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. 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, PIGA-related CNS dysplasia, Ogden syndrome, and Lenz microphthalmia syndrome. A recent focus has been to understand the relationship of Proteus syndrome to deep vein thrombosis and pulmonary embolism. To address this we have collaborated with Dr. Lozier of the NIH Clinical Center and are performing a systematic evaluation of both vascular and plasma mediators of coagulation in these patients. 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 24 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 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 are working on two primary approaches - the first is an MRI volumetric approach in collaboration with Dr. Turkbey in NIH Clinical Center imaging. The second approach is a quantitative surface measurement technique with Dr. Darling of USUHS. We are pursuing collaborative agreements with pharmaceutical companies to repurpose oncology drugs for these trials. Behavioral studies We have also undertaken studies to explore the behavioral aspects of these disorders. Adaptation to these conditions is a key component of quality of life for patients. To that end, we have developed interview studies to evaluate self-perception and adaptation in patients with Bardet-Biedl syndrome. We have also developed a qualitative interview study for patients with these disorders who receive genomic testing results to gauge their interest and reactions to this testing, a key attribute that clinicians will need to consider when undertaking such analyses, whether clinical or research sequencing. In addition, Dr. Biesecker is a co-founder and co-director of the Elements of Morphology dysmorphology standards working group. This group is working to standardize malformation descriptions to increase the utility of clinical descriptions and journal reports. The group is currently working on definitions for genital anomalies and an expanded set of limb morphology terms.

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Lamb, Amanda E; Biesecker, Barbara B; Umstead, Kendall L et al. (2016) Family functioning mediates adaptation in caregivers of individuals with Rett syndrome. Patient Educ Couns 99:1873-1879
Opitz, John M; Biesecker, Leslie G; Hennekam, Raoul C (2016) GAUDEAMUS IGITUR…In gratitude to John Carey for his stewardship of the American Journal of Medical Genetics 2001-2016. Am J Med Genet A 170:2501-2
Keppler-Noreuil, Kim M; Baker, Eva H; Sapp, Julie C et al. (2016) Somatic AKT1 mutations cause meningiomas colocalizing with a characteristic pattern of cranial hyperostosis. Am J Med Genet A 170:2605-10
Bennett, James T; Tan, Tiong Yang; Alcantara, Diana et al. (2016) Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. Am J Hum Genet 98:579-87
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Russell, Bianca; Johnston, Jennifer J; Biesecker, Leslie G et al. (2015) Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance. Am J Med Genet A 167A:2122-31
Wentzensen, Ingrid M; Johnston, Jennifer J; Keppler-Noreuil, Kim et al. (2015) Exome sequencing identifies novel mutations in C5orf42 in patients with Joubert syndrome with oral-facial-digital anomalies. Hum Genome Var 2:15045
Hamlington, Barbara; Ivey, Lauren E; Brenna, Ethan et al. (2015) Characterization of Courtesy Stigma Perceived by Parents of Overweight Children with Bardet-Biedl Syndrome. PLoS One 10:e0140705
Wee, Jamie S; Mortimer, Peter S; Lindhurst, Marjorie J et al. (2014) A limited form of proteus syndrome with bilateral plantar cerebriform collagenomas and varicose veins secondary to a mosaic AKT1 mutation. JAMA Dermatol 150:990-3

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