Gretchen Oswald

Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2+/− mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1C1039G/+) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β–mediated vasculopathies.

Infantile Restrictive Cardiomyopathy Resulting From a Mutation in the Cardiac Troponin T Gene

Here we report the first infantile case of restrictive cardiomyopathy caused by a de novo mutation of the cardiac troponin T gene. The patient presented with an apparent life-threatening event. She developed malignant arrhythmias and hemodynamic instability, requiring initial rescue support with extracorporeal membrane oxygenation, and subsequently underwent insertion of a biventricular assist device (VAD). She successfully received an orthotopic heart transplant 172 days after VAD implantation.

The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome.

Shprintzen–Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys–Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS.

Rhizomelic chondrodysplasia punctata type 1 and fulminant neonatal respiratory failure, a case report and discussion of pathophysiology.

Rhizomelic Chondrodysplasia Punctata Type 1 and Fulminant Neonatal Respiratory Failure, a Case Report and Discussion of Pathophysiology Gretchen Oswald, Cathleen Lawson, Gerald Raymond, W. Christopher Golden, and Nancy Braverman* McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Medical Center, Baltimore, Maryland Prenatal Diagnosis and Treatment Center, Johns Hopkins Medical Center, Baltimore, Maryland Department of Neurogenetics and Neurology, Kennedy Krieger Institute, Johns Hopkins Medical Center, Baltimore, Maryland Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Johns Hopkins Medical Center, Baltimore, Maryland Department of Human Genetics and Pediatrics, McGill University, Montreal Children’s Hospital Research Institute, Montreal, Quebec, Canada

Increased fracture risk and low bone mineral density in patients with loeys-dietz syndrome.

Loeys–Dietz syndrome is a recently recognized connective tissue disorder with widespread systemic involvement. Little is known about its skeletal phenotype. Our goal was to investigate the risk of fracture and incidence of low bone mineral density in patients with Loeys–Dietz syndrome. We performed a cross‐sectional, descriptive, survey‐based study with subsequent chart review from July 2011 to April 2012. Fifty‐seven patients (26 men, 31 women) with Loeys–Dietz syndrome confirmed by genetic testing completed the survey (average age, 25.3 years; range, 0.9–79.6 years). There were a total of 51 fractures (33 patients): 35 fractures in the upper extremities, 14 in the lower extremities, and two in the spine. Fourteen patients (24.6%) reported two or more fractures. There was a 50% risk of fracture by age 14 years. The incidence of any fracture in this cohort was 3.86 per 100 person‐years. Seventeen patients had dual‐energy X‐ray absorptiometry scans available for review, 11 (64.7%) of whom had at least one fracture. Thirteen included lumbar spine absorptiometry reports; eight (61.5%) indicated low or very low bone mineral density. In the left hip, ten of 14 participants (71.4%) had low or very low bone mineral density. In the left femoral neck, nine of 13 participants (69.2%) had low or very low bone mineral density. The lowest Z‐ and T‐scores were not associated with an increased number of fractures. Patients with Loeys–Dietz syndrome have a high risk of fracture and a high incidence of low bone mineral density.