Rare & Mosaic Disorders - Clinical Research

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

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 have studied in the past include non-syndromic polydactyly, Proteus syndrome, fibroadipose overgrowth syndrome, a progeriod syndrome, and Lenz microphthalmia syndrome. Our current focus is on Proteus syndrome and related disorders. 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 segmental overgrowth disorders, specifically, Proteus syndrome and have developed 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. Therapeutic Studies The identification of the molecular etiology for Proteus syndrome provided 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 Merck, Inc 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 opened a phase 2 study for Proteus syndrome under a CRADA from the Pharma partner and have nearly completed enrollment in that study.