Gayle Fischer

Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast‐flow vascular anomalies are caused by RASA1 mutations

Capillary malformation‐arteriovenous malformation (CM‐AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one‐third had fast‐flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast‐flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM‐AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity. Hum Mutat 29(7), 959–965, 2008.

Oral Propranolol Therapy for Infantile Hemangiomas Beyond the Proliferation Phase: A Multicenter Retrospective Study

Abstract:  Pharmacological therapies for infantile hemangiomas were considered effective only during the proliferative phases. Recently reported beneficial effects of propranolol may extend beyond the proliferative phase of infantile hemangiomas. The purpose of the study was to assess the effect of oral propranolol therapy for infantile hemangiomas beyond the proliferative phase of these lesions. Members of the Society for Pediatric Dermatology were invited to participate in a multicenter retrospective study. Only children with infantile hemangiomas with documented cessation of lesions’ growth or those older than 12 months of age were eligible for the study. Clinical and demographic information and digital photographs before, at the start, and following the treatment were collected. Scaled panels of photographs were distributed among preselected experienced pediatric dermatologists. Visual analog scale was used to assess photographs for each case. Paired t‐test was used for statistical analyses. Data on 49 eligible patients from eight pediatric dermatology centers was collected. Seven cases were excluded because of insufficient photographic documentation. The age of the patients at the start of propranolol therapy ranged 7 to 120 months (mean 28 mos, median 22 mos). The duration of propranolol therapy ranged 1 to 8 months (mean 3.6 mos). The mean visual analog scale score before the treatment was 6.8 ± 2.15, and mean reduction in the visual analog scale score at the assessment was 2.6 ± 1.74 (p < 0.001). The rate of visual analog scale reduction was 0.4 per month before the start of the therapy, while this rate was accelerated to 0.9 per months following the therapy (p < 0.001). No significant side effects were reported. We conclude that propranolol is effective in infantile hemangiomas, including post‐proliferative phase, and should be considered as the first‐line therapy in that setting.

IFAP Syndrome Is Caused by Deficiency in MBTPS2, an Intramembrane Zinc Metalloprotease Essential for Cholesterol Homeostasis and ER Stress Response

Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder. Here, we assign the IFAP locus to the 5.4 Mb region between DXS989 and DXS8019 on Xp22.11-p22.13 and provide evidence that missense mutations exchanging highly conserved amino acids of membrane-bound transcription factor protease, site 2 (MBTPS2) are associated with this phenotype. MBTPS2, a membrane-embedded zinc metalloprotease, activates signaling proteins involved in sterol control of transcription and ER stress response. Wild-type MBTPS2 was able to complement the protease deficiency in Chinese hamster M19 cells as shown by induction of an SRE-regulated reporter gene in transient transfection experiments and by growth of stably transfected cells in media devoid of cholesterol and lipids. These functions were impaired in five mutations as detected in unrelated patients. The degree of diminished activity correlated with clinical severity as noted in male patients. Our findings indicate that the phenotypic expression of IFAP syndrome is quantitatively related to a reduced function of a key cellular regulatory system affecting cholesterol homeostasis and ability to cope with ER stress.

Corticosteroid phobia and other confounders in the treatment of childhood atopic dermatitis explored using parent focus groups.

Background/Objectives:  Anxieties associated with corticosteroid treatment and preference for ‘safer natural therapy’ are common in parents of children with atopic dermatitis. We used focus groups to explore the source of these attitudes.

Long-term Management of Adult Vulvar Lichen Sclerosus: A Prospective Cohort Study of 507 Women

IMPORTANCE Adult vulvar lichen sclerosis (VLS) may be complicated by loss of vulvar structure and vulvar carcinoma. There is a lack of evidence as to the ideal method to maintain long-term remission and prevent complications. OBJECTIVES To determine whether long-term preventive topical corticosteroid (TCS) treatment of VLS, with a target outcome of induction and maintenance of normal skin texture and color, reduces the risk of vulvar carcinoma, relieves symptoms, improves function, and preserves vulvar architecture, and to evaluate the adverse effects of treatment. DESIGN, SETTING, AND PARTICIPANTS A prospective longitudinal cohort study was conducted in 507 women with biopsy-proved VLS from January 2, 2008, through September 26, 2014, in the private practice of a dermatologist and a gynecologist in Sydney, Australia. INTERVENTIONS Preventive treatment using TCSs of various potencies, adjusted to meet a target outcome of normal skin color and texture, with regular long-term follow-up by a dermatologist or gynecologist. MAIN OUTCOMES AND MEASURES Symptoms or signs of VLS, scarring, development of malignant neoplasms, and adverse effects. RESULTS The mean age at presentation was 55.4 years (range, 18-86 years); duration of symptoms at presentation, 5.0 years (range, 0.1-40.0 years); and duration of follow-up, 4.7 years (range, 2.0-6.8 years). Remission was induced with a potent TCS, followed by regular preventive TCS treatment of a potency titrated to achieve the target outcome. Patients were followed up at least annually. A total of 150 patients (29.6%) did not carry out the advised treatment and were considered partially compliant. A total of 357 patients (70.4%) adhered to treatment instructions and were considered compliant. Biopsy-proved squamous cell carcinoma or vulvar intraepithelial neoplasia occurred during follow-up in 0 of the compliant patients vs. 7 (4.7%) of the partially compliant patients (P < .001). Suppression of symptoms occurred in 333 (93.3%) compliant patients vs. 87 (58.0%) partially compliant patients (P < .001). Adhesions and scarring occurred during follow-up in 12 (3.4%) compliant patients and 60 (40.0%) partially compliant patients (P < .001). Reversible TCS-induced cutaneous atrophy occurred in 4 (1.1%) compliant patients and 3 (2.0%) partially compliant patients. CONCLUSIONS AND RELEVANCE This prospective, single-center, longitudinal cohort study of adult patients with VLS suggests that individualized preventive TCS regimens that achieve objective normality of skin color and texture and are used by compliant patients who attend regular long-term follow-up visits may modify the course of the disease. There was a significant difference in symptom control, scarring, and occurrence of vulvar carcinoma between compliant and partially compliant patients. The adverse effects of TCSs were minimal.

Long-term management of vulval lichen sclerosus in adult women

Background:  Adult vulval lichen sclerosus (VLS) is usually a lifelong disease with an estimated remission rate after treatment of only 16% [Arch Dermatol 2004; 140 (6): 709]. Although superpotent topical corticosteroid (TCS) is the validated gold standard treatment to induce remission, little data are available on how remission should be maintained.

Vulval disease in pre‐pubertal girls

Children present with vulval complaints less frequently than do adults; although there are many similarities between paediatric and adult groups of patients with vulval disease, there are also important differences. In both groups, dermatitis, psoriasis and lichen sclerosus are the most frequently seen dermatoses. Birthmarks and congenital abnormalities presenting for the first time are more of an issue in children than in adults. Fusion of the labia and streptococcal vulvovaginitis are conditions seen only in the paediatric group. Sexually transmitted diseases such as genital warts and genital herpes are not common in this group and should always raise the possibility of child sexual abuse. Chronic vulvovaginal candidiasis, although a very common problem in adult patients, is not seen in the prepubertal group.

Management of vulvovaginal lichen planus: a new approach.

Objective This study aimed to report on a novel approach to therapy in a large private dermatogynecology practice using multimodal therapies with adjunctive use of systemic agents where necessary. Materials and Methods This was a retrospective audit of the presentation and management of 131 patients with a clinical diagnosis of vulvovaginal lichen planus. Results The most frequently presenting symptoms were genital soreness, itch, and burning. Of the 131 patients, 39 (30%) had extragenital disease, mainly oral. Eighty-four (64%) had no external disease. Twenty-two (17%) had introital erosions as the only visible abnormality. Fifty-five (42%) had some degree of labial fusion. Two had full-thickness vulval intraepithelial neoplasia (VIN). Remission induction was achieved in most patients with superpotent topical steroids, but 53 (40%) of 131 patients used oral prednisolone either as an adjunct therapy or alone. All compliant patients achieved symptomatic and objective disease control in a mean of 7.5 weeks. Of the 131 patients, 48 (37%) required multimodal therapy to maintain their initial improvement. Forty-five (34.3%) patients used topical tacrolimus, usually with topical corticosteroids, for maintenance. Eleven (8.5%) required low-dose weekly methotrexate. Fourteen patients experienced adverse reactions severe enough to lead to the cessation of that treatment. The mean length of follow-up was 6.4 years (range = 1 mo to 15 y). The 2 patients with VIN at presentation have had no recurrence. No other patient has yet developed VIN or carcinoma. Conclusions Long-term symptomatic and objective control of vulvovaginal lichen planus is possible but requires multimodal therapies, flexible treatment programs, and the judicious use of oral agents.

Childhood Onset Vulvar Lichen Sclerosus Does Not Resolve at Puberty: A Prospective Case Series

Abstract:  When vulvar lichen sclerosus occurs in prepubertal children it is widely believed that it is likely to remit at puberty. However when it occurs in adult women it is accepted that remission is unlikely and that in addition untreated or inadequately treated disease may be complicated by significant disturbance of vulvar architecture and less commonly squamous cell carcinoma. Our database reveals 18 girls who developed lichen sclerosus prior to puberty who are now adolescents or young adults. Twelve have remained under surveillance and the other six patients have been lost to follow‐up. We report a prospective series of these 12 patients. Three patients have achieved complete remission sustained for three or more years, all prior to menarche. Nine patients, or 75% of the cohort, who still had active lichen sclerosus at puberty continue to require maintenance therapy after menarche. Of the 12, six have had significant disturbance of vulvar architecture. The concept that prepubertal lichen sclerosus resolves at puberty would appear not to be true in the majority of patients. Even when diagnosed early and treated effectively, childhood onset lichen sclerosus may be complicated by distortion of vulvar architecture.

Treatment of erosive vulvovaginal lichen planus with methotrexate

We report the successful treatment of severe long‐standing erosive vulvovaginal lichen planus in four adult female patients using 2.5–7.5 mg of oral methotrexate once weekly in conjunction with topical clobetasol dipropionate 0.05% ointment and tacrolimus 0.03–0.10% ointment. All cases experienced improvement in symptoms and healing of lesions within 4–8 weeks. Methotrexate was well tolerated and no adverse events have been observed in any of the patients at follow up 4–6 months later.