Natural history studies We operate several clinical research protocols to assess the range of severity, spectrum of malformations, and natural history of pleiotropic developmental anomalies and segmental overgrowth disorders. We use clinical evaluations that include history and physical examination, imaging studies including radiography, ultrasound, and tomography, as well as EEG, pulmonary function testing, etc. to characterize functional and structural anomalies. In selected cases we also perform surgical treatments if they offer clinical benefit and can advance our understanding of the disease under study. Some of the disorders that we are currently studying include non-syndromic polydactyly, Proteus syndrome, fibroadipose overgrowth syndrome, a progeriod syndrome, and Lenz microphthalmia syndrome. A recent focus has been to understand the relationship of Proteus syndrome to deep vein thrombosis and pulmonary embolism, meningiomas, and gastrointestinal complications. Genotype-Phenotype studies A key objective of genetic research is to understand not only what genes are associated with what phenotypes, but to understand in detail how specific variants are correlated with specific manifestations and the severity and complications of these disorders. These studies take a great deal of time and effort to attract sufficient patients. We are currently focusing on fibroadipose overgrowth disorders and are developing a cohort of >100 patients with detailed clinical analysis coupled to mutation detection from biopsied specimens. The challenge here is greater than it is for germline (inherited) disorders because in addition to gene, variant, and genetic background, one must take into account the mosaicism level in the patient, which is clearly an important variable. We have published interim results on the first 32 such patients, the largest in the world. Therapeutic Studies The identification of the molecular etiology for Proteus syndrome and fibroadipose overgrowth and CLOVES syndrome provide an exciting new opportunity to develop therapeutic approaches to these devastating disorders. We have undertaken efforts to develop data for valid therapeutic endpoints for therapy of overgrowth disorders. We have established a productive collaborative agreement with a pharmaceutical companies to repurpose an oncology drug for these trials. We have performed significant in vitro work (see companion Z01 on molecular studies) and have completed a phase 0 dose finding trial for this drug which has shown good safety and preliminary efficacy (NCT02594215). We have also cofounded an international consortium to test therapeutic agents in PIK3CA related overgrowth disorders with the University of Cambridge and Lyon University. This trial was completed in the spring of 2018 and the paper has been accepted.
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