Prospective evaluation of treatment response and disease reversibility of paediatric localized scleroderma (morphoea) to steroids and methotrexate using multi-modal imaging.

BACKGROUND: Paediatric localized scleroderma is a severe inflammatory disorder associated with tissue atrophy, often leading to disability. Assessing disease activity and response to treatment has always been challenging and remains an important difficulty in clinical practice. OBJECTIVES: To investigate prospectively the efficacy of systemic treatment with corticosteroids and methotrexate in children with localized scleroderma and the validity of infrared thermography, laser Doppler flowmetry and high-frequency ultrasound in assessing disease activity. METHODS: Children with localized scleroderma were prospectively treated with corticosteroids (initially pulsed IV methylprednisolone 30 mg/kg/day, maximum 500 mg/day and/or oral prednisolone 0.5-1 mg/kg/day) and methotrexate (15 mg/m2 weekly). Treatment response was evaluated using a clinical activity score. Skin temperature, blood flow, dermal thickness and dermal echogenicity of clinically active skin lesions were determined in relation to the unaffected contralateral site at baseline and after 3, 6, 12 and 18 months. Patient charts were later reviewed for long-term follow-up. RESULTS: Twenty-two patients were included [age 6.0 (0.2-14.4] years; female-to-male ratio 3.4 : 1) All responded well to therapy. Disease reversibility was demonstrated in the majority of children with partial resolution of skin sclerosis and regrowth of hair. Laser Doppler flowmetry and high-frequency ultrasound findings correlated with disease activity at baseline. Thermography had no added value in this cohort. The recurrence rate was 36% in the follow-up period. CONCLUSIONS: Corticosteroids and methotrexate are highly effective as first-line therapy in paediatric localized scleroderma, leading to partial reversal of skin manifestations. However, the recurrence rate is substantial and affected children require long-term follow-up. Laser Doppler flowmetry and high-frequency ultrasound correlate with disease activity in the acute phase and may assist decision-making in these patients.

Great Ormond Street Hospital treatment guidelines for use of propranolol in infantile isolated subglottic haemangioma.

OBJECTIVE: Treatment options for large subglottic haemangioma include steroids, laser ablation, open excision, tracheostomy and, more recently, propranolol. This article aims to present the Great Ormond Street Hospital guidelines for using propranolol to treat infantile isolated subglottic haemangioma by ENT surgeons. METHODS: The vascular malformations multidisciplinary team at Great Ormond Street Hospital has developed guidelines for treating infantile haemangioma with propranolol. RESULTS: The Great Ormond Street Hospital guidelines for propranolol treatment for infantile subglottic haemangioma include investigation, treatment and follow up. Propranolol is started at 1 mg/kg/day divided into three doses, increasing to 2 mg/kg/day one week later. On starting propranolol and when increasing the dose, the pulse rate and blood pressure must be checked every 30 minutes for the first 2 hours. Lesion response to treatment is assessed via serial endoscopy. CONCLUSION: Recent reports of dramatic responses to oral propranolol in children with haemangioma and acute airway obstruction have led to increased use. We advocate caution, and have developed guidelines (including pre-treatment investigation and monitoring) to improve treatment safety. Propranolol may in time prove to be the best medical treatment for subglottic haemangioma, but at present is considered to be still under evaluation.

Misdiagnosis and delay in referral of children with localized scleroderma.

BACKGROUND: Localized scleroderma (LS) usually begins in childhood with a broad clinical spectrum and the diagnosis is often delayed. OBJECTIVES: To investigate the diagnostic pathway in a large cohort of paediatric patients with LS, to identify the duration until correct diagnosis and to characterize clinical clues for early diagnosis. METHODS: A retrospective case note review of 50 children with LS. RESULTS: The median (range) age at disease onset was 5·2 (0·1-14·4) years and disease duration until diagnosis 11·1 (1·8-79) months. The patients were first seen by a general practitioner (or paediatrician) after 1·2 (0·2-48·7) months and in none of the cases was the condition recognized at presentation according to a parental questionnaire (no diagnosis in 44%, misdiagnosis of atopic eczema 20%, melanocytic naevus 8%, fungal infection 6%, bruise 4%, varicose vein 4%, bacterial infection 4% and others). The patients were referred to a local specialist (dermatologist in 72%) after a disease duration of 7·5 (1·0-70·9) months and in 64% the correct diagnosis was established. In 20% the diagnosis remained unknown, 8% were misdiagnosed as port-wine stains and others as atopic eczema and melanocytic naevus. The correct diagnosis was eventually identified by the referring dermatologists, the paediatric dermatologists at our hospital, external maxillofacial surgeons and a paediatrician in 29 (58%), 17 (34%), 3 (6%) and 1 (2%), respectively. Histology was performed in 15 (30%). The patients were commenced on appropriate treatment after a disease duration of 16·6 (1·8-113·4) months. The main clinical diagnostic clues were: Blaschko-linear distribution 76%, atrophic changes 68%, skin fibrosis 40% and loss of scalp hair or eyelashes 36%. CONCLUSIONS: Physicians involved in the care of these children need to be aware of the characteristic clinical appearance of LS for early recognition and prompt initiation of treatment.

A study of matrix metalloproteinase expression and activity in atopic dermatitis using a novel skin wash sampling assay for functional biomarker analysis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin condition that is characterized by a defective skin barrier. Despite the well-recognized role of proteases in skin barrier maintenance, relatively little is known of the contribution made by matrix metalloproteinases (MMPs) to the inflammatory process in AD. OBJECTIVES: To test a simple, novel ex vivo bioassay technique in an analysis of the MMPs present in wash samples taken from the skin surface of patients with AD. METHODS: Saline wash samples were collected from eczematous and unaffected areas of the skin of patients with AD and from the skin of normal controls. Wash samples were analysed for their MMP content using a functional peptide cleavage assay, gelatin zymography and an antibody array. RESULTS: Using a functional substrate cleavage assay, skin wash samples from AD lesions were shown to contain 10- to 24-fold more MMP activity than those from normal control skin (P < 0.02) and fivefold more than those from unaffected AD skin (P < 0.05); this activity was inhibited by a broad-spectrum MMP inhibitor Ro 31-9790. Gelatin zymography and antibody array analysis revealed substantial levels of MMP-8 (neutrophil collagenase) and MMP-9 (92-kDa gelatinase) in AD skin wash samples as well as lower levels of MMP-10 (stromelysin 2) and tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2; low levels of MMP-1 (fibroblast collagenase), MMP-3 (stromelysin 1) and TIMP-4 were also detected. CONCLUSIONS: A simple skin wash technique suitable for the quantitative and functional analysis of biomolecules in AD is described. Using this method we show that MMPs, and in particular MMP-8 and MMP-9, represent an important potential component of the pathology of AD. The method is expected to prove useful in advancing our understanding of AD and in identifying biomarkers for the evaluation of new therapies.

Neonatal haemangiomatosis associated with placental chorioangiomas: report of three cases and review of the literature.

We report three cases of neonatal haemangiomatosis associated with large placental chorioangioma. Pregnancies were complicated by polyhydramnios, and all mothers underwent amniocentesis to drain the liquid. Steroid treatment was required for two children. Although the theory has been largely disproved in normal haemangiomas, embolization of precursor endothelial cells derived from placental vessels is a likely explanation for the pathogenesis of haemangiomatosis associated with large placental chorioangiomas.

A heterozygous null mutation combined with the G1258A polymorphism of SPINK5 causes impaired LEKTI function and abnormal expression of skin barrier proteins.

BACKGROUND: Loss-of-function mutations in the Kazal-type serine protease inhibitor, LEKTI, encoded by the SPINK5 gene cause the rare autosomal recessive skin disease Netherton syndrome (NS). G1258A polymorphism in SPINK5 may be associated with atopic dermatitis, which shares several clinical features with NS. OBJECTIVES: To determine if the phenotype of NS can be caused by a single null mutation in SPINK5 combined with the homozygous G1258A polymorphism. METHODS: We screened mutations in the gene SPINK5 by direct DNA sequencing and position cloning and examined the expressions of the SPINK5-encoded protein LEKTI and other relevant proteins by immunostaining and immunoblot. RESULTS: We describe here a patient who was clinically diagnosed with NS and carried a single null mutation in SPINK5 combined with the homozygous G1258A polymorphism. SPINK5 mRNA was present at normal levels and LEKTI was expressed in the epidermis. Nonetheless, the putative downstream LEKTI substrates stratum corneum trypsin-like enzyme (SCTE), desmoglein 1 and protein markers of keratinocyte differentiation were expressed abnormally, similar to that seen in NS if two null mutant alleles are present. CONCLUSION: This finding indicates that haploinsufficiency of SPINK5 can cause the NS phenotype in the presence of one null mutation with homozygous G1258A polymorphisms in SPINK5, and this could impair the function of LEKTI and therefore acts as a true mutation.

Bullous pemphigoid in an infant using complementary medicine.

Bullous pemphigoid (BP) is an acquired immunobullous disorder rarely seen in childhood. We report the case of an infant with BP successfully treated with oral corticosteroids. The onset of BP was associated with use of complementary medications and we speculate that these may have been triggering factors.

Linear morphoea follows Blaschko's lines.

BACKGROUND: The aetiology of morphoea (or localized scleroderma) remains unknown. It has previously been suggested that lesions of linear morphoea may follow Blaschko's lines and thus reflect an embryological development. However, the distribution of linear morphoea has never been accurately evaluated. OBJECTIVES: We aimed to identify common patterns of clinical presentation in children with linear morphoea and to establish whether linear morphoea follows the lines of Blaschko. METHODS: A retrospective chart review of 65 children with linear morphoea was performed. According to clinical photographs the skin lesions of these patients were plotted on to standardized head and body charts. With the aid of Adobe Illustrator a final figure was produced including an overlay of all individual lesions which was used for comparison with the published lines of Blaschko. RESULTS: Thirty-four (53%) patients had the en coup de sabre subtype, 27 (41%) presented with linear morphoea on the trunk and/or limbs and four (6%) children had a combination of the two. In 55 (85%) children the skin lesions were confined to one side of the body, showing no preference for either left or right side. On comparing the overlays of all body and head lesions with the original lines of Blaschko there was an excellent correlation. CONCLUSIONS: Our data indicate that linear morphoea follows the lines of Blaschko. We hypothesize that in patients with linear morphoea susceptible cells are present in a mosaic state and that exposure to some trigger factor may result in the development of this condition.

A pilot study showing pulsed-dye laser treatment improves localized areas of chronic atopic dermatitis.

BACKGROUND: Eczematous skin changes overlying port-wine stains have been reported to improve with pulsed-dye laser (PDL) treatment. However, PDL has not as yet been evaluated for the treatment of atopic dermatitis (AD; eczema). AIM: To evaluate in a controlled trial the effects and safety of PDL treatment in children with AD who had chronic localized lesions. METHODS: Twelve children with localized, chronic eczema were treated with PDL (595 nm), with untreated areas used as an intrapatient control. Treatment was given at baseline and patients were followed up at 2 and 6 weeks. Clinical outcome measures were localized Eczema Severity Score (ESS), a visual analogue scale (VAS) indicating eczema severity assessed by photographs, and adverse events. RESULTS: After 2 and 6 weeks, a significant decrease in ESS was seen for the PDL-treated areas compared with the control areas (mean +/- SEM reduction in ESS 7.0 +/- 1.0 vs. 3.3 +/- 0.8 at 2 weeks, P = 0.003, and 7.8 +/- 1.4 vs. 4.9 +/- 1.3 at 6 weeks, P = 0.002). A significant difference in eczema severity assessed by VAS at 6 weeks was seen in favour of PDL (mean +/- SEM improvement 78% +/- 20% vs. 52% +/- 10%, P = 0.003). Treatment was well-tolerated. CONCLUSIONS: In this pilot study, PDL treatment was effective in treating small areas of chronic localized eczema. This may suggest that in AD dermal vasculature plays an important role or that PDL may have an effect on cutaneous immunological activation.

Histopathological features of Proteus syndrome.

BACKGROUND: Proteus syndrome is a rare, sporadic overgrowth disorder for which the underlying genetic defect remains unknown. Although the clinical course is well-described there is no systematic histopathological description of the lesional pathology. OBJECTIVE: To describe the histopathological features encountered in a series of patients with Proteus syndrome from a single centre. METHODS: Patients with Proteus syndrome who had undergone therapeutic surgical resection or biopsy were identified from a database and the histopathological findings were reviewed, with particular regard to descriptive features of the underlying tissue abnormality. RESULTS: There were 18 surgical specimens from nine patients, median age 4 years (range 1-9), classified into four main categories: soft-tissue swellings (lipomatous lesions), vascular anomalies (vascular malformation and haemangioma), macrodactyly (hamartomatous overgrowth) and others (sebaceous naevus and nonspecific features). In all cases, the clinical features of overgrowth were due to increased amounts of disorganized tissue, indicating a hamartomatous-type defect in which normal tissue constituents were present, but with an abnormal distribution and architecture. Vascular malformations represented a prominent category of lesions, accounting for 50% of the specimens, predominantly comprising lymphatic and lymphovascular malformations. No malignancy or cytological atypia was identified in any case. CONCLUSIONS: The histopathological features of lesions resected from children with Proteus syndrome predominantly include hamartomatous mixed connective tissue lesions, benign neoplasms such as lipomata, and lymphatic-rich vascular malformations.

Extensive venous/lymphatic malformations causing life-threatening haematological complications.

BACKGROUND: Large venous/lymphatic slow-flow malformations (SFM) can be associated with a coagulopathy resulting in thrombosis and haemorrhage. Such potentially life-threatening complications of SFM have been reported only rarely. OBJECTIVES: To better define the clinical characteristics of haematological complications associated with SFM, to highlight the importance of recognition and to discuss the management of these difficult-to-treat patients. PATIENTS AND METHODS: A cohort of six children who presented with massive SFM associated with serious haematological complications was seen between January 1980 and June 2005 in the Department of Paediatric Dermatology, Great Ormond Street Hospital for Children, London, U.K. (tertiary referral centre for vascular anomalies). Clinical and haematological characteristics were recorded. RESULTS: Patients were aged 1-20 years. All suffered with recurrent episodes of pain, localized skin necrosis and bleeding. All had intravascular coagulopathy and life-threatening complications. These included brain haemorrhage, massive bleeding from the uterus and colon, large and extensive thromboses of the deep vessels in the abdomen and pelvis and severe haemoptysis. One patient died suddenly at the age of 20 years from pulmonary thromboembolism and thrombosis within the deep vessels of the vascular malformation. The youngest patient underwent a leg amputation to remove the huge vascular malformation due to the major risk of complications and lack of limb function. Three of the patients underwent anticoagulation treatment and showed improvement in their coagulopathy. CONCLUSIONS: It is essential that patients with extensive SFM have their coagulation screened regularly to detect intravascular coagulopathy. This may progress to disseminated vascular coagulopathy and a serious risk of thrombosis and haemorrhage. Such patients require early anticoagulation in an attempt to prevent these secondary complications.

Hutchinson-Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature ageing disorder that belongs to a group of conditions called laminopathies which affect nuclear lamins. Classical and atypical forms of HGPS have been reported and there are clinical overlaps with mandibulo-acral dysplasia and restrictive dermopathy. To date, mutations in two genes, LMNA and ZMPSTE24, have been found in patients with HGPS. The p.G608G LMNA mutation is the most commonly reported mutation. Correlations between genotype and phenotype in children with progeroid syndromes are beginning to emerge. OBJECTIVES: To establish whether the LMNA p.G608G mutation is associated with a particular phenotype of HGPS. METHODS: We reviewed the clinical features and skin histology of three children with HGPS associated with the p.G608G LMNA mutation, and compared our findings with those reported in the literature. RESULTS: Our patients shared a very similar presentation and clinical course. Skin changes were the earliest finding in all three. Skin histology showed nonspecific changes only. CONCLUSIONS: The LMNA p.G608G mutation results in a uniform phenotype through early to mid-childhood, in keeping with that described in classical HGPS. Skin changes are the earliest distinctive clinical finding and should prompt careful physical and radiological examination for other features of HGPS. Skin biopsy for histology is not a useful investigation when a diagnosis of HGPS is suspected.

Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients.

BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by the association of skin lesions, hearing loss and vascularizing keratitis. KID syndrome is caused by autosomal dominant mutations in the connexin 26 gene (GJB2). OBJECTIVES: To establish whether there is a correlation between genotype and phenotype in KID syndrome. METHODS: Clinical examination and molecular analysis of GJB2 were performed in a cohort of 14 patients with KID syndrome originating from 11 families. We also reviewed the 23 cases with molecular analysis previously reported in the literature. RESULTS: The patients displayed the classical signs of KID syndrome with the additional finding of inflammatory nodules in six patients (43%); this clinical finding has not been described previously in the literature. One patient presented at the age of 18 years with a fatal carcinoma of the tongue, an extremely rare reported complication. For seven of the 11 families (64%) the disease was sporadic, whereas it was familial in the remaining four families (36%). Twelve patients (86%) were heterozygous for the p.Asp50Asn mutation and two patients (14%) were heterozygous for the p.Ser17Phe mutation. Surprisingly, a family in which we personally examined the healthy parents had two affected children heterozygous for the p.Asp50Asn mutation, suggesting germinal mosaicism. Compared with patients with the p.Asp50Asn mutation, the two patients with the p.Ser17Phe mutation had more severe skin involvement. One of these two patients experienced a carcinoma of the tongue. CONCLUSIONS: Familial cases appear to be more frequent than reported in the literature. The possibility of germinal mosaicism must be taken into account for genetic counselling. This study also suggests that patients with the p.Ser17Phe mutation may have a more severe phenotype and could be at higher risk for tongue carcinoma.

Serine proteases, their inhibitors and allergy.

This paper reviews four serine protease inhibitors and three protease gene defects that are associated with allergic conditions, suggesting an important role for these genes and their products in the development of allergy. Serine protease inhibitors may have a therapeutic potential in the treatment of allergy.

Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children.

BACKGROUND: Localized scleroderma (LS) or morphoea is often considered to be a benign self-limiting condition confined to the skin and subcutaneous tissue. However, the course of the disease is unpredictable and severe functional and cosmetic disability may result. Drug treatment with systemic corticosteroids in combination with methotrexate has been reported to be beneficial in LS, but data in children is limited. OBJECTIVES: To evaluate the efficacy and tolerability of systemic corticosteroids in combination with methotrexate in children with LS. METHODS: Treatment and outcome of 34 patients with LS were retrospectively analysed. Pulsed intravenous methylprednisolone was given, followed by oral prednisolone on a reducing regimen and maintenance treatment with methotrexate. We assessed treatment outcome clinically and by thermography and monitored adverse events. RESULTS: From the onset of treatment, the disease stopped progressing in 94% of the patients. All patients demonstrated significant clinical improvement within a mean time of 5.7 +/- 3.9 months. Mean duration of follow-up over the treatment period and beyond was 2.9 +/- 2.0 years. In 16 (47%) patients therapy was discontinued when the disease was considered to be inactive clinically; however, seven (44%) of the 16 developed a relapse, necessitating repeat treatment. At last follow-up (range 0.2-7.0 years), 24 (71%) of the 34 patients had completely inactive disease. Observed adverse events were moderate and transient and no patient had to stop therapy. CONCLUSIONS: These data suggest that systemic corticosteroids and methotrexate in combination are beneficial and well tolerated in the treatment of children with LS. Because of the risk of relapse after discontinuing therapy, long-term monitoring is mandatory.

Absent/reduced glucose transporter-1 protein expression in infantile subglottic haemangiomas.

BACKGROUND: Positive immunohistochemical staining for glucose transporter-1 protein (GLUT1) is a characteristic of cutaneous infantile haemangiomas. OBJECTIVES: To examine GLUT1 expression in subglottic haemangiomas. METHODS: Review of clinical notes and biopsy tissue with immunostaining for GLUT1 in 14 patients with subglottic haemangiomas. RESULTS: GLUT1 immunostaining was negative in 11 cases, and focally positive in three. No subglottic haemangiomas demonstrated the intense diffuse positive GLUT1 staining seen in cutaneous infantile haemangiomas. Five patients had cutaneous as well as subglottic haemangiomas, one of whom had a GLUT1-negative subglottic haemangioma and a GLUT1-positive cutaneous haemangioma of the lip. CONCLUSIONS: Subglottic haemangiomas appear immunohistochemically different from cutaneous infantile haemangiomas, which may reflect differences in endothelial cell differentiation or underlying aetiology.