Latanya T. Benjamin

A Randomized, Controlled Trial of Oral Propranolol in Infantile Hemangioma

BACKGROUND Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).

An open-label study to evaluate sildenafil for the treatment of lymphatic malformations

BACKGROUND Lymphatic malformations can be challenging to treat. Mainstay interventions including surgery and sclerotherapy are invasive and can result in local recurrence and complications. OBJECTIVE We sought to assess the effect of 20 weeks of oral sildenafil on reducing lymphatic malformation volume and symptoms in children. METHODS Seven children (4 boys, 3 girls; ages 13-85 months) with lymphatic malformations were given oral sildenafil for 20 weeks in this open-label study. The volume of the lymphatic malformation was calculated blindly using magnetic resonance imaging performed before and after 20 weeks of sildenafil. Lymphatic malformations were assessed clinically on weeks 4, 12, 20, and 32. Both the physician and parents evaluated the lymphatic malformation in comparison with baseline. RESULTS Four subjects had a lymphatic malformation volume decrease (1.0%-31.7%). In 2 subjects, despite a lymphatic malformation volume increase (1.1%-3.7%), clinical improvement was noted while on sildenafil. One subject had a 29.6% increase in lymphatic malformation volume and no therapeutic response. Lymphatic malformations of all 6 subjects who experienced a therapeutic response on sildenafil softened and became easily compressible. Adverse events were minimal. LIMITATIONS A randomized controlled trial will be necessary to verify the effects of sildenafil on lymphatic malformations. CONCLUSIONS Sildenafil can reduce lymphatic malformation volume and symptoms in some children.

Mosaic Activating RAS Mutations in Nevus Sebaceus and Nevus Sebaceus Syndrome

To the editor: Nevus sebaceus is a common congenital skin hamartoma, classically appearing as a yellow-hued plaque on the scalp, face, or neck. It is the hallmark lesion of Schimmelpenning/nevus sebaceus syndrome (MIM: 163200), a multisystem disorder that includes a spectrum of central nervous system, ocular, skeletal, and cardiovascular defects. Secondary neoplasms arise within nevus sebaceus at a modest but elevated rate (Moody et al, 2012), prompting disagreement about whether they should be routinely excised (Shwayder, 2011). Determining the pathogenesis of nevus sebaceus would provide a framework to better understand this lesion and its associated syndrome. The appearance of nevus sebaceus along Blaschko’s lines suggests that a mosaic genetic mutation causes the lesion, with more extensive multisystem involvement potentially underlying the syndromic form (Happle, 1993). Here, we report a case of an individual with nevus sebaceus syndrome. As individuals with this syndrome are uncommon, we sought to identify associated mutations by comparing the exome sequence of the nevus sebaceus from our patient with those of sporadic nevus sebaceus. Our index patient is a 38-year old female who was born with Chiari malformation, myelomeningocele, and resultant paraplegia. Due to hydrocephalus and marked ventricomegaly, she required ventriculo-peritoneal shunt placement. Imaging studies demonstrated rotoscoliosis. She has had cognitive developmental delay and suffered from generalized seizures during childhood. In her early thirties, she experienced a middle right cerebral artery stroke. Despite her condition, she remains high functioning and lives in an assisted care facility. No other family members are affected by similar medical conditions, and no cause has been attributed to her findings. In the past year, the patient became bothered by growths on her forehead and presented to our clinic. On examination, she exhibited frontal bossing and a ~4 cm × ~3 cm yellow-tan, papillomatous plaque on the paramidline forehead that had been present since birth (Figure 1a). Several pedunculated papules were noted within the lesion. No other significant cutaneous findings were appreciated. Figure 1 Clinical and histologic features of a patient with nevus sebaceus syndrome Per patient request, the lesion was excised and a portion of the excision specimen was collected with her written informed consent. Our study complied with the Declaration of Helsinki Principles and was approved by the Stanford IRB. Histologic evaluation confirmed features of nevus sebaceus with no secondary neoplasms (Figure 1b). Accordingly, in light of the extensive neurological and skeletal involvement, a diagnosis of Schimmelpenning/nevus sebaceus syndrome was made. In efforts to determine an underlying genetic mutation, four additional, independent nevus sebaceus were collected from elective excisions along with adjacent normal skin controls. The five samples were subjected to exome sequencing and analyzed for mutations using Seqgene (Deng, 2011) and DNAnexus (www.dnanexus.com) as described in the Supplemental Text. Analysis of recurrent lesion-specific variants identified an HRAS point mutation (c.37G>C, p.Gly13Arg) in the index case and 2 of 4 isolated nevus sebaceus, with a variant allele frequency ranging from 17–43%. Sanger sequencing confirmed the HRAS mutation in all five lesional samples and its absence in all matched controls (Figure 2a). Examination of the two HRAS mutation-negative exomes showed low sequence coverage (<20 reads) at the mutation site, which may account for the false-negative calls. Figure 2 Activating mosaic RAS mutations in nevus sebaceus Lesions arising along Blaschko’s lines are hypothesized to stem from a mosaic mutation affecting a specific cell lineage during development. To evaluate whether the candidate mutation fit this criterion, we used laser capture microdissection to isolate DNA from the lesional epidermis and dermis from the index case and one of the sporadic nevus sebaceus. In both cases, the mutation was limited to the epidermis, supporting the hypothesis of an acquired mutation affecting ectodermal precursors (Figure 2b). Both alleles were represented in approximately equal intensities, indicating that the mutation is likely heterozygous. We next performed targeted Sanger sequencing on a validation set of 31 independent nevus sebaceus from archived tissues, and identified the HRAS p.Gly13Arg mutation in 24/31 samples and p.Gly12Asp in one sample. Remaining mutation-negative cases were evaluated for KRAS and NRAS hotspot mutations, identifying two samples carrying KRAS p.Gly12Asp mutations. Six validation samples had patient-matched normal skin tissue available, and the corresponding RAS mutations were absent in all six control samples. In total, 32 of 36 samples (89%) demonstrated HRAS or KRAS mutations, confirming a strong correlation between activating RAS mutations and nevus sebaceus (Figure 2c). We suspect that the remaining negative cases may be due to genetic heterogeneity, or to a low mutant allele frequency secondary to admixture with normal tissue. RAS promotes cell growth through activation of multiple pathways, chief among them the mitogen-activated protein kinase (MAPK) signal transduction pathway. Activating mutations in this gene family have well-established links to cancer (Schubbert et al, 2007). Germline activating HRAS mutations cause Costello syndrome, which features predisposition to neoplasia and development of cutaneous papillomas (Gripp and Lin, 2012). Taken together, the known biologic features of activated RAS genes are consistent with the hamartomatous overgrowth and elevated neoplasia risk observed in nevus sebaceus. To evaluate RAS-MAPK signaling, we performed phosphorylated ERK (pERK) staining on a set of nevi with confirmed HRAS mutations. Immunohistochemistry revealed increased pERK staining in lesional vs. normal epidermis, consistent with RAS-MAPK hyperactivation (Figure 2d). In one sample, a squamous cell carcinoma was identified arising from nevus sebaceus, highlighted by elevated p16 staining (Hodges and Smoller, 2002). The pattern of neoplasia arising from a background of upregulated pERK supports the hypothesis that RAS-MAPK hyperactivation may predispose towards development of secondary neoplasms in nevus sebaceus. Basal cell carcinomas were once thought to arise commonly from nevus sebaceus, but others have subsequently contended that the majority of these tumors are actually trichoblastomas (Cribier et al, 2000). Our data provide genetic support for the latter opinion, as most basal cell carcinomas arise from Hedgehog pathway dysregulation and lack RAS mutations (Reifenberger et al, 2005). Our findings also raise the possibility that tumors arising from nevus sebaceus, such as syringocystadenoma papilliferum and trichoblastomas, may be associated with RAS mutations as well. Using targeted sequencing and SNaPshot assays, Hafner and colleagues have recently profiled oncogenic hotspot mutations in epidermal and sebaceous nevi (Groesser et al, 2012; Hafner et al, 2012). Together with the results presented here and by others in this issue (Levinsohn et al, 2012), the cumulative data demonstrate that keratinocytic epidermal nevi and sebaceous nevi are both associated with activating HRAS p.Gly13Arg and KRAS p.Gly12Asp mutations, supporting the belief held by some clinicians they represent a spectrum of the same entity (Sybert, 2010). We postulate that the phenotypic difference between these nevi may be related to the extent of the mutation, as well as body site-specific embryologic patterns and environment. The knowledge of the genetic basis of nevus sebaceus and its associated syndrome represents a further step towards understanding genotype-phenotype correlations arising from genetic mosaicism.

Congenital epidermolysis bullosa acquisita: Vertical transfer of maternal autoantibody from mother to infant

BACKGROUND Epidermolysis bullosa acquisita (EBA) is a rare, chronic, autoimmune bullous dermatosis that is caused by autoantibodies against the noncollagenous terminus of the α chain of type VII collagen, resulting in decreased anchoring fibrils in the lamina densa. It classically presents with skin fragility and trauma-induced blisters that are particularly extensive over the distal aspect of the extremities and that heal with milia, dyspigmentation, and scarring, similar in presentation to dystrophic epidermolysis bullosa. Disease onset is typically in adulthood, although rare cases of childhood disease occur. To our knowledge, a case involving a neonate with congenital EBA has not yet been reported in the literature. We describe a newborn with transient EBA due to the passive transfer of maternal autoantibodies. OBSERVATIONS A 2-day-old girl was evaluated for tense blisters and areas of denuded skin that had been present since birth. Her mother carried the diagnosis of EBA. The results of histopathologic analysis, immunofluorescence studies, and enzyme-linked immunosorbent assay confirmed the diagnosis of neonatal EBA. The patient improved with supportive therapy and has not required systemic intervention. CONCLUSIONS Autoimmune neonatal bullous skin disease caused by placental transfer of maternal IgG autoantibodies is rare. It has been reported in neonates born to mothers with pemphigus vulgaris, pemphigus foliaceus, and gestational pemphigoid. To our knowledge, congenital EBA has not been previously reported. Vertically acquired congenital autoimmune blistering disorders appear to be self-limited and resolve with supportive therapy, concomitant with the presumed clearance of maternal autoantibodies from the neonates circulation.

Giant Aplasia Cutis Congenita without Associated Anomalies

Abstract:  Aplasia cutis congenita is a congenital condition in which skin, bone, and dura can be absent. The condition can present in isolation or with associated conditions such as limb anomalies or embryologic malformations. The majority of cases affect the scalp and are limited to the dermis and epidermis. Vertex aplasia cutis typically range in size from 0.5 to 3 cm. The rare larger scalp defects are prone to complications of hemorrhage and infection, and subsequently patients are at risk for death. For these reasons, surgical intervention for large defects may be required. We report the case of a 12‐month‐old Haitian boy who presented with aplasia cutis congenita of the scalp involving 10 cm of skin and 9 cm of underlying bone. There were no other associated anomalies.

Excess Adiposity Preceding Pediatric Psoriasis

As for adult psoriasis, pediatric psoriasis has recently been associated with obesity, increased waist circumference percentiles and waist-to-height ratios, and metabolic laboratory abnormalities1-3 (Supplemental Table 1). Although obesity could theoretically result from the functional limitations and psychosocial impact of psoriasis, adult females self-reported that obesity developed before psoriasis4 and high BMI in adolescent girls preceded psoriasis hospitalization in adults5. Whether obesity precedes pediatric psoriasis or psoriasis leads to childhood obesity has not been addressed. In a pilot study with a new cohort, we addressed the temporal association of pediatric psoriasis and increased adiposity in 27 overweight and obese psoriatic children.

Treatment of complex periorbital venolymphatic malformation in a neonate with a combination therapy of sirolimus and prednisolone.

Venolymphatic malformations (VLMs) are vascular anomalies consisting of both veins and lymph vessels. A 2‐week‐old newborn presented with large VLMs on the left forehead, temple, preauricular area, and orbit. Patient was at imminent risk for permanent vision loss due to a localized mass effect. Surgical excision or debulking was contraindicated due to its complexity and proximity to the left eye, and the patient failed to respond to the sildenafil treatment and sclerotherapy. Patient was subsequently started on oral sirolimus 0.8 mg/m2 twice daily in combination with prednisolone 2 mg/kg daily. The patient had an excellent therapeutic outcome for 7 months with complete preservation of vision before treatment was discontinued. However, 2 months after the medical treatments were discontinued, her VLM rebounded. She responded to the combination therapy again after a failed treatment with the mTOR inhibitor alone. This case demonstrates that the sirolimus and prednisolone combination therapy could be beneficial for treatment of complex VLM intractable to other treatments.

Distraction Anesthesia for Pediatric Dermatology Procedures

Minor dermatologic surgery procedures performed on pediatric patients pose significant challenges not apparent in adult patients. Most pediatric patients are frightened when they enter the doctor’s office, especially if they are expecting a painful procedure. Studies have shown that it is imperative to provide a workflow that is tailored to the child’s needs, such as providing a comfortable ambiance and having an understanding of child development appropriate for a particular age group (1,2). The power of the child’s mind is remarkable; therefore, it is advantageous to integrate distraction techniques while performing a painful procedure. These techniques are beneficial for dermatologists in order to perform minor surgical procedures on children more efficiently. We report a method of distraction anesthesia unique to pediatric patients. We feel our guidelines for distraction anesthesia can minimize pain and psychologic trauma, decrease the time of the average pediatric procedure by avoiding unnecessary steps such as bargaining or using further restraints, lower medical costs, and ultimately circumvent risky side effects by evading general anesthesia. These simple surgical pearls will provide effective perioperative pain therapy for minor, out-patient surgical dermatologic procedures on children.

Successful acne management in Apert syndrome twins.

Abstract:  Apert syndrome, or acrocephalosyndactyly, is characterized by craniosynostosis and early epiphyseal closure resulting in various deformities of the skull, hands, and feet. Typically a sporadic condition, autosomal dominant inheritance with complete penetrance has been known to occur. Most adolescents with the disorder are prone to the development of severe pustular facial and truncal acne, with extension to the upper arms and forearm. We report twin brothers with Apert syndrome who, after 2 years of standard management by their pediatrician, were referred for management of complicated acne. In our patients there were a constellation of findings consistent with the disorder and, of importance to this report, significant dermatological manifestations. On presentation, each brother was found to have acne vulgaris of a different stage. Our patients were refractory to conventional treatment for acne but one required and had a significant response to isotretinoin. The risk/benefit ratio in treating acne lesions with isotretinoin in a teenager with Apert syndrome is reviewed.

Delineating capillary malformations in the operating suite using white eyeliner pencil.

Abstract:  Delineating the extent of capillary malformations in the operating suite can be challenging because of a variety of physiologic modifiers, including vasodilatation induced by anesthesia, reactive erythema, and filtering of colors with protective laser eyewear. The use of traditional surgical pens to mark the treatment field has limitations; we have found the use of a white eyeliner pencil to delineate lesions a contemporary technique that assists in identifying the target tissue intraoperatively.