Questioning the Clinical Utility of Exome Sequencing in Developing Countries.

The availability of whole-exome sequencing has revolutionized the study of genetic disease in recent years, particularly in dermatology, where clinical phenotypes are readily recognized. As this technology becomes increasingly affordable and accessible, questions are emerging regarding the clinical and ethical responsibilities of physicians who determine variants underlying disease, especially with regard to children, for whom treatment may be warranted and clinical course improved based on a known genotype. These responsibilities are accentuated in the developing countries, which harbor most consanguineous populations and thus bear the brunt of monogenic genodermatoses. Although many genetic disorders are identified in these populations, limited educational and clinical infrastructure rarely offers opportunities to improve the course of disease. Here we report a genetic study that illustrates these challenges.

Atypical Fibroxanthoma in a 13-Year-Old Guatemalan Girl with Xeroderma Pigmentosum.

Xeroderma pigmentosum (XP) is a rare, autosomal recessive disease involving a defect in DNA repair leading to the premature development of numerous aggressive cutaneous malignancies. Although atypical fibroxanthoma (AFX) is a neoplasm typically found in the setting of extensive sun exposure or therapeutic radiation, AFXs are rarely associated with children with XP. We report the case of a 13-year-old Guatemalan girl with the XP type C variant who developed one of the largest AFXs reported on a child's finger.

Photodynamic therapy in a teenage girl with xeroderma pigmentosum type C.

Despite aggressive sun protection, most individuals with xeroderma pigmentosum (XP) develop cutaneous neoplasia, including actinic keratoses. We describe the case of a 16-year-old girl with XP type C treated safely with photodynamic therapy (PDT). Although there is little if any evidence in the literature supporting the use of aminolevulinic acid PDT in individuals with XP, they may be the ideal candidates for PDT treatment because the profound post-treatment photosensitivity and strict post-therapy sun avoidance necessitated by PDT treatment is already part of the everyday lifestyle of people with XP.

Allergic contact dermatitis to Pampers Drymax.

We present four cases of children less than 2 years of age, seen in four different practices, with a similar, unique, and specific presentation of diaper dermatitis, all while using Pampers Baby Dry with Drymax technology. To date, no reported cases exist of allergic contact dermatitis to Pampers Dryweave in medical literature.

Diagnosing xeroderma pigmentosum group C by immunohistochemistry.

Xeroderma pigmentosum (XP) is a group of rare inherited human neurocutaneous diseases, and the group C (XPC) is the major group of patients with XP in Europe, North America, and South America. Current molecular diagnostic methods for XP require specialized, expensive, and time-consuming UV sensitivity and DNA repair assays followed by gene sequencing. To determine whether immunohistochemistry (IHC) would be a robust alternative method to diagnose patients with XPC, we stained sections of paraffin-embedded skin biopsies for XPC by IHC, using 69 archived blocks from confirmed or clinically suspect patients with XPA, XPC, XPD, XPE, and without XP. We found that XPC expression was strong in all skin biopsies from patients without (14 of 14) and other patients with XP (4 of 4), whereas XPC expression was lost in all biopsies from confirmed XPC patients (29 of 29). Patches of strong XPC signal could be detected in sun-damaged skin, squamous and basal cell carcinomas from patients with XPC that colocalized with strong expression of p53 and Ki-67. Patients with XPC can therefore be diagnosed by IHC from paraffin-embedded skin biopsies from regions of skin that are without sun damage or sun-induced tumors. IHC is therefore a robust alternative method to diagnose patients with XPC. This fast and inexpensive method should increase the options for the diagnosis of patients with XPC from paraffin-embedded skin biopsies and could be developed for other complementation groups.

5% 5-Fluorouracil cream for treatment of verruca vulgaris in children.

Warts are a common pediatric skin disease. Most treatments show only modest benefit, and some are poorly tolerated because of pain. 5-fluorouracil interferes with deoxyribonucleic acid and ribonucleic acid synthesis, and is used to treat genital warts in adults. Efficacy, safety, and tolerability of topical 5% 5-fluorouracil for treatment of common warts were examined in an open-label pilot study with pediatric patients. Thirty-nine children who have at least two hand warts applied 5% 5-fluorouracil cream (Efudex, Valeant Pharmaceuticals International) once or twice daily, under occlusion for 6 weeks. Assessment of treatment response and side effects was performed at baseline, treatment completion, and 3- and 6-month follow-ups. Hematology measures, liver function tests, and medication blood levels were reassessed at treatment completion. Eighty-eight percent of treated warts improved after 6 weeks of treatment, and 41% of subjects had complete resolution of at least one wart. Treatment response did not differ between once or twice daily applications. Tolerability and patient satisfaction were excellent. No subject had clinically significant blood levels of 5-fluorouracil. At 6 month follow-up, 87% of complete responders had no wart recurrence. Topical 5% 5-fluorouracil is a safe, effective, and well-tolerated treatment for warts in children.

SCALP syndrome: sebaceous nevus syndrome, CNS malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus (giant congenital melanocytic nevus) with neurocutaneous melanosis: a distinct syndromic entity.

Nevus sebaceus syndrome (SNS) is a constellation of nevus sebaceus with extracutaneous findings, including the ophthalmologic nervous, and musculoskeletal systems. Didymosis aplasticosebacea is a recently described entity consisting of aplasia cutis congenita and nevus sebaceus, implying twin spotting (didymosis). We describe a neonate with a nevus sebaceus on the scalp and a limbal dermoid on her left eye. Contiguous with the nevus sebaceus was a giant congenital melanocytic nevus and numerous areas of membranous aplasia cutis congenita. We propose the acronym SCALP (nevus sebaceus, central nervous system malformations, aplasia cutis congenita, limbal dermoid, pigmented nevus) to summarize the unique features of this case and review the two similar cases in the literature.

Toddler wrap for abdominal biopsy or excision.

Young children, especially toddlers, are anxious and uncooperative during skin procedures. Wrapping a sheet or blanket around the child is an effective way to restrain the child to maintain a sterile field. The wrap can be used for skin biopsies and small excisions on the midsection of the body, arms, and legs.

Ectopic acanthosis nigricans occurring in a child after syndactyly repair.

Skin grafts from the groin area were used to repair syndactyly of the fourth and fifth fingers in an 8-month-old infant with oculodentodigital dysplasia (ODD). At 12 years of age, he developed hyperpigmented velvety plaques at the repair sites. This patient is the first reported case of acanthosis nigricans (AN) occurring in a graft site after syndactyly repair. We propose the term ectopic acanthosis nigricans to describe the phenomenon of AN occurring in transplanted skin away from the original donor site.

Pediatric surgical pearls: minimizing complications.

Performing dermatologic surgery in infants and children presents unique challenges. A thorough understanding of both pediatric developmental milestones and their unique surgical circumstances is essential to providing optimal dermatologic care of the pediatric patient. In this work, we combine the authors' experiences with data from the literature to provide pediatric dermatologic procedural pearls.

Sjögren-Larsson syndrome: a case report and literature review.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive neurocutaneous disorder most commonly seen in the Scandinavian population and characterized by congenital ichthyosis, mental retardation, and spastic diplegia or quadriplegia. We report a case of SLS in an 11-month-old girl of Lebanese and Mexican-Syrian ancestry who presented with ichthyosis, developmental delay, and spasticity. Results of an enzymatic assay and genomic DNA testing in cultured skin fibroblasts confirmed a homozygous C237Y mutation. These findings support the rich diversity of mutations associated with this syndrome.

Generalized atrophic dells in a newborn.

Infantile myofibromatosis (IM) is a nonmetastasizing locally invasive neoplasm. The behavior of the tumor is more hamartomatous than tumoral, and it is unclear whether the cell of origin is a fibroblast or a smooth muscle myocyte. Lesions typically present during infancy and range in size from a few millimeters to several centimeters. We present an unusual case of a patient with an atrophic variant of IM.

General anesthesia for pediatric dermatologic procedures: risks and complications.

OBJECTIVE: To assess the safety and adverse events associated with the use of general anesthesia in children undergoing elective dermatologic procedures. DESIGN: A multicenter retrospective review. SETTING: Children's Hospital and Health Center, San Diego, Calif, and Northwestern University School of Medicine, Chicago, Ill. PATIENTS: The study population comprised 269 children and adolescents ranging in age from 2 months to 18 years (881 procedures performed by 6 pediatric dermatologic and laser surgeons). MAIN OUTCOME MEASURES: The risk of an adverse event occurring during general anesthesia for pediatric dermatologic procedures. RESULTS: The risk of general anesthesia in elective pediatric dermatologic procedures was low: 90% of patients experienced no clinically relevant complications. The most common clinically relevant adverse effect of general anesthesia was perioperative nausea and emesis, which was noted in 4% of patients. There were no serious life-threatening events noted, and the mortality rate was 0%. CONCLUSION: The use of general anesthesia for dermatologic procedures in a children's hospital setting appears safe, with a low rate of complications.

Connective tissue disease in children.

As our understanding of connective tissue disease expands, so too does our therapeutic armamentarium. We have learned that autoimmunity triggers inflammation through unchecked, proliferative cell-mediated inflammation. By targeting this arm of the cytokine cascade, it may be possible to arrest further progression. Several biologic agents, such as etanercept, alefacept, infliximab, efaluzimab, and, recently, adalimumab, have come to market for adult psoriasis and are now undergoing trials for juvenile SLE, psoriasis, and psoriatic arthritis. Of note, etanercept has been used successfully in juvenile rheumatoid arthritis for more than 10 years. These agents target cell-mediated inflammation through various mechanisms and hold great promise for the treatment of many of the disease states discussed above. Moreover, the biologics carry an improved side-effect profile not seen with traditional agents such as corticosteroids and will be central in the evolution of targeted therapeutics for these complex immunologic diseases.

Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients.

We studied three newly diagnosed xeroderma pigmentosum complementation group G patients with markedly different clinical features. An Israeli-Palestinian girl (XP96TA) had severe abnormalities suggestive of the xeroderma pigmentosum/Cockayne syndrome complex including sun sensitivity, neurologic and developmental impairment, and death by age 6 y. A Caucasian girl (XP82DC) also had severe sun sensitivity with neurologic and developmental impairment and died at 5.8 y. In contrast, a mildly affected 14-y-old Caucasian female (XP65BE) had sun sensitivity but no neurologic abnormalities. XP96TA, XP82DC, and XP65BE fibroblasts showed marked reductions in post-ultraviolet cell survival and DNA repair but these were higher in XP65BE than in XP82DC. XP96TA fibroblasts had very low XPG mRNA expression levels whereas XP65BE fibroblasts had nearly normal levels. Host cell reactivation of an ultraviolet-treated reporter assigned all three fibroblast strains to the rare xeroderma pigmentosum complementation group G (only 10 other patients previously reported). XP96TA and XP82DC cells had mutations in both XPG alleles that are predicted to result in severely truncated proteins including stop codons and two base frameshifts. The mild XP65BE patient had an early stop codon mutation in the paternal allele. The XP65BE maternal allele had a single base missense mutation (G2817A, Ala874Thr) that showed residual ability to complement xeroderma pigmentosum complementation group G cells. These observations agree with earlier studies demonstrating that XPG mutations, which are predicted to lead to severely truncated proteins in both alleles, were associated with severe xeroderma pigmentosum/Cockayne syndrome neurologic symptoms. Retaining residual functional activity in one allele was associated with mild clinical features without neurologic abnormalities.

Identifying potential regulators of infantile hemangioma progression through large-scale expression analysis: a possible role for the immune system and indoleamine 2,3 dioxygenase (IDO) during involution.

Hemangiomas are benign endothelial tumors. Often referred to as hemangiomas of infancy (HOI), these tumors are the most common tumor of infancy. Most of these lesions proliferate rapidly in the first months of life, and subsequently slowly involute during early childhood without significant complications. However, they often develop on the head or neck, and may pose a significant cosmetic concern for families. In addition, a fraction of these tumors can grow explosively and ulcerate, bleed, or obstruct vision or airway structures. Current treatments for these tumors are associated with significant side effects, and our knowledge of the biology of hemangiomas is limited. The natural evolution of these lesions creates a unique opportunity to study the changes in gene expression that occur as the endothelium of these tumors proliferates and then subsequently regresses. Such information may also increase our understanding of the basic principals of angiogenesis in normal and abnormal tissue. We have performed large-scale genomic analysis of hemangioma gene expression using DNA microarrays. We recently identified insulin-like growth factor 2 as a potentially important regulator of hemangioma growth using this approach. However, little is known about the mechanisms involved in hemangioma involution. Here we explore the idea that hemangioma involution might be an immune-mediated process and present data to support this concept. We also demonstrate that proliferating hemangiomas express indoleamine 2,3 dioxygenase (IDO) and discuss a possible mechanism that accounts for the often slow regression of these lesions.

Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes.

Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC(-/-) background. XPC(-/-) cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.