Vascular aneurysms in Ehlers-Danlos syndrome subtypes: A systematic review.

Aneurysmal lesions are commonly seen in Ehlers-Danlos Syndrome (EDS). To better identify the regional and vessel-specific spectrum of aneurysms in different subtypes of EDS, we performed a systematic review. We searched Medline for relevant studies from 1963 to April 2022. Studies providing a report of any EDS subtype by genetic diagnosis, histologic analysis, or clinical criteria were included. A total of 448 patients from 220 studies were included. 720 vessel-specific aneurysms were reported: 386 in the abdominopelvic area, 165 in the intracranial region, 98 in the thorax, 2 in the extremities, and 6 in the venous system. In 27 out of the 65 patients with ruptured aneurysms, the ruptured aneurysm was the initial presentation. Multiple aneurysms were present in 163 out of 249 patients who had been systematically evaluated for other locations of aneurysms. The head and neck and abdominopelvic regions are two potential foci for aneurysm formation in patients with EDS. The aneurysm development in EDS is not confined to arteries; the venous system and cardiac septa may also be affected. Many patients develop multiple aneurysms, either at the time of the initial presentation or throughout their lifetime and aneurysm formation or rupture may be the first presentation of EDS.

Management of Scoliosis in Patients With Loeys-Dietz Syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder. We sought to determine the incidence of scoliosis in patients with LDS, characterize the spectrum of spinal deformity, determine the results of bracing and surgery, and define surgical complications. METHODS: Patients were selected from our institution's database of 183 patients with LDS. Imaging measurements were performed for 141 patients whose records permitted spinal evaluation. Deformity changes and complications after intervention were recorded for patients who underwent bracing or surgery, and associations were tested using Student t tests (significance, P<0.05). RESULTS: Eighty-eight of 141 (62%) patients with LDS had scoliosis, with main thoracic and thoracolumbar curves being most common. Fifteen patients were braced (mean age, 9±3 y) for a mean of 2.3 years. They had a mean postbracing curve progression of 12±21 degrees (5±9 deg./y). There were no significant differences in age, sex, curve type, or prebracing curve magnitude between successfully braced (n=4) and unsuccessfully braced (n=11) patients (P>0.05). Nine patients, (mean age, 12±3 y), underwent 24 surgical procedures (16 growing rod procedures, 8 fusions). Mean curve corrections were 61% for growing rods and 73% for fusions. Associated blood loss for these procedures was 400 mL and 1293 mL, respectively, and normalized blood loss for fusion was 2.34 mL/kg/level. Fifteen of 24 surgical procedures involved complications (63%), including cerebrospinal fluid leaks (n=7) and blood loss >20% of estimated total blood volume (n=11). CONCLUSIONS: Scoliosis was present in 62% of our sample of LDS patients. Bracing did not halt curves in 11 of 15 patients, whose curves progressed >5 degrees or to >50 degrees by completion of bracing. At latest follow-up, 47% of the braced patients had undergone surgery after prior bracing attempts. The high blood loss associated with these operations is believed to be related to vascular fragility in patients with LDS. LEVEL OF EVIDENCE: Level IV-retrospective cohort study.

Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGFß.

BACKGROUND: TGFß is a multifunctional cytokine that is critical in regulating mucosal immunity. Murine studies have revealed that disruption of canonical TGFß signaling leads to systemic inflammation including colitis. Loeys-Dietz syndrome (LDS) results from heterozygous mutations in the genes encoding the subunits of the TGFß receptor. METHODS: All patients with confirmed mutations in TGFBR1 or TGFBR2, seen in the Johns Hopkins Connective Tissue Disorders clinic, were asked to participate in the study. Ninety-three consecutive patients were enrolled, including 4 with inflammatory bowel disease (IBD). Using the Illumina Immunochip array, we undertook an exploratory analysis to evaluate the potential genetic risk factors that could predict which patients with LDS would develop IBD. RESULTS: We report an increased prevalence of IBD in patients with LDS types I and II. We describe the course of several patients. In this small sample, the 3 whites with IBD had a genetic risk score in the top 6 highest scores of patients evaluated. CONCLUSION: We report a 10-fold increase in the prevalence of IBD in patients with LDS compared with the general population. Onset of disease in 3 of the 4 patients was at less than 18 years, and the clinical course in 2 of the 4 was severe with a poor response to traditional medications. Further evaluation of the genetic risk score is needed to determine whether it can predict which patients with LDS are most likely to develop IBD. This case series of patients with LDS with IBD suggests that defective TGFß signaling may have an influence on IBD risk.

High prevalence of cervical deformity and instability requires surveillance in Loeys-Dietz syndrome.

BACKGROUND: Loeys-Dietz syndrome is a connective tissue disorder characterized by vascular, craniofacial, and musculoskeletal malformation. Our goal was to report the manifestations, surgical treatment, and complications in the cervical spine in patients with Loeys-Dietz syndrome. METHODS: We reviewed the clinical and cervical spine imaging data of eighty patients with Loeys-Dietz syndrome who were seen at our institution from January 2005 through January 2014. Their mean age at presentation was 17.3 years (range, three months to seventy-five years). We tested associations with use of the Fisher exact test (type of TGF-ßR [transforming growth factor-beta receptor] mutation and cervical abnormalities) and the Student t test (age at presentation and type of TGF-ßR mutation) (significance, p = 0.05). RESULTS: Vertebral anomalies and cervical instability were common; we found no significant association of TGF-ßR-type with cervical abnormalities or age at presentation. Twenty-eight patients had atlas defects (anterior and/or posterior arch defects or hypoplasia), fifty-three had axis malformations (elongation, apex-anterior dens angulation, or spondylolysis), and twelve had focal kyphosis. Ten patients had hypoplastic subaxial vertebrae, leading to focal kyphosis (eight) and subaxial instability (nine). Eight patients had atlantoaxial instability. Of the thirteen patients with cervical instability, nine were treated surgically: fusion (eight patients) and halo application (one) (mean age, four years; range, three months to twelve years). Postoperative complications (seven patients) were pseudarthrosis, failure of fixation, junctional kyphosis or instability, and development of occipital-cervical instability. CONCLUSIONS: Cervical midline defects (most often C1-C3) are common in Loeys-Dietz syndrome. Patients have a high prevalence of cervical instability, particularly a pattern of instability at C2-C3 associated with C3 vertebral body hypoplasia and C2-C3 focal kyphosis. Patients requiring surgery typically present in early childhood.