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

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Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-04-14 , DOI: 10.1111/cge.13752
Alison Foster _{1,

2} , Basile Chalot _{3,

4,

5} , Thalia Antoniadi ₆ , Elise Schaefer ₇ , Rebecca Keelagher ₆ , Gavin Ryan ₆ , Quentin Thomas ₈ , Christophe Philippe _{4,

5} , Ange-Line Bruel _{4,

5} , Arthur Sorlin _{3,

4,

5} , Christel Thauvin-Robinet _{3,

4,

5} , Marc Bardou _{9,

10} , Maxime Luu _{9,

10} , Veronique Quenardelle ₁₁ , Valerie Wolff _{11,

12} , Jessica Woodley ₆ , Pierre Vabres ₁₃ , Derek Lim ₂ , Rebecca Igbokwe ₂ , Annie Joseph ₁₄ , Harriet Walker ₁₅ , Andrea Jester ₁₅ , Jonathan Ellenbogen ₁₆ , Diana Johnson ₁₇ , Bethanie Rooke ₁₈ , Celia Moss _{1,

18} , Trevor Cole ₂ , Laurence Faivre _{3,

5}

Affiliation

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
Centre de Génétique et Centre de référence « Anomalies du Développement et Syndromes Malformatifs », Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France.
Laboratoire de Génétique chromosomique et moléculaire, UF Innovation en diagnostic génomique des maladies rares, Centre Hospitalier Universitaire de Dijon, Dijon, France.
UMR-Inserm 1231 GAD team, Génétique des Anomalies du développement, Université de Bourgogne Franche-Comté, Dijon, France.
West Midlands Regional Genetics Laboratory, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Service de génétique médicale - Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d'Alsace, Strasbourg, France.
Service de Neurologie, Centre Hospitalier Universitaire de Dijon, Dijon, France.
Service de Pharmacologie et Centre d'Investigation Clinique, Centre Hospitalier Universitaire de Dijon, Dijon, France.
INSERM CIC 1432, Université de Bourgogne Franche-Comté, Dijon, France.
Stroke Unit, University Hospital, Strasbourg, France.
Federation of Translational Medicine of Strasbourg, University of Strasbourg, Strasbourg, France.
Service de Dermatologie, CHU de Dijon, Université de Bourgogne, France.
Ophthalmology Department, Royal Stoke University Hospital, Stoke-on-Trent, UK.
Hand and Upper Limb Service, Plastic and Reconstructive Surgery, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Paediatric Neurosurgery, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
Department of Dermatology, Birmingham Children's Hospital, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

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 contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS‐like disorders and suggest vascular imaging is indicated in these patients.

中文翻译：

Kosaki过度生长综合症：PDGFRB中的一种新型致病变异，其表型扩展包括脑血管并发症。

血小板衍生的生长因子，β（PDGFRB）与表型相关，包括Kosaki过度生长综合症（KOGS），Penttinen综合征和婴儿肌纤维瘤病（IM）。在这里，我们介绍了KOGS的三例新病例，包括一名患有新的从头突变c.1477A> T p。（Ser493Cys）的患者，以及已知的最老的53岁。KOGS表型包括特征性的面部特征，身材高大，脊柱侧弯，超弹性薄皮，脂肪营养不良，智力和神经系统变差以及脑成像异常。长期结果未知。我们的病例证实了表型谱包括进行性屈曲挛缩，弯曲畸形，牙齿间距大和收缩环。我们还提出了一些新颖的偶发性特征，包括颅突增生，眼部翼状ery肉，前房劈裂综合征，早期骨质疏松症，色素沉着增加，反复发作的血肿，易患蜂窝织炎，指甲营养不良，腕管综合症，婴儿反复出现低血糖症，关节脱位和脾肿大。重要的是，我们报告了两名患者的基底动脉梭状动脉瘤。并发症包括最古老的患者血栓形成和中风，以及新变异患者在21岁时发生致命性破裂。我们得出的结论是，脑血管并发症是KOGS和KOGS样疾病表型谱的一部分，并建议在这些患者中进行血管成像。并发症包括最古老的患者血栓形成和中风，以及新变异患者在21岁时发生致命性破裂。我们得出的结论是，脑血管并发症是KOGS和KOGS样疾病表型谱的一部分，并建议在这些患者中进行血管成像。并发症包括最古老的患者血栓形成和中风，以及新变异患者在21岁时发生致命性破裂。我们得出的结论是，脑血管并发症是KOGS和KOGS样疾病表型谱的一部分，并建议在这些患者中进行血管成像。

更新日期：2020-04-14

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