elastin and Abnormalities--Multiple

To explore the clinical and genetic characteristics of Williams-Beuren syndrome (WBS) and to raise awareness of the disease. The characteristics of clinical manifestations, personal history, cardiac ultrasound, brain magnetic resonance imaging (MRI), electroencephalogram (EEG) and chromosome detection results of two cases with WBS were analyzed. The two patients were both male and the age was 11 months and 1 day, and 9 months and 9 days, respectively. They both suffered from cardiovascular malformation: case one presented supravalvular aortic stenosis, and case two showed atrial septal defect and patent ductus arteriosus. Both of the cases were exhibited characteristic facial features of WBS, including full orbital, spherical nose, flat nasal bridge, long philtrum and thick lips. For the mental development, case one displayed moderate to severe developmental retardation, and case two showed severe developmental retardation. In addition, case one presented bilateral indirect inguinal hernia and hydrocele, and case two manifested feeding difficulties, buried penis and infantile spasms. Personal history: case one's mother had tocolytic therapy during pregnancy period, and case one was born at full-term by cesarean section due to amniotic fluid pollution. Supplementary examination: brain MRI of the two cases were no significant abnormalities; the EEG of case two showed hypsarrhythmia, and the epileptic spasms were recorded. Chromosome detection results: case one was identified as 7q11.23 deletion including the fragment deletion mutation of elastin (ELN) gene by multiplex ligation dependent probe amplification method, and case two was found with 7q11.21q11.23 deletion by high resolution G-band method. The two cases with WBS both had cardiovascular malformations, special facial features, mental retardation and connective tissue or urinary system abnormality. The supravalvular aortic stenosis of case one may be associated with the deletion of ELN gene, and the occurrence of epilepsy of case two may be related to the q11.21 deletion beyond the 7q11.23 region.

Topics: Abnormalities, Multiple; Cesarean Section; Chromosomes, Human, Pair 7; Elastin; Epilepsy; Female; Humans; Male; Pregnancy; Sequence Deletion; Williams Syndrome

Topics: Abnormalities, Multiple; Beckwith-Wiedemann Syndrome; Child, Preschool; Chromosome Duplication; Chromosomes, Human, Pair 11; Cleft Lip; Cleft Palate; Costello Syndrome; Cutis Laxa; Elastin; Female; Humans; Hydrocephalus; Karyotype; Proto-Oncogene Proteins p21(ras)

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the last step in proline synthesis. Deficiency of PYCR1, caused by a defect in PYCR1, was recently described in patients with cutis laxa, intrauterine growth retardation, developmental dysplasia of the hips and mental retardation. In this paper, we describe additional six patients (ages ranging from 4 months to 55 years) from four Iranian families with clinical manifestations of a wrinkly skin disorder. All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose. Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints. Three of the patients from a large consanguineous family do not have mental retardation, while the remaining three patients from three unrelated families have mental and developmental delay. Mutation analysis revealed the presence of disease-causing variants in PYCR1, including a novel deletion of the entire PYCR1 gene in one family, and in each of the other patients the homozygous missense mutations c.616G > A (p.Gly206Arg), c.89T > A (p.Ile30Lys) and c.572G > A (p.Gly191Glu) respectively, the latter two of which are novel. Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size. In conclusion, this study adds information on the natural course of PYCR1 deficiency and sheds light on the pathophysiology of this disorder. However, the exact pathogenesis of this new disorder and the role of proline in the development of the clinical phenotype remain to be fully explained.

Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Collagen; delta-1-Pyrroline-5-Carboxylate Reductase; DNA Mutational Analysis; Elastin; Family; Female; Humans; Infant; Male; Metabolism, Inborn Errors; Middle Aged; Models, Biological; Mutation, Missense; Phenotype; Proline; Pyrroles; Pyrroline Carboxylate Reductases; Young Adult

Topics: Abnormalities, Multiple; Adolescent; Collagen; Dermis; Elastin; Female; Foot Deformities, Congenital; Golgi Apparatus; Hand Deformities, Congenital; Humans; Infant, Newborn; Male; Pregnancy; Protein Transport; Syndrome

Costello syndrome is a connective tissue disorder associated with sparse, thin, and fragmented elastic fibers in tissues. In this study we demonstrated a significant decrease in the expression of tropoelastin mRNA in fibroblasts derived from a Japanese Costello syndrome patient with impaired elastogenesis and enhanced proliferation. In contrast, there were no changes in expression of the Harvey ras (HRAS), fibrillin-1, fibulin-5, microfibril-associated glycoprotein-1 (MAGP-1), lysyl oxidase (LOX), or 67-kDa non-integrin elastin-binding protein (EBP) gene. The proliferative activity of the Costello fibroblasts was about 4-fold higher than that of the normal and pathological control ones. However, no mutations were detected in the coding region of HRAS mRNA. Transduction of the bovine tropoelastin (bTE) gene with the lentiviral vector restored the elastic fiber formation and decreased the growth rate in the Costello fibroblasts. These results strongly suggest that the defect of human tropoelastin (hTE) gene expression should induce the impaired elastogenesis and enhanced proliferation of Costello fibroblasts, and that a primary cause other than the HRAS gene mutation should contribute to the pathogenesis in the present Costello case.

Topics: Abnormalities, Multiple; Adolescent; Animals; Asian People; Cattle; Cell Proliferation; Connective Tissue Diseases; DNA, Complementary; Elastin; Female; Fibroblasts; Gene Expression Regulation; Humans; RNA, Messenger; Skin; Transduction, Genetic; Tropoelastin

Topics: Abnormalities, Multiple; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 7; Elastin; Female; Gene Deletion; Humans; Male; Microsatellite Repeats; Pedigree; Spasm; Syndrome; Williams Syndrome

Topics: Abnormalities, Multiple; Calcium-Binding Proteins; Child; Child, Preschool; Cleft Palate; Contractile Proteins; Cutis Laxa; Elastin; Extracellular Matrix Proteins; Face; Family Health; Fatal Outcome; Female; Genetic Linkage; Haplotypes; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Microsatellite Repeats; Pedigree; Protein-Lysine 6-Oxidase; Skin; Syndrome

In 1968, De Barsy reported on a girl exhibiting an aged aspect, 'dwarfism, oligophrenia, and degeneration of the elastic tissue in cornea and skin'. The disorder was recognized as a subgroup of cutis laxa syndrome and termed De Barsy-Moens-Dierckx syndrome. The pathogenesis of the disorder is unknown.. To improve the comprehension of the pathogenetic mechanisms involved in the De Barsy syndrome, we performed an ultrastructural, morphometric, immunocytochemical study on a skin biopsy of a boy with the De Barsy phenotype, who has been clinically followed for 12 years from birth. Moreover, the lysyl oxidase activity was measured on skin fibroblasts cultured in vitro.. Light and electron microscopy, morphometry, and immunocytochemical observations showed a significant reduction of the elastic fibers in the papillary and in the reticular dermis of patient compared to an age-matched control (p < 0.05). By contrast, the collagen structure, content, and the distribution were normal, as well as lysyl oxidase activity in the medium of in vitro fibroblasts (12,323 DPM/10(6) cells). The immunoreaction for antibodies recognizing fibrillin-1, neutrophilic elastase, and tumor necrosis factor-alpha was stronger, whereas that for antibodies against transforming growth factor-beta was less pronounced in the dermis of the De Barsy boy compared to control.. Clinical, phenotypic, and structural data were consistent with the diagnosis of De Barsy syndrome. This is the first case described in Italy. Clinical and structural data confirm that the elastic component is mostly affected in this disorder. Moreover, ultrastructural and immunochemical findings suggest that both elastic fiber degradative and very likely synthetic processes are involved.

Topics: Abnormalities, Multiple; Cells, Cultured; Child; Child, Preschool; Elastin; Fibroblasts; Humans; Immunohistochemistry; Infant; Infant, Newborn; Male; Microscopy, Electron; Progeria; Protein-Lysine 6-Oxidase; Skin; Skin Abnormalities; Syndrome

Topics: Abnormalities, Multiple; DNA; DNA Mutational Analysis; Elastin; Growth Disorders; Humans; Intellectual Disability; Polymorphism, Single-Stranded Conformational; Syndrome

The form and function of the heart are the final result of an integration of cells, tissues, and extracellular material. The extracellular matrix (ECM) is a complex array of different molecular components, and it plays an important role for the transfer of mechanical force in both contraction and relaxation phases in the cardiac cycle. ECM plays also a significant role in the development of the heart. The aim of this study was to evaluate the expression of important ECM components in the heart of rats with induced CDH to test the hypothesis that an alteration of ECM may contribute to the cardiac maldevelopment, which recently has been identified as a contributive factor for the high mortality rate in babies with congenital diaphragmatic hernia (CDH).. CDH model was induced in pregnant rats after administration of 100 mg of nitrofen on day 9.5 of gestation (term, 22 days). In control animals the same dose of olive oil was given without nitrofen. Cesarean section was performed on day 21 of gestation. The fetuses were divided into 2 groups: normal control (n = 10) and nitrofen-induced CDH (n = 10). Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of tropoelastin and alpha1 (I) procollagen mRNA expression. Elastin protein content was measured using enzyme-linked immunosorbent assay (ELISA).. There was a reduction in tropoelastin mRNA (P <.05) and procollagen mRNA (P <.05) in CDH compared with controls. The cardiac alpha-elastin content also was reduced in CDH (P <.01).. The reduced cardiac tropoelastin and procollagen gene expression and the reduced alpha-elastin content indicate that the heart in CDH structurally is immature. The reduced production of cardiac ECM may contribute to a contractile dysfunction, which makes the heart unable to respond to the hemodynamic load accompanying persistent pulmonary hypertension (PPH).

Topics: Abnormalities, Multiple; Actins; Animals; Disease Models, Animal; Elastin; Enzyme-Linked Immunosorbent Assay; Fetal Organ Maturity; Heart; Heart Defects, Congenital; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Phenyl Ethers; Procollagen; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Tropoelastin

Costello syndrome is characterized by mental retardation, loose skin, coarse face, skeletal deformations, cardiomyopathy, and predisposition to numerous malignancies. The genetic origin of Costello syndrome has not yet been defined. Using immunohistochemistry and metabolic labeling with [3H]-valine, we have established that cultured skin fibroblasts obtained from patients with Costello syndrome did not assemble elastic fibers, despite an adequate synthesis of tropoelastin and normal deposition of the microfibrillar scaffold. We found that impaired production of elastic fibers by these fibroblasts is associated with a functional deficiency of the 67-kD elastin-binding protein (EBP), which is normally required to chaperone tropoelastin through the secretory pathways and to its extracellular assembly. Metabolic pulse labeling of the 67-kD EBP with radioactive serine and further chase of this tracer indicated that both normal fibroblasts and fibroblasts from patients with Costello syndrome initially synthesized comparable amounts of this protein; however, the fibroblasts from Costello syndrome patients quickly lost it into the conditioned media. Because the normal association between EBP and tropoelastin can be disrupted on contact with galactosugar-bearing moieties, and the fibroblasts from patients with Costello syndrome revealed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 and biglycan), we postulate that a chondroitin sulfate may be responsible for shedding EBP from Costello cells and in turn for their impaired elastogenesis. This was further supported by the fact that exposure to chondroitinase ABC, an enzyme capable of chondroitin sulfate degradation, restored normal production of elastic fibers by fibroblasts from patients with Costello syndrome. We also present evidence that loss of EBP from fibroblasts of Costello syndrome patients is associated with an unusually high rate of cellular proliferation.

Topics: Abnormalities, Multiple; Adolescent; Biglycan; Biopolymers; Cell Division; Cells, Cultured; Child; Child, Preschool; Chondroitin ABC Lyase; Chondroitin Sulfates; Culture Media, Conditioned; Elastin; Extracellular Matrix Proteins; Fibroblasts; Humans; Hyaluronan Receptors; Infant; Infant, Newborn; Molecular Chaperones; Molecular Weight; Proteoglycans; Receptors, Cell Surface; Syndrome; Tropoelastin

We report a case of Costello syndrome. A 2-year-old Japanese boy presented with a 'coarse' face, curly hair and loose skin of the dorsal aspect of the hands and feet with dark pigmentation. A skin biopsy of the dorsal aspect of the left hand revealed hyperkeratosis and papillomatosis of the epidermis, hyperpigmentation of the basal layer, and shortening and rupture of elastic fibers of the dermis. Electron microscopy of dermal elastic fibers showed a decreased amount of elastin with an exposed appearance of microfibrils. In Northern blot analysis of cultured dermal fibroblasts, elastin mRNA levels were reduced, suggesting a decrease in elastin production at the lesions of loose skin.

Topics: Abnormalities, Multiple; Blotting, Northern; Cells, Cultured; Child, Preschool; Elastin; Face; Fibroblasts; Gene Expression; Humans; Male; Microscopy, Electron; RNA, Messenger; Skin; Skin Abnormalities

Clinical and pathological observations of a 6-month-old-boy with Costello syndrome are reported. The main clinical findings were loose skin of the neck, hands, and feet, deep palmar and plantar creases, typical "coarse" face with thick lips and macroglossia, relative macrocephaly, mental retardation, short stature, arrhythmia, large size for gestational age, and poor feeding. At age 6 months he died of rhabdomyolysis. The major pathological findings were fine, disrupted, and loosely-constructed elastic fibers in the skin, tongue, pharynx, larynx, and upper esophagus, but not in the bronchi, alveoli, aorta, or coronary arteries. Hyperplasia of collagen fibers in the skin, hyperplasia of the mucous glands in the bronchus, narrowing of the pulmonary artery, degeneration of the atrial conduction system, calcification and ballooning of skeletal muscle fibers with infiltration of macrophages, and myoglobin depositions in the collecting ducts in the kidney were also observed. The degeneration of elastic fibers was confirmed in the skin of a second Costello syndrome patient. Expression of elastin mRNA in the patient's fibroblasts was normal in size and amount. Given that elastic fiber degeneration was observed in the tissues with clinical symptoms, we speculate that a defect of elastic fibers, possibly relating to alternative splicing in the elastin gene or to defects in elastin microfibrils, might be involved in the pathogenesis of Costello syndrome.

Topics: Abnormalities, Multiple; Adult; Child, Preschool; Developmental Disabilities; Elastic Tissue; Elastin; Female; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Pregnancy; RNA, Messenger; Syndrome

To correlate presence or absence of a 7q11 microdeletion with the clinical picture of the Williams-Beuren syndrome (WBS), we investigated 29 patients with a clinical diagnosis of WBS or WBS-like features, aged 1-30 years, using molecular analysis and/or fluorescent in situ hybridization (FISH). Deletions at 7q11 were found in 75% of the patients (22 out of 29). Nine deletions occurred on a paternal, and ten on a maternal chromosome; three deletions were demonstrated by FISH only, and parental origin could thus not be determined. All deletion patients aged between 2 years and puberty displayed a distinct pattern of facial features (including periorbital fullness, short nose with flat bridge, wide mouth, and full lips and cheeks), the characteristic outgoing social behaviour, as well as moderate growth and mental retardation. Two-thirds (15 out of 22) had a cardiovascular malformation, but only one third (7 of 22) had supravalvular aortic stenosis (SVAS). A stellate iris pattern was also present in one-third of the patients only. In the four adult patients with 7q11 deletions, there was prominence of the lower lip whereas fullness of cheeks and periorbital tissue was not seen.. This study confirms that WBS has a unique clinical picture which can be diagnosed clinically, but also shows that the relative frequency of individual features may have been overemphasized in the past, and that a minority of patients may exist who are clinically indistinguishable from WBS but who appear to have no deletion at 7q11.

Topics: Abnormalities, Multiple; Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 7; Developmental Disabilities; Diagnosis, Differential; Elastin; Face; Female; Heart Defects, Congenital; Humans; Infant; Male; Pedigree; Phenotype; Syndrome

Williams syndrome (WS) is generally characterized by mental deficiency, gregarious personality, dysmorphic facies, supravalvular aortic stenosis, and idiopathic infantile hypercalcemia. Patients with WS show allelic loss of elastin (ELN), exhibiting a submicroscopic deletion, at 7q11.23, detectable by FISH. Hemizygosity is likely the cause of vascular abnormalities in WS patients. A series of 235 patients was studied, and molecular cytogenetic deletions were seen in 96% of patients with classic WS. Patients included 195 solicited through the Williams Syndrome Association (WSA), plus 40 clinical cytogenetics cases referred by primary-care physicians. Photographs and medical records of most WSA subjects were reviewed, and patients were identified as "classic" (n = 114) or "uncertain" (n = 39). An additional 42 WSA patients were evaluated without clinical information. FISH was performed with biotinylated ELN cosmids on metaphase cells from immortalized lymphoblastoid lines from WSA patients and after high-resolution banding analysis on clinical referral patients. An alpha-satellite probe for chromosome 7 was included in hybridizations, as an internal control. Ninety-six percent of the patients with classic WS showed a deletion in one ELN allele; four of these did not show a deletion. Of the uncertain WS patients, only 3 of 39 showed a deletion. Of the 42 who were not classified phenotypically, because of lack of clinical information, 25 patients (60%) showed a deletion. Thirty-eight percent (15/40) of clinical cytogenetics cases showed an ELN deletion and no cytogenetic deletion by banded analysis. These results support the usefulness of FISH for the detection of elastin deletions as an initial diagnostic assay for WS.

Topics: Abnormalities, Multiple; Child, Preschool; Chromosomes, Human, Pair 7; DNA Probes; Elastin; Face; Female; Gene Deletion; Growth Disorders; Heart Defects, Congenital; Humans; In Situ Hybridization, Fluorescence; Infant; Male; Phenotype; Syndrome

To investigate the frequency of deletions of the elastin gene in patients with Williams syndrome (WS), we screened 44 patients by both FISH and PCR amplification of a dinucleotide repeat polymorphism. FISH was performed using cosmids containing either the 5' or the 3' end of the elastin gene. PCR analysis was performed on the patients and their parents with a (CA)n repeat polymorphism found in intron 17 of the elastin locus. Of the 44 patients screened, 91% were shown to be deleted by FISH. Using the DNA polymorphism, both maternally (39%) and paternally (61%) derived deletions were found. Four patients were not deleted for elastin but have clinical features of WS. Since deletions of elastin cannot account for several features found in WS, these patients will be valuable in further delineation of the critical region responsible for the WS phenotype. Although PCR can be useful for determining the parental origin of the deletion, our results demonstrate that FISH analysis of the elastin locus provides a more rapid and informative test to confirm a clinical diagnosis of WS. The presence of two copies of the elastin locus in a patient does not, however, rule out WS as a diagnosis.

Topics: Abnormalities, Multiple; Aortic Valve Stenosis; Chromosomes, Human, Pair 7; Elastin; Face; Female; Gene Deletion; Growth Disorders; Humans; In Situ Hybridization, Fluorescence; Intellectual Disability; Karyotyping; Male; Polymerase Chain Reaction

Topics: Abnormalities, Multiple; Adolescent; Adult; Base Sequence; Child; Child, Preschool; Chromosome Mapping; Chromosomes, Human, Pair 7; DNA, Satellite; Elastin; Female; Genetic Markers; Humans; Male; Molecular Sequence Data; Monosomy; Sequence Deletion; Syndrome

A small pilot study has been carried out in order to assess the reliability of the detection of hemizygosity at the elastin locus by fluorescence in situ hybridisation (FISH) analysis, as a diagnostic test in both classical and atypical cases of Williams syndrome (WS). Five subjects with WS and five others in whom a diagnosis could not be confirmed on clinical criteria alone were evaluated. Hemizygosity at the elastin locus by FISH analysis was detected in all classical Williams syndrome cases and in three of the five atypical subjects. Furthermore, a combination of a few specific facial features found to be present in all subjects with the elastin gene hemizygosity has been suggested to aid the index of clinical suspicion.

Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Chromosome Banding; Elastin; Facies; Female; Humans; In Situ Hybridization, Fluorescence; Male; Williams Syndrome

A rare case of Williams syndrome diagnosed at the age of 41 is documented. The first subjective symptom was chest pain and the patient displayed many other features in addition to severe supravalvular aortic stenosis with a systolic gradient of 60 mmHg. The stenotic lesion had an area of 0.5 cm2, and was associated with dilated and tortuous coronary arteries. Extended aortoplasty was successfully performed and the postoperative course has been excellent without any cardiac symptoms. In spite of the severe cardiac lesions, this case had been largely asymptomatic and presented unusual features related to the diagnosis and management of this syndrome in an adult. The pattern of abnormalities found in this case suggested problems in relation to the calcitonin/calcitonin gene related peptide (CGRP) and the elastin gene occurring in embryonic organogenesis.

Topics: Abnormalities, Multiple; Adult; Aortic Valve Stenosis; Calcitonin Gene-Related Peptide; Elastin; Face; Female; Humans; Intellectual Disability; Syndrome; Time Factors