[Show abstract][Hide abstract] ABSTRACT: Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome.
Fifteen families were identified with multiple members with TAAs/dissections. DNA from affected members from 2 of the families was used for a genome-wide search for the location of the defective gene by use of random polymorphic markers. The data were analyzed by the affected-pedigree-member method of linkage analysis. This analysis revealed 3 chromosomal loci with multiple markers demonstrating evidence of linkage to the phenotype. Linkage analysis using further markers in these regions and DNA from 15 families confirmed linkage of some of the families to 5q13-14. Genetic heterogeneity for the condition was confirmed by a heterogeneity test. Data from 9 families with the highest conditional probability of being linked to 5q were used to calculate the pairwise and multipoint logarithm of the odds (LOD) scores, with a maximum LOD of 4.74, with no recombination being obtained for the marker D5S2029. In 6 families, the phenotype was not linked to the 5q locus.
A major locus for familial TAAs and dissections maps to 5q13-14, with the majority (9 of 15) of the families identified demonstrating evidence of linkage to this locus. The condition is genetically heterogeneous, with 6 families not demonstrating evidence of linkage to any loci previously associated with aneurysm formation.
[Show abstract][Hide abstract] ABSTRACT: We describe the case of a 13-year-old girl with an apparently de novo unbalanced translocation resulting in the presence of additional chromosomal material on the short arm of one X chromosome, which was detected by conventional G-banding studies. Fluorescence in situ hybridization (FISH) using the Chromoprobe Multiprobe-M protocol confirmed that the additional chromosomal material originated from chromosome 5. The karyotype of this patient is now established to be 46,X,der(X) t(X;5)(p22.3;q33), with a deletion of Xp22.3-pter and partial trisomy of 5q33-qter. The distal 5q trisomy genotype has been associated with clinical signs that include growth and mental retardation, eczema, craniofacial anomalies, and malformations of heart, lungs, abdomen, limbs, and genitalia. Our patient also has short stature, a prominent nasal bridge, a flat philtrum, a thin upper lip, dental caries, and limb and cardiac malformations, but she appears to be mildly affected compared with previously reported cases. This is the first case of distal 5q trisomy arising from a translocation with the X chromosome. Replication studies on this patient show that the derivative t(X;5) chromosome is late replicating in almost all cells examined, which indicates that this chromosome is preferentially inactivated. However, the translocated segment of chromosome 5 appears to be early replicating, which implies that the trisomic 5q segment is transcriptionally active. We cannot determine from these studies whether all or only some genes in this segment are expressed, but this patient's relatively mild clinical signs suggest that the critical region(s) that contribute to the distal 5q trisomy phenotype are at least partly suppressed. A review of other patients with X-chromosome translocations indicates that many but not all of them also have attenuated phenotypes. The mechanism of inactivation of autosomal material attached to the X chromosome is complex, with varying effects on the phenotype of the patients that depend on the nature of the autosomal chromatin. Replication studies are of limited utility in predicting expression of autosomal genes involved in X-chromosome translocations.
Preview · Article · Nov 2000 · American Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: Thoracic aortic aneurysms and dissections can occur in families with autosomal dominant inheritance. Mutations in the fibrillin-1 gene on chromosome 15 cause Marfan syndrome (MFS), a known cause of familial aortic aneurysms and dissections. Affected individuals have phenotypic stigmata involving the skeletal, ophthalmologic and other systems. Mutations in the type III procollagen gene cause the vascular type of Ehlers-Danlos syndrome (EDS IV), which can include aneurysms that involve the aorta and other arteries, but account for a small minority of aortic aneurysms. Affected individuals have characteristic skin and joint findings. Families with no external phenotypic stigmata of connective tissue disorders have been reported as cases of Erdheim disease or annuloaortic ectasia. The causative gene(s) have not yet been identified.
Preview · Article · Jan 2000 · Genetics in Medicine
[Show abstract][Hide abstract] ABSTRACT: Fibroblast growth factor receptor (FGFR) mutations have been found in craniosynostosis syndromes with and without limb and/or dermatologic anomalies. Ocular manifestations of FGFR2 syndromes are reported to include shallow orbits, proptosis, strabismus, and hypertelorism, but no ocular anterior chamber, structural abnormalities have been reported until now. We evaluated three unrelated patients with severe Crouzon or Pfeiffer syndrome. Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles. Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present. These patients had airway compromise, seizures, and two died by age 15 months. All three cases were found to have the same FGFR2 Ser351Cys (1231C to G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding. Seven patients with isolated Peters anomaly, two patients with Peters plus syndrome, and three cases with typical Antley-Bixler syndrome were screened for this mutation, but none was found. These phenotype/genotype data demonstrate that FGFR2 is involved in the development of the anterior chamber of the eye and that the Ser351Cys mutation is associated with a severe phenotype and clinical course.
Full-text · Article · Aug 1999 · American Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: We report on a family with severe X-linked mental retardation (XLMR) and progressive, severe central nervous system deterioration. Three of the five affected males died of secondary complications before the age of 10 years and none have survived past the age of 10. These complications included swallowing dysfunction and gastroesophageal reflux with secondary recurrent respiratory infections. In addition, hypotonia and a mild myopathy were also present. All had a characteristic facies, including downslanting palpebral fissures, hypertelorism, and a short nose with a low nasal bridge. The two older boys showed cerebral atrophy by CT. No metabolic abnormalities were identified. Three obligate carriers had an IQ less than 80. The causal gene has been localized distal to DXS8103 in Xq28, a region spanning 5cM. No other XLMR disorder with these manifestations have been localized to this region and this appears to be a new disorder.
No preview · Article · Aug 1999 · American Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: The Smith-Lemli-Opitz syndrome, characterized by limb, face and organ abnormalities, and mental retardation, is caused by an inherited block in the step of cholesterol biosynthesis in which the delta 7 double bond of 7-dehydrocholesterol is reduced. It is diagnosed by the presence of markedly elevated levels of 7-dehydrocholesterol and 8-dehydrocholesterol in plasma and tissue. We measured amniotic fluid sterols in 15 pregnancies in 13 women who had previously carried an affected fetus. Cholesterol, 7-dehydrocholesterol and 8-dehydrocholesterol concentrations averaged 18 +/- 3, 9.8 +/- 2.9 and 5.0 +/- 1.7 micrograms/ml, respectively, in seven pregnancies with an affected fetus or child. In contrast, these levels were 19 +/- 3, 0.05 +/- 0.01 and < 0.005 micrograms/ml, respectively, in eight increased-risk pregnancies with normal outcomes and 16 +/- 2, 0.07 +/- 0.01 and < 0.005 micrograms/ml in normal controls. 7-dehydrocholesterol concentrations, 2.2-26 and 0.05-0.10 micrograms/ml in pregnancies with an affected and unaffected fetus, respectively, did not overlap. Thus, abnormally elevated amniotic fluid dehydrocholesterol concentrations are an accurate predictor of fetal Smith-Lemli-Opitz syndrome. A false-positive or a false-negative result is highly unlikely.
No preview · Article · Jul 1998 · Prenatal Diagnosis
[Show abstract][Hide abstract] ABSTRACT: We describe 13 unrelated children with abnormalities of somatic growth, face, brain, and connective tissue including vasculature. Although the condition in these children falls under the general group of disorders known as cutis marmorata telangiectatica congenita (CMTC), the constellation of abnormalities appears to constitute a distinct and easily recognizable phenotype within this general group. In contrast to most children reported with CMTC, children in this subgroup have a high risk for neurologic abnormalities, including developmental delay, mental retardation, megalencephaly, and hydrocephalus. Early recognition of this condition is important for appropriate surveillance for known complications and parental counseling.
No preview · Article · Jun 1997 · American Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: We describe an infant with homozygous alpha-thalassemia, genital abnormalities, and terminal transverse limb defects, whose limbs demonstrate evidence of loss of tissue and abnormal morphogenesis. We propose these defects were due to either severe fetal anemia or to vascular occlusion by abnormal erythrocytes, resulting in hypoxia of the developing distal limbs and genitalia.
No preview · Article · Feb 1997 · American Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: We have used bivariate flow karyotyping to quantify the deletions involving chromosome 17 in sixteen patients with Smith-Magenis syndrome (SMS). The fluorescence intensities of mitotic chromosomes stained with Hoechst 33258 and chromomycin were quantified in a dual-beam flow cytometer. For each patient, the position of the peak representing the deleted chromosome 17 was compared to those of the normal homologs of an unaffected parent. The patients could be classified into four groups based on the size of their deletions. The deletions ranged from approximately 9-10 Mb (approximately 10-11% of the chromosome) to below the detection limit of the technique (2 Mb). Different deletion sizes were detected among patients whose high-resolution banding results were similar. Some deletions detected by banding were not detected by flow analyses. Deletion estimates are largely consistent with the results of molecular analyses. Patients with larger deletions that extend into band 17p 12 have abnormal electrophysiologic studies of peripheral nerves. Deletion size does not appear to correlate with the degree of mental retardation, presence of behavioral abnormalities, craniofacial anomalies or common skeletal findings in SMS. By identifying patients with varying deletion sizes, these data will aid the construction of a long-range deletion-based map of 17p11.2 and identification of the genes involved in this syndrome.
[Show abstract][Hide abstract] ABSTRACT: Autopsy records from the Women and Infants' Hospital from January 1974 through January 1994 were reviewed to identify cardiac malformations in the presence of skeletal dysplasia. Of 24 cases of lethal fetal or neonatal osteochondrodysplasias, 4 were given diagnoses in which disorders of type II collagen are regarded as causative. These 4 were categorized in the spondyloepiphyseal dysplasia (SED) spectrum of disorders; specifically two patients with hypochondrogenesis and two with spondyloepiphyseal dysplasia congenita were identified. Defects in cardiac septation were noted in the 2 patients with hypochondrogenesis. No cardiovascular abnormalities were present in the remaining cases, which included thanatophoric dysplasia, osteogenesis imperfecta, and asphyxiating thoracic dystrophy.
Although cardiovascular malformations have been described in other types of osteochondrodysplasias, e.g., short rib polydactyly syndrome type II and chondroectodermal (Ellis van Creveld) dysplasia, congenital heart disease has not been described in hypochondrogenesis. Type II collagen, which has been found to be abnormal in some patients with hypochondrogenesis, is considered to have a limited tissue distribution, and has not been detected as yet in human myocardium. The findings presented here suggest that type II collagen may function in human cardiogenesis.
No preview · Article · Nov 1995 · American Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: To determine whether type I and the more severe type II variant of Smith-Lemli-Opitz syndrome have the same metabolic defect and to learn which plasma sterol measurements best predict survival.
Plasma sterols were measured in 33 individuals (24 type I, 9 type II) with a clinical diagnosis of the syndrome.
Cholesterol levels were abnormally low (61 +/- 34 mg/dl) in type I subjects, whereas concentrations of the cholesterol precursor 7-dehydrocholesterol and its isomer 8-dehydrocholesterol were elevated 40- to 10,000-fold. Plasma cholesterol levels were significantly lower and total dehydrocholesterol levels higher in type II than in type I. Six children with the type II variant died by 13 weeks with mean plasma cholesterol levels 6.2 +/- 3.1 mg/dl, versus 17 +/- 11 mg/dl in the three surviving children with type II (p < 0.05). No child with a cholesterol level 7 mg/dl or less lived longer than 13 weeks.
Patients with type I and type II variants of Smith-Lemli-Opitz syndrome have markedly reduced activity of the enzyme that converts 7-dehydrocholesterol to cholesterol, but the extent of the block is far more complete in type II. Survival correlates strongly with higher plasma cholesterol concentrations.
No preview · Article · Aug 1995 · Journal of Pediatrics
[Show abstract][Hide abstract] ABSTRACT: Cholesta-5,8-dien-3 beta-ol (8-dehydrocholesterol) and cholesta-5,7-dien-3 beta-ol (7-dehydrocholesterol) were isolated from the fecal neutral sterol fraction from homozygotes with Smith-Lemli-Opitz syndrome. The structures of the sterols were conclusively established from their mass spectra and 1H and 13C nuclear magnetic resonance spectra. It is probable that 8-dehydrocholesterol arises from 7-dehydrocholesterol and is not a direct precursor of cholesterol.
Full-text · Article · May 1995 · The Journal of Lipid Research
[Show abstract][Hide abstract] ABSTRACT: The Smith-Lemli-Opitz (SLO or RSH) syndrome is an autosomal recessive disorder characterized by a recognizable pattern of minor facial anomalies, congenital anomalies of many organs, failure to thrive, and mental retardation. Its cause is a defect in cholesterol biosynthesis characterized by abnormally low plasma cholesterol levels and concentrations of the cholesterol precursor 7-dehydrocholesterol (7DHC) elevated up to several thousand-fold above normal. We used capillary column gas-chromatography to quantify sterols in amniotic fluid, amniotic cells, plasma, placenta, and breast milk from a heterozygous mother who had previously given birth to an affected son and in cord blood and plasma from her affected newborn daughter. The cholesterol concentration in amniotic fluid at 16 weeks gestation was normal, but 7DHC, normally undetectable, was greatly elevated. In cultured amniocytes, the level of 7DHC was 11% of total cholesterol, similar to cultured fibroblasts from patients with SLO syndrome. At 38 weeks, a girl with phenotype consistent with the syndrome was born. Cholesterol concentrations were abnormally low in cord blood and in the baby's plasma at 12 weeks, while levels of 7DHC were grossly elevated, confirming the prenatal diagnosis. The mother's plasma cholesterol increased steadily during gestation but remained below the lower 95% limit reported for normal control women. We conclude that it is now possible to detect the SLO syndrome at 16 weeks gestation by analyzing amniotic fluid sterols.
No preview · Article · Apr 1995 · American Journal of Medical Genetics