guzail M, Al-Azzawi F. Diﬀerential expression of oestrogen receptor isoforms and androgen receptor in the normal vulva and vagina compared with vulval lichen sclerosus and chronic vaginitis. Br J Dermatol 2008;158:319–328. 18. Friedrich EG Jr, Kalra PS. Serum levels of sex hormones in vulvar lichen sclerosus, and the eﬀect of topical testosterone. N Engl J Med 1984;310:488–491. 19. Eisendle K, Grabner T, Kutzner H et al. Possible role of Borrelia burgdorferi sensu lato infection in lichen sclerosus. Arch Dermatol 2008;144:591–598. 20. Saunders NA, Haefner HK. Vulvar lichen sclerosus in the elderly: pathophysiology and treatment update. Drugs Aging 2009;26:803–812. 21. Depasquale I, Park AJ, Bracka A. The treatment of balanitis xerotica obliterans. BJU Int 2000;86:459–465. 22. Laymon CW. Lichen sclerosus et atrophicus and related disorders. AMA Arch Derm Syphilol 1951;64:620–627. 23. Kiss A, Kiraly L, Kutasy B et al. High incidence of balanitis xerotica obliterans in boys with phimosis: prospective 10-year study. Pediatr Dermatol 2005;22:305–308. 24. Giles GG, Kneale BL. Vulvar cancer: the Cinderella of gynaecological oncology. Aust N Z J Obstet Gynaecol 1995;35:71–75. 25. Powell J, Robson A, Cranston D et al. High incidence of lichen sclerosus in patients with squamous cell carcinoma of the penis. Br J Dermatol 2001;145:85–89. 26. Nasca MR, Innocenzi D, Micali G. Penile cancer among patients with genital lichen sclerosus. J Am Acad Dermatol 1999;41:911–914. 27. Pugliese JM, Morey AF, Peterson AC. Lichen sclerosus: review of the literature and current recommendations for management. J Urol 2007;178:2268–2276.
28. Lis-Swiety A, Mierzwinska K, Wodok-Wieczorek K et al. Co-existence of lichen sclerosus and localized scleroderma in female monozygotic twins. J Pediatr Adolesc Gynecol 2014;27:e133–e136. 29. Uitto J, Santa Cruz DJ, Bauer EA et al. Morphea and lichen sclerosus et atrophicus. Clinical and histopathologic studies in patients with combined features. J Am Acad Dermatol 1980;3:271–279. 30. Lutz V, Frances C, Bessis D et al. High frequency of genital lichen sclerosus in a prospective series of 76 patients with morphea: toward a better understanding of the spectrum of morphea. Arch Dermatol 2012;148:24–28. 31. Kreuter A, Wischnewski J, Terras S et al. Coexistence of lichen sclerosus and morphea: a retrospective analysis of 472 patients with localized scleroderma from a German tertiary referral center. J Am Acad Dermatol 2012;67:1157–1162. 32. Pope E, Laxer RM. Diagnosis and management of morphea and lichen sclerosus and atrophicus in children. Pediatr Clin North Am 2014;61:309–319. 33. Farrell AM, Marren PM, Wojnarowska F. Genital lichen sclerosus associated with morphoea or systemic sclerosis: clinical and HLA characteristics. Br J Dermatol 2000;143:598–603. 34. Val I, Almeida G. An overview of lichen sclerosus. Clin Obstet Gynecol 2005;48:808–817. 35. Bercaw-Pratt JL, Boardman LA, Simms-Cendan JS. Clinical recommendation: pediatric lichen sclerosus. J Pediatr Adolesc Gynecol 2014;27:111–116. 36. Bracco GL, Carli P, Sonni L et al. Clinical and histologic eﬀects of topical treatments of vulval lichen sclerosus. A critical evaluation. J Reprod Med 1993;38:37–40. 37. Chi CC, Kirtschig G, Baldo M et al. Systematic review and meta-analysis of randomized controlled trials on topical interventions for genital lichen sclerosus. J Am Acad Dermatol 2012;67:305–312. 38. Focseneanu MA, Gupta M, Squires KC et al. The course of lichen sclerosus diagnosed prior to puberty. J Pediatr Adolesc Gynecol 2013;26:153–155. 39. Fischer G, Rogers M. Treatment of childhood vulvar lichen sclerosus with potent topical corticosteroid. Pediatr Dermatol 1997;14:235–238. 40. Garzon MC, Paller AS. Ultrapotent topical corticosteroid treatment of childhood genital lichen sclerosus. Arch Dermatol 1999;135:525–528. 41. Vincent MV, Mackinnon E. The response of clinical balanitis xerotica obliterans to the application of topical steroid-based creams. J Pediatr Surg 2005;40:709–712. 42. Jorgensen ET, Svensson A. The treatment of phimosis in boys, with a potent topical steroid (clobetasol propionate 0.05%) cream. Acta Derm Venereol 1993;73:55–56. 43. Kiss A, Csontai A, Pirot L et al. The response of balanitis xerotica obliterans to local steroid application compared with placebo in children. J Urol 2001;165:219–220. 44. Smith YR, Quint EH. Clobetasol propionate in the treatment of premenarchal vulvar lichen sclerosus. Obstet Gynecol 2001;98:588–591. 45. Bohm M, Frieling U, Luger TA et al. Successful treatment of anogenital lichen sclerosus with topical tacrolimus. Arch Dermatol 2003;139:922–924.
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46. Goldstein AT, Creasey A, Pfau R et al. A double-blind, randomized controlled trial of clobetasol versus pimecrolimus in patients with vulvar lichen sclerosus. J Am Acad Dermatol 2011;64:e99–e104. 47. Hengge UR, Krause W, Hofmann H et al. Multicentre, phase II trial on the safety and eﬃcacy of topical tacrolimus ointment for the treatment of lichen sclerosus. Br J Dermatol 2006;155:1021–1028. 48. US Department of Health and Human Services. ODS post-marketing safety review (PID 040754, PID 040752): update on malignancy-related events in all age groups. Pimecrolimus (Elidel, NDA 21-302) topical tacrolimus (Protopic, NDA 50-777) 2012 [online]. http://www. fda.gov/ohrms/dockets/ac/05/brieﬁng/2005-4089b2_01_ 06_Pimecrolimus %20Tacrolimus%20Malignancy% 20Update%20Pitts%20PID%20040754%20040752.pdf. Accessed on July 19, 2014. 49. Matsumoto Y, Yamamoto T, Isobe T et al. Successful treatment of vulvar lichen sclerosus in a child with lowconcentration topical tacrolimus ointment. J Dermatol 2007;34:114–116. 50. Bousema MT, Romppanen U, Geiger JM et al. Acitretin in the treatment of severe lichen sclerosus et atrophicus of the vulva: a double-blind, placebo-controlled study. J Am Acad Dermatol 1994;30(Pt 1):225–231. 51. Ioannides D, Lazaridou E, Apalla Z et al. Acitretin for severe lichen sclerosus of male genitalia: a randomized, placebo controlled study. J Urol 2010;183:1395–1399. 52. Niinimaki A, Kallioinen M, Oikarinen A. Etretinate reduces connective tissue degeneration in lichen sclerosus et atrophicus. Acta Derm Venereol 1989;69:439–442. 53. Virgili A, Corazza M, Bianchi A et al. Open study of topical 0.025% tretinoin in the treatment of vulvar lichen sclerosus. One year of therapy. J Reprod Med 1995;40:614–618. 54. Friedrich EG Jr. Topical testosterone for benign vulvar dystrophy. Obstet Gynecol 1971;37:677–686.
55. Wakelin SH, James MP. Extensive lichen sclerosus et atrophicus with bullae and ulceration—improvement with hydroxychloroquine. Clin Exp Dermatol 1994;19:332–334. 56. Smith YR, Haefner HK. Vulvar lichen sclerosus: pathophysiology and treatment. Am J Clin Dermatol 2004;5:105–125. 57. Parsad D, Saini R. Oral stanozolol in lichen sclerosus et atrophicus. J Am Acad Dermatol 1998;38(Pt 1):278– 279. 58. Ronger S, Viallard AM, Meunier-Mure F et al. Oral calcitriol: a new therapeutic agent in cutaneous lichen sclerosis. J Drugs Dermatol 2003;2:23–28. 59. Penneys NS. Treatment of lichen sclerosus with potassium para-aminobenzoate. J Am Acad Dermatol 1984;10:1039–1042. 60. Colbert RL, Chiang MP, Carlin CS et al. Progressive extragenital lichen sclerosus successfully treated with narrowband UV-B phototherapy. Arch Dermatol 2007;143:19–20. 61. Funaro D. Lichen sclerosus: a review and practical approach. Dermatol Ther 2004;17:28–37. 62. Das S, Tunuguntla HS. Balanitis xerotica obliterans—a review. World J Urol 2000;18:382–387. 63. Edmonds EV, Hunt S, Hawkins D et al. Clinical parameters in male genital lichen sclerosus: a case series of 329 patients. J Eur Acad Dermatol Venereol 2012;26:730–737. 64. Helm KF, Gibson LE, Muller SA. Lichen sclerosus et atrophicus in children and young adults. Pediatr Dermatol 1991;8:97–101. 65. Powell J, Wojnarowska F, Winsey S et al. Lichen sclerosus premenarche: autoimmunity and immunogenetics. Br J Dermatol 2000;142:481–484. 66. Powell J, Wojnarowska F. Childhood vulvar lichen sclerosus. The course after puberty. J Reprod Med 2002;47:706–709.