O. Boccara

A Randomized, Controlled Trial of Oral Propranolol in Infantile Hemangioma

BACKGROUNDnOral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited.nnnMETHODSnWe performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs.nnnRESULTSnOf 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol.nnnCONCLUSIONSnThis trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).

Cutaneous hematologic disorders in children

To determine and list the clinical and pathological features of cutaneous hematologic diseases in childhood.

Propranolol-resistant infantile haemangiomas

Propranolol is now widely used to treat severe infantile haemangiomas (IHs). Very few cases of propranolol‐resistant IH (PRIH) are mentioned in the literature.

Cutaneous B-cell lymphoblastic lymphoma in children: A rare diagnosis

BACKGROUNDnLymphoblastic lymphoma (LBL) is a rare malignant neoplasm usually occurring in the mediastinum of children and adolescents. The B-cell immunophenotype of LBL (B-LBL) accounts for less than 20% of all cases and may involve extramediastinal areas, such as the skin. Although highly aggressive, LBL is potentially curable if diagnosed early.nnnOBJECTIVEnWe sought to describe the clinical and histopathologic features of B-LBL in children presenting with cutaneous lesions, and to highlight the specific features of this rare and serious disease.nnnMETHODSnSeven children with a confirmed diagnosis of cutaneous B-LBL were identified by retrospective chart review. The clinical and histopathologic features were documented, analyzed, and compared with cases previously published in the literature.nnnRESULTSnSix children developed nodules on the head, and one child presented with lesions on the back and abdomen. Histopathology showed a diffuse dermal and subcutaneous monomorphous infiltrate made up of atypical cells with an immature B-cell phenotype. The average duration of the lesions before diagnosis was 3.2 months. A staging workup revealed extracutaneous disease in 5 patients, including bone-marrow involvement in 4 children.nnnLIMITATIONSnThis was a retrospective study with a small number of patients.nnnCONCLUSIONnThe cutaneous lesions of B-LBL typically manifest as rapidly growing erythematous firm nodules located on the head. Awareness of these clinical features is important for the diagnosis to be reached rapidly and treatment started without delay.

Calcinosis cutis: a rare reaction to subcutaneous injections of calcium-containing heparin in patients with renal failure.

Calcinosis of the cutis and the subcutis is a rare complication of calcium-containing heparin cutaneous injections, mostly occurring in a context of severe renal failure. We report 2 cases. The first patient developed firm erythematous nodules on his thighs and right arm, in a context of disseminated tuberculosis and acute severe renal failure related to human immunodeficiency virus nephropathy. Cutaneous location of tuberculosis was suspected. Histological features allowed to establish the diagnosis of calcinosis of the cutis and the subcutis, showing violaceous and crackled von Kossa-positive calcium deposits in the whole reticular dermis and in thin collagenous septa of subcutaneous tissue. A retrospective inquiry confirmed that subcutaneous injections of calcium-containing heparin had been performed on the sites where lesions occurred. The second patient developed similar lesions at injection sites of calcium-containing heparin, in a context of non-Hodgkin lymphoma and end-stage renal failure. Similar histological features were observed. Calcinosis of the cutis and the subcutis after subcutaneous injections of calcium-containing heparin is rare. It always occurs in a context of elevated calcium-phosphate product, a situation mostly encountered in severe renal failure. Early cutaneous lesions do not bear specific clinical features.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.A PI3KCA inhibitor reverses symptoms in a mouse model of PROS/CLOVES syndrome, which results from gain-of-function mutations in PI3KCA, and produces improvements in patients with PROS/CLOVES syndrome.

The scalp hair collar and tuft signs: A retrospective multicenter study of 78 patients with a systematic review of the literature

Background: Hair collar sign (HCS) and hair tuft of the scalp (HTS) are cutaneous signs of an underlying neuroectodermal defect, but most available data are based on case reports. Objective: We sought to define the clinical spectrum of HCS and HTS, clarify the risk for underlying neurovascular anomalies, and provide imaging recommendations. Methods: A 10‐year multicenter retrospective and prospective analysis of clinical, radiologic, and histopathologic features of HCS and HTS in pediatric patients was performed. Results: Of the 78 patients included in the study, 56 underwent cranial and brain imaging. Twenty‐three of the 56 patients (41%) had abnormal findings, including the following: (1) cranial/bone defect (30.4%), with direct communication with the central nervous system in 28.6%; (2) venous malformations (25%); or (3) central nervous system abnormalities (12.5%). Meningeal heterotopia in 34.6% (9/26) was the most common neuroectodermal association. Sinus pericranii, paraganglioma, and combined nevus were also identified. Limitations: The partial retrospective design and predominant recruitment from the dermatology department are limitations of this study. Conclusions: Infants with HCS or HTS are at high risk for underlying neurovascular anomalies. Magnetic resonance imaging scans should be performed in order to refer the infant to the appropriate specialist for management.

Mycosis fungoides following pityriasis lichenoides: An exceptional event or a potential evolution?

To the Editor: We read with interest the comments from Pileri et al. [1] regarding the article of Boccara et al. [2] recently published in Pediatric Blood & Cancer. In this article we reported that 4/5 of children affected by mycosis fungoides (MF) had pre-existing pityriasis lichenoides chronica (PLC) and, therefore, we stated that this association was not fortuitous and that PLC could represent a predisposing factor for MF. Pityriasis lichenoides (PL), which includes PLC and its acute form, PL varioliformis acuta, is a skin disease of unknown origin. It is probably caused by a non-specific hypersensitivity reaction secondary to an antigenic stimulation, possibly microbiologic in children. PL must certainly be seen as a benign disorder in this population. However, the frequent detection of a clonal T cell population in both the chronic and acute forms [3–6] suggests that it could belong to the spectrum of primary cutaneous T cell lymphoproliferations. Moreover, some cases of PLC evolving into MF have already been described, mainly in children [7–10]. Therefore, even if we agree with Pileri et al. that the clinical course of PL is benign in most cases—our clinical experience being exactly the same—, we do believe that the puzzling PL-MF combination is not coincidental. The cutaneous immunologic environment induced by PL could promote growth of a tumoral clone in some patients with a predisposition to lymphoma development. This minority of patients remains to be identified. We think that these children should be followed-up until adulthood, bearing in mind the possibility of a morbid link between PL and lymphoma and/or a real transformation of PL into cutaneous lymphoma in certain patients with underlying predisposing factors, whose mechanisms it is important to understand more fully. Lastly, it is true than only one of our five cases was biopsied, the other being diagnosed on the basis of clinical criteria only. Indeed, while in these cases PL could not be diagnosed with 100% certainty, the other diagnosis to be considered would have been Pityriasis-like MF, which has already been described in children, leading to the same discussion [11].

Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design

BackgroundSlow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes.ObjectiveThe objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs.Methods/designThis French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18xa0years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12xa0months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor).DiscussionThe main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study).Trial registrationClinicalTrials.gov Identifier: NCT02509468, first received: 28 July 2015.EU Clinical Trials Register EudraCT Number: 2015-001096-43.

Clinical and hemodynamic risk factors associated with discrepancies in lower limb length with capillary malformations – data from the national paediatric French cohort CONAPE

Genetics discoveries have allowed for a better understanding of capillary malformations (CMs) associated with overgrowth syndrome. However, molecular analyses are still not easy to perform or interpret. Other analytical methods are needed.