Publications by authors named "Christine Léauté-Labrèze"

55 Publications

Critical role of Aquaporin-1 and telocytes in infantile hemangioma response to propranolol beta blockade.

Proc Natl Acad Sci U S A 2021 Feb;118(7)

Inserm, Biothérapie des Maladies Génétiques Inflammatoires et Cancers (BMGIC), UMR 1035, University of Bordeaux, F-33076 Bordeaux, France.

Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.
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http://dx.doi.org/10.1073/pnas.2018690118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896303PMC
February 2021

Congenital haemangiomas: a single-centre retrospective review.

BMJ Paediatr Open 2020 7;4(1):e000816. Epub 2020 Dec 7.

Dermatology, CHU de Bordeaux, Bordeaux, France.

Objective: Congenital haemangiomas (CHs) are rare, benign vascular tumours that are fully developed at birth. Three subtypes of CHs have been described based on clinical behaviour: rapidly involuting CHs (RICHs), non-involuting CHs (NICHs) and partially involuting CHs (PICHs). We explore in our study clinical, evolutionary and paraclinical characteristics of the three CH subtypes.

Design: Children with CH attending our department of paediatric dermatology at Bordeaux University Hospital over a 13-year period were retrospectively included. Epidemiological, clinical and evolutionary data, photographs and imaging results were reviewed. All available tissue samples were histologically examined.

Results: We included 57 patients: 22 with RICH, 22 with NICH and 13 with PICH. Males predominated (ratio 1.7); the most common CH location was on the limbs. RICH, NICH and PICH exhibited overlapping characteristics; all were single telangiectatic lesions with pale peripheral halos. At birth, NICHs were flat but RICHs and PICHs bulky. The median age at complete RICH involution was 12 months. One-third of CHs that appeared RICH-like at birth underwent incomplete involution to become PICHs. Heart failure and thrombocytopenia were rare complications. PICHs were frequently ulcerated. Pain was common for NICH and PICH. The imaging and histological data of the three CH subtypes were rather similar.

Conclusions: We describe the characteristics and evolution of the three CH subtypes using a case series. Certain overlapping features were apparent, reinforcing the hypothesis that RICH, NICH and PICH lie on the same pathological spectrum.
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http://dx.doi.org/10.1136/bmjpo-2020-000816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722829PMC
December 2020

Cutaneous Infantile Haemangiomas with Intracranial and Intraspinal Involvement: A European Multicentre Experience and Review.

Acta Derm Venereol 2020 Sep 8;100(16):adv00255. Epub 2020 Sep 8.

Dermatology Unit, Bambino Gesù Childrens Hospital, IRCCS, IT-00165 Rome, Italy.

Infantile haemangiomas are very common benign tumours in the first months of life. They are mostly cutaneous; however, extracutaneous lesions are possible, and occur in very rare cases in the central nervous system. A European multicentre observational retrospective study was conducted in the last 5 years. Seven patients with intracranial or intraspinal infantile haemangiomas were selected and treated with oral propranolol. Propranolol was interrupted after complete or almost complete resolution of infantile haemangiomas. All patients tolerated the treatment well without side-effects. Central nervous system infantile haemangiomas are probably underestimated due to the frequent absence of symptoms and their spontaneous involution. However, they should be investigated in case of segmental cutaneous infantile haemangiomas, particularly on the head, neck, upper trunk, lumbar or sacral area in order to diagnosis intra-central nervous system involvement at an early stage.
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http://dx.doi.org/10.2340/00015555-3608DOI Listing
September 2020

The Infantile Hemangioma Referral Score: A Validated Tool for Physicians.

Pediatrics 2020 04 11;145(4). Epub 2020 Mar 11.

Centre for Laser and Vascular Anomalies, Department of Dermatology, Skåne University Hospital, Malmö, Sweden.

Objectives: Infantile hemangiomas (IHs) are common; some cases require timely referral and treatment to prevent complications. We developed and validated a reliable instrument for timely and adequate referral of patients with IH to experts by nonexpert primary physicians.

Methods: In this multicenter, cross-sectional, observational study, we used a 3-stage process: (1) development of the Infantile Hemangioma Referral Score (IHReS) tool by IH experts who selected a representative set of 42 IH cases comprising images and a short clinical history, (2) definition of the gold standard for the 42 cases by a second independent committee of IH experts, and (3) IHReS validation by nonexpert primary physicians using the 42 gold standard cases.

Results: A total of 60 primary physicians from 7 different countries evaluated the 42 gold standard cases (without reference to the IHReS tool); 45 primary physicians evaluated these cases using the IHReS questionnaire, and 44 completed retesting using the instrument. IHReS had a sensitivity of 96.9% (95% confidence interval 96.1%-97.8%) and a specificity of 55.0% (95% confidence interval 51.0%-59.0%). The positive predictive value and negative predictive value were 40.5% and 98.3%, respectively. Validation by experts and primary physicians revealed substantial agreement for interrater reliability and intrarater repeatability.

Conclusions: IHReS, a 2-part algorithm with a total of 12 questions, is an easy-to-use tool for primary physicians for the purpose of facilitating correct and timely referral of patients with IH. IHReS may help practitioners in their decision to refer patients to expert centers.
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http://dx.doi.org/10.1542/peds.2019-1628DOI Listing
April 2020

Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial.

Trials 2019 Dec 17;20(1):739. Epub 2019 Dec 17.

INSERM U1246 -SPHERE « MethodS in Patients-centered outcomes and HEalth REsearch », University of Nantes, University of Tours, 37000, Tours, France.

Background: Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults.

Methods: This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm.

Discussion: For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment.

Trial Registration: ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018-001359-11.
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http://dx.doi.org/10.1186/s13063-019-3767-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918625PMC
December 2019

Hereditary Mucoepithelial Dysplasia Results from Heterozygous Variants at p.Arg557 Mutational Hotspot in SREBF1, Encoding a Transcription Factor Involved in Cholesterol Homeostasis.

J Invest Dermatol 2020 06 29;140(6):1289-1292.e2. Epub 2019 Nov 29.

Paediatric Dermatology Department, Bordeaux University Hospital, Bordeaux, France; University of Bordeaux, INSERM, U1211, Bordeaux, France.

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http://dx.doi.org/10.1016/j.jid.2019.10.014DOI Listing
June 2020

Propranolol pharmacokinetics in infants treated for Infantile Hemangiomas requiring systemic therapy: Modeling and dosing regimen recommendations.

Pharmacol Res Perspect 2018 06 30;6(3):e00399. Epub 2018 Apr 30.

SERVIER Laboratories Center of Excellence Pharmacokinetics Suresnes France.

Propranolol has become the first choice therapy for complicated Infantile Hemangiomas (IH). The pharmacokinetics of propranolol were evaluated after repeated oral administration of a new pediatric solution of propranolol at 3 mg kg day given twice daily (BID) in infants (77-243 days) with IH. A population model was built to describe the pharmacokinetics of propranolol in infants and to simulate different dosing regimens. One hundred and sixty-seven plasma concentrations from 22 infants were used in the population analysis. Weight effect was tested on apparent clearance and volume of distribution. Monte-Carlo simulations were performed for 4 dosing regimens: BID dosing with irregular or strict 12-hour intervals and 2 different 3 time daily dosing (TID) regimens. The best model was a one-compartment model with first-order absorption and elimination rates. The weight affected the clearance but not the volume. Typical oral clearance was estimated at 3.06 L hour kg (95% CI: 1.14-8.61 L hour kg), close to adult clearance data. When regular BID dosing was compared to TID or irregular BID regimens, simulated median Cmin and Cmax were <20% different. To conclude, a model using a weight allometric function on clearance was established and confirmed that the dose in mg/kg should be used without adaptation by range of age in treatment of complicated IH. The simulations support the use of a BID dosing preferably to a TID dosing thanks to close Cmin and Cmax at steady state between both regimen and showed the possibility of irregular BID dosing, allowing early administration in the evening when needed.
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http://dx.doi.org/10.1002/prp2.399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925426PMC
June 2018

[Benign aggressive vascular anomalies in children].

Bull Cancer 2018 Jun 20;105(6):610-625. Epub 2018 Mar 20.

Centre de référence des maladies rares de la peau d'origine génétique, hôpital Pellegrin-Enfants, centre hospitalier universitaire de Bordeaux, unité de dermatologie pédiatrique, 33076 Bordeaux cedex, France.

Superficial vascular anomalies constitute a large group of malformative and tumoral conditions developed from all types of vessels. Vascular tumors are the result of cellular hyperplasia, whereas vascular malformations (VMs) are constituted of dysplastic vessels. The classification from International Society for the Study of Vascular Anomalies (ISSVA) is based on this pathogenic difference. The most common vascular tumor is infantile hemangioma, which treatment, when necessary, is propranolol. Congenital hemangiomas and tumors that might be complicated with Kasabach-Merritt phenomenon, i.e. deep thrombocytopenia, are much rarer. Management of Kasabach-Merritt phenomenon is now largely based on sirolimus. Low-flow VMs include capillary, venous and lymphatic malformations; arteriovenous malformations are high-flow malformations. These different types of VMs might be combined. Currently, there is an increasing work in delineating the different entities based on molecular findings. Treatment of VMs depends on the impairment linked to them, and is decided case by case, in pluridisciplinary consultations. Interventional treatments, especially surgery and sclerotherapy, are usually partially efficient, and management of patients with VMs increasingly involves medical drugs. First-line treatment of coagulation disorders associated with venous malformations is based on low molecular weight heparin; sirolimus seems efficient in hemorrhagic complications refractory to usual treatment. Sirolimus is about to become the standard treatment in painful inflammatory manifestations of mixed and/or complicated lymphatic malformations.
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http://dx.doi.org/10.1016/j.bulcan.2018.01.016DOI Listing
June 2018

Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting.

Pigment Cell Melanoma Res 2018 03 21;31(2):318-329. Epub 2017 Oct 21.

Paediatric Dermatology Unit, National Reference Center for Rare Skin Disorders, Hôpital Pellegrin-Enfants, Bordeaux University Hospitals, Bordeaux, France.

Albinism is a rare genetic disease, comprising syndromic and non-syndromic forms. We assessed clinical and genetic characteristics in a prospective evaluation of 64 patients (33 children and 31 adults) seen at a specialized day hospital. Causative genetic mutations were found in TYR (23/64, 35.9%), OCA2 (19/64, 29.7%), TYRP1 (1/64, 1.6%), SLC45A2 (12/64, 18.7%), C10orf11 (1/64, 1.6%), HPS1 (3/64, 4.7%), HPS5 (1/64, 1.5%), HPS6 (1/64, 1.6%) and GPR143 (2/64, 3.1%). Causative mutations remained undetermined for one patient (1.6%). Heterogeneity for hair and skin phenotype was noted across and within the different genotypes. Skin and hair hypopigmentation did not correlate with visual impairment. The diagnosis of unrecognized syndromic forms and of cases of ocular albinism in this prospective and comprehensive series of patients with albinism in a European setting is remarkable. Photoprotection was overall good but not optimal.
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http://dx.doi.org/10.1111/pcmr.12651DOI Listing
March 2018

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

Circulation 2017 Sep 7;136(11):1037-1048. Epub 2017 Jul 7.

From Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium (M.A., R.H., M.V.); Center for Human Genetics, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium (N.R.); Université catholique de Louvain, Brussels, Belgium (E.P.); Department of Dermatology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain (E.B.); Department of Dermatology, Hospital Garrahan, Buenos Aires, Argentina (M.C.); Strong Hospital, University of Rochester School of Medicine and Dentistry, Rochester, NY (M.C.); Departments of Pediatrics and Medicine, Columbia University, New York (W.C., A.B.); Department of Medical Imaging, Sainte-Justine Mother- Child University Hospital, Montreal, Canada (J.D.); Service de Dermatologie, Centre Hospitalo-Universitaire de Nice, France (J.-P.L.); Genética Molecular, Hospital Sant Joan de Déu, Barcelona, Spain (L.M.); Service de Dermatologie, Centre de Référence des Maladies rares de la peau, Hôpital Larrey, Toulouse, France (J.M.-H.); Departments of Medicine and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.E.P.); Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia (D.J.A.); Department of Neuroradiology, Lariboisière Hospital, Paris, France (A.B.); Vascular Anomalies Program, Lenox Hill Hospital, New York (F.B.); Vascular Birthmark Institute of New York, Roosevelt Hospital (F.B.); Department of Pediatrics, Medical Genetics University of Iowa Carver College of Medicine, Iowa City (H.B.); Department of Dermatology, Université de Caen Basse Normandie, CHU Caen, France (A.D.); Department of Urology, Wake Forest School of Medicine, Winston Salem, NC (D.B.); Genetics Service, Paediatric Department, University Hospital Santa Maria, Lisbon, Portugal (J.D.); Department of Dermatology, Hospital Sant Joan de Deu, Barcelona, Spain (M.A.G.-E.); Departement of Dermatology, School of Medicine, University of California, San Francisco (I.P.); Department of Genetics, University Hospital, Caen, France (M.G.); Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (M.K.); Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, CA (A.K.H.-K., L.H.); Hopital Pellegrin Enfants, Bordeaux, France (C.L.-L.); Hôpital Sainte-Justine, Montréal, Quebec, Canada (C.M.); Department of Dermatology, Texas Children's Hospital, Houston (D.M.); Département de Pédiatrie et Génétique Médicale, CHRU Hôpital Morvan, Brest, France (P.P.); Department of Dermatology, Paul Sabatier University, Toulouse, France (C.P.); Service de Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France (F.P.); Pediatric Dermatology Unit, Claude Bernard-Lyon, University and Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, France (A.P.); Centre Hospitalier Universitaire, Montpellier, France (I.Q.); Dermatolgie, Faculté de Médecine d'Alger, Algeria (A.S.); Department of Medical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia (A.T.); Service de Dermatologie, Centre Hospitalo-Universitaire Dijon-Bourgogne, France (P.V.); Department of Dermatology, Hospital Sant Joan de Deu, Barcelona, Spain (A.V.); Department of Paediatric Dermatology, Sydney Children's Hospital, School of Women's and Children's Health University of New South Wales, Sydney, Australia (O.W.); Department of Plastic and Reconstructive Surgery, University of Tokyo, Hongo, Japan (S.W.); Department of Pediatric Dermatology, University Children's Hospital Zurich, Switzerland (L.W.); Children's Hospital of New York (A.W.); University of Iowa Hospitals and Clinics, Iowa City (M.W.); Department of Pediatrics, Washington University, St. Louis, MO (M.W.); and Vascular Anomalies Center, Boston Children's Hospital, Harvard Medical School, Boston, MA (L.M.B.).

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 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 in 5 families that cosegregated with CM-AVM. Overall, screening of 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 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics -related CM-AVM1 and also hereditary hemorrhagic telangiectasia. -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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026886DOI Listing
September 2017

Hemangiomas and cutaneous vascular malformations

Rev Prat 2017 04;67(4):e197-e204

Service de dermatologie, hôpital Pellegrin, 33000 Bordeaux, France.

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April 2017

Genetics and vascular malformations

Rev Prat 2017 04;67(4):e196

Service de dermatologie, hôpital Pellegrin, 33000 Bordeaux, France.

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April 2017

Infantile haemangioma.

Lancet 2017 07 13;390(10089):85-94. Epub 2017 Jan 13.

Departments of Paediatrics and Paediatric Dermatology, Catholic Children's Hospital Wilhelmstift, Hamburg, Germany.

With a prevalence of 4·5%, infantile haemangiomas are the most common benign tumours of infancy, arising in the first few weeks of life and exhibiting a characteristic sequence of growth and spontaneous involution. Most infantile haemangiomas do not require therapy. However, to identify at-risk haemangiomas, close follow-up is crucial in the first weeks of life; 80% of all haemangiomas reach their final size by 3 months of age. The main indications for treatment are life-threatening infantile haemangioma (causing heart failure or respiratory distress), tumours posing functional risks (eg, visual obstruction, amblyopia, or feeding difficulties), ulceration, and severe anatomic distortion, especially on the face. Oral propranolol is now the first-line treatment, which should be administered as early as possible to avoid potential complications. Haemangioma shrinkage is rapidly observed with oral propranolol, but a minimum of 6 months of therapy is recommended.
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http://dx.doi.org/10.1016/S0140-6736(16)00645-0DOI Listing
July 2017

Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review.

Pediatrics 2016 10;138(4)

Pierre Fabre Dermatologie, Lavaur, France.

Background And Objectives: Given the widespread use of propranolol in infantile hemangioma (IH) it was considered essential to perform a systematic review of its safety. The objectives of this review were to evaluate the safety profile of oral propranolol in the treatment of IH.

Methods: We searched Embase and Medline databases (2007-July 2014) and unpublished data from the manufacturer of Hemangiol/Hemangeol (marketed pediatric formulation of oral propranolol; Pierre Fabre Dermatologie, Lavaur, France). Selected studies included ≥10 patients treated with oral propranolol for IH and that either reported ≥1 adverse event or effect (AE) or planned to capture AEs. Data capture was standardized and extracted study design, demographic characteristics, IH characteristics, intervention, and safety outcomes. AEs were assigned a system organ class and preferred term.

Results: A total of 83 of 398 identified literature records met the inclusion criteria, covering 3766 propranolol-treated patients. The manufacturer's data for 3 pooled clinical trials (435 propranolol-treated patients) and 1 Compassionate Use Program (1661 patients) were included. AE data were reported for 1945 of 5862 propranolol-treated patients. The most frequently reported AEs included a range of sleep disturbances, peripheral coldness, and agitation. The most serious AEs (atrioventricular block, bradycardia, hypotension, bronchospasm/bronchial hyperreactivity, and hypoglycemia-related seizures) were managed by decreasing doses or temporary/permanent discontinuation of propranolol. Limitations included the variety of included study designs; monitoring, collection, and reporting of AE data; small sample sizes for some articles; and the wide scope of review.

Conclusions: Oral propranolol is well tolerated if appropriate pretreatment assessments and within-treatment monitoring are performed to exclude patients with contraindications and to minimize serious side effects during treatment.
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http://dx.doi.org/10.1542/peds.2016-0353DOI Listing
October 2016

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

J Invest Dermatol 2017 01 9;137(1):207-216. Epub 2016 Aug 9.

Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jid.2016.07.034DOI Listing
January 2017

Multifocal infantile haemangioma: a diagnostic challenge.

BMJ Case Rep 2016 Jun 17;2016. Epub 2016 Jun 17.

Department of Dermatology, Hospital de Santa Maria-Centro Hospitalar de Lisboa Norte, Lisbon, Portugal.

We describe a case of a newborn who presented with multiple dark red macules that developed into red-to-purple papules associated with thrombocytopaenia. Abdominal ultrasound showed multiple hyperechoic papules and nodules. Endothelial cells from a skin biopsy stained positively for endothelial cell glucose transporter 1, which was consistent with a diagnosis of multifocal infantile haemangioma. At the age of 2 months, the child developed intestinal bleeding and anaemia. Upper and lower endoscopies showed no intestinal haemangiomas. Oral treatment with propranolol (3 mg/kg/day) resulted in complete involution of the skin and hepatic haemangiomas over the period of treatment, which lasted until the child was aged 15 months. This is a rare case of multifocal cutaneous haemangioma with hepatic and probable intestinal involvement, successfully treated with propranolol.
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http://dx.doi.org/10.1136/bcr-2016-214827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932334PMC
June 2016

Skin Patterns Associated with Upper Airway Infantile Haemangiomas: A Retrospective Multicentre Study.

Acta Derm Venereol 2016 Nov;96(7):963-966

Department of Dermatology, CHU Larrey, 24 chemin de Pourvourville, FR-31059 Toulouse, France.

The aim of this study was to define the skin patterns at high risk for upper airway infantile haemangioma. A retrospective multicentre French observational study was conducted between January 2006 and January 2015 and all confirmed airway haemangioma were included. Thirty-eight patients with airway haemangioma from 9 centres were included. Thirty-one patients had a cutaneous or mucosal haemangioma: 21 with a location considered at high risk for airway haemangioma (large segmental mandibular haemangioma), 4 with a very mild facial involvement (lower lip or S1 (frontotemporal segment according to Haggstrom and Frieden)) and 6 with either lesions of the neck or body, or association of both. We report here the largest cohort of airway haemangioma. A third of patients do not completely fit with the definition of the high-risk area of airway haemangioma. Segmental lower lip and neck involvement also seem to be very suggestive areas. Clinicians must be able to recognize these areas.
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http://dx.doi.org/10.2340/00015555-2357DOI Listing
November 2016

Safety of Propranolol Therapy for Severe Infantile Hemangioma.

JAMA 2016 Jan;315(4):413-5

Service de Dermatologie, CIC P 1401 et Inserm U1035-CHU et Université de Bordeaux, Bordeaux, France.

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http://dx.doi.org/10.1001/jama.2015.13969DOI Listing
January 2016

In Memoriam: Jean Maleville, 1927-2015.

Pediatr Dermatol 2016 Jan-Feb;33(1):117-8. Epub 2015 Dec 13.

Department of Dermatology and Pediatric Dermatology, National Reference Centre for Rare Skin Disorders, Bordeaux Children's Hospital, France.

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http://dx.doi.org/10.1111/pde.12720DOI Listing
October 2016

Oral Propranolol for Infantile Hemangioma.

N Engl J Med 2015 07;373(3):284-5

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http://dx.doi.org/10.1056/NEJMc1503811DOI Listing
July 2015

Treatment of infantile haemangiomas: recommendations of a European expert group.

Eur J Pediatr 2015 Jul 29;174(7):855-65. Epub 2015 May 29.

Department of Paediatrics and Paediatric Dermatology, Catholic Children's Hospital Wilhelmstift, Liliencronstr. 130, Hamburg, 22149, Germany,

Unlabelled: With a prevalence of 2.6-4.5 %, infantile haemangiomas (IH) represent the most common tumour of infancy. While the majority of IH does not require therapy and regresses spontaneously, about 10 % of IH exhibit complications such as obstruction, ulceration or disfigurement. With the advent of oral propranolol, many conventional treatment options have become obsolete. This paper summarizes current recommendations for management of complicated IH. These recommendations have been written by an expert group after a consensus process including bibliographic review, several drafts of synthesis, meetings with quantitative voting system and redaction of an approved final manuscript.

Conclusion: Oral propranolol is the first-line agent for the treatment of complicated IH.

What Is Known: • Infantile haemangiomas (IH) are the most common tumours of infancy. Within a very short period after its discovery and long before the publication of randomized controlled trials, propranolol has become the number one agent for the treatment of complicated IH. What is New: • We report IH treatment recommendations of an international, interdisciplinary team of experts, based on an up-to-date review of the literature.
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http://dx.doi.org/10.1007/s00431-015-2570-0DOI Listing
July 2015

A randomized, controlled trial of oral propranolol in infantile hemangioma.

N Engl J Med 2015 Feb;372(8):735-46

The authors' affiliations are listed in the Appendix.

Background: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited.

Methods: We 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.

Results: Of 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.

Conclusions: This 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.).
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http://dx.doi.org/10.1056/NEJMoa1404710DOI Listing
February 2015

[Infantile hemangiomas: the revolution of beta-blockers].

Rev Prat 2014 Dec;64(10):1421-8

Infantile hemangioma is the consequence of both postnatal vasculogenesis and angiogenesis. Hypoxia appears to play an important role as a contributory factor. Infantile hemangiomas have variable clinical features: superficial, deep or mixed. They can be localized or segmental involving a large skin area. Localized infantile hemangiomas are usually benign, unless they are located near a noble structure (airway orbit...), while segmental infantile hemangioma may be associated with complex underlying birth defects (PHACES and SACRAL syndromes). Clinical follow-up of infants with infantile hemangioma must be particularly careful in the first weeks of life since 80% of all infantile hemangiomas have reached their final size at age 5 months. A majority of infantile hemangiomas are mild and do not required any treatment. Main indications for treatment are: vital risk (heart failure, respiratory distress), functional risk (amblyopia, swallowing disorders...), painful ulceration and disfigurement (face involvement of nose, lips...). Propranolol, has been quickly adopted as the first line medical treatment for complicated infantile hemangioma; and it is the only treatment to have a marketing authorization in this indication. It is recommended to begin the treatment as early as possible before three months of age to minimize the risk of complications and sequelae.
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December 2014

A prospective study of risk for Sturge-Weber syndrome in children with upper facial port-wine stain.

J Am Acad Dermatol 2015 Mar 13;72(3):473-80. Epub 2015 Jan 13.

Department of Dermatology and Pediatric Dermatology, Pellegrin Children's Hospital, Bordeaux, France; National Center for Rare Skin Disorders-Institut National de la Santé Et de la Recherche Médicale (INSERM) U1035, Bordeaux Segalen University, Bordeaux, France.

Background: Upper facial port-wine stain (PWS) is a feature of Sturge-Weber syndrome (SWS). Recent studies suggest that the distribution of the PWS corresponds to genetic mosaicism rather than to trigeminal nerve impairment.

Objectives: We sought to refine the cutaneous distribution of upper facial PWS at risk for SWS.

Methods: This was a prospective multicenter study of consecutive cases of upper facial PWS larger than 1 cm² located in the ophthalmic division of trigeminal nerve distribution in infants aged less than 1 year, seen in 8 French pediatric dermatology departments between 2006 and 2012. Clinical data, magnetic resonance imaging, and photographs were systematically collected and studied. PWS were classified into 6 distinct patterns.

Results: In all, 66 patients were included. Eleven presented with SWS (magnetic resonance imaging signs and seizure). Four additional infants had suspected SWS without neurologic manifestations. Hemifacial (odds ratio 7.7, P = .003) and median (odds ratio 17.08, P = .008) PWS patterns were found to be at high risk for SWS. A nonmedian linear pattern was not associated with SWS.

Limitations: Small number of patients translated to limited power of the study.

Conclusions: Specific PWS distribution patterns are associated with an increased risk of SWS. These PWS patterns conform to areas of somatic mosaicism. Terminology stipulating ophthalmic division of trigeminal nerve territory involvement in SWS should be abandoned.
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http://dx.doi.org/10.1016/j.jaad.2014.11.009DOI Listing
March 2015

Haemangioma family burden: creation of a specific questionnaire.

Acta Derm Venereol 2015 Jan;95(1):78-82

Department of Dermatology, Hopital Universitaire Necker-Enfants Malades, FR-75000 Paris, France.

To develop and validate a specific questionnaire to assess burden on families of children with infantile haemangioma (IH): the Haemangioma Family Burden questionnaire (HFB). Items were generated from a literature review and a verbatim report from parents. Subsequently, a study was implemented at the Necker Hospital and the Pellegrin Children's Hospital for psychometric analysis. The HFB was refined via item reduction according to inter-question correlations, consensus among experts and exploratory factor analysis. A 20-item questionnaire, grouped into 5 dimensions, was obtained. Construct validity was demonstrated and HFB showed good internal coherence (Cronbach's α: 0.93). The HFB was significantly correlated with the mental dimension of the Short-Form-12 (r = -0.75), and the Psychological General Well-Being Index (r = -0.61). HFB scores differed significantly according to the size and localization of the IH. A validated tool for assessing the burden on families of children with IH is now available.
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http://dx.doi.org/10.2340/00015555-1847DOI Listing
January 2015

Mast cells as possible targets of propranolol therapy: an immunohistological study of beta-adrenergic receptors in infantile haemangiomas.

Histopathology 2014 Sep 5;65(3):436-9. Epub 2014 Jun 5.

Service de Dermatologie et Dermatologie pédiatrique, Centre de Référence des Maladies Rares de la Peau, Hôpital Pellegrin-Enfants, CHU de Bordeaux, Bordeaux, France; Université de Bordeaux, Bordeaux, France; INSERM U 1035, Biothérapies des maladies génétiques et cancers, Bordeaux, France.

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http://dx.doi.org/10.1111/his.12421DOI Listing
September 2014

Dermatological spectrum of hand, foot and mouth disease from classical to generalized exanthema.

Pediatr Infect Dis J 2014 Apr;33(4):e92-8

From the *Unité de Dermatologie Infectiologie, CHI Fréjus Saint Raphaël, Fréjus; †Centre National de Référence des Entérovirus, Laboratoire de Virologie Est des Hospices Civils deLyon, Groupement Hospitalier Est, Bron cedex; ‡Unité de Dermatologie pédiatrique, Centre de référence maladies rares de la peau, Hôpital Pellegrin-Enfants, CHU de Bordeaux, Bordeaux; §Service de Pédiatrie, CHG Grasse, Grasse; ¶Consultations de pédiatrie, hopitaux pediatriques CHU-Lenval, Service de Dermatologie, Hôpital Archet II, CHU de Nice, Nice; ‖Unité de Dermatologie Pédiatrique, Hôpital Femme Mère Enfant, CHU Lyon, Bron; **Service de dermatologie, Hôpital Trousseau, Université François Rabelais, Tours; ††Service de Dermatologie, CHU Pontchaillou, Rennes; and ‡‡Département de Virologie et d'Immunologie Biologique and Laboratoire EA 2968, Centre Hospitalo-Universitaire de Bordeaux, Bordeaux, France.

Background: Hand, foot and mouth disease (HFMD) is classically defined as a childhood fever accompanied by a rash with vesicles or erosions of the oral mucosa, hands, feet and sometimes the buttocks. Severe neurological complications are associated with enterovirus 71 outbreaks in Asia. Recently, it has been suggested that HFMD is related to coxsackie virus A6 (CV-A6) when there is an atypical rash. The objective of the study is to determine the dermatological pattern of HFMD and to identify the virus serotypes associated with a specific dermatological pattern.

Methods: A prospective, cross-sectional study was conducted in 7 pediatric dermatology units in France from March 2010 to February 2012. All children with clinically suspected diagnosis of HFMD were included. Clinical data were collected and swabs from the nasopharynx and vesicles were taken for reverse transcription polymerase chain reaction and genotyping. Only children with confirmed HFMD--defined by clinical diagnosis of HFMD and positive enterovirus polymerase chain reaction results--were included for analysis.

Results: One hundred and four children consulted for suspected HFMD, including 89 (mean age: 25.7 months; sex ratio M/F 1.54) with confirmed HFMD. Seventy-eight (87.6%) had skin lesions on sites other than hand, feet and mouth. Thirty-seven (41.5%) had 5 or more anatomical sites involved (hand, feet and mouth, buttocks, legs, arms and trunk) considered as widespread exanthema. Widespread vesicular exanthema was observed with both CV-A6 and CV-A16. Peri-oral rash was associated with CV-A6 (P < 0.001).

Conclusions: HFMD has a clinical spectrum ranging from classical to generalized vesicular exanthema. Generalized and atypical exanthema were observed with both CV-A6 and CV-A16 infections. CV-A6 is associated with peri-oral rash.
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http://dx.doi.org/10.1097/INF.0000000000000120DOI Listing
April 2014

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

Hum Mutat 2013 Dec 10;34(12):1632-41. Epub 2013 Oct 10.

Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium; Center for Human Genetics, Cliniques universitaires St Luc, Université catholique de Louvain, Brussels, Belgium.

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.
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http://dx.doi.org/10.1002/humu.22431DOI Listing
December 2013

Diagnostic value of polymerase chain reaction analysis of skin biopsies in purpura fulminans.

Pediatr Dermatol 2013 Nov-Dec;30(6):e276-7. Epub 2013 Jul 9.

Pediatric Dermatology Unit, Hôpital Pellegrin-Enfants, Bordeaux, France; Department of Pediatrics, Hôpital Pellegrin-Enfants, Bordeaux, France.

Even though prompt diagnosis and treatment of purpura fulminans (PF) is essential to reduce mortality, early administration of antibiotics may preclude identification of the causative agent by standard bacterial cultures and thus render definitive diagnosis impossible. Here we present a case of an infant with PF and negative bacterial cultures for whom polymerase chain reaction (PCR) analysis of a cutaneous biopsy specimen obtained 4 days after initiation of antibiotics identified the genomic sequence of Neisseria meningitidis genogroup C. When bacterial cultures fail to provide useful information, PCR of skin biopsy specimens can be a valuable diagnostic tool in PF.
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http://dx.doi.org/10.1111/pde.12181DOI Listing
August 2014

IFAG and childhood rosacea: a possible link?

Pediatr Dermatol 2013 Jul-Aug;30(4):429-32. Epub 2013 Apr 8.

Pediatric Dermatology Unit, Pellegrin Children's Hospital, Bordeaux, France.

Idiopathic facial aseptic granuloma (IFAG) is a disorder that usually occurs during early childhood. Its pathogenesis remains poorly understood. The objective of this study was to investigate possible relationships between IFAG and childhood rosacea. This was a retrospective multicenter study of patients attending four French dermatologic centers diagnosed with IFAG between October 2000 and July 2007. Patients and their parents were asked to come for a follow-up visit or to make an appointment for a telephone interview. Clinical symptoms of childhood rosacea were recorded: flushing, permanent or recurrent erythema; facial telangiectasia; papules and pustules on the face without comedones or microcysts; preferential location of the lesions on the convexity of the face; and ophthalmologic involvement of rosacea (recurrent chalazions, conjunctival hyperemia, keratitis). Thirty-eight patients, 20 girls and 18 boys, were included in the study. The median age at the time of diagnosis of IFAG was 43 months, with a median follow-up of 3.9 years. Sixteen patients (42.1%) had at least two criteria of childhood rosacea, 11 of 32 (34.4%) with a single lesion and 5 of 6 (83.3%) with multiple lesions. Children with IFAG are at risk for childhood rosacea, and follow-up is advised, including periodic ophthalmologic assessment.
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http://dx.doi.org/10.1111/pde.12137DOI Listing
February 2014