Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

Nagashima-type palmoplantar keratoderma: Case series and two novel variants.

Nagashima-type palmoplantar keratoderma (PPK) is an autosomal recessive PPK. We report four patients, highlight two new genetic variants, and emphasize the possibility of misdiagnosing the condition. Concomitant atopic dermatitis, specifically, may make correct diagnosis challenging. Clinicians should consider the diagnosis of Nagashima-type PPK in patients presenting with mild PPK with transgrediens and understand the importance of individualized multimodal treatment regimens.

Long-pulsed neodymium-doped yttrium aluminum garnet for hair reduction in pediatric microtia repair.

Microtia is the term for congenital malformation of the ear in which the external and internal ear are absent or malformed. Surgical reconstruction is a common management approach and occasionally requires hair reduction of the newly constructed auricle. Few studies have investigated lasers for this purpose. We conducted a retrospective chart review of patients seen at a single institution between 2012 and 2021 who underwent laser hair reduction with long-pulsed neodymium-doped yttrium aluminum garnet laser (Nd:YAG). Efficacy ratings were done through review of clinical photographs. Twelve patients were identified with 14 total ears treated. The number of laser treatments varied from 1 to 9 sessions with an average of 5.1 treatments. The majority (8/12) had an "excellent" or "very good" response, one patient had a "good" response, and three were lost to follow-up. Other than pain, there were no side effects documented. Nd:YAG laser was both effective and safe in our pediatric cohort, without any cutaneous side effects in patients with darker skin.

Multicenter retrospective review of pulsed dye laser in nonulcerated infantile hemangioma.

BACKGROUND/OBJECTIVES: We sought to describe the experience among members of the Hemangioma Investigator Group with pulsed dye laser (PDL) in the treatment of nonulcerated infantile hemangioma (IH) in pediatric patients in the pre- and post-beta-blocker era. METHODS: A multicenter retrospective cohort study was conducted in patients with nonulcerated IH treated with laser therapy. Patient demographics, IH characteristics, indications for/timing of laser therapy, as well as laser parameters were collected. Responses to laser therapy were evaluated using a visual analog scale (VAS). RESULTS: One hundred and seventeen patients with IH were treated with PDL. 18/117 (15.4%) had early intervention (defined as <12 months of life), and 99/117 (84.6%) had late intervention (≥12 months of life). In the late intervention group, 73.7% (73/99) had additional medical management of their IH. The mean age at PDL initiation for the late intervention group was 46.7 ± 35.3 months of life (range 12-172 months) with total number of treatments to maximal clearing of 4.2 ± 2.8 (range 1-17). Those who received propranolol prior to PDL received fewer sessions (1.1 fewer sessions, approaching significance [p = .056]).     On the VAS, there was a mean 85% overall improvement compared to baseline (range 18%-100%), with most improvement noted in erythema and/or telangiectasias. The incidence of adverse effects was 6/99 (6.1%). CONCLUSIONS: PDL is a useful tool in the treatment of IH, with notable improvement of telangiectasia and erythema and low risk of complications.   PDL is often introduced after the maximal proliferative phase.

Successful use of telemedicine for evaluation of infantile hemangiomas during the early COVID-19 pandemic: A cross-sectional study.

BACKGROUND/OBJECTIVES: The COVID-19 pandemic prompted a rapid expansion in the use of telemedicine. This study aimed to assess the experiences of hemangioma specialists utilizing telemedicine during the COVID-19 pandemic to evaluate and manage infantile hemangiomas (IH), including perceived effectiveness of different modalities and barriers to care delivery. METHODS: Multicenter cross-sectional study asking providers to describe their experiences using telemedicine for initial evaluation of IH from March to September 2020. RESULTS: The study included 281 patients from 15 medical centers internationally. Median time from referral to evaluation was 17 days. Median physician confidence in performing evaluations via telemedicine was 95.0 (IQR 90.0-100.0). Most evaluations were performed via video communication with photographs or audio communication with photographs; when not initially available, photographs were requested in 51.4%. Providers preferred follow-up modalities that included photographs. CONCLUSIONS: Physicians with extensive expertise in managing IH are confident in their abilities to assess and manage IH via telemedicine including initiating treatment in patients without risk factors for beta-blocker therapy. There was a preference for hybrid modalities that included photographs. The data suggest that telemedicine can be effective for managing IH and may decrease wait times and improve specialist reach to underserved areas.

Mapping of Segmental and Partial Segmental Infantile Hemangiomas of the Face and Scalp.

IMPORTANCE: Recognizing segmental infantile hemangioma (IH) patterns is important for risk stratification and provides clues to pathogenesis. Previously, segmental hemangiomas were mapped to 4 facial regions, 3 corresponding to known facial metameres. OBJECTIVES: To refine existing maps of facial segmental IHs, examine so-called indeterminate hemangiomas as they relate to known segmental patterns, and define a novel pattern of segmental scalp hemangiomas. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted at 4 pediatric dermatology centers (University of California, San Francisco; Indiana University; Medical College of Wisconsin; and Northwestern University/Ann & Robert H. Lurie Children's Hospital of Chicago) using photographic archives of patients younger than 12 years with segmental and indeterminate hemangiomas on the face and scalp. Clinical images were used to map hemangioma distribution onto standardized facial templates. Heat map densiometry identified recurrent patterns that were compared with previously published patterns of facial segmental hemangiomas. Patterns of indeterminate hemangiomas were compared with those of segmental hemangiomas. Data collection took place in 2017, and analysis took place from 2017 to 2019. MAIN OUTCOMES AND MEASURES: Distribution and patterning of segmental and indeterminate IHs of the face and scalp. RESULTS: A total of 549 IHs were mapped. The borders of the frontotemporal (S1) and frontonasal (S4) segments agreed with previous segmental maps; however, the maxillary (S2) and mandibular (S3) segment borders differed with respect to the preauricular skin. In contrast with previous reports, preauricular skin segregated with the mandibular (S3) rather than the maxillary (S2) segment. Indeterminate hemangiomas occurred within and respected the same borders as segmental hemangiomas. Hemangiomas on the lateral scalp commonly occurred in a C shape extending from the posterior auricular region. CONCLUSIONS AND RELEVANCE: This cohort study provides an updated map of facial segmental IHs with redefined maxillary (S2) and mandibular (S3) segment borders. It provides evidence that indeterminate hemangiomas are partial segmental hemangiomas respecting anatomic boundaries of their larger segmental counterparts. A newly recognized C-shaped pattern of segmental scalp hemangioma is reported.

Management of infantile hemangiomas during the COVID pandemic.

The COVID-19 pandemic has caused significant shifts in patient care including a steep decline in ambulatory visits and a marked increase in the use of telemedicine. Infantile hemangiomas (IH) can require urgent evaluation and risk stratification to determine which infants need treatment and which can be managed with continued observation. For those requiring treatment, prompt initiation decreases morbidity and improves long-term outcomes. The Hemangioma Investigator Group has created consensus recommendations for management of IH via telemedicine. FDA/EMA-approved monitoring guidelines, clinical practice guidelines, and relevant, up-to-date publications regarding initiation and monitoring of beta-blocker therapy were used to inform the recommendations. Clinical decision-making guidelines about when telehealth is an appropriate alternative to in-office visits, including medication initiation, dosage changes, and ongoing evaluation, are included. The importance of communication with caregivers in the context of telemedicine is discussed, and online resources for both hemangioma education and propranolol therapy are provided.

The biker-glove pattern of congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are common birthmarks with 20% occurring on the limbs. We describe 4 patients with acral CMN with a "biker-glove" distribution with sparing of the distal digits, as has previously been described in acral infantile hemangiomas (IH). The existence of the biker-glove pattern suggests that CMN arise from early mutations in melanocyte precursors and supports the recently described Kinsler-Larue hypothesis of mesenchymal distribution of melanocyte migration occurring in a circular field from a central point. Developmental errors in mesenchymal precursors with similar migration patterns may explain this shared pattern among CMN and IH.

Topical timolol: An effective treatment option for agminated pyogenic granuloma.

We present three patients with agminated pyogenic granulomas who experienced significant decrease in size and bleeding with treatment with topical timolol solution with minimal side effects. One patient had complete clinical resolution. For patients with agminated pyogenic granuloma who may otherwise have limited treatment options, timolol is an effective potential solution.

Hearing loss in PHACE syndrome: clinical and radiologic findings.

PURPOSE: To characterize the types of hearing loss, auditory-related imaging findings, and hemangioma characteristics in patients with Posterior fossa malformations, Hemangiomas, Arterial anomalies, Cardiac defects, and abnormalities of the Eye (PHACE) syndrome. METHODS: Retrospective medical records, audiologic data, and imaging review of all patients presenting to a tertiary care children's hospital with a proven diagnosis of PHACE syndrome from 2005 to 2016. RESULTS: Twelve patients were identified with hearing and imaging data. 5/12 had hearing loss, 1 had unilateral severe sensorineural loss with minor conductive component, 1 had unilateral moderate sensorineural loss with minor conductive component, 1 had mild bilateral conductive loss, 1 had bilateral hearing loss (left severe mixed and right severe sensorineural), and 1 had moderate bilateral conductive loss. All patients passed their newborn hearing screening. Of the 5 patients with hearing loss, 3 had IAC hemangiomas (1 bilateral), 3 had enlarged IACs with prominent posterior petrous bones (1 bilateral), 2 had dysgenesis of the cerebellar vermis and hemispheres, there was 1 patient each with a deformed pinna and middle ear and mastoid effusions, and 1 patient had no abnormal auditory-related imaging findings. Patients with hearing loss were more likely to have more areas of cutaneous hemangioma involvement (mean 6.4 vs 3.1, p = .05). Laterality of hearing impairment correlated with the side of cutaneous hemangioma in all patients with hearing loss. Treatment with systemic propranolol did not improve hearing. CONCLUSIONS: Patients with PHACE are at risk for hearing loss and may demonstrate radiologic abnormalities within the ear structures, although the type of hearing loss, imaging findings, and their respective correlation vary. While our results are limited by our small sample size, comprehensive audiology evaluations (as opposed to newborn screening testing only) should be considered for PHACE patients who have extensive cutaneous hemangioma or auditory-related imaging abnormalities, such as internal auditory canal hemangiomas.

Infantile hemangiomas with conjunctival involvement: An underreported occurrence.

BACKGROUND/OBJECTIVES: Infantile hemangiomas (IHs) involving the conjunctiva are only anecdotally reported in the literature and little is known about their clinical course. In a retrospective case series we aimed to better delineate the clinical presentation, complications, and response to treatment of this uncommon subtype of IH. A classification of conjunctival IH is proposed. METHODS: Medical charts at three academic pediatric dermatology institutions were retrospectively analyzed. Data were collected on the clinical characteristics, ophthalmologic findings, treatments, and outcomes of 22 individuals with conjunctival IH. RESULTS: Growth characteristics of conjunctival IH closely mirrored those of their cutaneous counterparts. Ophthalmologic abnormalities were associated with the IH in six individuals (27%); in three, they were considered severe. Seventeen subjects (77%) required treatment, most commonly because of risk of ocular compromise. All treated individuals responded favorably to topical timolol or systemic propranolol. CONCLUSION: Conjunctival IH have clinical characteristics similar to those of cutaneous IH and respond readily to beta-blocker treatment. Ocular complications may occur in a minority of individuals receiving treatment.

Eosinophilic Pustular Folliculitis in Children after Stem Cell Transplantation: An Eruption Distinct from Graft-Versus-Host Disease.

Eosinophilic pustular folliculitis (EPF) is a rare cutaneous disorder that typically occurs in three clinical contexts: men, individuals who are immunosuppressed or have human immunodeficiency virus, and infants. A fourth subtype occurring 2 to 3 months after hematopoietic stem cell transplantation (HSCT) has recently been described in several adults. We report two cases of EPF arising in children after HSCT. It is important to recognize this form of EPF after HSCT and differentiate it from graft-versus-host disease since it responds readily to topical steroids and appears to have an excellent prognosis.

Neutrophil-rich subcutaneous fat necrosis of the newborn: A potential mimic of infection.

BACKGROUND: The inflammatory infiltrate seen in biopsy specimens obtained from patients with subcutaneous fat necrosis of the newborn (SCFN) has classically been described as consisting mostly of histiocytes. However, we encountered patients with SCFN whose biopsy specimens revealed mostly neutrophils, prompting infection to be an initial consideration. OBJECTIVES: We sought to describe cases of SCFN in which neutrophils formed the majority of the infiltrate at our institution and in the literature. METHODS: We performed a retrospective analysis of patients with SCFN reported at our institution and a literature review of SCFN. RESULTS: Thirteen cases of SCFN were identified at our institution. In 2 of 13 cases, neutrophils composed >75% of the inflammatory infiltrate, and both lesions were 1 day old. From the literature review, neutrophils were mentioned as a component of the infiltrate in 10 of 124 cases, but in none were neutrophils described as forming the majority of the infiltrate. LIMITATIONS: This study is limited by its retrospective nature and small sample size. CONCLUSIONS: Neutrophils can comprise most of the inflammatory cells in patients with SCFN, especially early in the course of the disease. This variant of SCFN can be easily mistaken for infection.

PHACE syndrome and congenitally absent thyroid gland at MR imaging.

PHACE syndrome is a rare neurocutaneous disorder characterized by posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, and abnormalities of the eye. Thyroid disorders associated with PHACE syndrome have been described, although there are limited reports of this rare occurrence. We report a case of PHACE syndrome with congenital hypothyroidism in an infant, for which absent thyroid gland was diagnosed at magnetic resonance imaging.

Role of Sirolimus in Advanced Kaposiform Hemangioendothelioma.

Kaposiform hemangioendothelioma (KHE) is an infiltrative vascular tumor that classically presents in infancy. Management typically focuses on treating Kasabach-Merritt phenomenon (KMP), a disorder of severe and at times life-threatening platelet trapping. However, the morbidity of KHE extends beyond KMP. The infiltrative nature of the tumor can lead to long-term disability and often makes complete surgical resection impossible. We report the case of a 10-year-old boy with a KHE of his right distal thigh who was unable to walk without assistance due to fibrotic change and right knee contracture. He had no laboratory evidence of KMP at the time of representation. Rapamycin was started in hopes of reducing the tumor burden. Within 2 months of therapy, fibrotic areas softened, his contracture nearly resolved, and there was marked improvement in his mobility. Rapamycin has been previously reported to be effective in managing cases of KHE complicated by KMP. Our report emphasizes the role for rapamycin in the treatment of KHE in the absence of KMP through the inhibition of vasculogenesis and fibrotic pathways.

A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.

A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year of life, with uncontrollable bullous pemphigoid, colitis, and proteinuria. The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome. Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity. The early onset, severity, and distinctive findings suggested a single gene disorder underlying the phenotype. Whole-exome sequencing performed on five family members revealed the affected siblings to be compound heterozygous for two unique missense mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70). Healthy relatives were heterozygous mutation carriers. Although pre-HCT patient T cells were not available, mutation effects were determined using transfected cell lines and peripheral blood from carriers and controls. Mutation R192W in the C-SH2 domain exhibited reduced binding to phosphorylated ζ-chain, whereas mutation R360P in the N lobe of the catalytic domain disrupted an autoinhibitory mechanism, producing a weakly hyperactive ZAP-70 protein. Although human ZAP-70 deficiency can have dysregulated T cells, and autoreactive mouse thymocytes with weak Zap-70 signaling can escape tolerance, our patients' combination of hypomorphic and activating mutations suggested a new disease mechanism and produced previously undescribed human ZAP-70-associated autoimmune disease.

Mycoplasma pneumoniae-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systematic review.

BACKGROUND: Mycoplasma pneumoniae infection is associated with extrapulmonary complications, including mucocutaneous eruptions. These eruptions, which have been termed either "Stevens-Johnson syndrome" or "erythema multiforme" in the literature, may differ from drug-induced Stevens-Johnson syndrome or viral-associated erythema multiforme. OBJECTIVE: We sought to review the literature characterizing morphology and disease course of M pneumoniae-associated mucocutaneous disease. METHODS: A comprehensive literature search identified 95 articles with 202 cases. RESULTS: Patients were often young (mean age: 11.9 years) and male (66%). Cutaneous involvement ranged from absent (34%), to sparse (47%), to moderate (19%). Oral, ocular, and urogenital mucositis was reported in 94%, 82%, and 63% of cases, respectively. Treatments included antibiotics (80%), systemic corticosteroids (35%), supportive care alone (8%), and/or intravenous immunoglobulin (8%). Complications included mucosal damage (10%), cutaneous scarring (5.6%), recurrence (8%), and mortality (3%). LIMITATIONS: Mild cases may not have been published; thus this review may have a bias toward more severe disease. CONCLUSION: M pneumoniae-associated mucocutaneous disease has prominent mucositis and sparse cutaneous involvement, although cutaneous involvement varies. Because of the distinct morphology, mild disease course, and potentially important clinical implications regarding treatment, we propose a revision of the nomenclature system and suggest the term "Mycoplasma-induced rash and mucositis" for these cases.

Ventral midline blanching in the setting of segmental infantile hemangiomas: clinical observations and pathogenetic implications.

Areas of blanched skin in children may be seen as an independent finding or in association with vascular birthmarks. We performed a retrospective chart review to identify and describe infants with areas of ventral midline blanching in the presence of segmental infantile hemangiomas. We identified nine full-term infants with partial or full segmental hemangiomas and areas of midline ventral blanching. Additional ventral wall defects were seen in five patients. Six had cardiac anomalies and six had intracranial anomalies. Five were diagnosed with definite PHACE (posterior fossa, hemangioma, arterial, cardiac, and eye abnormalities) syndrome and three had possible PHACE syndrome. Eight were complicated by ulceration. Treatment varied according to the case. Ventral blanching, even in the absence of overt midline defects, can be seen in infants with segmental hemangiomas at risk for PHACE syndrome. We hypothesize that midline blanching may represent a minor manifestation of a developmental ventral defect.