Endemic Treponemal Infections in International Adoptees and Immigrant Children: How Common are they?

Blueberry muffin baby révélateur d’un xantogranulome juvénile congénital disséminé d’évolution létale

Introduction Le xanthogranulome juvenile (XGJ) est une histiocytose non-langerhansienne commune de l’enfant de localisation principalement cutanee. Nous rapportons un cas exceptionnel d’atteinte multisytemique congenitale d’evolution letale revele par un blueberry muffin baby . Observations Un nouveau-ne a terme (37 SA) etait pris en charge en reanimation au premier jour de vie pour une volumineuse hepatomegalie, une detresse respiratoire et une hypotonie globale. Un dacryocystocele gauche avait ete suspecte a l’echographie antenatale devant une tumeur orbitaire. L’enfant etait icterique avec de multiples nodules cutanes rouges sombres diffus, d’aspect angiomateux mais fermes et congenitaux…

Postzygotic KITLG mutation in a congenital non-progressive linear nevoid hyperpigmentation

International audience

Fertilité chez la femme McCune Albright : une étude de cas axée sur l’AMH en tant que marqueur du dysfonctionnement ovarien et revue systématique

La plupart des filles porteuses d’un syndrome de McCune Albright (SMA) presentent une puberte precoce, causee par le developpement de kystes ovariens responsables d’une hyperestrogenie. Apres la puberte, peuvent etre retrouves troubles du cycle et infertilite. Nous avons souhaite faire le point sur la fertilite et la grossesse chez les femmes presentant un SMA, par un report de cas detaille et une revue exhaustive de la litterature. Nous presentons le cas d’une femme infertile, unilateralement ovariectomise, prise en charge par FIV. La stimulation a necessite des doses elevees de FSH. Huit ovocytes avec de nombreuses anomalies morphologiques ont ete recuperes, avec developpement de 4 embryo…

Postzygotic BRAF p.Lys601Asn Mutation in Phacomatosis Pigmentokeratotica with Woolly Hair Nevus and Focal Cortical Dysplasia

International audience

The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance

IF 2.264; International audience; The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features…

Reconstruction of hyperspectral cutaneous data from an artificial neural network-based multispectral imaging system.

International audience; The development of an integrated MultiSpectral Imaging (MSI) system yielding hyperspectral cubes by means of artificial neural networks is described. The MSI system is based on a CCD camera, a rotating wheel bearing a set of seven interference filters, a light source and a computer. The resulting device has been elaborated for in vivo imaging of skin lesions. It provides multispectral images and is coupled with a software reconstructing hyperspectral cubes from multispectral images. Reconstruction is performed by a neural network-based algorithm using heteroassociative memories. The resulting hyperspectral cube provides skin optical reflectance spectral data combined…

Juvenile Xanthogranuloma and Nevus Anemicus in the Diagnosis of Neurofibromatosis Type 1

Importance The diagnosis of neurofibromatosis type 1 (NF1) is based on 7 clinical criteria. However, they are of limited value before the age of 2 years. Juvenile xanthogranuloma (JXG) and nevus anemicus (NA) are commonly observed in children with NF1 and may be useful diagnostic clues. Objectives To evaluate the frequency of JXG and NA, to describe their clinical features, and to determine their diagnostic value in patients with NF1. Design, Setting, and Participants Retrospective medical record review of outpatients seen between January 1, 2005, and December 31, 2011. University hospital dermatology department affiliated with the French NF1 referral center network. Patients with NF1 diagn…

Syndrome de Maffucci unilatéral avec malformations lymphatiques prédominantes

Introduction Le syndrome de Maffucci (SM) est une maladie genetique extremement rare (prevalence  Observation Il s’agissait d’une patiente de 51 ans, aux antecedents d’encephalopathie vasculaire sans etiologie trouvee. Elle presentait depuis l’enfance des anomalies osseuses uniquement localisees a gauche, a type d’enchondromes, certains ayant fait l’objet d’une exerese (chondrosarcome). Les anomalies cutanees etaient apparues vers l’âge de 20 ans, de maniere strictement unilaterale gauche, allant du visage au pied. On notait des lesions hypertrophiques papillomateuses, hyperkeratosiques et vesiculeuses, en particulier sur la jambe et le pubis. On notait egalement quelques macules d’allure c…

Deciphering exome sequencing data: Bringing mitochondrial DNA variants to light

The expanding use of exome sequencing (ES) in diagnosis generates a huge amount of data, including untargeted mitochondrial DNA (mtDNA) sequences. We developed a strategy to deeply study ES data, focusing on the mtDNA genome on a large unspecific cohort to increase diagnostic yield. A targeted bioinformatics pipeline assembled mitochondrial genome from ES data to detect pathogenic mtDNA variants in parallel with the "in-house" nuclear exome pipeline. mtDNA data coming from off-target sequences (indirect sequencing) were extracted from the BAM files in 928 individuals with developmental and/or neurological anomalies. The mtDNA variants were filtered out based on database information, cohort …

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 pat…

De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or with…

Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia

International audience; Focal dermal hypoplasia (FDH, Goltz syndrome, MIM: #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X-linked dominant trait and is caused by mutations in PORCN. In males, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are males presenting either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue b…

Phenotypic and genotypic characterization of extensive dermal melanocytosis: co24

International audience

Spectre clinique des syndromes en mosaïque avec atteinte cutanée vasculaire ou pigmentaire par mutations GNAQ et GNA11

Introduction GNAQ et GNA11 sont des genes homologues codant des sous-unites alpha des proteines G heterotrimeriques. Des mutations activatrices en mosaique de GNAQ ont ete impliquees dans le syndrome de Sturge-Weber (SSW). Plus recemment, nous avons identifie des mutations de GNA11 dans des melanocytoses dermiques etendues (MDE) et de GNAQ et GNA11 dans la phacomatose pigmento-vasculaire (PPV). Il existe donc une grande variabilite d’expression du phenotype lie a ces mutations, qui reste inexpliquee et dont le spectre clinique est encore mal decrit. Materiel et methodes Nous avons effectue un sequencage haut debit en profondeur (500 X a 2000X) de GNAQ et GNA11 sur 87 biopsies de peau attein…

Cerebriform sebaceous nevus: a subtype of organoid nevus due to specific postzygotic FGFR2 mutations.

Background Postzygotic mutations in FGFR2 have been identified in mosaic forms of acne, keratinocytic epidermal nevi, nevoid acanthosis nigricans / rounded and velvety epidermal nevus and in two fetuses with papillomatous pedunculated sebaceous nevus (PPSN). Objectives To determine the clinical and genetic characteristics of children with cerebriform, papillomatous, and pedunculated variants of sebaceous nevi. Methods Infants diagnosed with sebaceous nevi characterized by a cerebriform, papillomatous, and/or pedunculated morphology over a 10-year period (2010 - 2019) at three pediatric dermatology centers in Switzerland and France were included in this case series. Clinical and histological…

In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome

International audience; Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mut…

Mutations activatrices de mTOR en mosaïque dans l’hypomélanose d’Ito avec mégalencéphalie

Introduction L’hypomelanose d’Ito (HI) est definie par une hypopigmentation suivant les lignes de Blaschko, isolee ou associee a des manifestations principalement neurologiques. Nous rapportons ici une anomalie genetique en mosaique commune chez des patients atteints d’HI avec megalencephalie. Materiel et methodes Cinq enfants (3 filles, 2 garcons), sans antecedents familiaux, ayant des troubles pigmentaires et une megalencephalie ont ete etudies. Quatre avaient une hypopigmentation blaschko-lineaire, et un avait une meche blanche avec hypochromie scapulaire en quadrant et heterochromie irienne. Tous avaient une macrocrânie precoce (PC > 3 DS) et un retard des acquisitions. La patiente prin…

Blind source separation of skin chromophores on a hyperspectral cube

International audience; Background/Purpose The ASCLEPIOS system developed by the M2D+ team of the Le2i laboratory (Université de Bourgogne, France) allows determination of a skin reflectance spectrum over the visible wavelength range in each pixel of a 2D image, thereby generating a hyperspectral (3D) cube. Reflectance spectra mainly result from the reflectance of two skin chromophores, epidermal melanin and dermal haemoglobin. A source separation method was applied on the mixed reflectance spectra, resulting in two component spectra for melanin and haemoglobin, respectively. We also obtained through this process quantification of each chromophore in each pixel of a 2D skin image. The accur…

Traitement innovant des malformations artério-veineuses multiples associées à PTEN par l’alpélisib

Introduction Le syndrome des hamartomes et tumeurs lie a PTEN (PHTS) comporte parfois des malformations arterio-veineuses (MAV) pour lesquelles les options therapeutiques telles que l’embolisation ou la resection chirurgicale sont limitees. Le developpement en cancerologie d’inhibiteurs de la voie PI3K-AKT-MTOR permet d’escompter leur repositionnement comme medicaments cibles sur l’anomalie genetique. Nous rapportons la premiere observation de reponse a un traitement par alpelisib (BYL719), inhibiteur specifique de la sous-unite alpha de la PI3-kinase. Observations Un patient de 27 ans etait suivi depuis l’âge de 16 ans pour des MAV des parties molles du membre inferieur gauche, a l’origine…

Une mutation post-zygotique activatrice de FGFR2 est responsable d’une forme sévère et atypique de nævus sébacé en prénatal

Objet Le naevus sebace (NS) est une lesion congenitale de la peau, localisee de maniere predominante au niveau du crâne et du visage. Il a ete decrit une presentation phenotypique variable et inhabituelle de NS chez des nouveaux-nes, caracterisee par des lesions pediculees et sessiles de distribution asymetrique [1] , [2] . Nous rapportons une forme comparable de NS atypique et severe chez trois fœtus, sans anomalie extracutanee associee. Methodes L’examen histologique des lesions des trois fœtus a montre la presence d’un hamartome verruqueux dans une forme hyperplasique compatible avec un NS a un stade immature. Chez le premier fœtus, le sequencage de HRAS, KRAS et AKT1 a permis d’eliminer…

Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were det…

Fertility in McCune Albright syndrome female: A case study focusing on AMH as a marker of ovarian dysfunction and a literature review.

Abstract Background The molecular basis of McCune Albright syndrome (MAS) is a recurrent GNAS Postzygotic gain of function sporadic mutation, resulting in a mosaic disease. Most of girls present precocious puberty, caused by the development of recurrent ovarian cysts with autonomous Hyperestrogenic stimulation. After menarche, the majority of patients with ovarian GNAS mutation have menstrual disturbances and infertility. Objectives We wanted to focus on the fertility of MAS females and propose an appropriate management, by a detailed case report and an exhaustive review of the literature on fertility and pregnancy in MAS females. Results We present the case of a 29-year-old MAS female, who…

Systematic search for neutropenia should be part of the first screening in patients with poikiloderma.

Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund-Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia,…

Genetic Testing for Melanoma—Where Are We With Moderate-Penetrance Genes?

International audience

Naevus épidermique cérébriforme associé à FGFR2 : élargissement du spectre du naevus sébacé papillomateux et pédonculé

Introduction Des mutations postzygotiques de FGFR2 ont ete identifiees dans des formes d’acne en mosaique, dans le naevus epidermique keratinocytaire, l’acanthosis nigricans naevoide ou RAVEN (rounded and velvety epidermal nevus) et le naevus sebace papillomateux et pedoncule (NSPP) [1] . Objectifs Determiner les caracteristiques cliniques et genetiques du NSPP et d’une forme de naevus epidermique cerebriforme (NEC), proches sur le plan clinique. Patients et methodes Nourrissons diagnostiques avec des NSPP et NEC sur une periode de 10 ans (2010-2019) dans deux centres de dermatologie pediatrique en Suisse et en France. Les caracteristiques cliniques et histologiques ont ete evaluees. Le seq…

Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation

Abstract The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomali…

Clinical whole-exome sequencing for the diagnosis of rare disorders with congenital anomalies and/or intellectual disability: substantial interest of prospective annual reanalysis

International audience; PurposeCongenital anomalies and intellectual disability (CA/ID) are a major diagnostic challenge in medical genetics—50% of patients still have no molecular diagnosis after a long and stressful diagnostic “odyssey.” Solo clinical whole-exome sequencing (WES) was applied in our genetics center to improve diagnosis in patients with CA/ID.MethodsThis retrospective study examined 416 consecutive tests performed over 3 years to demonstrate the effectiveness of periodically reanalyzing WES data. The raw data from each nonpositive test was reanalyzed at 12 months with the most recent pipeline and in the light of new data in the literature. The results of the reanalysis for …

Validation of a 2D multispectral camera: application to dermatology/cosmetology on a population covering five skin phototypes

International audience; This paper presents the validation of a new multispectral camera specifically developed for dermatological application based on healthy participants from five different Skin PhotoTypes (SPT). The multispectral system provides images of the skin reflectance at different spectral bands, coupled with a neural network-based algorithm that reconstructs a hyperspectral cube of cutaneous data from a multispectral image. The flexibility of neural network based algorithm allows reconstruction at different wave ranges. The hyperspectral cube provides both high spectral and spatial information. The study population involves 150 healthy participants. The participants are classif…

Mutations in theERCC2(XPD) gene associated with severe fetal ichthyosis and dysmorphic features

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Soreze 2009

Background: Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification; typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. Objective: We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. Methods: The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventua…

Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications

Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contrac…

Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth.

International audience; Dacarbazine (DTIC) is a cytotoxic drug widely used for melanoma treatment. However, the putative contribution of anticancer immune responses in the efficacy of DTIC has not been evaluated. By testing how DTIC affects host immune responses to cancer in a mouse model of melanoma, we unexpectedly found that both natural killer (NK) and CD8(+) T cells were indispensable for DTIC therapeutic effect. Although DTIC did not directly affect immune cells, it triggered the upregulation of NKG2D ligands on tumor cells, leading to NK cell activation and IFNγ secretion in mice and humans. NK cell-derived IFNγ subsequently favored upregulation of major histocompatibility complex cl…

Mutations activatrices de GNA11 et GNAQ en mosaïque dans les phacomatoses pigmento-vasculaires et les taches mongoliques étendues

Introduction Les taches mongoliques, correspondant a une melanocytose dermique, sont frequentes a la naissance mais generalement transitoires. Elles peuvent parfois persister isolement ou en association a des angiomes plans dans les phacomatoses pigmento-vasculaires (types cesioflammea et cesiomarmorata), affections ou nous avons identifie des mutations en mosaique de deux genes de proteines G. Materiel et methodes Huit patients atteints de divers types de phacomatose pigmento-vasculaire et trois presentant une melanocytose dermique persistante etendue ont ete etudies par sequencage cible des genes GNAQ et GNA11 sur ADN de biopsie de peau pigmentee, d’angiome plan, de sang, ou dans un cas d…

Pourquoi et comment rechercher les anomalies chromosomiques et les mutations ponctuelles post-zygotiques dans les dyschromies cutanées en mosaïque

Introduction La determination de l’etiologie genetique des anomalies de la pigmentation cutanee en mosaique est un enjeu a double titre: d’une part, elle necessite des methodes adaptees a la detection de variations genetiques a faible taux et confinees au tissu atteint, et d’autre part elle est un element d’orientation determinant pour la prise en charge des patients (mise en evidence d’une cible therapeutique, etablissement de la strategie de surveillance, conseil genetique). Le sequencage d’exome (ES) est en 2019 la methode de reference pour la detection des mutations ponctuelles post-zygotiques (mSNV), mais la detection d’anomalies chromosomiques en mosaique (mCNV) repose habituellement …

L’échographie des ongles dans le rhumatisme psoriasique : étude pilote sur la faisabilité, la reproductibilité et la validité de mesure

Resume Objectif Etude de la faisabilite, de la reproductibilite et de la validite externe versus criteres de reference des parametres echographiques de l’ongle dans le rhumatisme psoriasique. Methodes Etude pilote prospective monocentrique sur huit parametres echographiques en mode B et doppler puissance portant sur l’interphalangienne distale (IPD), la matrice, le lit et la tablette ungueale. La reproductibilite intra-observateur et inter-observateur a ete evaluee pour les sept parametres quantitatifs (ICC et kappa). La recherche de correlations entre les variables echographiques et cliniques a permis d’estimer la validite externe. La faisabilite a ete appreciee par le temps d’examen et le…

A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

International audience; So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney canc…

Search forReCQL4mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a…

Congenital Plaque-Type Glomuvenous Malformations Associated with Fetal Pleural Effusion and Ascites

Glomuvenous malformations are hereditary vascular anomalies, usually without extracutaneous involvement. We report two cases of extensive thoracic plaque-type glomuvenous malformation in newborns who had previously been diagnosed in utero with pleural effusion and ascites, suggesting a pathogenic link between the two conditions.

Expanding the clinical spectrum of mosaic BRAF skin phenotypes

BRAF postzygotic activating mutations have been found in 50% of cases of syringocystadenoma papilliferum (SCAP)1 and in phacomatosis pigmentokeratotica (PPK)2,3 , also possibly caused by HRAS4 mutations. BRAF is a RAS-activating serine/threonine kinase of the MAP kinase pathway, resulting in cell growth and proliferation. BRAF mutations, particularly p.(Val600Glu), are frequently identified in melanoma and other human cancers5 . We report clinical presentations of three patients with postzygotic BRAF mutations in affected skin, identified by next generation sequencing (NGS).

Severe X-linked chondrodysplasia punctata in nine new female fetuses

ObjectivesConradi-Hunermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. MethodsTo better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. ResultsThe mean age at diagnosis was 22weeks of gestation. The ultrasound features mainly included bon…

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849…

Prospective Study of the Evolution of Blood Lymphoid Immune Parameters during Dacarbazine Chemotherapy in Metastatic and Locally Advanced Melanoma Patients

BackgroundThe importance of immune responses in the control of melanoma growth is well known. However, the implication of these antitumor immune responses in the efficacy of dacarbazine, a cytotoxic drug classically used in the treatment of melanoma, remains poorly understood in humans.MethodsIn this prospective observational study, we performed an immunomonitoring of eleven metastatic or locally advanced patients treated with dacarbazine as a first line of treatment. We assessed by flow cytometry lymphoid populations and their activation state; we also isolated NK cells to perform in vitro cytotoxicity tests.ResultsWe found that chemotherapy induces lymphopenia and that a significantly hig…

Quoi de neuf en dermatologie pédiatrique ?

The main selected articles in pediatric dermatology covered the following topics: development and maturation of the epidermal barrier in the neonate, iatrogenic events in the neonatal ICU, diagnostic value of minor birthmarks, complications, risk factors and treatment of hemangiomas, coagulopathy in venous malformations, epidemiology and dermoscopy of congenital and acquired melanocytic nevi in childhood, growth of the body surface area, new pathogenic concepts and treatment in atopic dermatitis, the impact of filaggrin deficiency, hereditary factors in Kawasaki disease, severe and drug resistant cases, management of juvenile dermatomyositis, treatment of childhood psoriasis with biologics,…

Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K‐AKT‐mTOR signaling pathway

To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K-AKT-mTOR signaling pathway.We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K-AKT-mTOR pathway genes by next-generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid.During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the…

Vitamine D et soleil : risques et bénéfices chez l’enfant

Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3

International audience; Self-renewal and differentiation of pluripotent murine embryonic stem cells (ESCs) is regulated by extrinsic signaling pathways. It is less clear whether cellular metabolism instructs developmental progression. In an unbiased genome-wide CRISPR/Cas9 screen, we identified components of a conserved amino-acid-sensing pathway as critical drivers of ESC differentiation. Functional analysis revealed that lysosome activity, the Ragulator protein complex, and the tumor-suppressor protein Folliculin enable the Rag GTPases C and D to bind and seclude the bHLH transcription factor Tfe3 in the cytoplasm. In contrast, ectopic nuclear Tfe3 represses specific developmental and met…

Mosaic-activating FGFR2 mutation in two fetuses with papillomatous pedunculated sebaceous naevus

International audience; Papillomatous pedunculated sebaceous naevus (PPSN) has been described as a subtype of sebaceous naevus (SN), typically affecting the scalp and face. In contrast with Schimmelpenning syndrome, no cerebral, ocular or skeletal anomalies have hitherto been reported. We report two unrelated fetuses with PPSN, one with large pink exophytic tumours, the other with minor features but similar microscopic findings. We performed whole-exome sequencing in affected skin tissue from fetus 1, which identified a postzygotic de novo FGFR2 c.1144T>C (p.Cys382Arg) mutation in 34[middle dot]6% of reads which was absent in the parents' blood. Targeted deep sequencing of FGFR2 confirmed i…

Atypical dermal melanocytosis: a diagnostic clue in constitutional mismatch repair deficiency syndrome

Source separation on hyperspectral cube applied to dermatology

International audience; This paper proposes a method of quantification of the components underlying the human skin that are supposed to be responsible for the effective reflectance spectrum of the skin over the visible wavelength. The method is based on independent component analysis assuming that the epidermal melanin and the dermal haemoglobin absorbance spectra are independent of each other. The method extracts the source spectra that correspond to the ideal absorbance spectra of melanin and haemoglobin. The noisy melanin spectrum is fixed using a polynomial fit and the quantifications associated with it are reestimated. The results produce feasible quantifications of each source compone…

Extending the ALDH18A1 clinical spectrum to severe autosomal recessive fetal cutis laxa with corpus callosum agenesis

IF 3.822 (2018); International audience

Reliability, validity and feasibility of nail ultrasonography in psoriatic arthritis

International audience; Objective: To determine the feasibility, reliability and validity of nails ultrasonography in psoriatic arthritis as an outcome measure.Methods: Pilot prospective single-centre study of eight ultrasonography parameters in B mode and power Doppler concerning the distal interphalangeal (DIP) joint, the matrix, the bed and nail plate. Intraobserver and inter-observer reliability was evaluated for the seven quantitative parameters (ICC and kappa). Correlations between ultrasonography and clinical variables were searched to assess external validity. Feasibility was assessed by the time to carry out the examination and the percentage of missing data.Results: Twenty-seven p…

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

International audience; Purpose Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. Methods Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individu…

Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.

Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10−5). We identified 40 different mutations and found stro…

SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia

Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status i…