20 research outputs found
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
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
Mosaic BRAF fusions are a recurrent cause of congenital melanocytic naevi targetable by MEK inhibition
Among children with multiple congenital melanocytic naevi (CMN), 25% have no established genetic cause, of which many develop a hyperproliferative and severely pruritic phenotype resistant to treatment. Gene fusions have been reported in individual cases of CMN. Here, we study 169 CMN patients, 38 of whom were double wild-type for NRAS/BRAF mutations. Nineteen of these 38 patients had sufficient tissue to undergo RNAseq, which revealed mosaic BRAF fusions in 11/19 patients and mosaic RAF1 fusions in 1/19. 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 naevi in 5/12 patients, confirming clonality. The absence of the fusion in blood in 8/12 patients indicated mosaicism. Primary culture of BRAF-fusion naevus cells from 3/12 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 Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification
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
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 β-adrenergic receptor (β-AR) signaling in IH and the mechanisms of action for which β-AR blockers regulate hemangioma cell proliferation. However, β-AR agonists and antagonists are known to act antithetically via the same intracellular β-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 β2-adrenergic agonist, for an episode of severe obstructive bronchitis. This observation brings forward the clinical implication of β-signaling effects in IH and raises awareness of the potential proliferative response of IH to β-AR agonists such as salbutamol
Sparing of the nipple-areola complex by capillary malformations: Vascular variant of the Bork-Baykal phenomenon
The"Bork-Baykal phenomenon" refers to the sparing of the nipple-areola complex in large congenital melanocytic nevi involving the breast. So far, this finding has not been reported in vascular anomalies. We present four patients with an extensive capillary malformation (CM) involving the breast that was found to exhibit a similar sparing of the nipple and areola. All of these capillary nevi were associated with asymmetric overgrowth
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