Knoepfel Capelinha, Nicole; (2024) Disease mechanisms in cutaneous vascular disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cutaneous vascular anomalies encompass a wide group of disorders that can also affect other organs and the majority are monogenic, caused by either mosaic or germline mutations. Whilst many of the causative genes have been identified in recent years, these conditions are still poorly understood biologically, and not all cases fit neatly into existing classifications. GNAQ/GNA11 mosaicism is a spectrum of disease which arises as a result of a postzygotic de novo mutational event in a cell within the developing embryo/fetus, and includes Sturge-Weber syndrome and Phakomatosis pigmentovascularis. Current treatment options are limited to symptoms such as seizures and headaches that arise during the progressive neurological deteriorating course. Characteristic "tramlining" on skull radiography, indicating neurovascular calcifications, prompted to explore the role of calcium metabolism in a cohort of 40 children. This investigation revealed that 40% had moderately low serum ionized calcium levels, which were significantly associated with seizures and status epilepticus. Neuroradiological assessment demonstrated progressive calcium deposition over time. In addition, neuropathological examination enabled the characterization of mineral deposits, revealing microvascular calcification. These new observations suggest that neurovascular calcium deposition in individuals with GNAQ/GNA11 mosaicism may represent a pivotal postnatal pathological process and not an indicator of tissue damage as previously assumed. Extensive or atypical dermal melanocytosis represents the counterpart of the spectrum displaying a purely pigmentary phenotype only. Genetic investigation in a cohort of 38 patients identified GNAQ mosaicism in 15% and the first description of a GNA11 and HRAS mosaic variant. RNA sequencing analysis lacked the expected depth, yet we identified potential variants in GNB2 and KRAS, currently pending validation. The third aspect of this research delves into a unique family presenting with multifocal congenital and acquired haemangiomas. Whole exome and subsequent whole genome sequencing of the parents and two siblings and affected skin from the two siblings unveiled a novel germline heterozygous variant in THSD1 predicted to be pathogenic in silico, in both affected children and father, with a rare single nucleotide variant in both affected children and mother. This gene encodes Thrombospondin type 1 domain containing 1 that is highly expressed in endothelial cells, and as a member of matricellular proteins, it plays an important role in vascular integrity through cellextracellular matrix interaction. This discovery provides a likely genetic basis for vascular tumours with a tendency to bleed in this family, opening new venues for further investigation of cases of sporadic multiple haemangiomas.

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