Mosaic BRAF Fusions Are a Recurrent Cause of Congenital Melanocytic Nevi Targetable by MAPK Pathway Inhibition.

Among children with multiple congenital melanocytic nevi, 25% have no established genetic cause, of whom many develop a hyperproliferative and severely pruritic phenotype resistant to treatment. Gene fusions have been reported in individual cases of congenital melanocytic nevi. We studied 169 patients with congenital melanocytic nevi in this study, 38 of whom were double wild type for pathogenic NRAS/BRAF variants. Nineteen of these 38 patients had sufficient tissue to undergo RNA sequencing, which revealed mosaic BRAF fusions in 11 of 19 patients and mosaic RAF1 fusions in 1 of 19. Recurrently, fusions involved the loss of the 5´ regulatory domain of BRAF or RAF1 but preserved the kinase domain. We validated all cases and detected the fusions in two separate nevi in 5 of 12 patients, confirming clonality. The absence of the fusion in blood in 8 of 12 patients indicated mosaicism. Primary culture of BRAF-fusion nevus cells from 3 of 12 patients demonstrated highly increased MAPK activation, despite only mildly increased BRAF expression, suggesting additional mechanisms of kinase activation. Trametinib quenched MAPK hyperactivation in vitro, and treatment of two patients caused rapid improvement in bulk tissue, improving bodily movement and reducing inflammation and severe pruritus. These findings offer a genetic diagnosis to an additional group of patients and trametinib as a treatment option for the severe associated phenotypes.

GNAQ/GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics.

Mosaic variants in genes GNAQ or GNA11 lead to a spectrum of vascular and pigmentary diseases including Sturge-Weber syndrome, in which progressive postnatal neurological deterioration led us to seek biologically targeted therapeutics. Using two cellular models, we find that disease-causing GNAQ/11 variants hyperactivate constitutive and G-protein coupled receptor ligand-induced intracellular calcium signaling in endothelial cells. We go on to show that the aberrant ligand-activated intracellular calcium signal is fueled by extracellular calcium influx through calcium-release-activated channels. Treatment with targeted small interfering RNAs designed to silence the variant allele preferentially corrects both the constitutive and ligand-activated calcium signaling, whereas treatment with a calcium-release-activated channel inhibitor rescues the ligand-activated signal. This work identifies hyperactivated calcium signaling as the primary biological abnormality in GNAQ/11 mosaicism and paves the way for clinical trials with genetic or small molecule therapies.

GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification.

Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome and phakomatosis pigmentovascularis with dermal melanocytosis. The pathognomonic finding of localized "tramlining" on plain skull radiography, representing medium-sized neurovascular calcification and associated with postnatal neurological deterioration, led us to study calcium metabolism in a cohort of 42 children. In this study, we find that 74% of patients had at least one abnormal measurement of calcium metabolism, the commonest being moderately low serum ionized calcium (41%) or high parathyroid hormone (17%). Lower levels of ionized calcium even within the normal range were significantly associated with seizures, and with specific antiepileptics despite normal vitamin D levels. Successive measurements documented substantial intrapersonal fluctuation in indices over time, and DEXA scans were normal in patients with hypocalcemia. Neurohistology from epilepsy surgery in five patients revealed not only intravascular, but perivascular and intraparenchymal mineral deposition and intraparenchymal microvascular disease in addition to previously reported findings. Neuroradiology review clearly demonstrated progressive calcium deposition in individuals over time. These findings and those of the adjoining paper suggest that calcium deposition in the brain of patients with GNAQ/GNA11 mosaicism may not be a nonspecific sign of damage as was previously thought, but may instead reflect the central postnatal pathological process in this disease spectrum.

Gianotti-Crosti Syndrom-ähnliche Reaktion bei Molluscum contagiosum -Klinische Charakteristika und Therapieansprechen.

HINTERGRUND UND ZIELE: Molluscum contagiosum (MC) ist eine häufige Virusinfektion der Haut. Bei gewissen Patienten mit MC kann eine Hypersensitivitätsreaktion ähnlich des Gianotti-Crosti-Syndroms beobachtet werden. Diese wird Gianotti-Crosti syndrome-like reaction (GCLR, Gianotti-Crosti-Syndrom-ähnliche Reaktion) genannt. Wir berichten über eine Kohorte von Patienten mit GCLR, um deren klinische Präsentation und Verlauf besser zu charakterisieren. PATIENTEN UND METHODIK: Retrospektive Studie mit Einschluss aller Kinder, welche sich zwischen 2015 und 2020 mit einer GCLR in unserem pädiatrischen Hautzentrum vorgestellt haben. RESULTATE: 26 Patienten (14 männlich) mit einem medianen Alter von 6.5 (3-11,3) Jahren wurden eingeschlossen. Die GCLR hat bei allen Patienten die Streckseiten der Extremitäten betroffen. Bei Kindern mit ausgedehntem Ausschlag waren bei 7 (27 %) auch der Stamm und bei 6 (23 %) auch das Gesicht mitbetroffen. Der Befall der Haut über der Achillessehne war ein auffälliges Phänomen bei 4 (15 %) Kindern. Juckreiz war das vorherrschende Symptom bei 20 (77 %) Patienten. Der Ausschlag hat gut auf die Behandlung mit topischen und/oder systemischen Kortikosteroiden angesprochen und ist innerhalb von 4 Wochen abgeklungen. Bei allen Patienten folgte innerhalb von 9 (4-24) Wochen nach der GCLR die Abheilung der MC. SCHLUSSFOLGERUNGEN: GCLR ist ein charakteristischer, akuter, ausgedehnter, juckender papulöser Ausschlag und führt häufig zu Notfallkonsultationen und Verunsicherung der betroffenen Patienten. Die GCLR spricht gut auf eine Behandlung mit Kortikosteroiden an, hat einen gutartigen Verlauf und geht der Abheilung der MC voraus.

Gianotti-Crosti syndrome-like reaction to molluscum contagiosum-Clinical characteristics and response to treatment.

BACKGROUND AND OBJECTIVES: Molluscum contagiosum (MC) is a common viral infection. Hypersensitivity reactions reminiscent of Gianotti-Crosti syndrome, termed Gianotti-Crosti syndrome-like reaction (GCLR), have been reported in a subset of patients. We report a series of patients with GCLR, better delineating its clinical presentation and course. PATIENTS AND METHODS: Retrospective chart review of all children presenting with GCLR at our Pediatric Skin Center between 2015 and 2020. RESULTS: 26 children (14 boys) with a median age of 6.5 (3-11.3) years were included. GCLR involved the extensor surfaces of the extremities in all patients. More widespread eruptions also affected the trunk and face in 7 (27 %) and 6 (23 %) children respectively. Involvement of the skin overlying the Achilles tendons was a new finding in 4 (15 %) children. Itch was the predominant symptom in 20 (77 %) patients. The rash responded to topical and/or systemic corticosteroids and resolved within four weeks. GCLR was followed by clearance of MC in all patients within 9 (4-24) weeks. CONCLUSIONS: GCLR is a characteristic acute, wide-spread, pruritic papular eruption, which often leads to emergency consultations and anxiety in affected patients. GCLR responds well to corticosteroid treatment, has a benign course, and heralds the healing of MC.

Venous Malformations in Childhood: Clinical, Histopathological and Genetics Update.

Our knowledge in vascular anomalies has grown tremendously in the past decade with the identification of key molecular pathways and genetic mutations that drive the development of vascular tumors and vascular malformations. This has led us to better understand the pathogenesis of vascular lesions, refine their diagnosis and update their classification while also exploring the opportunity for a targeted molecular treatment. This paper aims to provide an overview of venous malformations (VM) in childhood. Specific entities include common VMs, cutaneo-mucosal VM, blue rubber bleb nevus syndrome or Bean syndrome, glomuvenous malformation, cerebral cavernous malformation, familial intraosseous vascular malformation and verrucous venous malformation. The clinicopathological features and the molecular basis of each entity are reviewed.

Sleep behavior of infants with infantile hemangioma treated with propranolol-a cohort study.

Sleep problems are frequently reported in infants treated with propranolol for infantile hemangiomas, possibly serving as a marker for a negative impact on central nervous system function. In this cohort study, we objectively investigate the sleep behavior of infants with infantile hemangiomas on propranolol compared to a healthy, untreated control group. Sleep of propranolol-treated infants and controls was investigated using ankle actigraphy and a 24-h diary for 7-10 days at ages 3 and 6 months. The main outcome measures were the Number of Nighttime Awakenings and Sleep Efficiency. The main secondary outcome measures included 24-hour Total Sleep, daytime sleep behavior, and parent-rated infant sleep quality and behavioral development based on the Brief Infant Sleep Questionnaire (BISQ) and the age-appropriate Ages-and-Stages Questionnaire (ASQ), respectively. Fifty-four term-born infants were included in each cohort. No group difference in any investigated parameter was seen at age 3 months. At age 6 months, the propranolol group exhibited a decrease in Sleep Efficiency and a trend towards an increased Number of Nighttime Awakenings compared to the control group. Treated infants at 6 months also had shorter daytime waking periods. 24-hour Total Sleep was unaffected by propranolol. No negative impact of propranolol on subjective sleep quality and behavioral development was noted.Conclusion: Propranolol exerts a measurable yet mild impact on objectively assessed infants' sleep measures. Behavioral developmental scores were unaffected. Our results support propranolol as first-line therapy for complicated infantile hemangiomas. What is Known: • Sleep disorders are frequently reported in infants with infantile hemangiomas treated with propranolol and often lead to treatment discontinuation. • Investigations of the sleep pattern in this patient group using objective measures are lacking. What is New: • The sleep pattern of propranolol-treated infants is assessed using actigraphy and a 24-h sleep diary and compared to healthy, untreated controls. • Propranolol leads to a decreased sleep efficiency at night and an increased demand of daytime sleep, yet effects are mild overall.

Sinus pericranii with facial involvement-A great mimicker.

Sinus pericranii is a rare vascular anomaly characterized by an abnormal communication between the intra- and extracranial venous systems through a calvarial defect(s). We present three cases of congenital sinus pericranii with facial involvement, emphasizing its cutaneous presentation with diagnostic pitfalls and discuss the multidisciplinary management of this vascular anomaly.

Sequelae following infantile haemangiomas treated with propranolol.

BACKGROUND: Oral propranolol accelerates the involution of infantile haemangiomas (IHs). However, it is not clear whether IHs treated with oral propranolol are associated with fewer sequelae than when left untreated. OBJECTIVES: To quantify and describe sequelae associated with IHs treated with oral propranolol, and to explore whether treated IHs are associated with fewer sequelae than untreated IHs. MATERIALS & METHODS: This multicentre, retrospective, cohort study included patients with IH treated with oral propranolol ≥2 mg/kg for at least six months, with photographic images available at baseline and at age 4-5 years. A historical comparison cohort comprised 185 patients with untreated IHs. Main outcomes/measures were: IH features, treatment characteristics and type/degree of sequelae. RESULTS: Oral propranolol, most commonly at 2 mg/kg/day (mean duration: nine months), was initiated in 171 patients (mean age: 6.02 months). After treatment, 125 of 171 (73.1%) IHs were associated with no/minimal sequelae. The most common sequelae were telangiectasia (78%), fibrofatty tissue (37%) and anetodermic skin (28%). Deep IHs were associated with significantly fewer sequelae than other subtypes. Ulceration appeared to increase the likelihood of severe sequelae. IHs with a stepped border was associated with more severe sequelae than those with a progressive border (44% versus 27%, p < 0.05). Treated IHs resolved without sequelae or were associated with a sequela that did not need correction in 27.7% more cases than untreated IHs (RR: 1.61; p < 0.001). CONCLUSION: Among IHs treated with oral propranolol, 73% resolved without, or were associated with minimal sequelae. Deep IHs were associated fewer sequelae than other subtypes. Oral propranolol decreased the likelihood of IH sequelae requiring correction.

Infliximab for the treatment of recalcitrant bullous Sweet syndrome in a 10-year-old girl.

We report the case of a 10-year-old girl with bullous Sweet syndrome, recalcitrant to high-dose systemic corticosteroids. Subsequent treatment with infliximab resulted in a rapid improvement in cutaneous lesions and systemic symptoms. Cutis laxa was noted in the healed skin. We propose early second-line treatment with infliximab in children with steroid-refractory Sweet syndrome.

Secukinumab Therapy for Netherton Syndrome.

Importance: Netherton syndrome (NS) is a rare, severe genetic disorder of cornification with high morbidity. Treatment for NS has been notoriously difficult. Recent studies showed an upregulated helper T cell (TH) 17/interleukin 23 (IL-23) pathway in NS, suggesting the possibility of treatment strategies that target IL-17. Objective: To evaluate the clinical response of NS to treatment with the IL-17 antagonist secukinumab. Design, Setting, and Participants: This case series study reports the experience of compassionate use therapy with secukinumab in 4 patients with severe NS, including 2 children, from December 1, 2018, to December 1, 2019, with 3 patients still undergoing treatment at the time of final analysis. Data were analyzed from December 1, 2018, to December 1, 2019. Main Outcomes and Measures: Expression of IL-17 in the skin was evaluated by immunohistochemical analysis, and serum cytokine concentrations were measured using a commercially available assay. Treatment response was assessed using the Ichthyosis Area and Severity Index (IASI) total score, including measures of erythema and scaling, the Dermatology Life Quality Index (DLQI), and the 5-D itch scale. Results: In all 4 patients (age range, 9-27 years; 3 male and 1 female), immunostaining with an IL-17A antibody showed an increased number of positive cells in lesional skin. Cytokine assessment in serum samples revealed increased levels of CCL20. Treatment duration with secukinumab was 3 to 12 months at the time of this report. After 3 months of therapy, IASI scores were reduced by 44% to 88%, DLQI scores were reduced by 40% to 76%, and 5-D itch scale scores were reduced by 27% to 62%. This outcome was sustained at the 6-month follow-up. Two patients with an erythrodermic phenotype showed marked improvement of all parameters. A refractory palmoplantar eczematous eruption occurred in 2 patients, and a candidal nail infection developed in 2 patients. No severe adverse events were reported. Conclusions and Relevance: This initial case series reporting the use of anti-IL-17 therapy in NS demonstrated marked cutaneous improvement, particularly in 2 pediatric patients with erythrodermic phenotypes. Further studies are needed to evaluate the long-term benefit of this potential treatment modality.

Rebound of Involuted Infantile Hemangioma After Administration of Salbutamol.

Since the discovery of propranolol in the treatment of infantile hemangioma (IH), there has been emergent investigation of ß-adrenergic receptor (ß-AR) signaling in IH and the mechanisms of action for which ß-AR blockers regulate hemangioma cell proliferation. However, ß-AR agonists and antagonists are known to act antithetically via the same intracellular ß-AR-driven proangiogenic pathways. We present the case of a patient with involuted IH treated with propranolol that showed a full and rapid regrowth during the intravenous administration of salbutamol, a selective ß2-adrenergic agonist, for an episode of severe obstructive bronchitis. This observation brings forward the clinical implication of ß-signaling effects in IH and raises awareness of the potential proliferative response of IH to ß-AR agonists such as salbutamol.