Genetic heterogeneity in Wilson disease: lessons from rare alleles.
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Alleles↗
Biomedical subjects
R E Pyeritz
Publications and source records attributed to R E Pyeritz.
The cervical spine in Marfan syndrome.
STUDY DESIGN: Prospective radiographic and clinical analysis of a consecutive unselected population of persons with Marfan Syndrome. OBJECTIVES: To determine cervical spine abnormalities present in the Marfan population compared with that seen in the general population. SUMMARY OF BACKGROUND DATA: In the treatment of a large population of patients with Marfan Syndrome, three serious cervical spine disorders were noted. To the authors' knowledge, no report of cervical abnormalities in patients with Marfan Syndrome exists in the literature. Therefore, the cervical spine in these patients was studied in a systematic fashion. METHODS: An unselected group of 104 consecutive patients with Marfan Syndrome seen at a medical genetics follow-up examination underwent lateral neutral and flexion-extension cervical spine radiographs. Parameters of alignment, size, and stability were measured. Patients with Marfan Syndrome aged 35-45 years and matched controls were given a pain questionnaire to complete. RESULTS: The prevalence of focal kyphosis was 16%. A large number of patients with Marfan Syndrome (54%) had increased atlantoaxial translation. The preadolescent Marfan population has a greater range of motion than either the adolescent or adult populations. The Marfan population has an increased radiographic prevalence of basilar impression (36%), and the odontoid height (3.69 +/- 0.53 cm) was larger than reported norms (2.34 +/- 0.22 cm). Cervical stenosis was rare, with 3% having a critical Torg ratio at C3 and 2% having a critical Torg ratio at C6. Neck pain frequency did not differ significantly from that of age-matched controls. CONCLUSION: Based on the increased prevalence of several cervical bony and ligamentous abnormalities, patients with Marfan Syndrome were recommended to avoid sports with risks of high-impact loading of the cervical spine. Given the rarity of actual neurologic injuries in the Marfan population, however, radiographs for all patients with Marfan Syndrome undergoing general anesthesia is not recommended.
Adolescent↗
Infantile scoliosis in Marfan syndrome.
STUDY DESIGN: A retrospective review of clinical data was conducted. OBJECTIVES: To determine the characteristics of infantile scoliosis in Marfan syndrome and the response to treatment of patients with this condition. SUMMARY OF BACKGROUND DATA: No previous study has reported the features of this condition nor the effect of treatment on patients with this syndrome. METHODS: The data on all patients seen at one institution who had Marfan syndrome and scoliosis by age three were reviewed. Fourteen of the 600 patients from the group examined who had Marfan syndrome fit the above criteria. Skeletal and general features were studied. RESULTS: Thirteen of the 14 patients had no family history of Marfan syndrome, a finding which does not fit the usual autosomal dominant inheritance pattern. All 14 patients had exaggeration of the Marfan. All but one patient had cardiac valvular insufficiency that required repair by age 11. Thirteen patients had thoracic aortic aneurysm, 10 had lens dislocation, and eight had sternal deformity. Three patients had hip dislocations, two had pyloric stenosis, and two had dural ectasia. Motor delay was evidenced by onset of walking past 18 months in nine patients; three of these patients were never able to walk independently. One patient each died at ages 1, 3, 4, and 8 years; all others have survived to present (mean age, 13 years). The mean curve of the patients' spines at presentation was 38 degrees. Eleven curves were double major, two were thoracolumbar, and one was double thoracic. Brace wear did not halt curve progression in any of the nine patients for whom it was used. Instrumentation without fusion was used in three patients for a mean of 3 years, with best results in one nonkyphotic curve. Nine patients underwent instrumented fusion at a mean age of 6.6 years (range, 3-13 years). Mean curve correction was 51% (from 72 degrees to 34 degrees). Final mean curve was 54 degrees for a mean correction of 20% at the 5-year (average, 5.4 years) follow-up examination. Acute complications occurred in three patients, and five patients needed a second surgery for late complications. Causes for curve increase after surgery included growth and loss of fixation. CONCLUSIONS: In this most severe form of Marfan syndrome, bracing has a limited role and is only to be used if the curve is less than 40 degrees. Surgery should not be performed on a patient younger than four years of age because many patients with large curves before this age will succumb spontaneously to cardiac complications. Instrumentation without fusion should be considered only for patients with no significant kyphosis. Results of fusion are better for patients who are older than five years of age.
Adolescent↗
Fine mapping of the nail-patella syndrome locus at 9q34.
Nail-patella syndrome (NPS), or onychoosteodysplasia, is an autosomal dominant, pleiotropic disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns, and nephropathy. Previous studies have demonstrated linkage of the nail-patella locus to the ABO and adenylate kinase loci on human chromosome 9q34. As a first step toward isolating the NPS gene, we present linkage analysis with 13 polymorphic markers in five families with a total of 69 affected persons. Two-point linkage analysis with the program MLINK showed tight linkage of NPS and the anonymous markers D9S112 (LOD = 27.0; theta = .00) and D9S315 (LOD = 22.0; theta = .00). Informative recombination events place the NPS locus within a 1-2-cM interval between D9S60 and the adenylate kinase gene (AK1).
Chromosome Mapping↗
The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16.
Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.
Brazil↗
Revised diagnostic criteria for the Marfan syndrome.
In 1986, the diagnosis of the Marfan syndrome was codified on the basis of clinical criteria in the Berlin nosology [Beighton et al., 1988]. Over time, weaknesses have emerged in these criteria, a problem accentuated by the advent of molecular testing. In this paper, we propose a revision of diagnostic criteria for Marfan syndrome and related conditions. Most notable are: more stringent requirements for diagnosis of the Marfan syndrome in relatives of an unequivocally affected individual; skeletal involvement as a major criterion if at least 4 of 8 typical skeletal manifestations are present; potential contribution of molecular analysis to the diagnosis of Marfan syndrome; and delineation of initial criteria for diagnosis of other heritable conditions with partially overlapping phenotypes.
Humans↗
The Marfan syndrome and the cardiovascular surgeon.
The authors present the current status of surgery for the cardiovascular manifestations of the Marfan syndrome. In addition, a brief review of current Marfan genetic research is presented. Data on all Marfan patients undergoing aortic root replacement at the Johns Hopkins Hospital (September 1976-June 1995) were analyzed. Survival and event-free curves were calculated and risk factors for early and late death were determined by univariate and multivariate analysis. Two hundred twelve Marfan patients underwent aortic root replacement using composite graft (202), homograft (8) or valve-sparing procedures (2). One hundred eighty-five patients underwent elective repair with no 30-day mortality. Twenty-seven patients underwent urgent surgery, primarily for acute dissection; two patients with aortic rupture died in the operating room. Actuarial survival of the 212 patients was 88% at 5 years, 78% at 10 years and 71% at 14 years. By multivariate analysis, only poor NYHA class, male gender and urgent surgery emerged as significant independent predictors of early or late mortality. Histologic examination of excised Marfan aortic leaflets by immunofluorescent staining for fibrillin showed fragmentation of elastin-associated microfibrils. These studies suggest cautious use of valve-sparing procedures in Marfan patients. Over the last 5 years significant progress has been made in identifying mutant genes that code for defective fibrillin microfibrils in Marfan patients. Attempts are underway to develop animal models of Marfan disease for study of possible gene therapy. Aortic root replacement can be performed in Marfan patients with operative risk under 5%. Long-term results are gratifying. At present, valve-sparing procedures should be used cautiously in Marfan patients because of fibrillin abnormalities in the preserved aortic valve leaflets.
Adolescent↗
Professional healthcare workers' attitudes toward treating patients with multidrug-resistant tuberculosis.
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Attitude of Health Personnel↗
Interstitial deletion of the long arm of chromosome 6 associated with unusual limb anomalies: report of two new patients and review of the literature.
We report on unusual manifestations in 2 unrelated children with interstitial deletion of 6q, with nearly identical breakpoints of 6q16.2q23.1 and 6q16.3q22.3. Major findings include growth retardation, profound developmental delay, microcephaly, facial anomalies, sparse hair, congenital heart defects, and striking hand malformations. Discordant anomalies were duodenal atresia and hypoplastic genitalia in 1 child. Split-hand defect, polydactyly, gastrointestinal anomalies, and ectodermal dysplasia have not been described previously in children with 6q deletion. The presence of hand malformations in 2 children with similar deletion breakpoints strongly suggests that this is a candidate region for one or more genes involved in limb development. Comparison of the clinical findings of other patients with 6q2 deletion suggests a recognizable phenotype.
Chromosome Banding↗
Immunohistochemical localization of fibrillin in human ocular tissues. Relevance to the Marfan syndrome.
OBJECTIVE: To better understand the ocular manifestations of the Marfan syndrome, we investigated the distribution of fibrillin in normal human ocular tissues. Fibrillin, a microfibrillar glycoprotein component of the extracellular matrix, has been found to be the defective gene product in the Marfan syndrome. METHODS: Frozen sections from seven pairs of normal eyes were stained with mouse anti-human fibrillin antibodies using the avidin-biotin immunoperoxidase technique. RESULTS: In the anterior segment, the following exhibited positive staining for fibrillin: the lens capsule and zonules; connective tissues of the iris, ciliary body, ciliary processes, and conjunctiva; and the basement membrane regions of the corneal epithelium and endothelium of Schlemm's canal. Posteriorly, fibrillin localized to the lamina cribrosa, sclera, choroid, and Bruch's membrane. CONCLUSIONS: Fibrillin is widely distributed in ocular connective tissues. The implications of defects in these tissues and the resultant ocular abnormalities in the Marfan syndrome such as ectopia lentis and glaucoma are discussed.
Aged↗
A prospective longitudinal evaluation of pregnancy in the Marfan syndrome.
OBJECTIVE: We undertook a prospective evaluation of the outcomes of pregnancy, both maternal and fetal, and the long-term impact of pregnancy on Marfan syndrome in a series of consecutive, unselected patients. STUDY DESIGN: Forty-five pregnancies in 21 Marfan syndrome patients were prospectively observed in one institution between 1983 and 1992. During pregnancy, patients were monitored with serial echocardiograms and close attention to symptoms. Maternal and fetal outcomes were monitored with serial echocardiographic data were analyzed by least-squares regression. Eighteen of the patients were followed up for 15 months to 13 years after the completion of their last pregnancy for investigation of the long-term impact of pregnancy on the cardiovascular manifestations of Marfan syndrome. RESULTS: Aortic dissection occurred in two patients, both with increased risk for dissection established before pregnancy. The incidence of obstetric complications otherwise did not exceed that in the general population. Echocardiographic data demonstrated little to no change in aortic root diameter throughout pregnancy in most patients. Long-term follow-up showed no apparent worsening of cardiovascular status attributable to pregnancy in comparison with a group of 18 women with Marfan syndrome who were of similar age, had a similar degree of disease severity, and underwent no pregnancies. CONCLUSIONS: Patients with Marfan syndrome in whom cardiovascular involvement is minor and aortic root diameter is < 40 mm usually tolerate pregnancy well, with favorable maternal and fetal outcomes, and without subsequent evidence of aggravated aortic root dilatation over time.
Abortion, Spontaneous↗
Aortic root replacement. Risk factor analysis of a seventeen-year experience with 270 patients.
Between September 1976 and September 1993, 270 patients underwent aortic root replacement at our institution. Two hundred fifty-two patients underwent a Bentall composite graft repair and 18 patients received a cryopreserved homograft aortic root. One hundred eighty-seven patients had a Marfan aneurysm of the ascending aorta (41 with dissection) and 53 patients had an aneurysm resulting from nonspecific medial degeneration (17 with dissection). These 240 patients were considered to have annuloaortic ectasia. Thirty patients were operated on for miscellaneous lesions of the aortic root. Thirty-day mortality for the overall series of 270 patients was 4.8% (13/270). There was no 30-day mortality among 182 patients undergoing elective root replacement for annuloaortic ectasia without dissection. Thirty-six of the 270 patients having root replacement also had mitral valve operations. There was no hospital mortality for aortic root replacement in these 36 patients, but there were seven late deaths. Twenty-two patients received a cryopreserved homograft aortic root; 18 of these were primary root replacements and four were repeat root replacements for late endocarditis. One early death and two late deaths occurred in this group. Actuarial survival for the overall group of 270 patients was 73% at 10 years. In a multivariate analysis, only poor New Year Heart Association class (III and IV), non-Marfan status, preoperative dissection, and male gender emerged as significant predictors of early or late death. Endocarditis was the most common late complication (14 of 256 hospital survivors) and was optimally treated by root replacement with a cryopreserved aortic homograft. Late problems with the part of the aorta not operated on occur with moderate frequency; careful follow-up of the distal aorta is critical to long-term survival.
Actuarial Analysis↗
Effect on splicing of a silent FGFR2 mutation in Crouzon syndrome.
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Base Sequence↗
Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders.
The extracellular microfibril, 10-14 nm in diameter, performs a number of functions, including serving as the scaffolding for deposition of tropoelastin to form elastic fibers. A variety of proteins compose the structure of microfibrils, the most prominent of which are the two fibrillins. Fibrillin-1 is encoded by FBN1 on human chromosome 15q21 and fibrillin-2 is encoded by FBN2 on 5q23. Each fibrillin monomer contains a large number of epidermal growth factor-like motifs, most capable of binding calcium ions, and a few motifs resembling the binding protein for transforming growth factor beta. In vitro polymerization of fibrillin monomers produces 'beads on a string' structures that look on electron microscopy much like microfibrils purified from the extracellular matrices of a variety of tissues. Mutations in FBN1 produce Marfan syndrome, a pleiotropic autosomal dominant connective tissue disorder with prominent manifestations in the skeleton, eye and cardiovascular system. A number of conditions related to Marfan syndrome are also due to FBN1 mutations. Contractural arachnodactyly is due to mutations in FBN2. In this paper we review the published mutations in these genes, preliminary results of genotype-phenotype correlations, and speculations regarding molecular pathogenesis.
Fibrillin-1↗
The Marfan syndrome: joint and skin manifestations are prevalent and correlated.
The objective of the study was to ascertain the occurrence and inter-relationships of locomotor symptoms, joint hypermobility and skin involvement in patients with the Marfan syndrome. A single clinical evaluation, using a standardized protocol, of randomly selected out-patients was made. Joint hypermobility was measured by two scales in wide clinical use (Beighton and Contompasis), skin hyperextensibility was assessed on the dorsum of the hand, and skin thickness and light transmissibility was measured at the same site with a modified Harpenden caliper. The setting was an out-patient medical genetics clinic at an urban teaching hospital in Baltimore, Maryland, USA. The subjects comprised 27 children and 48 adults who met strict diagnostic criteria for the Marfan syndrome. In patients less than 18 yr old, 70% had experienced at least one locomotor syndrome, and 40% had had multiple symptoms, of which arthralgia, myalgia and ligamentous injury were the most frequent. Symptoms were absent in children younger than 5 yr. Thereafter, the number of symptoms increased with age. Considerable joint hyperextensibility (> 3/9 of Beighton's criteria) was present in 85%. While one-third had received orthopaedic attention, there had been little if any rheumatological input. In adult patients, locomotor symptoms had occurred in 96%, with 88% having experienced more than one complaint. Spinal pain, arthralgia, ligament injury and fracture were the most common. Most (81%) of the adults had some (> 1/9), and 56% had considerable (> 2/9) evidence of joint hypermobility. Only 20% had received specialist attention for their locomotor symptoms. Skin changes are documented in the Marfan syndrome for the first time in this study.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
The thoracolumbar spine in Marfan syndrome.
We analyzed the prevalence, inheritance, progression, and functional implications of spinal deformity in Marfan syndrome using four different groups of patients. We studied 113 patients who had Marfan syndrome, eighty-two of whom were skeletally immature, in order to characterize the alignment and function of the spine. The patients were selected from a clinic that provides total care with no bias toward the presence of orthopaedic conditions. Scoliosis was identified in fifty-two of the eighty-two patients, and the prevalences for the sexes were equal. The thoracic portion of the curve was convex to the right in all but two patients. The mean kyphosis was greater than that in the general population. Five distinct sagittal profiles were identified on the basis of whether the thoracic kyphosis was within, greater than, or less than normal limits and whether the transition between the kyphosis and lordosis occurred at or caudad to the normal level or whether the curves were reversed. Spondylolisthesis was present in five patients (6 per cent), with a mean slip of 30 per cent. Fourteen pedigrees were studied in depth. There was no familial pattern of the scoliosis. A separate group of fifty-six patients with scoliosis, for whom serial follow-up radiographs were available, was studied for progression. Patients who had a curve of more than 30 degrees had mild progression, and those who had a curve of more than 50 degrees had marked progression (mean, 3 +/- 4 degrees per year). Pain and function of the back were studied in thirty patients who were thirty-five to forty-five years old; these patients were found to be more impaired than matched controls. The presence of scoliosis was associated with pain in the region of the curve in these patients.
Adolescent↗
Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons.
Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause the Marfan syndrome (MFS). This statement is supported by the observations that the classic Marfan phenotype cosegregates with intragenic and/or flanking marker alleles in all families tested and that a significant number of FBN1 mutations have been identified in affected individuals. We have now devised a method to screen the entire coding sequence and flanking splice junctions of FBN1. On completion for a panel of nine probands with classic MFS, six new mutations were identified that accounted for disease in seven (78%) of nine patients. Nine additional new mutations have been characterized in the early stages of a larger screening project. These 15 mutations were equally distributed throughout the gene and, with one exception, were specific to single families. One-third of mutations created premature termination codons, and 6 of 15 substituted residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. Mutations causing severe and rapidly progressive disease that presents in the neonatal period can occur in a larger region of the gene than previously demonstrated, and the nature of the mutation is as important a determinant as its location, in predisposing to this phenotype.
Base Sequence↗
Effect of beta-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome.
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Adolescent↗