Jennifer T. Huang

Hand, foot, and mouth disease caused by coxsackievirus a6.

To the Editor: Coxsackievirus A6 (CVA6) is a human enterovirus associated with herpangina in infants. In the winter of 2012, we evaluated a cluster of 8 patients, 4 months–3 years of age, who were brought for treatment at Boston Children’s Hospital (Boston, MA, USA) with a variant of hand, foot, and mouth disease (HFMD) that has now been linked to CVA6 (Table). During this same period, the Boston Public Health Commission’s syndromic surveillance system detected a 3.3-fold increase in emergency department discharge diagnoses of HFMD. In the United States, HFMD typically occurs in the summer and early autumn and is characterized by a febrile enanthem of oral ulcers and macular or vesicular lesions on the palms and soles; the etiologic agents are most often CVA16 and enterovirus 71. Table Demographic and clinical characteristics of patients with CVA6-associated HFMD, Boston, Massachusetts, USA, 2012* In contrast to the typical manifestation, the patients in the Boston cluster exhibited symptoms in late winter (Table) and had perioral (Figure, panel A) and perirectal (Figure, panel B) papules and vesicles on the dorsal aspects of the hands and feet (Figure, panel C). Patients experienced a prodrome lasting 1–3 days, consisting of fever (8 patients), upper respiratory tract symptoms (4 patients), and irritability (7 patients). This prodrome was followed by the development of a perioral papular rash (8 patients), which was often impetiginized with secondary crusting; a prominent papulovesicular rash on the dorsum of the hands and feet (6 patients); and a perirectal eruption (7 patients). Half of the patients had intraoral lesions. Fever abated in most of the patients within a day after onset of the exanthem. The rash resolved over 7–14 days with no residual scarring. Samples from the oropharynx, rectum, and vesicles from these patients were sent to the Centers for Disease Control and Prevention (Atlanta, GA, USA) for analysis. Reverse transcription PCR and sequencing by using primers specific for a portion of the viral protein 1 coding region identified CVA6 (1) (Table). Figure Manifestations of hand, foot, and mouth disease in patients, Boston, Massachusetts, USA, 2012. Discrete superficial crusted erosions and vesicles symmetrically distributed in the perioral region (A), in the perianal region (B), and on the dorsum of the ... Outbreaks of HFMD caused by CVA6 have been described in Singapore, Finland, Taiwan, and most recently in Japan; most cases have occurred in the warmer months (2–6). Cases in the cluster described here are likely related to an emerging outbreak of CVA6-associated HFMD in the United States (7). The atypical seasonality of the outbreak, during the winter in Boston, could be related to the unusually mild temperatures in the winter of 2012. Recent CVA6 outbreaks have been characterized by a febrile illness associated with an oral enanthem and lesions on the palms, soles, and buttocks. CVA6 infections in Taiwan during 2004–2009 were associated with HFMD in 13% of cases, with disease defined as oral ulcers on the tongue or buccal mucosa and vesicular rashes on the palms, soles, knees, or buttocks (2). In Singapore, where CVA6 accounted for 24% of HFMD cases, patients had oral lesions and <5 peripheral papules, placing them on a spectrum closer to the herpangina more typically observed in CVA6 infection (8). The patients we report in this cluster most typically had perioral and perirectal papules in addition to vesicles on the dorsum of their hands. Two reports of CVA6-associated HFMD outbreaks describe cases that more closely resemble patients in the Boston outbreak. In a series from Finland in 2008, representative patients had both perioral lesions and vesicles on the dorsum of their hands (6). In a large series of patients with HFMD in Taiwan in 2010, patients with CVA6 had perioral lesions in addition to an enanthem (3). Outbreaks of CVA6-associated HFMD in Finland, Taiwan, and Japan were associated with onychomadesis, with the loss of nails occurring 1–2 months after initial symptoms (3,4,6). The association between more typical HFMD and onychomadesis has additionally been described in the United States and Europe but without a link to specific serotype or with a small percentage of CVA6-associated cases (9). Cases from the Boston epidemic may fit into an emerging clinical phenotype of CVA6, and it will be interesting to see whether nail loss develops in those patients. Given the numerous CVA6 outbreaks in multiple countries in 2008 and a US population that may be relatively naive to this serotype, CVA6 is likely to spread throughout North America. Clinicians should be aware that, although standard precautions are routinely recommended for managing enteroviral infections in health care settings, contact precautions are indicated for children in diapers to control institutional outbreaks (10). In addition, the presence of perioral lesions and peripheral vesicles on the dorsum rather than palmar/plantar surface of the hands and feet represents a unique phenotype of HFMD that could be confused with herpes simplex or varicella-zoster virus infections. Because of the atypical presentation of CVA6-associated HFMD, clinical vigilance is needed to recognize emerging regional outbreaks. More detailed epidemiologic and genetic analyses will be required to characterize the role of CVA6 in US outbreaks of HFMD.

Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children's Oncology Group Report.

Hematopoietic cell transplantation (HCT) is an important curative treatment for children with high-risk hematologic malignancies, solid tumors, and, increasingly, nonmalignant diseases. Given improvements in care, there are a growing number of long-term survivors of pediatric HCT. Compared with childhood cancer survivors who did not undergo transplantation, HCT survivors have a substantially increased burden of serious chronic conditions and impairments involving virtually every organ system and overall quality of life. This likely reflects the joint contributions of pretransplantation treatment exposures and organ dysfunction, the transplantation conditioning regimen, and any post-transplantation graft-versus-host disease (GVHD). In response, the Childrens Oncology Group (COG) has created long-term follow-up guidelines (www.survivorshipguidelines.org) for survivors of childhood, adolescent, and young adult cancer, including those who were treated with HCT. Guideline task forces, consisting of HCT specialists, other pediatric oncologists, radiation oncologists, organ-specific subspecialists, nurses, social workers, other health care professionals, and patient advocates systematically reviewed the literature with regards to late effects after childhood cancer and HCT since 2002, with the most recent review completed in 2013. For the most recent review cycle, over 800 articles from the medical literature relevant to childhood cancer and HCT survivorship were reviewed, including 586 original research articles. Provided herein is an organ system-based overview that emphasizes the most relevant COG recommendations (with accompanying evidence grade) for the long-term follow-up care of childhood HCT survivors (regardless of current age) based on a rigorous review of the available evidence. These recommendations cover both autologous and allogeneic HCT survivors, those who underwent transplantation for nonmalignant diseases, and those with a history of chronic GVHD.

Voriconazole phototoxicity in children: A retrospective review

BACKGROUND Voriconazole, an antifungal agent, is associated with various cutaneous reactions, including phototoxicity, accelerated photoaging, and skin cancer. Incidence and risk factors for these reactions in children have not been well described. OBJECTIVE We sought to determine the incidence of and factors associated with phototoxic reactions and nonmelanoma skin cancer in pediatric patients treated with voriconazole. METHODS This was a retrospective analysis of 430 pediatric patients treated with voriconazole between 2003 and 2013 at Boston Childrens Hospital. RESULTS Incidence of phototoxicity was 20% in all children treated with voriconazole and 47% in children treated for 6 months or longer. Factors associated with phototoxicity included white race, cystic fibrosis, cumulative treatment time, and cumulative dose. Four patients (1%) had nonmelanoma skin cancer; all experienced a phototoxic reaction during voriconazole treatment. Of those with phototoxicity, 5% were discontinued on voriconazole, 6% were referred to dermatology, and 26% received counseling about sun protection from their primary physician. LIMITATIONS Our study is limited by its retrospective design and potential referral bias associated with a tertiary-care center. CONCLUSIONS Voriconazole-associated phototoxicity is relatively common in children and may lead to nonmelanoma skin cancer. However, those with phototoxic reactions are often continued on therapy, rarely referred to dermatology, and infrequently counseled on sun protection.

Nonmelanoma skin cancer in childhood after hematopoietic stem cell transplant: a report of 4 cases.

Although it is known that hematopoietic stem cell transplantation (HSCT) survivors are at risk of nonmelanoma skin cancer (NMSC), there is limited literature on the incidence of NMSC during childhood in this population. We present 4 HSCT patients ages 13 to 20 years diagnosed with NMSC in our clinic over a 1-year period. Each patient had multiple risk factors associated with NMSC including chronic graft-versus-host disease, prolonged immunosuppression, total-body irradiation, and voriconazole therapy. We conclude that the incidence of NMSC in children after HSCT may be underestimated and should be further investigated. Appropriate skin cancer screening, including annual skin examinations, are advised for pediatric patients with identifiable risk factors.

Langerhans cell histiocytosis mimicking molluscum contagiosum

features suggest that this patient is an atypical presentation of chemotherapy-induced acral erythema, sparing the classic palmar location. The suggestion for an overlapping spectrum of chemotherapyinduced toxic injury of the skin helps resolve the clinicopathological challenge of this case. Toxic erythema of chemotherapy describes a particular category of toxin-associated diseases, some of which are specific, eg, chemotherapyassociated neutrophilic hidradenitis, and others, such as the eruption presented, defy further classification. Although dermatologists will likely preserve some of their preferred appellations, the field of dermatology will benefit from including toxic erythema of chemotherapy within the conceptual framework of chemotherapy-associated dermatoses.

Characteristics and outcomes of nonmelanoma skin cancer (NMSC) in children and young adults

BACKGROUND Pediatric and young adult nonmelanoma skin cancer (NMSC) is rare and traditionally associated with predisposing heritable or congenital conditions. Clinical characteristics, outcomes, and iatrogenic risk factors have not been well described. OBJECTIVES We sought to characterize clinical features, potential risk factors, and gaps in care associated with NMSC in children and young adults. METHODS This was a retrospective chart review of children and young adults with squamous and basal cell carcinoma. RESULTS We identified 28 patients with a total of 182 NMSC tumors. Of patients, 50% had predisposing conditions, and 46% had exposure to iatrogenic risk factors of prolonged immunosuppression, radiation therapy, chemotherapy, voriconazole use, or a combination of these. Of patients with iatrogenic risk factors, 62% developed subsequent cancerous or precancerous skin lesions. No patient was found to have chemotherapy or voriconazole exposure as a sole risk factor. Mean time to diagnosis of NMSC was 948 days with initial misdiagnosis in 36% of patients. The majority of patients underwent surgical excision. LIMITATIONS This was a retrospective single institution study with a small number of cases. CONCLUSIONS Physicians should be aware of risk factors associated with NMSC in children and young adults to provide appropriate counseling and early diagnosis and treatment.

Nail dystrophy, edema, and eosinophilia: harbingers of severe chronic GVHD of the skin in children

The prognostic value of adnexal findings in chronic GVHD (cGVHD) has not been investigated in children. Dermatologic examinations were performed in a severe cohort of 11 children with skin cGVHD seen over a 2-year period. Findings were compared with 25 additional patients with skin cGVHD and 97 control patients. In 36 patients with skin cGVHD, nail dystrophy was present in 45% of patients, and was significantly associated with sclerotic disease and lung cGVHD. Pterygium inversum unguis (PIU) was associated with severe lung disease, with significantly lower % predicted FVC and FEV1 in those with PIU than those without. Forty-four percent of GVHD patients had preceding peripheral edema and 56% had preceding peripheral eosinophilia. Peripheral edema and eosinophilia were significantly associated with sclerotic cGVHD and persisted until the diagnosis of cGVHD in all patients. Comparison of data with control patients showed that incidence of nail dystrophy, incidence of peripheral edema and mean peak peripheral eosinophil count of patients with skin cGVHD was significantly higher than those without cGVHD. This study suggests that nail dystrophy, persistent peripheral edema and persistent peripheral eosinophilia are harbingers of severe cGVHD of the skin in children. The presence of PIU may be a harbinger of severe lung involvement.

Merkel cell carcinoma in a patient with GATA2 deficiency: a novel association with primary immunodeficiency.

A 55‐year‐old woman with GATA2 deficiency and neurofibromatosis 1 was diagnosed with Merkel cell carcinoma (MCC). This polyomavirus‐associated cutaneous malignancy has previously been associated with immunosuppression and acquired immunodeficiencies such as HIV/AIDS. However, MCC has not been previously reported in the setting of underlying primary or inherited immunodeficiency.

Frequency of Ear Symptoms and Hearing Loss in Ichthyosis: A Pilot Survey Study

Ichthyoses comprise a heterogeneous array of skin conditions resulting from impairment of cornification. Although ear structures can be affected, ear‐related symptoms have never been investigated in patients with ichthyosis. In this pilot survey study, our aim was to determine the frequency of ear symptoms, hearing loss, and related medical interventions in patients with ichthyosis. Our secondary aim was to compare the frequency of these items according to age group. An online survey using Redcap was developed and posted online on the Foundation for Ichthyosis and Related Skin Types website for 6 months. Patients or parents of patients with ichthyosis were asked to complete the survey. Data analysis excluded patients with keratitis‐ichthyosis‐deafness syndrome and surveys that had fewer than two completed items. One hundred thirty‐five unique surveys were used for data analysis. Of all participants, 80% reported ear pruritus, 66% reported trouble hearing, 29% reported frequent ear pain, 28% had abnormal hearing test results, and 16% had used hearing aids. Of the 88 participants who reported trouble hearing, 24 (27.3%) had never been to a hearing specialist. Significantly more participants older than 18 years of age (74%, 57/77) reported trouble hearing than participants age 18 years and younger (53%, 31/58; p = 0.02). The frequencies of other ear symptoms and hearing loss were not statistically significantly different between the age groups. Ear pruritus, ear pain, and hearing loss are important concerns in patients with all forms of ichthyosis in all age groups. Early diagnosis and intervention may improve the quality of life of patients with ichthyosis.

Risk of melanocytic nevi and nonmelanoma skin cancer in children after allogeneic hematopoietic stem cell transplantation

There is a known increased risk of skin cancer in the adult population after hematopoietic stem cell transplantation (HSCT). However, late dermatologic effects that children may experience after HSCT have not been well described. The primary objective of this study was to characterize nevi and skin cancers affecting children after allogeneic HSCT. A cross-sectional cohort study of 85 pediatric HSCT recipients and 85 controls matched for age, sex and skin phototype was performed at a single institution. All participants underwent a full skin examination. Median age at study visit was 13.8 years in HSCT patients with median time post-HSCT of 3.6 years. HSCT patients had significantly more nevi than control patients (median (range): 44 (0–150) vs 11 (0–94), P<0.0001). HSCT patients also had significantly more nevi >5 mm in diameter and atypical nevi than controls. Factors associated with increased nevus count included malignant indication for HSCT, pretransplant chemotherapy, TBI exposure and myeloablative conditioning. A total of 16.5% of HSCT patients developed cancerous, precancerous lesions and/or lentigines. Our study suggests that pediatric HSCT recipients have an increased risk of benign and atypical melanocytic proliferations and nonmelanoma skin cancer that can manifest even during childhood.