- Email: [email protected]
Co-existence of Lichen Sclerosus and Localized Scleroderma in Female Monozygotic Twins
Case Report Co-existence of Lichen Sclerosus and Localized Scleroderma in Female Monozygotic Twins ska MD 1, Karolina Wodok-Wieczorek MD 1, Anna Lis-Swięty MD, PhD 1,*, Katarzyna Mierzwin ska-Wcis1o MD, PhD 1 Ma1gorzata Widuchowska MD, PhD 2, Ligia Brzezin 1 2
Department of Dermatology, Medical University of Silesia, Katowice, Poland Department of Internal Medicine and Rheumatology, Medical University of Silesia, Katowice, Poland
a b s t r a c t Background: Etiology of lichen sclerosus (LiS) and localized scleroderma (LoS) is uncertain and probably multifactorial. Case: We describe a case of female monozygotic twins who presented co-existence of LiS and LoS. Skin lesions typical for LoS occurred in both patients, at the age of 10. One sister was diagnosed with linear LoS of the lower limb affecting deeper situated subcutaneous tissue and muscles. The other sister was diagnosed with guttate LoS of the trunk, with slow progression of the skin lesions. In both sisters vulvar LiS developed at the age of 19. Conclusions: Co-existence of LiS and LoS in monozygotic twins indicates the possible genetic contribution to the pathogenesis of these diseases and the close relationship between them. Key Words: Lichen sclerosus, Localized scleroderma, Familial occurrence
Introduction
Lichen sclerosus (LiS) and localized scleroderma (LoS) are classified as connective tissue diseases. Both diseases affect the skin. Neither of them involves the internal organs. Early stage lesions of LiS appear as pale patches and spots with surrounding violaceous border. After some time, the skin lesions form atrophic areas with hypo/hyperpigmentation. LiS often involves the anogenital region and causes such symptoms as itching, burning sensation, and soreness. According to some authors, LiS is a superficial, special variant of LoS, also known as morphea or scleroderma circumscripta.1,2 Like LiS, LoS is characterized by occurrence of initial inflammatory phase that is followed by fibrosis of the affected skin. It may involve all layers of skin and/or underlying tissues. Based on clinical presentation many subtypes of LoS are distinguished: linear, plaque, generalized, papular, nodular, atrophoderma of Pasini and Pierini, panatrophia Gowers. A typical location is the trunk or/and limbs. Unlike LiS, LoS doesn’t involve the anogenital region. In most of the cases, histopathologic examination distinguishes between LiS and LoS. The epidermis in LiS is hyperkeratotic with hydropic degeneration of the basal layer. The elastic fibers are characteristically decreased. Elastic fibers are not affected by LoS.3 The incidence of LoS is 0.4 to 2.7 per 100,000 people. The disease is twice as common in women as in men. The prevalence is similar in children and in adults.3 The prevalence of LiS is difficult to estimate. Tasker and Wojnarowska4 found that the general population prevalence of LiS was
The authors indicate no conflicts of interest. * Address correspondence to: Anna Lis-Swięty, MD, PhD, Department of Dermatology, Francuska Str. 20/24, 40-027 Katowice, Poland; Phone: þ48 602720948; fax: þ48 322561182 E-mail address: [email protected] (A. Lis-Swięty).
about 0.3%. Women were more commonly affected than men.4 There was a typical bimodal onset, in prepubertal children and postmenopausal women.4 Etiology of LiS and LoS is uncertain and probably multifactorial. The relationship between both disorders still remains controversial. Several reports have been published on the co-existence of LiS and LoS. In some cases, these 2 disorders occurred within the same skin lesion.5 Based on these reports, some authors consider that pathogenesis of both diseases is similar. Familial cases of LiS6 and LoS7 indicate the role of genetic factors. Co-existence of these disorders with other autoimmune diseases suggests that autoimmune mechanisms play a major role in their pathogenesis.4 The influence of environmental factors is also considered.3,8 The aim of this case series is to highlight the possible genetic contribution to the pathogenesis of LiS and LoS and the co-existence of the diseases. Clinical Reports Patient 1
A 20-year-old female was referred to the Department of Dermatology for sclerotic and atrophic lesions of the left lower limb. Linear sclerosis with progressive loss of subcutaneous tissue and muscles of the affected limb had been observed since the age of 10. Treatment with procaine penicillin, PUVA, oral corticosteroid, and methotrexate resulted in a transient remission. Flare-ups appeared again after discontinuation of immunosuppressive therapy. At the age of 19, the patient noticed atrophic lesions of the vulva without accompanying subjective symptoms. Skin lesions due to trauma, infection, or other external factors were excluded in the differential diagnosis. Family history: her
1083-3188/$ - see front matter Ó 2014 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpag.2013.11.010
2
A. Lis-Swięty et al. / J Pediatr Adolesc Gynecol xxx (2014) 1e4
Fig. 1. Patient 1. Linear sclerotic lesions on the left lower limb along the medial and anterior thigh (A), leg, to the medio-dorsal part of the foot (B). Lichen sclerosus (C).Ă
sister, monozygotic twin, was diagnosed with localized scleroderma at the age of 10. At the time of admission to the Department of Dermatology, the physical examination revealed linear lesions on
the left lower limb, extending from the inguinal region along the medial and anterior thigh to the lower leg and to the medial malleolus area and medio-dorsal part of the foot. The affected part of the lower limb was hypopigmented
A. Lis-Swięty et al. / J Pediatr Adolesc Gynecol xxx (2014) 1e4
3
with white sclerotic lesions and violaceous spots (Fig. 1, A, B). Mild atrophy of subcutaneous tissue and muscles was also found. The left lower limb circumference was smaller compared to the right side, the difference was about 1.5 cm at the thigh (52.5 cm vs 54 cm) and 1 cm at the leg (35 cm vs 36 cm). The range of motion of the knee and ankle of the affected limb was slightly decreased. Furthermore atrophic, porcelain-white lesions of the vulvar labia majora and minora were detected (Fig. 1, C). Apart from these findings, physical examination revealed no abnormalities. The laboratory tests: erythrocyte sedimentation rate, complete blood count, biochemical parameters of liver and kidney, urinalysis, were all within normal limits. Antinuclear antibodies (ANA) detected by indirect immunofluorescence on HEP-2 cells were negative. Within the next 5 years ANA had been tested repeatedly with positive results (a titer of 160 and a granular fluorescence type). Tests for antibodies against antigens from ENA group were negative. Histopathologic examination of the lesion on the major labia revealed thinned epidermis with hyperkeratosis, vacuolar degeneration of the basal layer, dilatation of blood and lymphatic vessels, and mixed inflammatory infiltrate in the dermis. PUVA, creams and ointments without an active ingredient, and rehabilitation exercises were used in treatment. The therapy resulted in noticeable softening of the sclerotic lesions and improvement of the knee and ankle mobility. Patient 2
A 20-year-old female presented, monozygotic twin of the patient above. At the age of ten she was diagnosed with papular form of localized scleroderma of the trunk. The diagnosis was based on the clinical and histopathologic findings. Only a few new sclerotic and atrophic skin lesions were observed on the back 5 years after the onset of first symptoms. Skin lesions due to trauma, infection, or other external factors were excluded. Dermatologic examination revealed several disseminated, atrophic lesions on the trunk, especially on the upper back. They were small, a few millimeters in size, atrophic, round- to oval shaped, hyperpigmented patches (Fig. 2, A). Mild atrophy of the vulva and porcelain-white lesions on the labia majora were also observed (Fig. 2, B). The physical examination revealed no other abnormalities. Laboratory tests (erythrocyte sedimentation rate, complete blood count, biochemical parameters of liver and kidney, urinalysis) were normal. ANA detected by indirect immunofluorescence on HEP-2 cells were negative. Within the next 5 years ANA had been tested repeatedly with positive results (a titer of 160 and a speckled fluorescence type). Tests for antibodies against antigens from ENA group were negative. Histopathologic examination of the vulvar lesions confirmed the diagnosis of lichen sclerosus. Due to the benign course of the disease only the use of creams and ointments without an active ingredient were recommended for treatment. Discussion
A retrospective analysis of 472 patients with LoS showed higher prevalence of LiS in patients with LoS, compared to
Fig. 2. Patient 2. Variably sized small round to oval shaped, hyperpigmented patches on the back; the lesions were depressed below the level of the surrounding skin: “swiss cheese” appearance (A). Lichen sclerosus (B).
healthy population.2 Concomitant LiS lesions were located mostly on anogenital region in women and on the back and shoulders in men.2 Co-existence of LiS was observed mostly in patients with plaque and generalized LoS.2 A prospective study of Lutz et al9 revealed that genital LiS was significantly more frequent in patients with LoS than in unaffected individuals. Genital LiS occurred in 38% of patients with LoS.9 Moreover, only 20% of the patients with genital LiS reported genital symptoms like pruritus.9 Most cases of genital LiS were asymptomatic.9 These facts show that it is recommended to perform a complete physical examination, including genital regions, in all patients with LoS. These recommendations are of great importance, because 3%-7% of patients with genital LiS develop squamous cell carcinoma.10 Our report presents a case of female monozygotic twins with LoS who developed LiS in the genital region. First clinical symptoms of LoS and LiS appeared at the same age in both patients. However, the morphology of the skin lesions was different. In the presented patients 2 subtypes of LoS were diagnosed: in the first patient it was linear subtype, in the second one it was guttate subtype. We also observed different severity of the diseases. The etiology of LiS and LoS is still uncertain. Genetic factors seem to play important role in both conditions. A study of 1052 women with vulvar LiS revealed that 12% of patients had a positive family history of LiS.6 Human leukocyte antigen (HLA) DQ7
4
A. Lis-Swięty et al. / J Pediatr Adolesc Gynecol xxx (2014) 1e4
occurs equally frequent in women and in men with LiS.1 HLA DR11 and DR12 are more common in men with LiS. HLA DQ8 and DQ9 occur more frequently in women with LiS.1,2 The genes responsible for the increased susceptibility of LoS development are unidentified. About 20 cases of familial LoS were described in the literature, including one case of monozygotic twins.7 Although there were no specific genetic tests done in our and in other reported case series, we and other authors suspect the possible genetic association beyond familial cases. Most of reports of familial LoS indicated occurrence of the same subtype of the disease in the same family.7 Our case series is particularly interesting due to patients being twin sisters with various subtypes of LoS and co-existence with LiS. It should be noted that environmental factors also play important role in pathogenesis of connective tissue diseases. They are probably responsible for different clinical manifestation and course of the disease in our patients. Retrospective review of 750 children with LoS indicated a possible disease trigger only in 13% of patients: mechanical events (67%), infections (25%), drugs (5%), and psychological distress (3%).8 So far, no research on familial co-existence of LiS and LoS has been published. The presented case of female monozygotic twins highlights the possible genetic contribution to the pathogenesis of these diseases and the close relationship between them. The onset of LoS in our patients
was not associated with other concomitant diseases or external factors. In both presented patients the reason for a remarkable variation of the clinical phenotype was not identified.
References 1. 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 2. 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 3. Fett N, Werth VP: Update on morphea: part I. Epidemiology, clinical presentation, and pathogenesis. J Am Acad Dermatol 2011; 64:217 4. Tasker GL, Wojnarowska F: Lichen sclerosus. Clin Exp Dermatol 2003; 28:128 5. Kim DH, Lee KR, Kim TY, et al: Coexistence of lichen sclerosus with morphoea showing bilateral symmetry: a possible pathogenic link. Clin Exp Dermatol 2009; 34:e416 6. Sherman V, Mc Pherson 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 7. De Keyser F, Peene I, Joos R, et al: Occurrence of scleroderma in monozygotic twins. J Rheumatol 2000; 27:2267 8. Zulian F, Athreya BH, Laxer R, et al, Juvenile Scleroderma Working Group of the Pediatric Rheumatology European Society: Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology 2006; 45:614 s C, Bessis D, et al: High frequency of genital lichen sclerosus in a 9. Lutz V, France prospective series of 76 patients with morphea: toward a better understanding of the spectrum of morphea. Arch Dermatol 2012; 148:24 rrez-Pascual M, Vicente-Martın FJ, Lo pez-Estebaranz JL: Lichen sclerosus 10. Gutie and squamous cell carcinoma. Actas Dermosifiliogr 2012; 103:21
Department of Dermatology, Medical University of Silesia, Katowice, Poland Department of Internal Medicine and Rheumatology, Medical University of Silesia, Katowice, Poland
a b s t r a c t Background: Etiology of lichen sclerosus (LiS) and localized scleroderma (LoS) is uncertain and probably multifactorial. Case: We describe a case of female monozygotic twins who presented co-existence of LiS and LoS. Skin lesions typical for LoS occurred in both patients, at the age of 10. One sister was diagnosed with linear LoS of the lower limb affecting deeper situated subcutaneous tissue and muscles. The other sister was diagnosed with guttate LoS of the trunk, with slow progression of the skin lesions. In both sisters vulvar LiS developed at the age of 19. Conclusions: Co-existence of LiS and LoS in monozygotic twins indicates the possible genetic contribution to the pathogenesis of these diseases and the close relationship between them. Key Words: Lichen sclerosus, Localized scleroderma, Familial occurrence
Introduction
Lichen sclerosus (LiS) and localized scleroderma (LoS) are classified as connective tissue diseases. Both diseases affect the skin. Neither of them involves the internal organs. Early stage lesions of LiS appear as pale patches and spots with surrounding violaceous border. After some time, the skin lesions form atrophic areas with hypo/hyperpigmentation. LiS often involves the anogenital region and causes such symptoms as itching, burning sensation, and soreness. According to some authors, LiS is a superficial, special variant of LoS, also known as morphea or scleroderma circumscripta.1,2 Like LiS, LoS is characterized by occurrence of initial inflammatory phase that is followed by fibrosis of the affected skin. It may involve all layers of skin and/or underlying tissues. Based on clinical presentation many subtypes of LoS are distinguished: linear, plaque, generalized, papular, nodular, atrophoderma of Pasini and Pierini, panatrophia Gowers. A typical location is the trunk or/and limbs. Unlike LiS, LoS doesn’t involve the anogenital region. In most of the cases, histopathologic examination distinguishes between LiS and LoS. The epidermis in LiS is hyperkeratotic with hydropic degeneration of the basal layer. The elastic fibers are characteristically decreased. Elastic fibers are not affected by LoS.3 The incidence of LoS is 0.4 to 2.7 per 100,000 people. The disease is twice as common in women as in men. The prevalence is similar in children and in adults.3 The prevalence of LiS is difficult to estimate. Tasker and Wojnarowska4 found that the general population prevalence of LiS was
The authors indicate no conflicts of interest. * Address correspondence to: Anna Lis-Swięty, MD, PhD, Department of Dermatology, Francuska Str. 20/24, 40-027 Katowice, Poland; Phone: þ48 602720948; fax: þ48 322561182 E-mail address: [email protected] (A. Lis-Swięty).
about 0.3%. Women were more commonly affected than men.4 There was a typical bimodal onset, in prepubertal children and postmenopausal women.4 Etiology of LiS and LoS is uncertain and probably multifactorial. The relationship between both disorders still remains controversial. Several reports have been published on the co-existence of LiS and LoS. In some cases, these 2 disorders occurred within the same skin lesion.5 Based on these reports, some authors consider that pathogenesis of both diseases is similar. Familial cases of LiS6 and LoS7 indicate the role of genetic factors. Co-existence of these disorders with other autoimmune diseases suggests that autoimmune mechanisms play a major role in their pathogenesis.4 The influence of environmental factors is also considered.3,8 The aim of this case series is to highlight the possible genetic contribution to the pathogenesis of LiS and LoS and the co-existence of the diseases. Clinical Reports Patient 1
A 20-year-old female was referred to the Department of Dermatology for sclerotic and atrophic lesions of the left lower limb. Linear sclerosis with progressive loss of subcutaneous tissue and muscles of the affected limb had been observed since the age of 10. Treatment with procaine penicillin, PUVA, oral corticosteroid, and methotrexate resulted in a transient remission. Flare-ups appeared again after discontinuation of immunosuppressive therapy. At the age of 19, the patient noticed atrophic lesions of the vulva without accompanying subjective symptoms. Skin lesions due to trauma, infection, or other external factors were excluded in the differential diagnosis. Family history: her
1083-3188/$ - see front matter Ó 2014 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpag.2013.11.010
2
A. Lis-Swięty et al. / J Pediatr Adolesc Gynecol xxx (2014) 1e4
Fig. 1. Patient 1. Linear sclerotic lesions on the left lower limb along the medial and anterior thigh (A), leg, to the medio-dorsal part of the foot (B). Lichen sclerosus (C).Ă
sister, monozygotic twin, was diagnosed with localized scleroderma at the age of 10. At the time of admission to the Department of Dermatology, the physical examination revealed linear lesions on
the left lower limb, extending from the inguinal region along the medial and anterior thigh to the lower leg and to the medial malleolus area and medio-dorsal part of the foot. The affected part of the lower limb was hypopigmented
A. Lis-Swięty et al. / J Pediatr Adolesc Gynecol xxx (2014) 1e4
3
with white sclerotic lesions and violaceous spots (Fig. 1, A, B). Mild atrophy of subcutaneous tissue and muscles was also found. The left lower limb circumference was smaller compared to the right side, the difference was about 1.5 cm at the thigh (52.5 cm vs 54 cm) and 1 cm at the leg (35 cm vs 36 cm). The range of motion of the knee and ankle of the affected limb was slightly decreased. Furthermore atrophic, porcelain-white lesions of the vulvar labia majora and minora were detected (Fig. 1, C). Apart from these findings, physical examination revealed no abnormalities. The laboratory tests: erythrocyte sedimentation rate, complete blood count, biochemical parameters of liver and kidney, urinalysis, were all within normal limits. Antinuclear antibodies (ANA) detected by indirect immunofluorescence on HEP-2 cells were negative. Within the next 5 years ANA had been tested repeatedly with positive results (a titer of 160 and a granular fluorescence type). Tests for antibodies against antigens from ENA group were negative. Histopathologic examination of the lesion on the major labia revealed thinned epidermis with hyperkeratosis, vacuolar degeneration of the basal layer, dilatation of blood and lymphatic vessels, and mixed inflammatory infiltrate in the dermis. PUVA, creams and ointments without an active ingredient, and rehabilitation exercises were used in treatment. The therapy resulted in noticeable softening of the sclerotic lesions and improvement of the knee and ankle mobility. Patient 2
A 20-year-old female presented, monozygotic twin of the patient above. At the age of ten she was diagnosed with papular form of localized scleroderma of the trunk. The diagnosis was based on the clinical and histopathologic findings. Only a few new sclerotic and atrophic skin lesions were observed on the back 5 years after the onset of first symptoms. Skin lesions due to trauma, infection, or other external factors were excluded. Dermatologic examination revealed several disseminated, atrophic lesions on the trunk, especially on the upper back. They were small, a few millimeters in size, atrophic, round- to oval shaped, hyperpigmented patches (Fig. 2, A). Mild atrophy of the vulva and porcelain-white lesions on the labia majora were also observed (Fig. 2, B). The physical examination revealed no other abnormalities. Laboratory tests (erythrocyte sedimentation rate, complete blood count, biochemical parameters of liver and kidney, urinalysis) were normal. ANA detected by indirect immunofluorescence on HEP-2 cells were negative. Within the next 5 years ANA had been tested repeatedly with positive results (a titer of 160 and a speckled fluorescence type). Tests for antibodies against antigens from ENA group were negative. Histopathologic examination of the vulvar lesions confirmed the diagnosis of lichen sclerosus. Due to the benign course of the disease only the use of creams and ointments without an active ingredient were recommended for treatment. Discussion
A retrospective analysis of 472 patients with LoS showed higher prevalence of LiS in patients with LoS, compared to
Fig. 2. Patient 2. Variably sized small round to oval shaped, hyperpigmented patches on the back; the lesions were depressed below the level of the surrounding skin: “swiss cheese” appearance (A). Lichen sclerosus (B).
healthy population.2 Concomitant LiS lesions were located mostly on anogenital region in women and on the back and shoulders in men.2 Co-existence of LiS was observed mostly in patients with plaque and generalized LoS.2 A prospective study of Lutz et al9 revealed that genital LiS was significantly more frequent in patients with LoS than in unaffected individuals. Genital LiS occurred in 38% of patients with LoS.9 Moreover, only 20% of the patients with genital LiS reported genital symptoms like pruritus.9 Most cases of genital LiS were asymptomatic.9 These facts show that it is recommended to perform a complete physical examination, including genital regions, in all patients with LoS. These recommendations are of great importance, because 3%-7% of patients with genital LiS develop squamous cell carcinoma.10 Our report presents a case of female monozygotic twins with LoS who developed LiS in the genital region. First clinical symptoms of LoS and LiS appeared at the same age in both patients. However, the morphology of the skin lesions was different. In the presented patients 2 subtypes of LoS were diagnosed: in the first patient it was linear subtype, in the second one it was guttate subtype. We also observed different severity of the diseases. The etiology of LiS and LoS is still uncertain. Genetic factors seem to play important role in both conditions. A study of 1052 women with vulvar LiS revealed that 12% of patients had a positive family history of LiS.6 Human leukocyte antigen (HLA) DQ7
4
A. Lis-Swięty et al. / J Pediatr Adolesc Gynecol xxx (2014) 1e4
occurs equally frequent in women and in men with LiS.1 HLA DR11 and DR12 are more common in men with LiS. HLA DQ8 and DQ9 occur more frequently in women with LiS.1,2 The genes responsible for the increased susceptibility of LoS development are unidentified. About 20 cases of familial LoS were described in the literature, including one case of monozygotic twins.7 Although there were no specific genetic tests done in our and in other reported case series, we and other authors suspect the possible genetic association beyond familial cases. Most of reports of familial LoS indicated occurrence of the same subtype of the disease in the same family.7 Our case series is particularly interesting due to patients being twin sisters with various subtypes of LoS and co-existence with LiS. It should be noted that environmental factors also play important role in pathogenesis of connective tissue diseases. They are probably responsible for different clinical manifestation and course of the disease in our patients. Retrospective review of 750 children with LoS indicated a possible disease trigger only in 13% of patients: mechanical events (67%), infections (25%), drugs (5%), and psychological distress (3%).8 So far, no research on familial co-existence of LiS and LoS has been published. The presented case of female monozygotic twins highlights the possible genetic contribution to the pathogenesis of these diseases and the close relationship between them. The onset of LoS in our patients
was not associated with other concomitant diseases or external factors. In both presented patients the reason for a remarkable variation of the clinical phenotype was not identified.
References 1. 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 2. 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 3. Fett N, Werth VP: Update on morphea: part I. Epidemiology, clinical presentation, and pathogenesis. J Am Acad Dermatol 2011; 64:217 4. Tasker GL, Wojnarowska F: Lichen sclerosus. Clin Exp Dermatol 2003; 28:128 5. Kim DH, Lee KR, Kim TY, et al: Coexistence of lichen sclerosus with morphoea showing bilateral symmetry: a possible pathogenic link. Clin Exp Dermatol 2009; 34:e416 6. Sherman V, Mc Pherson 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 7. De Keyser F, Peene I, Joos R, et al: Occurrence of scleroderma in monozygotic twins. J Rheumatol 2000; 27:2267 8. Zulian F, Athreya BH, Laxer R, et al, Juvenile Scleroderma Working Group of the Pediatric Rheumatology European Society: Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology 2006; 45:614 s C, Bessis D, et al: High frequency of genital lichen sclerosus in a 9. Lutz V, France prospective series of 76 patients with morphea: toward a better understanding of the spectrum of morphea. Arch Dermatol 2012; 148:24 rrez-Pascual M, Vicente-Martın FJ, Lo pez-Estebaranz JL: Lichen sclerosus 10. Gutie and squamous cell carcinoma. Actas Dermosifiliogr 2012; 103:21