Reverse Phenotyping in Patients with Skin Capillary Malformations and Mosaic GNAQ or GNA11 Mutations Defines a Clinical Spectrum with Genotype-Phenotype Correlation

Jordan, Maud; Carmignac, Virginie; Sorlin, Arthur; Kuentz, Paul; Albuisson, Juliette; Borradori, Luca; Bourrat, E.; Boute, Odile; Bukvić, Nenad; Bursztejn, Anne‐Claire; Chiavérini, C.; Delobel, Bruno; Fournet, Marine; Martel, Jehanne; Goldenberg, Alice; Hadj‐Rabia, S.; Mahé, A.; Maruani, Annabel; Mazereeuw, J.; Mignot, Cyril; Morice‐Picard, Fanny; Moutard, Marie‐Laure; Petit, Florence; Pasteur, Justine; Phan, Alice; Whalen, Sandra; Willems, Marjolaine; Philippe, Christophe; Vabres, P.

doi:10.1016/j.jid.2019.08.455

Cited by 31 publications

(45 citation statements)

References 13 publications

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“…Previous authors have argued that the type of capillary malformation found in MCAP syndrome is not cutis marmorata stricto sensu 9 ; however, we consider the terms “cutis marmorata” and “reticulate capillary malformation” to be equivalent, in the absence of clear distinction criteria. This recognizable type of capillary malformation is a fairly specific marker for PIK3CA pathogenic variants, although it is also commonly observed in patients carrying mosaic GNA11 pathogenic variants 21 . Combined with median frontofacial capillary malformation (naevus flammeus) of the forehead, philtrum and lip (“salmon patch”), it is very suggestive of MCAP syndrome, as previously reported 5,8,9,22 .…”

Section: Discussionsupporting

confidence: 61%

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

et al. 2021

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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 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

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Section: Discussionsupporting

confidence: 61%

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

et al. 2021

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“…KTS was suggested initially in one case. Although, following its initial description 57 , the clinical definition of KTS has been under debate for more than a century, most cases now appear to be related to PIK3CA postzygotic variants, although other genes may be involved (RASA1, GNAQ, and GNA11) [58][59][60] .…”

Section: Discussionmentioning

confidence: 99%

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

Bourgon

Carmignac

Sorlin

et al. 2022

Ultrasound in Obstet & Gyne

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diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K-AKT-mTOR signaling pathway. MethodsWe 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. ResultsDuring the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the PI3K-AKT-mTOR pathway were referred for analysis. Of these, 17 fetuses had brain overgrowth, including six with isolated megalencephaly (MEG) and 11 with hemimegalencephaly (HMEG). Of the six with MEG, germline variants were identified in four cases, in either PIK3R2, AKT3 or MTOR, and a postzygotic PIK3R2 variant was found in the other two cases. Of the 11 with HMEG, a postzygotic PIK3CA variant was found in three fetuses with extracerebral features of PIK3CA-related overgrowth spectrum, and in seven fetuses with isolated

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“…This theory suggests the occurrence of somatic mutations in didymotic alleles that control the balance between vasodilation and vasoconstriction in cutaneous blood vessels, giving rise to two homozygous offspring cells that will determine the appearance of the two neighbouring or intermingled cell populations of TN and NAs 3,4 . However, this hypothesis seems less likely based on the recent reports of GNA11 and GNAQ mosaic mutations in some patients with MVN and MVN syndrome, 7–9 including two of our patients, which indicates that this condition could originate from a single heterozygous mutation.…”

Section: Reportmentioning

confidence: 62%

Mixed vascular naevus syndrome: report of three children with somatic GNA11 mutation and new systemic associations

Beteta-Gorriti

Vázquez‐Osorio

Dios-Velázquez

et al. 2021

Clin Experimental Derm

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Mixed vascular naevus (MVN) is characterized by the co-occurrence of telangiectatic capillary malformation and naevus anaemicus, which can appear as a pure cutaneous phenotype or be combined with systemic manifestations such as brain malformations, neurological abnormalities and musculoskeletal disorders. Recently, GNA11 and GNAQ somatic mutations have been reported in some patients with isolated and syndromic MVN. We report three children with MVN syndrome with generalized cutaneous manifestations and a number of systemic associations not reported to date, including ophthalmological anomalies, musculoskeletal abnormalities such as Sprengel deformity and posterior vertebral fusion anomalies, and septal heart defects. We also confirm a somatic mutation of GNA11 in both telangiectatic naevus and naevus anaemicus in two of our patients and discuss a possible common pathogenic mechanism underlying the different manifestations of the syndrome. Currently, there are no guidelines for the evaluation of patients with MVN syndrome, but according to the different known aspects of the disease, a complete clinical examination should be made, and complementary laboratory and imaging tests should be considered.

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Reverse Phenotyping in Patients with Skin Capillary Malformations and Mosaic GNAQ or GNA11 Mutations Defines a Clinical Spectrum with Genotype-Phenotype Correlation

Cited by 31 publications

References 13 publications

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

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

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

Mixed vascular naevus syndrome: report of three children with somatic GNA11 mutation and new systemic associations

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