ABSTRACT
Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures, strokes, and glaucoma, and only symptomatic treatment is available. CM are comprised of enlarged vessels with endothelial cells (ECs) and disorganized mural cells. Our recent finding indicated that the R183Q mutation in ECs leads to heightened signaling through phospholipase Cß3 and protein kinase C, leading to increased angiopoietin-2 (ANGPT2). Furthermore, knockdown of ANGPT2, a crucial mediator of pro-angiogenic signaling, inflammation, and vascular remodeling, in EC-R183Q rescued the enlarged vessel phenotype in vivo. This prompted us to look closer at the microenvironment in CM-affected vascular beds. We analyzed multiple brain histological sections from patients with GNAQ-R183Q CM and found enlarged vessels devoid of mural cells along with increased macrophage-like cells co-expressing MRC1 (CD206, a mannose receptor), CD163 (a scavenger receptor and marker of the monocyte/macrophage lineage), CD68 (a pan macrophage marker), and LYVE1 (a lymphatic marker expressed by some macrophages). These macrophages were not found in non-SWS control brain sections. To investigate the mechanism of increased macrophages in the perivascular environment, we examined THP1 (monocytic/macrophage cell line) cell adhesion to EC-R183Q versus EC-WT under static and laminar flow conditions. First, we observed increased THP1 cell adhesion to EC-R183Q compared to EC-WT under static conditions. Next, using live cell imaging, we found THP1 cell adhesion to EC-R183Q was dramatically increased under laminar flow conditions and could be inhibited by anti-ICAM1. ICAM1, an endothelial cell adhesion molecule required for leukocyte adhesion, was strongly expressed in the endothelium in SWS brain histological sections, suggesting a mechanism for recruitment of macrophages. In conclusion, our findings demonstrate that macrophages are an important component of the perivascular environment in CM suggesting they may contribute to the CM formation and SWS disease progression.
Subject(s)
Capillaries/abnormalities , Sturge-Weber Syndrome , Vascular Malformations , Humans , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/pathology , Sturge-Weber Syndrome/therapy , Endothelial Cells/metabolism , Capillaries/pathology , Macrophages/metabolism , Tumor Microenvironment , Vesicular Transport Proteins/metabolism , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , GTP-Binding Protein alpha Subunits, Gq-G11/metabolismABSTRACT
Episcleral vasculature malformation is a significant feature of Sturge-Weber syndrome (SWS) secondary glaucoma, the density and diameter of which are correlated with increased intraocular pressure. We previously reported that the GNAQ R183Q somatic mutation was located in the SWS episclera. However, the mechanism by which GNAQ R183Q leads to episcleral vascular malformation remains poorly understood. In this study, we investigated the correlation between GNAQ R183Q and episcleral vascular malformation via surgical specimens, human umbilical vein endothelial cells (HUVECs), and the HUVEC cell line EA.hy926. Our findings demonstrated a positive correlation between episcleral vessel diameter and the frequency of the GNAQ R183Q variant. Furthermore, the upregulation of genes from the Notch signaling pathway and abnormal coexpression of the arterial marker EphrinB2 and venous marker EphB4 were demonstrated in the scleral vasculature of SWS. Analysis of HUVECs overexpressing GNAQ R183Q in vitro confirmed the upregulation of Notch signaling and arterial markers. In addition, knocking down of Notch1 diminished the upregulation of arterial markers induced by GNAQ R183Q. Our findings strongly suggest that GNAQ R183Q leads to malformed episcleral vasculatures through Notch-induced aberrant arteriovenous specification. These insights into the molecular basis of episcleral vascular malformation will provide new pathways for the development of effective treatments for SWS secondary glaucoma.
Subject(s)
Glaucoma , Sturge-Weber Syndrome , Humans , Sturge-Weber Syndrome/genetics , Signal Transduction , Human Umbilical Vein Endothelial Cells , Mutation , GTP-Binding Protein alpha Subunits, Gq-G11/geneticsABSTRACT
Sturge-Weber Syndrome (SWS) is a sporadic (non-inherited) syndrome characterized by capillary vascular malformations in the facial skin, leptomeninges, or the choroid. A hallmark feature is the mosaic nature of the phenotype. SWS is caused by a somatic mosaic mutation in the GNAQ gene (p.R183Q), leading to activation of the G protein, Gαq. Decades ago, Rudolf Happle hypothesized SWS as an example of "paradominant inheritance", that is, a "lethal gene (mutation) surviving by mosaicism". He predicted that the "presence of the mutation in the zygote will lead to death of the embryo at an early stage of development". We have created a mouse model for SWS using gene targeting to conditionally express the GNAQ p.R183Q mutation. We have employed two different Cre-drivers to examine the phenotypic effects of expression of this mutation at different levels and stages of development. As predicted by Happle, global, ubiquitous expression of this mutation in the blastocyst stage results in 100% embryonic death. The majority of these developing embryos show vascular defects consistent with the human vascular phenotype. By contrast, global but mosaic expression of the mutation enables a fraction of the embryos to survive, but those that survive to birth and beyond do not exhibit obvious vascular defects. These data validate Happle's paradominant inheritance hypothesis for SWS and suggest the requirement of a tight temporal and developmental window of mutation expression for the generation of the vascular phenotype. Furthermore, these engineered murine alleles provide the template for the development of a mouse model of SWS that acquires the somatic mutation during embryonic development, but permits the embryo to progress to live birth and beyond, so that postnatal phenotypes can also be investigated. These mice could then also be employed in pre-clinical studies of novel therapies.
Subject(s)
Sturge-Weber Syndrome , Vascular Malformations , Animals , Humans , Male , Mice , Capillaries/metabolism , Mutation , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/metabolism , Sturge-Weber Syndrome/therapy , Vascular Malformations/geneticsABSTRACT
Sturge-Weber Syndrome (SWS) is a rare vascular malformation disorder characterized by abnormal blood vessels in the brain, skin, and eye. SWS is most commonly caused by a somatic mosaic GNAQ-p.Arg183Gln variant. In this series, 12 patients presented for clinical evaluation of SWS but were noted to have atypical features, and therefore germline and/or somatic genetic testing was performed. Atypical features included extensive capillary malformation on the body as well as the face, frontal bossing, macrocephaly, telangiectasia, overgrowth of extremities, absence of neurologic signs and symptoms, and family history of vascular malformations. Five patients had a somatic GNAQ or GNA11 pathogenic variant, one patient had a somatic mosaic likely-pathogenic variant in PIK3CA, and another one had a somatic mosaic deletion that disrupted PTPRD. The other five patients had germline variants in RASA1, EPHB4, or KIT. Our findings suggest that patients presenting for SWS evaluation who have atypical clinical characteristics may have pathogenic germline or somatic variants in genes other than GNAQ or GNA11. Broad germline and somatic genetic testing in these patients with atypical findings may have implications for medical care, prognosis, and trial eligibility.
Subject(s)
Sturge-Weber Syndrome , Humans , Sturge-Weber Syndrome/genetics , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , Capillaries/abnormalities , Skin/pathology , Genetic Testing , p120 GTPase Activating Protein/geneticsABSTRACT
Sturge-Weber syndrome (SWS) is a rare, noninherited neurovascular disorder characterized by abnormal vasculature in the brain, skin, and eye. Patients with SWS characteristically have facial capillary malformation, also known as port-wine birthmark, a leptomeningeal vascular malformation seen on contrast-enhanced magnetic resonance imaging images, abnormal blood vessels in the eye, and glaucoma. Patients with SWS have impaired perfusion to the brain and are at high risk of venous stroke and stroke-like episodes, seizures, and both motor and cognitive difficulties. While the activating R183Q GNAQ somatic mutation is the most common somatic mutation underlying SWS, recent research also implicates that GNA11 and GNB2 somatic mutations are related to SWS. Recent retrospective studies suggest the use of low-dose aspirin and vitamin D in treatment for SWS and prospective drug trials have supported the usefulness of cannabidiol and Sirolimus. Presymptomatic treatment with low-dose aspirin and antiepileptic drugs shows promising results in delaying seizure onset in some patients. This review focuses on the latest progress in the field of research for Sturge-Weber syndrome and highlights directions for future research.
Subject(s)
Stroke , Sturge-Weber Syndrome , Humans , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/pathology , Sturge-Weber Syndrome/therapy , Seizures , Brain/diagnostic imaging , Brain/pathology , Stroke/pathology , AspirinABSTRACT
BACKGROUND AND PURPOSE: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in G protein subunit Alpha Q (GNAQ). Five cases of subunit Alpha 11 (GNA11) mutations have been reported. We studied phenotypic features of GNA11-SWS and compared them with those of classic SWS. METHODS: Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a GNA11 mutation. Clinical and radiological data were collected retrospectively and prospectively. RESULTS: We identified three patients with SWS associated with a somatic GNA11 mutation. All had disseminated capillary malformation (CM) and hyper- or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age, evolving to a purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy with a lower degree of severity than that classically associated with SWS. Susceptibility-weighted imaging (SWI) and contrast-enhanced fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrated the best sensitivity to reveal the pial angiomas. CONCLUSIONS: We have differentiated two distinct clinical/radiological phenotypes of SWS; GNAQ- and GNA11-SWS. The classic GNAQ-SWS is characterized by a homogeneous dark-red CM, commonly associated with underlying soft tissue hypertrophy. The CM in GNA11-SWS is more reticulate and darkens with time, and the neurological picture is milder. SWI and post-contrast FLAIR sequences appear to be necessary to demonstrate leptomeningeal angiomatosis. Anti-epileptic medication or future targeted therapies may be useful, as in classic SWS.
Subject(s)
GTP-Binding Protein alpha Subunits , Sturge-Weber Syndrome , Anticonvulsants , Brain/diagnostic imaging , Brain/pathology , GTP-Binding Protein alpha Subunits/genetics , Humans , Magnetic Resonance Imaging , Retrospective Studies , Sturge-Weber Syndrome/complications , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/pathologyABSTRACT
Sturge-Weber syndrome (SWS) is a sporadic, congenital, neuro-cutaneous disorder characterized by a mosaic, capillary malformation. SWS and non-syndromic capillary malformations are both caused by a somatic activating mutation in GNAQ encoding the G protein subunit alpha-q protein. The missense mutation R183Q is the sole GNAQ mutation identified thus far in 90% of SWS-associated or isolated capillary malformations. In this study, we sequenced skin biopsies of capillary malformations from 9 patients. We identified the R183Q mutation in nearly all samples, but one sample exhibited a Q209R mutation. This new mutation occurs at the same residue as the constitutively-activating Q209L mutation, commonly seen in tumors. However, Q209R is a rare variant in this gene. To compare the effect of the Q209R mutation on downstream signaling, we performed reporter assays with a GNAQ-responsive reporter co-transfected with either GNAQ WT, R183Q, Q209L, Q209R, or C9X (representing a null allele). Q209L showed the highest reporter activation, with R183Q and Q209R showing significantly lower activation. To determine whether these mutations had similar or different downstream consequences we performed RNA-seq analysis in microvascular endothelial cells (HMEC-1) electroporated with the same GNAQ variants. The R183 and Q209 missense variants caused extensive dysregulation of a broad range of transcripts compared to the WT or null allele, confirming that these are all activating mutations. However, the missense variants exhibited very few differentially expressed genes (DEGs) when compared to each other. These data suggest that these activating GNAQ mutations differ in magnitude of activation but have similar downstream effects.
Subject(s)
Sturge-Weber Syndrome , Capillaries/abnormalities , Endothelial Cells/metabolism , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Humans , Mutation/genetics , Protein Subunits/metabolism , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/metabolism , Sturge-Weber Syndrome/pathology , Vascular MalformationsABSTRACT
OBJECTIVE: Capillary malformation (CM) occurs sporadically and is associated with Sturge-Weber syndrome. The somatic mosaic mutation in GNAQ (c.548G>A, p.R183Q) is enriched in endothelial cells (ECs) in skin CM and Sturge-Weber syndrome brain CM. Our goal was to investigate how the mutant Gαq (G-protein αq subunit) alters EC signaling and disrupts capillary morphogenesis. Approach and Results: We used lentiviral constructs to express p.R183Q or wild-type GNAQ in normal human endothelial colony forming cells (EC-R183Q and EC-WT, respectively). EC-R183Q constitutively activated PLC (phospholipase C) ß3, a downstream effector of Gαq. Activated PLCß3 was also detected in human CM tissue sections. Bulk RNA sequencing analyses of mutant versus wild-type EC indicated constitutive activation of PKC (protein kinase C), NF-κB (nuclear factor kappa B) and calcineurin signaling in EC-R183Q. Increased expression of downstream targets in these pathways, ANGPT2 (angiopoietin-2) and DSCR (Down syndrome critical region protein) 1.4 were confirmed by quantitative PCR and immunostaining of human CM tissue sections. The Gαq inhibitor YM-254890 as well as siRNA targeted to PLCß3 reduced mRNA expression levels of these targets in EC-R183Q while the pan-PKC inhibitor AEB071 reduced ANGPT2 but not DSCR1.4. EC-R183Q formed enlarged blood vessels in mice, reminiscent of those found in human CM. shRNA knockdown of ANGPT2 in EC-R183Q normalized the enlarged vessels to sizes comparable those formed by EC-WT. CONCLUSIONS: Gαq-R183Q, when expressed in ECs, establishes constitutively active PLCß3 signaling that leads to increased ANGPT2 and a proangiogenic, proinflammatory phenotype. EC-R183Q are sufficient to form enlarged CM-like vessels in mice, and suppression of ANGPT2 prevents the enlargement. Our study provides the first evidence that endothelial Gαq-R183Q is causative for CM and identifies ANGPT2 as a contributor to CM vascular phenotype.
Subject(s)
Angiopoietin-2/metabolism , Capillaries/metabolism , Endothelial Progenitor Cells/metabolism , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Neovascularization, Pathologic , Sturge-Weber Syndrome/metabolism , Adolescent , Adult , Aged , Angiopoietin-2/genetics , Animals , Capillaries/abnormalities , Cells, Cultured , Child , Child, Preschool , Endothelial Progenitor Cells/pathology , Endothelial Progenitor Cells/transplantation , Female , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/pathology , Humans , Infant , Infant, Newborn , Male , Mice, Nude , Mutation , Phenotype , Phospholipase C beta/genetics , Phospholipase C beta/metabolism , Protein Kinase C/metabolism , Signal Transduction , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/pathology , Up-RegulationABSTRACT
AIMS: To determine the correspondence between GNAQ R183Q (c.548Gï¼A) mutation in abnormal scleral tissue of patients with Sturge-Weber syndrome (SWS) secondary glaucoma and explore the role of GNAQ R183Q in glaucoma pathogenesis. METHODS: Episcleral tissues were obtained from 8 patients: SWS secondary glaucoma (n=5) and primary congenital glaucoma (PCG, n=3). Scleral tissues were obtained from 7 patients: SWS secondary glaucoma (n=2), PCG (n=1) and juvenile open-angle glaucoma (n=4). GNAQ R183Q mutation was detected in scleral tissue by droplet digital PCR. Tissue sections from SWS were examined by immunohistochemistry to determine the expression of p-ERK. RESULTS: The GNAQ R183Q mutation was present in 100% of the SWS abnormal sclera. Five cases were SWS patient-derived episcleral tissue, and the mutant allelic frequencies range from 6.9% to 12.5%. The other two were deep scleral tissues and the mutant frequencies were 1.5% and 5.3%. No mutations in GNAQ R183 codon were found in the sclera of PCG and juvenile open-angle glaucoma. Increased expression of p-ERK and p-JNK was detected in the endothelial cells of SWS abnormal scleral blood vessels. CONCLUSIONS: GNAQ R183Q occurred in all abnormal scleral tissue of SWS secondary glaucoma. Increased expression of p-ERK and p-JNK in endothelial cells of blood vessels was detected in the abnormal scleral tissue. This study suggests GNAQ R183Q may regulate episcleral vessels of patients with SWS through abnormal activation of ERK and JNK, providing new genetic evidence of pathogenesis of glaucoma in SWS, and the dysplasia of scleral tissue in anterior segment may be used as an early diagnostic method or treatment targets to prevent the development and progression of glaucoma in patients with SWS.
Subject(s)
Glaucoma, Open-Angle , Glaucoma , Sturge-Weber Syndrome , Endothelial Cells , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Glaucoma/pathology , Glaucoma, Open-Angle/diagnosis , Glaucoma, Open-Angle/genetics , Glaucoma, Open-Angle/metabolism , Humans , Mutation , Sclera/pathology , Sturge-Weber Syndrome/diagnosis , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/pathologySubject(s)
Port-Wine Stain , Sturge-Weber Syndrome , Brain , Humans , Sturge-Weber Syndrome/geneticsABSTRACT
Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK signalling. In this study of six Norwegian patients with classical SWS, we aimed to identify somatic mutations through deep sequencing of DNA from skin biopsies. Surprisingly, one patient was negative for the GNAQ mutation, but instead harbored a somatic mutation in GNB2 (NM_005273.3:c.232A>G, p.Lys78Glu), which encodes a beta chain of the same G-protein complex. The positions of the mutant amino acids in the G-protein are essential for complex reassembly. Therefore, failure of reassembly and continuous signalling is a likely consequence of both mutations. Ectopic expression of mutant proteins in endothelial cells revealed that expression of either mutant reduced cellular proliferation, yet regulated MAPK signalling differently, suggesting that dysregulated MAPK signalling cannot fully explain the SWS phenotype. Instead, both mutants reduced synthesis of Yes-associated protein (YAP), a transcriptional co-activator of the Hippo signalling pathway, suggesting a key role for this pathway in the vascular pathogenesis of SWS. The discovery of the GNB2 mutation sheds novel light on the pathogenesis of SWS and suggests that future research on targets of treatment should be directed towards the YAP, rather than the MAPK, signalling pathway.
Subject(s)
GTP-Binding Proteins/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Mutation , Sturge-Weber Syndrome/diagnosis , Sturge-Weber Syndrome/genetics , Adolescent , Adult , Child , DNA Mutational Analysis , GTP-Binding Proteins/chemistry , Gene Frequency , Genetic Association Studies/methods , Humans , Middle Aged , Models, Molecular , Nortriptyline , Phenotype , Protein Conformation , Protein Subunits/genetics , Structure-Activity Relationship , Exome Sequencing , Young AdultABSTRACT
Mutations occurring during embryonic development affect only a subset of cells resulting in two or more distinct cell populations that are present at different levels, also known as postzygotic mosaicism (PZM). Although PZM is a common biological phenomenon, it is often overlooked as a source of disease due to the challenges associated with its detection and characterization, especially for very low-frequency variants. Moreover, PZM can cause a different phenotype compared to constitutional mutations. Especially, lethal mutations in receptor tyrosine kinase (RTK) pathway genes, which exist only in a mosaic state, can have completely new clinical manifestations and can look very different from the associated monogenic disorder. However, some key questions are still not addressed, such as the level of mosaicism resulting in a pathogenic phenotype and how the clinical outcome changes with the development and age. Addressing these questions is not trivial as we require methods with the sensitivity to capture some of these variants hidden away in very few cells. Recent ultra-accurate deep-sequencing approaches can now identify these low-level mosaics and will be central to understand systemic and local effects of mosaicism in the RTK pathway. The main focus of this review is to highlight the importance of low-level mosaics and the need to include their detection in studies of genomic variation associated with disease.
Subject(s)
Fibrous Dysplasia, Polyostotic/genetics , Germ-Line Mutation , Mosaicism , Proteus Syndrome/genetics , Receptor Protein-Tyrosine Kinases/genetics , Sturge-Weber Syndrome/genetics , Child , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Embryo, Mammalian , Fibrous Dysplasia, Polyostotic/enzymology , Fibrous Dysplasia, Polyostotic/pathology , Gene Expression , Genes, Lethal , Humans , Infant , Infant, Newborn , Phenotype , Proteus Syndrome/enzymology , Proteus Syndrome/pathology , Receptor Protein-Tyrosine Kinases/deficiency , Signal Transduction , Sturge-Weber Syndrome/enzymology , Sturge-Weber Syndrome/pathologySubject(s)
GTP-Binding Protein alpha Subunits/genetics , Sturge-Weber Syndrome/genetics , Adolescent , Brain/pathology , Child, Preschool , DNA Mutational Analysis , Female , Gain of Function Mutation , Humans , Male , Middle Aged , Mosaicism , Skin/pathology , Sturge-Weber Syndrome/blood , Sturge-Weber Syndrome/pathology , Exome Sequencing , Young AdultABSTRACT
Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial for establishing the correct diagnosis and optimizing outcomes for these patients. Unique management considerations include increased risk for thrombosis and in some cases, cancer. In recent years, research has demonstrated that these disorders are primarily caused by somatic mutations in growth pathways, particularly the PI3K-mTOR pathway. This improved understanding had led to promising new therapies for this group of patients.
Subject(s)
Hamartoma Syndrome, Multiple , Klippel-Trenaunay-Weber Syndrome , Lipoma , Musculoskeletal Abnormalities , Nevus , Proteus Syndrome , Sturge-Weber Syndrome , Vascular Malformations , Child , Hamartoma Syndrome, Multiple/genetics , Hamartoma Syndrome, Multiple/pathology , Hamartoma Syndrome, Multiple/therapy , Humans , Klippel-Trenaunay-Weber Syndrome/genetics , Klippel-Trenaunay-Weber Syndrome/pathology , Klippel-Trenaunay-Weber Syndrome/therapy , Lipoma/genetics , Lipoma/pathology , Lipoma/therapy , Musculoskeletal Abnormalities/genetics , Musculoskeletal Abnormalities/pathology , Musculoskeletal Abnormalities/therapy , Nevus/genetics , Nevus/pathology , Nevus/therapy , Proteus Syndrome/genetics , Proteus Syndrome/pathology , Proteus Syndrome/therapy , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/pathology , Sturge-Weber Syndrome/therapy , Vascular Malformations/genetics , Vascular Malformations/pathology , Vascular Malformations/therapyABSTRACT
Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the RASA1 gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skeletal components. The focal nature and variable expressivity associated with this disease has led to the hypothesis that somatic "second hit" inactivating changes in RASA1 are necessary for disease development. We report a 2-yr-old male with extensive capillary malformation and segmental overgrowth of his lower left extremity. Ultrasound showed subcutaneous phlebectasia draining the capillary malformation; magnetic resonance imaging showed overgrowth of the extremity with prominence of fatty tissues, fatty infiltration, and enlargement of all the major muscle groups. Germline RASA1 testing was normal. Later somatic testing from affected tissue showed two pathogenic variants in RASA1 consistent with the c.934_938del, p.(Glu312Argfs*14) and the c.2925del, p.(Asn976Metfs*20) with variant allele fractions of 3.6% and 4.2%, respectively. The intrafamilial variability of Parkes Weber syndrome involving segmental overgrowth of soft tissue, endothelium, and bone is strongly suggestive of a somatic second-hit model. There are at least two reports of confirmed second somatic hits in RASA1 To our knowledge, this is the first report of an individual with two somatic pathogenic variants in the RASA1 gene in DNA from a vascular lesion.
Subject(s)
Sturge-Weber Syndrome/genetics , p120 GTPase Activating Protein/genetics , Alleles , Capillaries/abnormalities , Child, Preschool , Humans , Male , Mutation/genetics , Sturge-Weber Syndrome/metabolism , Vascular Malformations/genetics , p120 GTPase Activating Protein/metabolismABSTRACT
Patients with combined phenotypes of Sturge-Weber syndrome and Klippel-Trenaunay syndrome have been reported, though the underlying genetic spectrum in these individuals remains to be elucidated. We reported the patient presenting with Klippel-Trenaunay and Sturge-Weber overlap syndrome in mainland China. Histopathologic study confirmed the hemangioma of vein and capillary. Co-existence of a novel somatic KRAS c.182_183 delins TC mutation and GNAQ c.548G>A mutation was identified in the affected skin tissue rather than paired peripheral blood. The somatic mutations of GNAQ and KRAS may affect MAPK-ERK signaling pathway, resulting in endothelial anomaly and blood vessel malformation.
Subject(s)
GTP-Binding Protein alpha Subunits, Gq-G11/genetics , Klippel-Trenaunay-Weber Syndrome/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Sturge-Weber Syndrome/genetics , Adult , Humans , Klippel-Trenaunay-Weber Syndrome/diagnosis , Male , Sturge-Weber Syndrome/diagnosis , Young AdultABSTRACT
Overgrowth syndromes are a large group of rare disorders characterized by generalized or segmental excessive growth. Segmental overgrowth syndromes are mainly due to genetic anomalies appearing during the embryogenesis and leading to mosaicism. The numbers of patients with segmental overgrowth with an identified molecular defect has dramatically increased following the recent advances in molecular genetic using next-generation sequencing approaches. This review discusses various syndromes and pathways involved in segmental overgrowth syndromes and presents actual and future therapeutic strategies.
TITLE: Les syndromes de surcroissance segmentaire et les stratégies thérapeutiques. ABSTRACT: Les syndromes de surcroissance sont un groupe de pathologies caractérisées par une croissance excessive généralisée ou segmentaire. Les syndromes de surcroissance segmentaires sont principalement dus à des anomalies génétiques apparaissant durant l'embryogenèse et aboutissant à un mosaïcisme. Le nombre de patients atteints d'un syndrome de surcroissance avec une mutation identifiée a fortement augmenté grâce à des avancées récentes en génétique moléculaire, en utilisant le séquençage de nouvelle génération (NGS). Cette revue détaille les différents syndromes de surcroissance segmentaire ainsi que les voies moléculaires impliquées et les options thérapeutiques envisageables.
Subject(s)
Growth Disorders/genetics , Growth Disorders/therapy , Mosaicism , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/pathology , Beckwith-Wiedemann Syndrome/therapy , Eye Diseases/genetics , Eye Diseases/pathology , Eye Diseases/therapy , Genetic Testing , Growth Disorders/diagnosis , Growth Disorders/pathology , High-Throughput Nucleotide Sequencing , Humans , Lipomatosis/genetics , Lipomatosis/pathology , Lipomatosis/therapy , Mosaicism/embryology , Mutation , Neurocutaneous Syndromes/genetics , Neurocutaneous Syndromes/pathology , Neurocutaneous Syndromes/therapy , Nevus, Sebaceous of Jadassohn/genetics , Nevus, Sebaceous of Jadassohn/pathology , Nevus, Sebaceous of Jadassohn/therapy , Phosphatidylinositol 3-Kinases/genetics , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/pathology , Sturge-Weber Syndrome/therapy , SyndromeSubject(s)
GTP-Binding Protein alpha Subunits/genetics , Genotype , Mutation/genetics , Protein Domains/genetics , Skin/metabolism , Sturge-Weber Syndrome/genetics , Capillaries/abnormalities , Child , Child, Preschool , Cohort Studies , Female , Genetic Association Studies , Humans , Infant , Infant, Newborn , Male , Mosaicism , Phenotype , Prospective Studies , Skin/pathology , Skin Pigmentation , Sturge-Weber Syndrome/diagnosis , Vascular MalformationsABSTRACT
BACKGROUND: A somatic mutation of GNAQ (c.548G>A, p.Arg183Gln) plays a key role in capillary malformation development. The present study aimed to evaluate clinical manifestations of port-win stain (PWS) associated with this genetic mutation. METHODS: Skin tissue was obtained from 70 patients with capillary malformation who had been treated with excision for lesions. Droplet digital polymerase chain reaction was used to quantify the abundance of cells with the GNAQ mutation. RESULTS: The GNAQ mutation was found in 50 patients. Patients with lesions involving upper facial region, which included forehead, eyebrow, and upper eyelid, showed a significantly higher rate of positive GNAQ mutation than those not involving it. Cases with facial PWS involving all three facial regions (upper, middle, and lower) showed significantly higher positive rate of GNAQ mutation compared to those involving one or two. CONCLUSIONS: Presence of the somatic mutation GNAQ p.Arg183Gln might be associated with clinical manifestations of PWS.