- Email: [email protected]
Congenital localized scleroderma
CONGENITAL LOCALIZED SCLERODERMA FRANCESCO ZULIAN, MD, CRISTINA VALLONGO, MD, SHEILA KNUPP FEITOSA DE OLIVEIRA, MD, MARILYNN G. PUNARO, MD, JOAN ROS, MD, HENRYKA MAZUR-ZIELINSKA, MD, PAUL GALEA, MD, LIVIANA DA DALT, MD, AND LAWRENCE F. EICHENFIELD, MD
Objectives Juvenile localized scleroderma (JLS) usually has its onset during later childhood. This report describes the clinical and serologic features of six children with congenital localized scleroderma (CLS).
Study design A large, multinational study was conducted among pediatric rheumatology and dermatology centers by collecting information on demographics, family history, triggering environmental factors, clinical features, laboratory reports, and treatment of patients with JLS. Patients with onset at birth were carefully examined. Results Among 750 patients with JLS, 6 patients (0.8%) had scleroderma-related lesions at birth. Female-to-male ratio was 2:1. All patients had linear scleroderma, in four involving the face with en coup de sabre appearance. Two patients were misdiagnosed as having skin infection, one nevus, one salmon patch, and two undefined skin lesions. The mean diagnostic delay was 3.9 years. In comparison with the group of 733 patients with late-onset JLS, CLS presented a significantly more prolonged disease duration at diagnosis and a higher frequency of en coup de sabre subtypes. Conclusions Congenital localized scleroderma is a rare and probably underestimated condition in neonates. The linear subtype was the exclusive manifestation of the disease. CLS should be included in the differential diagnosis of infants with cutaneous erythematous fibrotic lesions to avoid functional and aesthetic sequelae and to allow prompt therapy. (J Pediatr 2006;149:248-51)
uvenile localized scleroderma (JLS) is an uncommon disease in children. In contrast to adults, it is much more frequent than systemic sclerosis.1 As part of a multiphase project aimed to define the different varieties of JLS, a large set of data has been collected. Herein we describe, for the first time, the clinical and serologic features of six children with localized scleroderma present at birth and discuss possible conditions in the differential diagnosis of infants with cutaneous erythematous-sclerotic lesions.
J
METHODS Study Design and Patient Selection A large data collection including information on demographics, epidemiologic and clinical features, laboratory reports, and treatment of children with JLS was performed among 270 pediatric rheumatology and dermatology centers in Europe (n ⫽ 166), North America (n ⫽ 42), South America (n ⫽ 28), Asia (n ⫽ 30), Australia (n ⫽ 2) and Africa (n ⫽ 2). The charts of 750 patients who met the criteria for the JLS diagnosis2 and disease onset by 16 years of age were reviewed. Patients with the onset of disease at birth (referred to as congenital localized scleroderma, CLS) were carefully analyzed. Clinical pictures and biopsy reports were collected to confirm the diagnosis. The clinical characteristics of the patients with CLS were compared with patients whose onset was after the first year of age (referred to as late-onset JLS, LO-JLS).
ACA ANA CLS ECDS ENA
248
Anticentromere antibodies Antinuclear antibodies Congenital localized scleroderma En Coup de sabre Extractable nuclear antigens antibodies
JLS LO-JLS RF SCL-70
Juvenile localized scleroderma Late-onset JLS Rheumatoid factor Anti–sclero-70 antibodies
From the Department of Pediatrics, University of Padua, Italy; Instituto de Puericultura e Pediatria Martagao Gesteira, Rio de Janeiro, Brazil; the University of Texas, Southwestern Medical School, Dallas, Texas; Hospital San Joan de Deu, Barcelona, Spain; Medical University of Silesia, Zabrze, Poland; Royal Hospital for Sick Children, Glasgow, United Kingdom; and the Departments of Pediatrics and Medicine (Dermatology), Children’s Hospital, San Diego, University of California, San Diego. Submitted for publication Dec 7, 2005; last revision received Feb 14, 2006; accepted Apr 13, 2006. Reprint requests: Francesco Zulian, MD, Dipartimento di Pediatria, Università di Padova, Via Giustiniani 3, 35128 Padova, Italy. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2006 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2006.04.052
Data Collection The following data were collected for each patient: (a) demographics (sex, age at the first signs or symptoms of the disease, age at diagnosis, duration of follow-up); (b) epidemiology (environmental factors, either affecting the patients or, indirectly, their mothers during the pregnancy and labor, considered by physicians or by the parents significantly related to disease onset); (c) family history of autoimmune diseases in first- and second-degree relatives; (d) clinical subtype according to the following Mayo Clinic classification criteria2: (1) plaque morphea with its subtypes guttate, bullous, nodular or keloid morphea and atrophoderma Pasini and Pierini; (2) generalized morphea; (3) linear scleroderma, including the head-face subtypes en coup de sabre (ECDS) and progressive hemifacial atrophy, known also as Parry-Romberg disease; and (4) deep morphea, including the four subtypes: subcutaneous morphea, morphea profunda, disabling pansclerotic morphea, and eosinophilic fasciitis; (e) presence of extracutaneous involvement (eye, central nervous system, osteoarticular); and (f) serum autoantibodies: antinuclear antibodies (ANA), extractable nuclear antigens antibodies (ENA), anti– sclero-70 antibodies (SCL-70), anticentromere antibodies (ACA), and rheumatoid factor (RF). Abnormal values were referred to the normal range of laboratory standards of each participating center. Statistical Analysis Descriptive statistics were used for reporting demographic, clinical, and laboratory characteristics of the patients and for their therapeutic approach. The differences between the two groups of patients, CLS and LO-JLS, were analyzed by t-test, 2 test, or by Fisher exact test, as appropriate. Case Histories We selected two case histories as examples of the different clinical pictures included in the present series. Patient 1 A white girl was born with a erythematous area on the left forehead. She was diagnosed as having a “salmon patch” (Figure 1A). The lesion slowly progressed in size until the age of 12 months, then stabilized (Figure 1B). At 3.5 years, an area of alopecia in close relation with the salmon patch was observed. At the same time, the reddish lesion became brown-pale, shiny, and indurated. A diagnosis of linear scleroderma ECDS was made (Figure 1C). Thermography confirmed active disease of both scalp and frontal lesions. Laboratory results showed negative ANA, ENA, and RF. She was then treated with oral steroids and methotrexate. Family history was negative for rheumatic or autoimmune diseases. No problems during pregnancy or labor were reported. After 18 months of follow-up, the lesions were stable in size and inactive both by physical examination and thermography. Congenital Localized Scleroderma
Figure 1. Patient 1. A, At birth; B, age, 1 year; C, age, 3.5 years, at time of diagnosis. En coup de sabre lesion of the face, with atrophy and hyperpigmentation is shown. Deformities of the scalp are also evident.
Patient 4 A white girl was born with a red patch on the sole of her left foot. The initial diagnosis was skin infection, and topical 249
derma (Figure 2). In one patient (patient 3), arthritis with functional impairment on the left knee was present. No patients had ocular or neurologic involvement.
Autoantibodies The most common autoantibodies, ANA, ENA, SCL70, ACA, and RF, were screened for diagnosis in all six patients. As shown in the Table, ANA was positive in three patients (50%) and RF in one (17%). ENA, SCL-70, and ACA were found to be negative in all patients.
Figure 2. Patient 4. Band of linear scleroderma with hyperpigmentation and atrophy on dorsal aspect of left foot is shown. Retractive deformities of four toes are also present.
antibiotic treatment was started, without clinical response. Within a few months, the skin lesion rapidly extended to the dorsal aspect of the foot and became hyperpigmented and indurated. A progressive retraction of the second, third, and fourth toes developed. Two years later, the diagnosis of linear scleroderma was made (Figure 2). RF was positive, and ANA were present (titer, 1:80, speckled). She was treated with D-penicillamine for 2 years, then with methotrexate. During the pregnancy, her mother was healthy and the delivery was not complicated. No significant environmental factors during pregnancy or family history positive for rheumatic or autoimmune diseases were reported. At the last evaluation, at 10 years, the involved area included the left foot and leg, with significant skin atrophy and hyperpigmentation.
RESULTS Demographics and Subtypes During the period January 2002 to June 2003, 70 centers (38 European, 12 North American, 11 South American, 8 Asian, and 1 Australian) took part in a multinational survey and reported 750 patients with onset of localized scleroderma by 16 years of age. Six children with scleroderma-related skin lesions at birth (0.8%) were reported, and data were analyzed. Their clinical characteristics are summarized in the Table. At birth, the skin lesions were described by the parents as erythematous and slightly pigmented in three patients (patients 4, 5, and 6), slightly pigmented and hard to touch in two, and only erythematous in one (patient 1). A linear appearance was present in all. The family histories were unremarkable, with one patient (patient 3) having a maternal grandmother with rheumatoid arthritis. A comprehensive clinical history concerning possible problems during pregnancy and/or labor was obtained from five mothers and revealed no drugs, infections, or other factors potentially involved in the disease onset. In five children, the diagnosis of localized scleroderma was confirmed by skin biopsy. In one (patient 4), biopsy was not performed but the lesion on the foot was quite specific and clearly compatible with the diagnosis of localized sclero250
Zulian et al
Comparison Between CLS and LO-JLS We compared the clinical-laboratory features of the 6 patients with CLS with those of 733 children with LO-JLS. The linear appearance of the lesions was present in 100% of the patients with CLS and in 65% of those with LO-JLS. However, although impressive, this difference did not reach statistical significance. The higher frequency of the linear ECDS subtype in CLS (67% vs 14%, P ⬍ .05) and the longer disease duration at diagnosis (3.9 years vs 1 year, 5 months, P ⬍ .01) were significant.
DISCUSSION Localized scleroderma, although uncommon, is a much more frequent type of scleroderma in childhood than is systemic sclerosis.1 However, to our knowledge, congenital onset has never been reported. We have described a series of six patients with onset of scleroderma-related findings at birth. Previous reported studies3-7 and one recent large, multicenter study8 show that JLS affects children during later childhood, with a mean age at disease onset ranging from 6.8 to 7.9 years, and without difference among the various subtypes.3-8 In these series, the youngest reported patients ranged in age between 1 and 2 years. In two prior studies, two cases, infants aged 2 weeks and 1 month, respectively, were reported.9,10 These probably had skin lesions at birth, but their clinical characteristics were not reported. Congenital localized scleroderma is rare or so underestimated a condition that it took almost 4 years for the patients to be correctly diagnosed. In two patients, a skin infection was initially considered, but antibiotic treatment was unsuccessful. In two patients, more common congenital conditions such as nevus or salmon patch were initially diagnosed, and in two, initial diagnostic considerations remain undefined. We were able to obtain pictures of the lesions at birth only for patient 1. In this patient, the lesion on the fronthead appeared consistent with a macular vascular stain known as a “salmon patch,” or “nevus simplex.” The lesion gradually became hyperpigmented and hard to the touch. In the other patients, the parents carefully described the lesions at birth as erythematous-hyperpigmented in three or hyperpigmented and hard in two. Vascular erythematous stains can sometimes precede other signs of more chronic localized scleroderma lesions, as in patient 1 in the present series. However, their relation with The Journal of Pediatrics • August 2006
Table. Clinical characteristics of patients with congenital localized scleroderma Patient
Sex
First diagnosis
1 2 3 4 5 6
F M F F F M
Salmon patch, alopecia Undefined skin lesion Undefined skin lesion Infection Infection, Borrelia Skin discoloration, naevus
Final diagnosis LS LS LS LS LS LS
(ECDS) (ECDS) (ECDS, limb, trunk) (limb) (limb) (ECDS)
Disease duration at diagnosis (y)
ANA
RF
3.5 4.8 5.1 2.2 2.4 5.2
neg 1/1280 1/640 1/80 neg neg
neg neg neg pos neg neg
LS, Linear scleroderma; ECDS, en coup de sabre; neg, negative; pos, positive; ANA, antinuclear antibodies; RF, rheumatoid factor.
CLS is not clearly defined. Alternatively, the erythema noted in several patients in this series may have been consistent with early inflammation of linear scleroderma. It has been observed that in some children with linear scleroderma, initial findings are misdiagnosed as “port wine stains” (personal observation, Lawrence F. Eichenfield, MD, Children’s Hospital, San Diego, CA). There are several congenital conditions that should be considered in the differential diagnosis. Stiff skin syndrome is a hereditary scleroderma-like disease that involves areas with abundant fascia such as thighs and buttocks. It causes symmetrical joint contractures and motion limitation of knees and hips. The symmetrical involvement of the limbs, the lack of epidermal discolorations, the sparing of the face, and histology picture of thick fascia with no inflammatory and muscle changes are the distinctive features of this condition.11,12 Giant congenital nevi, presenting as large, verrucous, brown or black plaques, can be sometimes surrounded by a sclerodermoid reaction resembling plaque morphea. This phenomenon is the result of an atypical host reaction to the nevus cells as proved by its involution after excision of the pigmented portion of the lesion. The oval-shaped morphology, the brown-dark color, and the pathology picture are distinctive differential features from CLS.13 Cafè-au-lait spots and mastocytosis may be present in the newborn infant. They have distinctive morphology, and mastocytosis lesions usually become edematous or erythematous with stroking (Darier sign). In neonates, macular stains, such as stork bite, salmon patches, or angel kiss, also known as “nevus simplex” are usually found on the nape of the neck, the eyelids, and on the glabellar region of the forehead. Distinct from scleroderma, they are usually transient.14 Portwine stains, as discussed above, may mimic early localized scleroderma. Congenital localized scleroderma in our series was characterized exclusively by linear lesions that involved the face, with ECDS features, in four of six patients. We do not have a clear explanation for the higher prevalence of this subtype at birth, but the possible role of potential
Congenital Localized Scleroderma
triggering events during pregnancy has been excluded because the medical history of the mothers was completely unremarkable. Finally, considering that ANAs were found to be positive in three of six patients, this may be of some help in differentiating CLS from other similar conditions.
REFERENCES 1. Zulian F. Scleroderma in children. Pediatr Clin North Am 2005;52:521-45. 2. Peterson LS, Nelson AM, Su WPD. Classification of morphea (localized scleroderma). Mayo Clin Proc 1995;70:1068-76. 3. Uziel Y, Krafchik BR, Silverman ED, Thorner PS, Laxer RM. Localized scleroderma in childhood: a report of 30 cases. Semin Arthritis Rheum 1994;23:328-40. 4. Vancheeswaran R, Black CM, David J, Hasson N, Harper J, Atherton D, et al. Childhood onset scleroderma: is it different from adult onset disease? Arthritis Rheum 1996;39:1041-9. 5. Marzano AV, Menni S, Parodi A, Borghi A, Fuligni A, Fabbri P, et al. Localized scleroderma in adults and children: clinical and laboratory investigations on 239 cases. Eur J Dermatol 2003;13:171-6. 6. Bodemer C, Belon M, Hamel-Teillac D, Amoric JC, Fraitag S, Prieur AM, et al. Scleroderma in children: a retrospective study of 70 cases. Ann Dermatol Venereol 1999;126:691-4. 7. Christianson HB, Dorsey CS, Kierland RR, O’Leary PA. Localized scleroderma: a clinical study of two-hundred and thirty-five cases. Arch Dermatol 1956;74:629-39. 8. Zulian F, Athreya BH, Laxer RM, Nelson AM, de Oliveira SKF, Punaro MG, et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children: an international study. Rheumatology (Oxford) 2006;45:614-20. 9. Chazen EM, Charles D, Cook CD, Cohen J. Focal scleroderma. J Pediatr 1962;60:385-93. 10. Dehen L, Roujeau JC, Cosnes A, Revuz J. Internal involvement in localized scleroderma. Medicine 1994;73:241-5. 11. Esterly NB, McKusick VA. Stiff skin syndrome. Pediatrics 1971;47:360-9. 12. Jablonska S, Blaszczyk M. Stiff skin syndrome is highly heterogeneous, and congenital fascial dystrophy is its distinct subset. Pediatr Dermatol 2004;21:508-10. 13. Pattee SF, Hansen RC, Bangert JL, Joganic EF. Giant congenital nevus with progressive sclerodermoid reaction in newborn. Pediatr Dermatol 2001;18:320-4. 14. Conlon DJ, Drolet BA. Skin lesions in the neonate. Pediatr Clin North Am 2004;51:863-88.
251
Objectives Juvenile localized scleroderma (JLS) usually has its onset during later childhood. This report describes the clinical and serologic features of six children with congenital localized scleroderma (CLS).
Study design A large, multinational study was conducted among pediatric rheumatology and dermatology centers by collecting information on demographics, family history, triggering environmental factors, clinical features, laboratory reports, and treatment of patients with JLS. Patients with onset at birth were carefully examined. Results Among 750 patients with JLS, 6 patients (0.8%) had scleroderma-related lesions at birth. Female-to-male ratio was 2:1. All patients had linear scleroderma, in four involving the face with en coup de sabre appearance. Two patients were misdiagnosed as having skin infection, one nevus, one salmon patch, and two undefined skin lesions. The mean diagnostic delay was 3.9 years. In comparison with the group of 733 patients with late-onset JLS, CLS presented a significantly more prolonged disease duration at diagnosis and a higher frequency of en coup de sabre subtypes. Conclusions Congenital localized scleroderma is a rare and probably underestimated condition in neonates. The linear subtype was the exclusive manifestation of the disease. CLS should be included in the differential diagnosis of infants with cutaneous erythematous fibrotic lesions to avoid functional and aesthetic sequelae and to allow prompt therapy. (J Pediatr 2006;149:248-51)
uvenile localized scleroderma (JLS) is an uncommon disease in children. In contrast to adults, it is much more frequent than systemic sclerosis.1 As part of a multiphase project aimed to define the different varieties of JLS, a large set of data has been collected. Herein we describe, for the first time, the clinical and serologic features of six children with localized scleroderma present at birth and discuss possible conditions in the differential diagnosis of infants with cutaneous erythematous-sclerotic lesions.
J
METHODS Study Design and Patient Selection A large data collection including information on demographics, epidemiologic and clinical features, laboratory reports, and treatment of children with JLS was performed among 270 pediatric rheumatology and dermatology centers in Europe (n ⫽ 166), North America (n ⫽ 42), South America (n ⫽ 28), Asia (n ⫽ 30), Australia (n ⫽ 2) and Africa (n ⫽ 2). The charts of 750 patients who met the criteria for the JLS diagnosis2 and disease onset by 16 years of age were reviewed. Patients with the onset of disease at birth (referred to as congenital localized scleroderma, CLS) were carefully analyzed. Clinical pictures and biopsy reports were collected to confirm the diagnosis. The clinical characteristics of the patients with CLS were compared with patients whose onset was after the first year of age (referred to as late-onset JLS, LO-JLS).
ACA ANA CLS ECDS ENA
248
Anticentromere antibodies Antinuclear antibodies Congenital localized scleroderma En Coup de sabre Extractable nuclear antigens antibodies
JLS LO-JLS RF SCL-70
Juvenile localized scleroderma Late-onset JLS Rheumatoid factor Anti–sclero-70 antibodies
From the Department of Pediatrics, University of Padua, Italy; Instituto de Puericultura e Pediatria Martagao Gesteira, Rio de Janeiro, Brazil; the University of Texas, Southwestern Medical School, Dallas, Texas; Hospital San Joan de Deu, Barcelona, Spain; Medical University of Silesia, Zabrze, Poland; Royal Hospital for Sick Children, Glasgow, United Kingdom; and the Departments of Pediatrics and Medicine (Dermatology), Children’s Hospital, San Diego, University of California, San Diego. Submitted for publication Dec 7, 2005; last revision received Feb 14, 2006; accepted Apr 13, 2006. Reprint requests: Francesco Zulian, MD, Dipartimento di Pediatria, Università di Padova, Via Giustiniani 3, 35128 Padova, Italy. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2006 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2006.04.052
Data Collection The following data were collected for each patient: (a) demographics (sex, age at the first signs or symptoms of the disease, age at diagnosis, duration of follow-up); (b) epidemiology (environmental factors, either affecting the patients or, indirectly, their mothers during the pregnancy and labor, considered by physicians or by the parents significantly related to disease onset); (c) family history of autoimmune diseases in first- and second-degree relatives; (d) clinical subtype according to the following Mayo Clinic classification criteria2: (1) plaque morphea with its subtypes guttate, bullous, nodular or keloid morphea and atrophoderma Pasini and Pierini; (2) generalized morphea; (3) linear scleroderma, including the head-face subtypes en coup de sabre (ECDS) and progressive hemifacial atrophy, known also as Parry-Romberg disease; and (4) deep morphea, including the four subtypes: subcutaneous morphea, morphea profunda, disabling pansclerotic morphea, and eosinophilic fasciitis; (e) presence of extracutaneous involvement (eye, central nervous system, osteoarticular); and (f) serum autoantibodies: antinuclear antibodies (ANA), extractable nuclear antigens antibodies (ENA), anti– sclero-70 antibodies (SCL-70), anticentromere antibodies (ACA), and rheumatoid factor (RF). Abnormal values were referred to the normal range of laboratory standards of each participating center. Statistical Analysis Descriptive statistics were used for reporting demographic, clinical, and laboratory characteristics of the patients and for their therapeutic approach. The differences between the two groups of patients, CLS and LO-JLS, were analyzed by t-test, 2 test, or by Fisher exact test, as appropriate. Case Histories We selected two case histories as examples of the different clinical pictures included in the present series. Patient 1 A white girl was born with a erythematous area on the left forehead. She was diagnosed as having a “salmon patch” (Figure 1A). The lesion slowly progressed in size until the age of 12 months, then stabilized (Figure 1B). At 3.5 years, an area of alopecia in close relation with the salmon patch was observed. At the same time, the reddish lesion became brown-pale, shiny, and indurated. A diagnosis of linear scleroderma ECDS was made (Figure 1C). Thermography confirmed active disease of both scalp and frontal lesions. Laboratory results showed negative ANA, ENA, and RF. She was then treated with oral steroids and methotrexate. Family history was negative for rheumatic or autoimmune diseases. No problems during pregnancy or labor were reported. After 18 months of follow-up, the lesions were stable in size and inactive both by physical examination and thermography. Congenital Localized Scleroderma
Figure 1. Patient 1. A, At birth; B, age, 1 year; C, age, 3.5 years, at time of diagnosis. En coup de sabre lesion of the face, with atrophy and hyperpigmentation is shown. Deformities of the scalp are also evident.
Patient 4 A white girl was born with a red patch on the sole of her left foot. The initial diagnosis was skin infection, and topical 249
derma (Figure 2). In one patient (patient 3), arthritis with functional impairment on the left knee was present. No patients had ocular or neurologic involvement.
Autoantibodies The most common autoantibodies, ANA, ENA, SCL70, ACA, and RF, were screened for diagnosis in all six patients. As shown in the Table, ANA was positive in three patients (50%) and RF in one (17%). ENA, SCL-70, and ACA were found to be negative in all patients.
Figure 2. Patient 4. Band of linear scleroderma with hyperpigmentation and atrophy on dorsal aspect of left foot is shown. Retractive deformities of four toes are also present.
antibiotic treatment was started, without clinical response. Within a few months, the skin lesion rapidly extended to the dorsal aspect of the foot and became hyperpigmented and indurated. A progressive retraction of the second, third, and fourth toes developed. Two years later, the diagnosis of linear scleroderma was made (Figure 2). RF was positive, and ANA were present (titer, 1:80, speckled). She was treated with D-penicillamine for 2 years, then with methotrexate. During the pregnancy, her mother was healthy and the delivery was not complicated. No significant environmental factors during pregnancy or family history positive for rheumatic or autoimmune diseases were reported. At the last evaluation, at 10 years, the involved area included the left foot and leg, with significant skin atrophy and hyperpigmentation.
RESULTS Demographics and Subtypes During the period January 2002 to June 2003, 70 centers (38 European, 12 North American, 11 South American, 8 Asian, and 1 Australian) took part in a multinational survey and reported 750 patients with onset of localized scleroderma by 16 years of age. Six children with scleroderma-related skin lesions at birth (0.8%) were reported, and data were analyzed. Their clinical characteristics are summarized in the Table. At birth, the skin lesions were described by the parents as erythematous and slightly pigmented in three patients (patients 4, 5, and 6), slightly pigmented and hard to touch in two, and only erythematous in one (patient 1). A linear appearance was present in all. The family histories were unremarkable, with one patient (patient 3) having a maternal grandmother with rheumatoid arthritis. A comprehensive clinical history concerning possible problems during pregnancy and/or labor was obtained from five mothers and revealed no drugs, infections, or other factors potentially involved in the disease onset. In five children, the diagnosis of localized scleroderma was confirmed by skin biopsy. In one (patient 4), biopsy was not performed but the lesion on the foot was quite specific and clearly compatible with the diagnosis of localized sclero250
Zulian et al
Comparison Between CLS and LO-JLS We compared the clinical-laboratory features of the 6 patients with CLS with those of 733 children with LO-JLS. The linear appearance of the lesions was present in 100% of the patients with CLS and in 65% of those with LO-JLS. However, although impressive, this difference did not reach statistical significance. The higher frequency of the linear ECDS subtype in CLS (67% vs 14%, P ⬍ .05) and the longer disease duration at diagnosis (3.9 years vs 1 year, 5 months, P ⬍ .01) were significant.
DISCUSSION Localized scleroderma, although uncommon, is a much more frequent type of scleroderma in childhood than is systemic sclerosis.1 However, to our knowledge, congenital onset has never been reported. We have described a series of six patients with onset of scleroderma-related findings at birth. Previous reported studies3-7 and one recent large, multicenter study8 show that JLS affects children during later childhood, with a mean age at disease onset ranging from 6.8 to 7.9 years, and without difference among the various subtypes.3-8 In these series, the youngest reported patients ranged in age between 1 and 2 years. In two prior studies, two cases, infants aged 2 weeks and 1 month, respectively, were reported.9,10 These probably had skin lesions at birth, but their clinical characteristics were not reported. Congenital localized scleroderma is rare or so underestimated a condition that it took almost 4 years for the patients to be correctly diagnosed. In two patients, a skin infection was initially considered, but antibiotic treatment was unsuccessful. In two patients, more common congenital conditions such as nevus or salmon patch were initially diagnosed, and in two, initial diagnostic considerations remain undefined. We were able to obtain pictures of the lesions at birth only for patient 1. In this patient, the lesion on the fronthead appeared consistent with a macular vascular stain known as a “salmon patch,” or “nevus simplex.” The lesion gradually became hyperpigmented and hard to the touch. In the other patients, the parents carefully described the lesions at birth as erythematous-hyperpigmented in three or hyperpigmented and hard in two. Vascular erythematous stains can sometimes precede other signs of more chronic localized scleroderma lesions, as in patient 1 in the present series. However, their relation with The Journal of Pediatrics • August 2006
Table. Clinical characteristics of patients with congenital localized scleroderma Patient
Sex
First diagnosis
1 2 3 4 5 6
F M F F F M
Salmon patch, alopecia Undefined skin lesion Undefined skin lesion Infection Infection, Borrelia Skin discoloration, naevus
Final diagnosis LS LS LS LS LS LS
(ECDS) (ECDS) (ECDS, limb, trunk) (limb) (limb) (ECDS)
Disease duration at diagnosis (y)
ANA
RF
3.5 4.8 5.1 2.2 2.4 5.2
neg 1/1280 1/640 1/80 neg neg
neg neg neg pos neg neg
LS, Linear scleroderma; ECDS, en coup de sabre; neg, negative; pos, positive; ANA, antinuclear antibodies; RF, rheumatoid factor.
CLS is not clearly defined. Alternatively, the erythema noted in several patients in this series may have been consistent with early inflammation of linear scleroderma. It has been observed that in some children with linear scleroderma, initial findings are misdiagnosed as “port wine stains” (personal observation, Lawrence F. Eichenfield, MD, Children’s Hospital, San Diego, CA). There are several congenital conditions that should be considered in the differential diagnosis. Stiff skin syndrome is a hereditary scleroderma-like disease that involves areas with abundant fascia such as thighs and buttocks. It causes symmetrical joint contractures and motion limitation of knees and hips. The symmetrical involvement of the limbs, the lack of epidermal discolorations, the sparing of the face, and histology picture of thick fascia with no inflammatory and muscle changes are the distinctive features of this condition.11,12 Giant congenital nevi, presenting as large, verrucous, brown or black plaques, can be sometimes surrounded by a sclerodermoid reaction resembling plaque morphea. This phenomenon is the result of an atypical host reaction to the nevus cells as proved by its involution after excision of the pigmented portion of the lesion. The oval-shaped morphology, the brown-dark color, and the pathology picture are distinctive differential features from CLS.13 Cafè-au-lait spots and mastocytosis may be present in the newborn infant. They have distinctive morphology, and mastocytosis lesions usually become edematous or erythematous with stroking (Darier sign). In neonates, macular stains, such as stork bite, salmon patches, or angel kiss, also known as “nevus simplex” are usually found on the nape of the neck, the eyelids, and on the glabellar region of the forehead. Distinct from scleroderma, they are usually transient.14 Portwine stains, as discussed above, may mimic early localized scleroderma. Congenital localized scleroderma in our series was characterized exclusively by linear lesions that involved the face, with ECDS features, in four of six patients. We do not have a clear explanation for the higher prevalence of this subtype at birth, but the possible role of potential
Congenital Localized Scleroderma
triggering events during pregnancy has been excluded because the medical history of the mothers was completely unremarkable. Finally, considering that ANAs were found to be positive in three of six patients, this may be of some help in differentiating CLS from other similar conditions.
REFERENCES 1. Zulian F. Scleroderma in children. Pediatr Clin North Am 2005;52:521-45. 2. Peterson LS, Nelson AM, Su WPD. Classification of morphea (localized scleroderma). Mayo Clin Proc 1995;70:1068-76. 3. Uziel Y, Krafchik BR, Silverman ED, Thorner PS, Laxer RM. Localized scleroderma in childhood: a report of 30 cases. Semin Arthritis Rheum 1994;23:328-40. 4. Vancheeswaran R, Black CM, David J, Hasson N, Harper J, Atherton D, et al. Childhood onset scleroderma: is it different from adult onset disease? Arthritis Rheum 1996;39:1041-9. 5. Marzano AV, Menni S, Parodi A, Borghi A, Fuligni A, Fabbri P, et al. Localized scleroderma in adults and children: clinical and laboratory investigations on 239 cases. Eur J Dermatol 2003;13:171-6. 6. Bodemer C, Belon M, Hamel-Teillac D, Amoric JC, Fraitag S, Prieur AM, et al. Scleroderma in children: a retrospective study of 70 cases. Ann Dermatol Venereol 1999;126:691-4. 7. Christianson HB, Dorsey CS, Kierland RR, O’Leary PA. Localized scleroderma: a clinical study of two-hundred and thirty-five cases. Arch Dermatol 1956;74:629-39. 8. Zulian F, Athreya BH, Laxer RM, Nelson AM, de Oliveira SKF, Punaro MG, et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children: an international study. Rheumatology (Oxford) 2006;45:614-20. 9. Chazen EM, Charles D, Cook CD, Cohen J. Focal scleroderma. J Pediatr 1962;60:385-93. 10. Dehen L, Roujeau JC, Cosnes A, Revuz J. Internal involvement in localized scleroderma. Medicine 1994;73:241-5. 11. Esterly NB, McKusick VA. Stiff skin syndrome. Pediatrics 1971;47:360-9. 12. Jablonska S, Blaszczyk M. Stiff skin syndrome is highly heterogeneous, and congenital fascial dystrophy is its distinct subset. Pediatr Dermatol 2004;21:508-10. 13. Pattee SF, Hansen RC, Bangert JL, Joganic EF. Giant congenital nevus with progressive sclerodermoid reaction in newborn. Pediatr Dermatol 2001;18:320-4. 14. Conlon DJ, Drolet BA. Skin lesions in the neonate. Pediatr Clin North Am 2004;51:863-88.
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