Research Abstracts

The abstracts below were presented at the American Society of Human Genetics Annual Meeting in October 2006.

A cohort of patients with generalized Fibromuscular Dysplasia and features of Ehlers-Danlos Syndrome: A new phenotype.

N.B. McDonnell, J. Yang, W. Chen1, B. Griswold, C.A. Francomano 1) National Institute on Aging, NIH, Baltimore, MD; 2) Harvey Inst Human Gen, Greater Baltimore Medical Center, Baltimore, MD.

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue. Vascular dissections and aneurysms are a cardinal feature of the vascular form of EDS (VEDS) caused by mutations in COL3A1. Loeys-Dietz syndrome, a closely related phenotype, is caused by mutations in TGFBR1 or TGFBR2. We have identified a group of patients without mutations in COL3A1, TGFBR1 or TGFBR2 who presented with arterial dissections and aneurysms as well as stenotic lesions with a diagnosis of fibromuscular dysplasia (FMD) by pathology or radiology. Varying features of Ehlers-Danlos syndrome, such as atrophic scars, velvety or stretchy skin, joint hypermobility as evidenced by a high Beighton score, history of articular dislocations, uterine prolapse, joint pain, pectus deformities, pes planus and scoliosis were also present. Several of the patients had a family history of premature death from vascular events, as well as a family history of joint and skin abnormalities compatible with an autosomal dominant inheritance pattern. There were no reports of uterine or bowel rupture, or pregnancy related death in personal or family histories. The facial features were not characteristic of VEDS or Loeys-Dietz syndrome. The first patient identified was a 44 year old woman who had a history of carotid dissection, ruptured cerebral aneurysms, FMD of renal arteries and iliac vessels, multiple atrophic scars, frequent joint dislocations, and stretchy and doughy skin. A cohort of thirty patients with this syndrome has been identified and detailed phenotype and family history information has been assembled. The etiology of fibromuscular dysplasia is thought to be heterogeneous, with genetic and environmental factors proposed as possible contributors. Our findings suggest that there is a previously unrecognized variant of EDS, distinct from the VEDS and Loeys-Dietz syndrome, with FMD as a major clinical feature in addition to the skin and joint abnormalities.


 

Genome wide association study for Fibromuscular Dysplasia (FMD)
J. Yang1, M. Nalls2, B. Traynor2, D. Hernandez2, N. Washecka2, B. Griswold1, L. Sloper1, A. Singleton2, N. B. McDonnell1 1) LCI, NIA/NIH, Baltimore, MD; 2) LNG,NIA/NIH, Bethesda, MD.

Fibromuscular dysplasia is a heterogeneous disorder characterized by angiopathy of the arteries, which predominantly affects women in mid-life, resulting in stenosis, dissection or aneurysm. It may involve renal arteries, carotid, vertebral, coronary and abdominal vessels. Autosomal dominant inheritance has been suggested, however no genes have been identified to date. On detailed clinical examination of a cohort of 69 patients seen at the National Institute on Aging, features of connective tissue dysplasia as exemplified by joint hypermobility, scoliosis, pectus deformity, pes planus and high myopia were frequently noted, suggesting a defect in the extracellular matrix pathways. In order to elucidate the genetic factors underlying this disorder, we performed genome wide association study in 46 sporadic cases and 540 controls utilizing the Illumina HumanCNV370-Duo BeadChip and HumanHap550 Beadchip. By permutation analysis, we have identified a number of marker SNPs with significant differences between cases and controls. The candidate genes include CDH12, EXOC2, PACRG, HECW1, ZAN, CSMD1, SRA and DIP2B with p scores <10-6. Although the disorders has been suggested to be dominant, we did homozygosity analyses for our samples, our results show chromosome 4, 5, 12 could include some specific overlapping homozygous runs in FMD patients.


Morphometric Analysis of the Posterior Fossa and Spinal Cord in patients with Hereditary Disorders of Connective Tissue
J. C. Quo1,2, L. Sloper1, R. Raza2, N. B. McDonnell1 1) Clinical Research Branch, NIA, NIH, Baltimore, MD; 2) Harbor Hospital Center, Baltimore, MD.

Patients with hereditary disorders of connective tissue (HDCT) have increased incidence of Chiari I malformation, however, abnormalities of the posterior fossa or the spinal cord has not been systematically evaluated to date. We retrospectively evaluated midline sagittal brain, midline sagittal lumbar spine, and axial lumbar magnetic resonance imaging (MRI) of 94 subjects with HDCT (70 Female, 24 Male, aged 12-71) and 209 age matched controls (138 Female, 71 Males). HDCT subjects included those with diagnoses of Ehlers-Danlos syndrome (EDS), Marfan syndrome, and Fibromuscular Dysplasia with connective tissue features (FMD). The MRI images were obtained on a 1.5 Tesla MRI machine (Philips Interna, USA) with system 11.1 software. The measurement that showed significant differences between the subjects and the controls included the basiocciput measurement (p=0.0115), foramen magnum distance (p=0.0101), opisthion to internal occipital protuberance (IOP) (p=0.0188), dorsa sella to IOP (p=0.0176), tonsillar herniation (p<0.0001), fourth ventricle height (p=0.0020), brainstem length to the craniocervical junction (p<0.0001), brainstem length to the inferior portion of the gracile tubercle (p=0.0016), tentorium slope (p=0.0109), tentorium slope to the twining line (p=0.0044), height of cerebellum (p<0.0001), conus medullaris level (p=0.0383), and filum terminale thickness (p<0.0001). Measurements that were not statistically significant included the basisphenoid length, ponto-medullary height, medullary height, and odontoid angle. The significant p value observed in 13 of the 17 measurements suggests that there are consistent morphometric differences that are seen in HDCT patients that can contribute to increased incidence of clinical abnormalities such as Chiari I malformation, tethered cord syndrome and related complaints.


 

Sex Hormone Abnormalities in patients with Fibromuscular Dysplasia with Connective Tissue Features
B. F. Griswold, L. Sloper, S. Basaria, J. M. Egan, N. B. McDonnell National Institute on Aging Baltimore, Maryland.

We have identified a group of patients (n=28) who presented with arterial dissections and aneurysms as well as stenotic lesions with a diagnosis of fibromuscular dysplasia (FMD). Varying features of Ehlers-Danlos syndrome, such as atrophic scars, velvety or stretchy skin, joint hypermobility as evidenced by a high Beighton score, history of articular dislocations, uterine prolapse, joint pain, pectus deformities, pes planus and scoliosis were also present in this group of patients, and family history data suggested autosomal dominant inheritance with reduced penetrance. There was a female preponderance, 24 women and 4 men, consistent with prior observations that FMD affects women predominantly, leading to the hypothesis that sex hormones played a role in the penetrance of the disorder. As part of a longitudinal protocol studying the natural history of this disorder, laboratory analysis of sex hormone levels was completed. Of the 24 female patients aged 33-62, 15 were post-menopausal. Of the women subjects, 8/24 (0.33) had high levels of Sex Hormone Binding Globulin (SHBG) which included four post menopausal patients. Free testosterone was low in 36 percent; of women patients, and 4/24 (0.17) had low bioavailable levels of testosterone. Of the 8 patients found to have high levels of SHBG, five also had corresponding low free testosterone. None of the patients had liver function abnormalities or current birth control pill use which are known to increase SHBG. None of the premenopausal patients had low FSH or LH along with low estrogen which would suggest pituitary failure. By contrast, the four male patients had normal levels of testosterone and SHBG, however the sample size was too small to draw conclusions. Elevated SHBG and low testosterone in women with FMD may be a clue to pathways involved in the etiology of this disorder.