A case of severe nivolumab-induced lichen planus pemphigoides in a child with metastatic spitzoid melanoma.

Dermatologic reactions are among the most common adverse events of antiprogrammed cell death-1 (anti-PD-1) monoclonal antibodies agents and include maculopapular rash, psoriasiform rash, lichenoid eruptions, autoimmune bullous disorders, and vitiligo. Here, we present a case of a 12-year-old African American male with metastatic spitzoid melanoma treated with nivolumab who developed a mild lichenoid eruption that progressed to a severe case of lichen planus pemphigoides (LPP). Management was complex given the patient's age and history and included hospitalization for intravenous steroids, an intensive topical steroid regimen, methotrexate, and discontinuation of nivolumab. This case illustrates a rare but dramatic progression from a mild LP-like eruption to severe bullous lichenoid eruption, most consistent with LPP, as well as the diagnostic and treatment challenges in the setting of a pediatric patient on nivolumab.

A Young Boy With Hemophagocytic Lymphohistiocytosis Presenting With Vaccine-Related Granulomatous Dermatitis: A Case Report and Literature Review.

ABSTRACT: Cutaneous eruptions associated with hemophagocytic lymphohistiocytosis (HLH) have been reported in 6%-63% of patients. Clinical findings of these skin lesions vary widely and include maculopapular rashes, ulcers, and violaceous nodules. Corresponding histologic findings are also variable and are considered nonspecific. We report the case of a 4-year-old boy who initially developed a widespread popular-pustular rash 2 weeks after his 12-month measles, mumps, and rubella vaccinations. These resolved with scarring then recurred following his 24-month vaccinations. Multiple skin biopsies were negative for infectious organisms and showed a granulomatous infiltrate with perforation and necrobiosis. The differential diagnosis included perforating granuloma annulare, infection, or rheumatoid nodules. At the age of 4, he developed fever, hepatosplenomegaly, pancytopenia and other laboratory abnormalities, requiring hospitalization. A number of studies were performed including biopsies of bone marrow and liver. Molecular testing revealed 2 mutations in UNC13D known to be associated with familial HLH. His prior cutaneous lesions were likely caused by immune dysregulation exacerbated by immunizations because of underlying familial HLH. This case illustrates the importance of recognizing an unusual cutaneous manifestation of a rare disease to arrive at an earlier diagnosis in a pediatric patient. Although cutaneous eruptions usually develop concurrently with other systemic symptoms of HLH, preceding unusual skin lesions may be the first indication of this rare disease.

Unrelenting facial segmental hemangiomas: A case series of late growth and recurrent ulcerations.

Late growth of infantile hemangiomas is an uncommon complication. We report three patients with segmental facial hemangiomas who experienced late growth and recurrent ulceration predominantly of the lower lip. These patients shared common clinical features including involvement of the S3 facial segment, oral and airway hemangiomas, and vascular anomalies associated with PHACE syndrome. This report highlights a clinical presentation at-risk for late growth and recurrent ulceration.

Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling.

BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.

Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository.

The cause of PHACE syndrome is unknown. In a study of 218 patients, we examined potential prenatal risk factors for PHACE syndrome. Rates of pre-eclampsia and placenta previa in affected individuals were significantly greater than in the general population. No significant risk factor differences were detected between male and female subjects.

RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation.

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n = 100), common CM(s) (port-wine stain; n = 100), Sturge-Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the "second-hit" hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up.

Characterizing Granuloma Annulare in 73 Pediatric Patients.

Background: Granuloma annulare (GA) is a common, benign, idiopathic inflammatory dermatosis. Aside from case reports and small studies, there are limited data about the characteristics of GA in children. Objective: This study aimed to better characterize the epidemiologic and clinical features, triggering factors, disease associations, and outcomes of GA in the pediatric population. Methods: We conducted a retrospective study of 73 pediatric patients diagnosed with GA at the University of Rochester Medical Center over a 7-year period. Results: The most common subtype was localized GA (71.2%, n = 52), followed by subcutaneous (also known as "deep GA"; 16.4%, n = 12) and generalized (12.3%, n = 9) subtypes. Over 90% of patients had idiopathic GA, with the remaining patients reporting viral infection or trauma as triggers. Half of the patients studied had comorbid conditions, most frequently atopic dermatitis (17.8%, n = 13), obesity (9.59%, n = 7), asthma (6.85%, n = 5), and allergic rhinitis (6.85%, n = 5). The median duration of the disease was 11.00 months (interquartile range (IQR) 15.75 months); generalized GA had the shortest duration (median 10.00 months, IQR 15.50 months), while subcutaneous GA had the longest duration (median 12.00 months and IQR 29.00 months). Although recurrence rates for subcutaneous and generalized GA were high at 45.5% and 33.3%, respectively, most patients achieved clearance or improvement with treatment. Conclusion: Most cases of GA in our study were idiopathic, with no clear differences between GA subtypes and associated comorbidities. Topical steroids were the most prescribed treatment with mixed efficacy.

Stroke in children with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome: a systematic review of the literature.

BACKGROUND AND PURPOSE: PHACE is an acronym for posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Several case reports of arterial ischemic stroke (AIS) in individuals with PHACE have been published, but risk factors for AIS in PHACE have not been clearly defined. The objective of this article is to review all cases of stroke in PHACE in children and describe clinical characteristics that may be associated with an increased risk of AIS. METHODS: A literature and registry search was conducted to identify patients with PHACE who had experienced AIS. Data were analyzed to determine age of onset, presenting signs and symptoms, and clinical features among this cohort compared with PHACE without AIS. RESULTS: Twenty-two individuals with PHACE and AIS were identified. Imaging of the arteries of the head and neck was reported in 20 of 22. Narrowing or nonvisualization of at least 1 great cerebral vessel was present in 19 of 20 and of those, 15 had ≥ 2 vessels involved. Aortic arch anomalies were reported in 13 of 22 individuals. CONCLUSIONS: Aplasia, hypoplasia, or occlusion of a major cerebral artery appears to be a significant risk factor for AIS in children with PHACE, especially when >1 vessel is involved or if there is coarctation of the aorta.

Agminated, eruptive pyogenic granuloma-like lesions developing over congenital vascular stains.

We report three infants who developed agminated pyogenic granulomas over congenital vascular malformations, all of which had an aggressive growth pattern. There were no precipitating events such as laser therapy or surgery. Lesions were excised.

HPV Vaccination Status and Resolution of Warts in Pediatric Patients.

Background: Warts are a common dermatologic complaint with an increased incidence within the pediatric population. Warts are caused by multiple strains of the human papillomavirus (HPV). There is little research on how a patient's HPV immunization status affects the response to treatment of warts in pediatric patients. Aims: The purpose of this study is to investigate the relationship between HPV vaccination status and wart resolution. Materials and Methods: This is a retrospective chart review that investigates the relationship between response to routine treatment of warts and a subject's HPV vaccination status. Results: There was no significant relationship found between HPV vaccination status and resolution of warts (p = 0.797). However, there was a significant positive correlation between having the HPV vaccine and number of visits for the treatment of warts (r = 0.180, P = 0.024). Conclusion: This study did not show a significant correlation between HPV vaccination status and wart resolution, although it demonstrated a significant positive relationship between those immunized with the HPV vaccine and an increased number of treatment visits. Possible explanations for this unexpected correlation include the variation in HPV vaccine formulation, vaccination status, and frequency of office visits, since vaccinated patients are more likely to be compliant with office visits.

An update on lasers in children.

PURPOSE OF REVIEW: A variety of new indications for laser treatment have been raised in the dermatology field recently. They offer significant opportunities to manage a large spectrum of conditions in the pediatric population. Therefore, it is necessary to know the current trends and limitations of their use for the treatment of pigmented and vascular lesions. RECENT FINDINGS: The pulsed dye laser for port wine stain treatment remains the gold standard. However, pulsed dye laser-resistant port wine stain constitutes a difficult management problem. New therapeutic modalities such as photodynamic therapy and the application of different topical angiogenesis inhibitors promise better results in avoiding port wine stain redarkening. The potential systemic effects also require further study. Traditionally, the Q-switched pigmented laser has been used for pigmented lesions. However, the 1550 nm wavelength erbium-doped fiber laser could be a new modality of treatment for Becker's nevus. SUMMARY: Since the development of the first laser in 1960, dermatology and dermatologic surgery have rapidly evolved over the last two decades, thanks to the numerous technological and scientific acquisitions focused on improvement in the treatment of skin conditions. A large spectrum of vascular and pigmented lesions and other conditions such as chronic inflammatory skin diseases, such as psoriasis and eczema, keloids and hypertrichosis, are now managed safely with laser treatment.

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.

A comparison of disease severity among affected male versus female patients with PHACE syndrome.

BACKGROUND: PHACE syndrome (Online Mendelian Inheritance in Man database No. 606519) refers to the association of large, plaquelike, or segmental hemangiomas of the face, with one or more of the following anomalies: posterior fossa brain malformations, arterial cerebrovascular anomalies, cardiovascular anomalies, eye anomalies, and ventral developmental defects, specifically sternal defects, supraumbilical raphe, or both. OBJECTIVE: The underlying pathogenesis of PHACE is unknown. A strong female predominance exists, leading some to suggest the possibility of X-linked dominant inheritance, with lethality in male patients. However, no familial cases have been reported, and disease severity among affected male patients has not been systematically studied. METHODS: We compared the incidence of syndrome-associated anomalies between 17 new and 42 published reports of male patients with PHACE versus 213 published reports of female patients with PHACE. RESULTS: A statistically significant difference was found only for structural brain anomalies, which were somewhat more common in male patients. LIMITATIONS: This was a retrospective study. Information was limited on some new and many previously reported cases. CONCLUSIONS: Overall, our results show no convincing trend toward greater or lesser disease severity among affected male patients with PHACE.

[Diagnosis and treatment of gastrointestinal bleeding in Bean syndrome]. / Diagnóstico y tratamiento de hemorragia digestiva en síndrome de Bean (Blue Rubber-Bleb Nevus Syndrome).

Blue Rubber-Bleb Nevus Syndrome (BRBNS, Bean Syndrome) is a rare disorder characterized by the presence of cutaneous and visceral vascular malformations. Although it may affect several organs, the gastrointestinal tract is one of the most frequently involved sites. It can cause gastrointestinal bleeding and chronic anemia. We report an 8-years-old girl who was admitted because of cutaneous malformations and anemia suspected to be caused by gastrointestinal bleeding. Cutaneous lesions were compatible with Blue Rubber-Bleb Nevus Syndrome. Vascular malformations were confirmed by diagnostic gastroduodenoscopy and colonoscopy and further therapeutical intervention was planned. We performed banding of 2 lesions located in the stomach and sclerotherapy of a duodenal lesion. Six colonic lesions were treated with banding and three other polypoid lesions were endoscopically resected A combined laparoscopic and endoscopic approach was performed for evaluation and treatment of small-bowel lesions. Eighteen lesions were found. We endoscopically resected 8 polipoid lesions. Eight other large transmural lesions were removed by wedge resection. Only one lesion required termino-terminal anastomosis. We consider that endoscopic treatment and laparoscopically assisted enteroscopy are safe and effective options in the treatment of gastrointestinal bleeding caused by vascular malformations.

Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.