Search PubMed⌕ Search

Biomedical subjects

Reed E Pyeritz

Publications and source records attributed to Reed E Pyeritz.

16 recordsLinked to original sources
PubMed2006

Aneurysm syndromes caused by mutations in the TGF-beta receptor.

BACKGROUND: The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). METHODS: We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys-Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys-Dietz syndrome. RESULTS: We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome. CONCLUSIONS: Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.

Abnormalities, Multiple↗
PubMed2005

Management of aortic disease in Marfan Syndrome: a decision analysis.

BACKGROUND: Marfan syndrome is a relatively common heritable disorder of connective tissue that affects numerous organ systems, but the most severe complication is aortic aneurysm and dissection. A variety of medical and surgical approaches are available for managing the cardiovascular complications. Our objective was to compare elective composite graft surgery, elective valve-sparing surgery, and medical management for patients with both Marfan syndrome and thoracic aortic disease on the basis of life expectancy with differing diameters of the aortic root and rate of increase in the aortic root size. METHODS: A Markov decision analysis model was constructed to compare the 2 surgical options with watchful waiting with medical therapy. RESULTS: For our base-case analysis of a 20-year-old patient with Marfan syndrome and thoracic aortic aneurysm, the aortic valve-sparing option was preferred. It extended life expectancy to 73.8 years compared with the medical treatment option (71.4 years) and with the composite graft surgery (72.7 years). Our results show that there is a better outcome for a patient with an aortic root diameter between 3.0 and 3.5 cm with early prophylactic surgery than with deferred or emergency surgery. Medical treatment was preferred when the aortic root diameter was smaller than 3.0 cm. CONCLUSIONS: Although long-term follow-up data are not yet available, it appears that advances in the technique of valve-sparing surgery have made it the preferred option to composite graft, primarily to avoid the complications of anticoagulation. Our study indicates that patients who have an aortic root diameter of larger than 3.0 cm should be considered for prophylactic aortic surgery.

Adult↗
PubMed2005

Characterization of the symptoms associated with dural ectasia in the Marfan patient.

Dural ectasia, an expansion of the dural sac surrounding the spinal cord, is one of the most common orthopedic manifestations of Marfan syndrome. The purpose of the present study was to characterize the clinical symptoms associated with dural ectasia in patients with Marfan syndrome and to understand the effects of symptomatic dural ectasia on the overall health of affected patients. Twenty-two volunteers aged 9-55 years with Marfan syndrome, and dural ectasia diagnosed by MRI or CT, filled out a "symptoms" questionnaire and completed an SF-36 health survey. Overall, It appears that the symptoms associated with dural ectasia have a marked impact on the overall health of patients with Marfan syndrome. Based on our findings, a "classic" picture of dural ectasia in the Marfan patient may consist of low back pain, headache, proximal leg pain, weakness and numbness above and below the knee, and genital/rectal pain. Symptoms, when present, are typically moderate to severe, occur several times per week (often daily), are commonly exacerbated by upright posture, and are not always relieved by recumbency.

Adolescent↗
PubMed2004

Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.

Splice site mutations in the COL1A2 gene of type I collagen can give rise to forms of Ehlers-Danlos syndrome (EDS) because of partial or complete skipping of exon 6, as well as to mild, moderate, or lethal forms of osteogenesis imperfecta as a consequence of skipping of other exons. We identified three unrelated individuals with a rare recessively inherited form of EDS (characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects); in two of them, COL1A2 messenger RNA (mRNA) instability results from compound heterozygosity for splice site mutations in the COL1A2 gene, and, in the third, it results from homozygosity for a nonsense codon. The splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature termination codon, and extremely unstable mRNA. In the wild-type allele, the two introns (IVS11 and IVS24) in which these mutations occurred were usually spliced slowly in relation to their respective immediate upstream introns. In the mutant alleles, the upstream intron was removed, so that exon skipping could not occur. In the context of the mutation in IVS24, computer-generated folding of a short stretch of mRNA surrounding the mutation site demonstrated realignment of the relationships between the donor and acceptor sites that could facilitate use of a cryptic donor site. These findings suggest that the order of intron removal is an important variable in prediction of mutation outcome at splice sites and that folding of the nascent mRNA could be one element that contributes to determination of order of splicing. The complete absence of pro alpha 2(I) chains has the surprising effect of producing cardiac valvular disease without bone involvement.

Adult↗
PubMed2004

A dysmorphic newborn infant with a complex rearrangement involving chromosomes 2, 4, and 6 detected by fluorescence in situ hybridization (FISH).

A newborn female infant with multiple congenital anomalies was found to have an unusual and abnormal karyotype. Cytogenetic studies revealed an apparent balanced translocation between chromosome 4q31.3 and chromosome 6q25.1. Additional material on chromosome 2p was identified and determined to be from chromosome 6q by analysis with fluorescence in situ hybridization (FISH). The karyotype is 46,XX,der(2)t(2;6)(p23;q25.1), t(4;6)(q31.3;q25.1). Her mother has a normal female karyotype. The father was unavailable for physical examination or cytogenetic analysis.

Abnormalities, Multiple↗
PubMed2003

Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion.

There is mounting evidence that perturbations in endoplasmic reticulum (ER) function play a key role in the pathogenesis of a broad range of diseases. We have examined the ability of ER stress to modulate leukocyte binding to colonic and aortic smooth muscle cells. In vitro, control smooth muscle cells bind few leukocytes, but treatment with compounds that induce ER stress, including tunicamycin, A23187, and thapsigargin, promotes leukocyte binding. Likewise, dextran sulfate, another agent capable of inducing ER stress and promoting inflammation in vivo, strongly induces leukocyte adhesion. The bound leukocytes are released by hyaluronidase treatment, indicating a critical role for hyaluronan-containing structures in mediating leukocyte binding. Affinity histochemistry demonstrated that hyaluronan accumulates and is present in cable-like structures in the treated, but not the untreated, cultures and that these structures serve as attachment sites for leukocytes. Hyaluronan-rich regions of both murine and human inflamed colon contain numerous cells that stain intensely for ER-resident chaperones containing the KDEL sequence, demonstrating a relationship between ER stress and hyaluronan deposition in vivo. These results indicate that ER stress may contribute to chronic inflammation by forming a hyaluronan-rich extracellular matrix that is conducive to leukocyte binding.

Animals↗
PubMed2002

Homocysteine binds to human plasma fibronectin and inhibits its interaction with fibrin.

OBJECTIVE: More than 70% of circulating homocysteine is disulfide-bonded to protein, but little is known about the specific proteins that bind homocysteine and their function as a consequence of homocysteine binding. METHODS AND RESULTS: When human plasma was incubated with [(35)S]L-homocysteine, most of the homocysteine bound to albumin. However, additional homocysteine-binding proteins were detected, and 1 of them comigrated with fibronectin. Treatment with 2-mercaptoethanol removed the bound homocysteine, demonstrating the involvement of disulfide bonding. In contrast, [35S]L-cysteine did not bind to fibronectin. Purified fibronectin bound approximately 5 homocysteine molecules per fibronectin dimer. SDS-PAGE of a limited trypsin digestion of homocysteinylated fibronectin showed that several tryptic fragments contained [35S]homocysteine. Sequence analysis demonstrated that the fragments containing bound homocysteine had localized mainly to the C-terminal region, within and adjacent to the fibrin-binding domain. Homocysteinylation of fibronectin significantly inhibited its capacity to bind fibrin by 62% (P<0.005). In contrast, neither the binding of fibronectin to gelatin nor its capacity to serve as an attachment factor for aortic smooth muscle cells was affected. CONCLUSIONS: These results suggest that homocysteine may alter normal thrombosis and delay or interfere with wound healing by impairing the interaction of fibronectin with fibrin.

Arteriosclerosis↗
PubMed2002

Growth and maturation in Marfan syndrome.

Understanding the growth pattern in Marfan syndrome is important for prediction of expected growth, prevention of excessive growth by hormone therapy, timing of surgical epiphysiodesis for cessation of growth, and instituting brace treatment for scoliosis. In this study, we analyze growth patterns and generate growth charts for persons with Marfan syndrome. From the charts of 180 clinically diagnosed Marfan patients, longitudinal height and weight measurements were obtained. From this data, growth charts and growth velocity charts were generated for males and females. Skeletal maturation was studied by determining the Risser signs from the x-rays of 71 males and 56 females. From 22 female patients, age of menarche was available and retrieved either by reviewing the charts or contacting the patients. Mean length at birth was 53 +/- 4.4 cm for males and 52.5 +/- 3.5 cm for females. Mean final height was 191.3 +/- 9 cm for males and 175.4 +/- 8.2 cm for females. Mean birth weight was 3.51 +/- 0.74 kg for males and 3.48 +/- 0.68 kg for females. The puberty-associated peak in growth velocity was 2.4 years earlier than the gender-matched general population for males with Marfan syndrome and 2.2 years earlier for females. Age of menarche was 11.7 +/- 2 years of age, which is also early compared to the general population. This study suggests that the growth spurt and pubertal skeletal maturation occur early in Marfan syndrome. The growth curves generated should help more accurately predict adult stature, as well as monitor progression toward it.

Adolescent↗
PubMed2002

Genetic counseling for congenital heart disease: new approaches for a new decade.

Congenital heart disease (CHD), which occurs in about 0.7% of all live-born children, is the leading cause of death from birth defects. Understandably, parents of patients, and increasingly patients themselves, are interested in the risk that further offspring will be affected. Advances in genetics now permit accurate estimation for many forms of CHD, especially the identification of patients and families with recurrence risks of up to 50%. The increased availability of genetic information, combined with the use of noninvasive imaging to look for subtle defects and targeted genetic testing, have demonstrated that the relevant question to ask about an individual's apparently isolated CHD is whether it is syndromic or familial. Syndromes that involve clinically important noncardiac findings may best be managed by, or in consultation with, a clinical geneticist. Other familial syndromes remain entirely within the purview of the cardiologist. The practicing cardiologist needs to continue to stay abreast of genetic discoveries in the field of CHD in order to provide proper management, including genetic counseling, to patients and their families.

Genetic Counseling↗
PubMed2002

Upregulation of smooth muscle cell collagen production by homocysteine-insight into the pathogenesis of homocystinuria.

Patients with untreated homocystinuria have widespread premature atherosclerosis with intimal thickening and collagen-rich, fibrous plaques. We previously demonstrated that homocysteine (Hcy) upregulates collagen synthesis and accumulation by arterial smooth muscle cells (SMCs) [A. Majors, L.A. Ehrhart, E.H. Pezacka, Arterioscler. Thromb. Vasc. Biol. 17 (1997) 2074-2081] but the underlying mechanisms are not known. Since many of the effects of Hcy on intact vessels and vascular cells are thought to involve reactive oxygen species generated from Hcy oxidation, we investigated the role of reactive oxygen species in the upregulation of collagen production by Hcy. Treatment of SMCs with 300 microM l-Hcy increased collagen accumulation 2-3-fold. When added to culture medium containing serum, the exogenous Hcy was rapidly oxidized with a half-life of approximately 1 h but only very low amounts of H(2)O(2) (up to 2 microM) were detected. Three lines of evidence demonstrate that the increased accumulation of collagen was not mediated by reactive oxygen species generated from Hcy oxidation: (1) catalase in the medium did not block the accumulation of collagen in Hcy-treated cultures; (2) the addition of xanthine/xanthine oxidase, a system that generates superoxide and H(2)O(2), did not increase collagen accumulation; and (3) the direct addition of H(2)O(2) did not substantially enhance collagen accumulation. In contrast, heparin, a potent modulator of SMC function, significantly blocked the accumulation of collagen in Hcy-treated cultures. Together, these results demonstrate that the increase in collagen accumulation in Hcy-treated cultures involves alternate mechanisms not involving H(2)O(2).

Animals↗
PubMed2002

Mechanisms and consequences of somatic mosaicism in humans.

Somatic mosaicism -- the presence of genetically distinct populations of somatic cells in a given organism -- is frequently masked, but it can also result in major phenotypic changes and reveal the expression of otherwise lethal genetic mutations. Mosaicism can be caused by DNA mutations, epigenetic alterations of DNA, chromosomal abnormalities and the spontaneous reversion of inherited mutations. In this review, we discuss the human disorders that result from somatic mosaicism, as well as the molecular genetic mechanisms by which they arise. Specifically, we emphasize the role of selection in the phenotypic manifestations of mosaicism.

Cell Lineage↗
PubMedDate not supplied

Outline of a medical genetics curriculum for internal medicine residency training programs.

To keep pace with the rapid advances in medical genetics, internal medicine residency training programs need to train internists to develop new attitudes, knowledge bases, and skill sets. Currently, such programs have no medical genetics curriculum. Thus, to set a minimum standard for genetics education in the context of training in internal medicine, the Internal Medicine Residency Training Program Genetics Curriculum Committee was formed, with members representing professional organizations of medical geneticists, internists, genetic counselors, internal medicine and genetics residency program directors, and internal medicine residents. The committee's task was to develop a concise outline of a medical genetics curriculum for residents in internal medicine in accordance with requirements of the Residency Review Committee for Internal Medicine of the Accreditation Council for Graduate Medical Education. The curriculum outline was drafted and circulated for comment. Before publication, the final document was approved by those member organizations that had a policy of approving curricula. Key learning objectives of the curriculum include appreciation of the rapid advances in genetics, the need for lifelong learning, the need for referral, and the role of genetic counselors and medical geneticists, as well as developing the ability to construct and analyze a three-generation pedigree. A wide variety of teaching methods can be useful in these regards, including didactic lectures, multimedia CD- ROMs, and clinical experience. Teaching should be related to clinical experiences whenever possible. The curriculum developed by the committee and presented in this article will assist in teaching residents the attitudes, knowledge, and skills they will require.

Accreditation↗
PubMedDate not supplied

Leg-length discrepancy and scoliosis in Marfan syndrome.

Leg-length discrepancy (LLD) greater than 2 cm is rare in the general population and is associated with a lumbar postural scoliosis; it has not been studied in the setting of Marfan syndrome. Thirteen LLDs of 2 cm or more were recorded from a group of 250 Marfan patients visiting a medical genetics clinic for complete care. Diagnosis was confirmed by standing anteroposterior pelvic radiograph and/or scanogram. Records and anteroposterior radiographs of the spine were reviewed to obtain Cobb angles for spinal curvatures. A mean discrepancy of 3.2 +/- 1.0 cm and a Cobb angle of 37.0 degrees +/- 28.4 degrees were found. Twelve of 13 curves were convex toward the shorter leg, caudally. Twelve patients had scoliosis greater than 10 degrees. Five curves were severe and progressive, suggesting the need for spinal fusion and prior equalization of leg lengths. LLD correlated weakly with Cobb angle. LLD is more common in individuals with Marfan syndrome than in the general population and is associated with increased structural scoliosis.

Adolescent↗