elastin and Syndrome

Supravalvular aortic stenosis is a systemic elastin (ELN) arteriopathy that disproportionately affects the supravalvular aorta. ELN arteriopathy may be present in a nonsyndromic condition or in syndromic conditions such as Williams-Beuren syndrome. The anatomic findings include congenital narrowing of the lumen of the aorta and other arteries, such as branches of pulmonary or coronary arteries. Given the systemic nature of the disease, accurate evaluation is recommended to establish the degree and extent of vascular involvement and to plan appropriate interventions, which are indicated whenever hemodynamically significant stenoses occur. ELN arteriopathy is genetically heterogeneous and occurs as a consequence of haploinsufficiency of the ELN gene on chromosome 7q11.23, owing to either microdeletion of the entire chromosomal region or ELN point mutations. Interestingly, there is a prevalence of premature termination mutations resulting in null alleles among ELN point mutations. The identification of the genetic defect in patients with supravalvular aortic stenosis is essential for a definitive diagnosis, prognosis, and genetic counseling.

Topics: Aorta; Aortic Stenosis, Supravalvular; Diagnosis, Differential; Elastin; Humans; Syndrome; Ultrasonography

Acute aortic syndromes (AAS) remain one of the most challenging medical emergencies. Making a prompt and accurate diagnosis is a race against time, where delay may be disastrous for the patient's life. Prompt and accurate diagnosis using imaging modalities has been available for many years, but the major concern is how the clinician's suspicion should be aroused concerning the possibility of an acute aortic syndrome, especially in cases of atypical clinical presentation and/or poor signs during clinical examination. Since the first case report publication in 1995, novel biochemical markers have been used for the rapid diagnosis of AAS, such as smooth muscle myosin heavy chains, serum soluble elastin fragments, and d-dimers, with the latter being the most widely used in clinical trials. Despite their potential, all these substances need to be re-evaluated in large randomized trials before they can be included as biomarkers of high sensitivity and specificity in clinical practice.

Topics: Acute Disease; Animals; Aorta, Thoracic; Biomarkers; Elastin; Fibrin Fibrinogen Degradation Products; Humans; Myosin Heavy Chains; Sensitivity and Specificity; Syndrome

Arterial Tortuosity Syndrome (ATS) is a heritable disease characterized by twisting and lengthening of the major arteries, hypermobility of the joints, and laxity of skin. ATS is caused by mutations in SLC2A10, encoding Glucose Transporter 10 (GLUT10). The current model of ATS holds that loss of GLUT10 at the nuclear periphery induces a glucose-dependent increase in Transforming Growth Factor-beta (TGFbeta) that stimulates vessel wall cell proliferation. Instead, we propose that GLUT10 transports ascorbate, a cofactor for collagen and elastin hydroxylases, into the secretory pathway. In ATS, loss of GLUT10 results in defective collagen and/or elastin. TGFbeta activation represents a secondary response to a defective extracellular matrix.

Topics: Animals; Arteries; Ascorbic Acid; Collagen; Elastin; Glucose; Glucose Transport Proteins, Facilitative; Mice; Models, Biological; Mutation; Skin; Syndrome; Transforming Growth Factor beta; Vitamins

Several "progeroid" syndromes have now been identified. The De Barsy syndrome is an autosomal recessive syndrome of dwarfism, mental deficiency, an "aged" appearance at birth, abnormal elastic fibers on skin biopsy, and lax skin, large helices, eye abnormalities, lax joints, hypotonia, and athetoid posturing. We report one case and review 11 cases from the literature. To understand the abnormal appearance of the elastic fibers on biopsy, we performed elastin gene expression studies on fibroblasts cultured from our patient's skin. Molecular hybridization studies revealed reduced elastin mRNA steady-state levels as compared with age matched control individuals. Assuming normal rates of mRNA translation, reduced elastin synthesis would occur. Diminished dermal elastin content could explain the altered cutaneous elasticity, decreased elastic fibers in the skin, and many clinical manifestations of individuals with this condition.

Topics: Child, Preschool; Diagnosis, Differential; Elastin; Female; Gene Expression; Humans; Phenotype; Progeria; RNA, Messenger; Skin; Syndrome

The exfoliation syndrome affects all structures of the ocular anterior segment, as well as the conjunctiva and occasionally, nonocular structures. The exfoliative material has been shown by a series of light microscopic and gross anatomic studies to be only loosely adherent to the anterior lens capsule, zonules and anterior vitreous face, and firmly adherent to the equatorial lens capsule and posterior epithelium of the iris and the nonpigmented ciliary epithelium. Electron microscopy demonstrates that, in these latter regions, exfoliation material consisting of characteristic, cross-banded fibrils embedded in an amorphous matrix, is present both within the epithelial cells and associated with a disorganized, reduplicated basement membrane. These findings suggest that the material arises from the epithelium of the lens, iris and ciliary body, possibly the result of an underlying metabolic disorder. From these areas, the material enters the aqueous humor and later deposits on the anterior lens capsule, zonules, vitreous face, anterior surface of the iris, and trabecular meshwork. Histochemical studies demonstrate the presence of glycosaminoglycans, which may comprise the interfibrillar portion of the exfoliative material. Other studies demonstrate histochemical similarities between exfoliative material and zonules and are supported by recent work suggesting that the exfoliative fibrils are related to the microfibrillar portion of elastin. Although some reports suggest similarities between exfoliative material and amyloid, a majority of histochemical studies do not support this possibility.

Topics: Amyloid; Anterior Eye Segment; Basement Membrane; Ciliary Body; Elastin; Eye Diseases; Humans; Iris Diseases; Lens Capsule, Crystalline; Lens Diseases; Syndrome; Trabecular Meshwork

The elastic properties of many tissues such as the lung, dermis, and large blood vessels are due to the presence of elastic fibers in the extracellular space. These fibers have been shown by biochemical and ultrastructural analysis to be comprised of two distinct components, a more abundant amorphous component and the microfibrillar component. The microfibrillar component is found in 10- to 12-nm fibrils which are located primarily around the periphery of the amorphous component but, to some extent, interspersed within it. The protein, elastin, makes up the highly insoluble amorphous component and is responsible for the elastic properties. Elastin is found throughout the vertebrate kingdom except for very primitive fish and possesses an unusual chemical composition consonant with its characteristic physical properties. Elastin is composed largely of glycine, proline, and other hydrophobic residues and contains multiple lysine-derived cross-links, such as the desmosines, which link the individual polypeptide chains into a rubber-like network. The intervening, hydrophobic regions of the polypeptide chains between the cross-links are highly mobile, and the elastic properties of the fibers can be described in terms of the theory of rubber elasticity. Recent application of recombinant DNA techniques has led to further understanding of the structure of elastin. Analyses of the bovine and human elastin genes have demonstrated that the hydrophobic and cross-linking domains are encoded in separate exons. These exons tend to be small, varying from 27 to 114 base pairs, and are separated by large intervening sequences. Furthermore, DNA sequence analysis has demonstrated that the elastin molecule contains two cysteine residues which were not previously identified near the carboxy terminus and which may be important in the interaction of elastin with other extracellular matrix proteins. Further DNA sequencing should determine the complete amino acid sequence of elastin. Biosynthetic studies and in vitro translation of elastin mRNA have demonstrated that a 72,000-dalton polypeptide, designated tropoelastin, is the initial translation product. Analysis of several developing systems has demonstrated that elastin synthesis is controlled by the level of elastin mRNA. After packaging into membrane-bound vesicles in the Golgi apparatus, tropoelastin is secreted by exocytosis into the extracellular space where it is cross-linked by a copper-requiring extracellular enzyme, lys

Topics: Amino Acid Sequence; Amino Acids; Animals; Aorta; Base Sequence; Biological Evolution; Bone Diseases; Chemical Phenomena; Chemistry; Cutis Laxa; DNA; Elastin; Genes; Genetic Diseases, Inborn; Humans; Lung Diseases, Obstructive; Macromolecular Substances; Marfan Syndrome; Microscopy, Electron; Protein-Lysine 6-Oxidase; Pseudoxanthoma Elasticum; RNA, Messenger; Species Specificity; Syndrome; Tropoelastin; Vascular Diseases

It is apparent that significant progress has been made in our understanding of the biosynthesis, modifications, and maturation of collagen and elastin. We now recognize and partially understand special reactions involved in hydroxylations within the cell and complex cross-linking processes occurring outside the cell. Recent experiments (191) have shown that in human diploid fibroblast cultures of limited doubling potential (191) the hydroxylation of collagen prolyl residues appears to be "age" or passage-level dependent. With increasing passage level of these cultures, both the ascorbate requirements and the extent of collagen hydroxylation decrease. "Young" cell cultures have a strong requirement for complete hydroxylation and without ascorbate there is only about 50% of the normal level. "Middle-aged" cultures show higher hydroxylation without and full hydroxylation with ascorbate, whereas "old" (or cultures close to "senescence") are incapable of full hydroxylation with or without ascorbic acid. Although the overall system may show some deterioration with increasing passage levels, it appears that with increasing passage levels other components in the cell replace the ascorbate dependence of the hydroxylase system to a greater exten. In some ways, aging WI-38 cultures begin to resemble some transformed cells in their biochemical reactions, although they continue to remain diploid and eventually lose the ability to replicate. It is not yet known whether old animals can produce collagen, which may now be underhydroxylated, perhaps contributing to certain senescent changes. Careful examination of the hydroxylation index of collagen produced in organoid cultures of tissue biopsies as a function of donor age might be informative, particularly if one looks at the quality of collagen by employing collagenase and other proteolytic digests with collagen (191). One could comare the levels of frequent and characteristic peptide triplet sequences such as Gly-Pro-Hyp to Gly-Pro-Pro, Gly-Ala-Hyp to Gly-Ala-Pro, or Gly-Pro-Hyl to Gly-Pro-Lys and others for evaluation of hydroxylation throughout the entire molecule or at selected sequences.

Topics: Amino Acid Sequence; Animals; Antibody Specificity; Ascorbic Acid; Collagen; Connective Tissue; Copper; Ehlers-Danlos Syndrome; Elastin; Epitopes; Homocystinuria; Humans; Hydralazine; Lathyrism; Marfan Syndrome; Molecular Conformation; Platelet Aggregation; Procollagen-Proline Dioxygenase; Skin Diseases; Syndrome

Mid-aortic syndrome (MAS) is characterized by the congenital coarctation of the abdominal aorta, abdominal and limb claudication, and hypertension. The etiology of this disorder is very diverse and often manifests in conjunction with Takayasu's arteritis, Williams-Beurens syndrome, and neurofibromatosis. The isolated mid-aortic syndrome is very rare with only a few cases reported in the literature.. A 45 years old man was admitted to the Emergency Department with sudden muscle weakness and facial paralysis on the left side. Imaging studies reveal right middle cerebral artery infarction at the M1 section. Incidental findings include multiple moderate to severe stenoses in the right internal carotid artery, and total abdominal aorta occlusion. A variant at the ELN gene (Elastin, OMIM*130,160): c.1768G > A/wt (p.Ala590Thr) was identified.. This is the first reported case of ELN related mid-aortic syndrome in Vietnam which was diagnosed through careful clinical and genetic workup. The finding of mid-aortic syndrome, in this case, was incidental and the decision to reverse the occlusion was postponed as there was no immediate risk of renal failure or reduced blood flow to the lower limb.

Topics: Aorta, Abdominal; Aortic Coarctation; Elastin; Humans; Male; Middle Aged; Mutation, Missense; Syndrome

Topics: Adolescent; Blood Platelet Disorders; Child; Elastin; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Hearing Loss, Sensorineural; Humans; Male; Myosin Heavy Chains; Pedigree; Platelet Aggregation; Rare Diseases; Sampling Studies; Sweat Glands; Syndrome; Thrombocytopenia; Young Adult

The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.

Topics: Biopsy; Cell Adhesion; Cell Movement; Collagen; DNA Mutational Analysis; Elastin; Extracellular Matrix; Family; Female; Fibrillin-1; Fibrillins; Humans; Immunohistochemistry; Male; Mesoderm; Microfibrils; Microfilament Proteins; Mutation; Pedigree; Phenotype; Scleroderma, Systemic; Signal Transduction; Skin; Syndrome; Transforming Growth Factor beta

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

We report here on the first case of a child with bilateral periventricular nodular heterotopia (PNH) and Williams syndrome. Fluorescent in situ hybridization (FISH) analyses demonstrated a deletion of the elastin gene in the Williams syndrome critical region (WSCR). Further mapping by loss of heterozygosity analysis both by microsatellite marker and SNP profiling demonstrated a 1.5 Mb deletion beyond the telomeric end of the typical WSCR. No mutations were identified in the X-linked filamin-A gene (the most common cause of PNH). These findings suggest another dominant PNH disorder along chromosome 7q11.23.

Topics: Cerebral Ventricles; Cerebral Ventriculography; Child; Chromosomes, Human, Pair 7; Contractile Proteins; Elastin; Female; Filamins; Gene Deletion; Genes, X-Linked; Genetic Markers; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Loss of Heterozygosity; Microfilament Proteins; Microsatellite Repeats; Mutation; Physical Chromosome Mapping; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Syndrome; Williams Syndrome

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

To investigate histopathologic alterations of eyelid biopsy specimens from patients with floppy eyelid syndrome (FES) with special regard to elastic fiber content and ultrastructure as well as to the expression of elastin-degrading enzymes to elucidate the pathogenesis of this disorder.. Retrospective, interventional case series.. Eleven consecutive patients with FES and 10 age-matched control patients with basal cell carcinoma of the eyelid.. Horizontal pentagonal eyelid resections of 16 upper lids were performed in 11 patients with FES. Full-thickness eyelid biopsy specimens from study and control patients were examined by light and transmission electron microscopy, semiquantitative morphometry, and immunohistochemistry using antibodies against matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MMP-12 and neutrophil elastase.. All patients treated with surgical horizontal eyelid shortening were asymptomatic at follow-up. Histopathologic analysis of the surgical specimens showed, apart from unspecific signs of chronic inflammation, a significant decrease in the amount of elastin within the tarsal plate and eyelid skin as compared with controls. Residual elastic fibers revealed an abnormal ultrastructure with a diminished elastin core. Immunohistochemistry demonstrated an increased immunoreactivity for elastolytic proteases, particularly MMP-7 and MMP-9, in areas of elastin depletion in FES specimens as compared with controls.. The findings indicate that upregulation of elastolytic enzymes, most probably induced by repeated mechanical stress, participates in elastic fiber degradation and subsequent tarsal laxity and eyelash ptosis in FES.

Topics: Aged; Biopsy; Carcinoma, Basal Cell; Elastic Tissue; Elastin; Eyelid Diseases; Eyelid Neoplasms; Female; Humans; Immunoenzyme Techniques; Male; Matrix Metalloproteinase 12; Matrix Metalloproteinase 2; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Metalloendopeptidases; Middle Aged; Retrospective Studies; 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

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

This study was performed on a family of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) subjects. Neuropathological alterations of small arteries consisting in thickening, reduplication and fragmentation of the internal elastic lamella, and granular periodic acid-Schiff-positive material deposited in the arterial media were demonstrated in 1 autopsy case by histochemistry and electron microscopy. This material reacted with a monoclonal antibody anti-elastin (aE), as demonstrated by immunohistochemistry and immunoelectron microscopy. Significant increases of aE-immunoreactivity and elastin mRNA expression were found in cultured skin fibroblasts from 5 family members genetically affected by CADASIL, but not genetically and clinically healthy members. These results suggest that alterations of the elastic apparatus are associated with CADASIL genotype and related to the clinical expression of the disease.

Topics: Adult; Analysis of Variance; Biopsy, Needle; Brain; Cells, Cultured; Cerebral Arterial Diseases; Cerebral Arteries; Cerebral Infarction; Collagen; Elastin; Female; Fibroblasts; Fibronectins; Follow-Up Studies; Humans; Immunohistochemistry; Ischemic Attack, Transient; Leukoencephalopathy, Progressive Multifocal; Male; Microscopy, Electron; Middle Aged; Reference Values; RNA, Messenger; Skin; Syndrome

We describe a 15-month-old girl with Michelin tyre syndrome. She had hirsuties and marked skin folds. Histological examination showed fragmented elastic fibres in addition to smooth muscle hamartoma. On electron microscopy, decreased deposition of elastin was observed. We speculate that elastic fibre abnormalities may account for the characteristic skin changes in the Michelin tyre syndrome.

Topics: Connective Tissue Diseases; Elastic Tissue; Elastin; Female; Hirsutism; Humans; Infant, Newborn; Muscle, Smooth; Syndrome

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

Although family history can be an important risk factor for cardiovascular disease, relatively little is known about the nature of specific genetic risk factors. One approach to this problem is to identify and characterize genes responsible for inherited disorders in the hope that this information will also provide mechanistic insight into common forms of cardiovascular disease.. Over the last decade, it has become possible to identify genes that cause human disease by use of the techniques of molecular genetics, specifically genetic linkage analysis, positional cloning, and mutational analyses. We have used these techniques to study three inherited cardiovascular disorders: supravalvular aortic stenosis, Williams syndrome, and long-QT syndrome. We have discovered that the vascular pathology of supravalvular aortic stenosis and Williams syndrome results from mutations involving the elastin gene on chromosome 7q11.23. These mutations include intragenic deletions, translocations, and complete deletion of the elastin gene, suggesting that a quantitative reduction in elastin during vascular development is pathogenically important. To date, only the elastin gene has proved important for supravalvular aortic stenosis. By contrast, genetic linkage analyses in families with long-QT syndrome indicate that at least four distinct genes can cause this disorder. We have identified three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Recently, we demonstrated that mutations in a putative cardiac potassium channel gene, HERG, are responsible for the chromosome 7-linked form of long-QT syndrome, whereas mutations in the cardiac sodium channel gene SCN5A cause the chromosome 3-linked form of this disorder. HERG mutations and potassium channel biophysics suggest a dominant-negative molecular mechanism and reduced repolarization currents. By contrast, SCN5A mutations probably cause subtle alterations of cardiac sodium channel function and prolonged depolarizing currents.. Molecular genetic analyses of long-QT syndrome, supravalvular aortic stenosis, and Williams syndrome have begun to unravel the mechanisms underlying these inherited disorders. Rapid genetic testing for Williams syndrome is now available using a simple cytogenetic test, fluorescence in situ hybridization, but additional work will be required for long-QT syndrome and autosomal-dominant supravalvular aortic stenosis. Improved diagnosis and mechanistic understanding of these disorders should lead to rational treatment and prevention.

Topics: Aortic Valve Stenosis; Chromosome Mapping; Elastin; Electrocardiography; Humans; Long QT Syndrome; Mutation; Sodium Channels; Syndrome

The human calcitonin receptor (CTR) is a transmembrane peptide with dual action as a receptor for the hormone calcitonin and as an extracellular calcium sensor. Therefore, CTR dysfunction could lead to disorders of calcium metabolism associated with hypercalcemia, such as the Williams syndrome (WS). WS is a developmental disorder caused by a deletion at chromosome 7q11.23 that includes the elastin locus (ELN). We have mapped the CTR gene (CALCR) to chromosome band 7q21.3 by polymerase chain reaction and single-strand conformation analysis of somatic cell hybrids as well as fluorescence in situ hybridization (FISH) to metaphase chromosome spreads. Two-color FISH cohybridizing CTR and ELN probes confirmed that CALCR maps telomeric to ELN. Subsequent analysis of chromosome spreads from four WS patients revealed deletion of the ELN locus in all of them and normal hybridization of CTR probes to both chromosome 7 homologues, indicating that CALCR lies outside the deleted region.

Topics: Animals; Base Sequence; Chromosome Deletion; Chromosome Mapping; Chromosomes, Human, Pair 7; Cricetinae; Cricetulus; DNA Primers; Elastin; Genomic Library; Growth Disorders; Humans; Hybrid Cells; In Situ Hybridization, Fluorescence; Molecular Sequence Data; Receptors, Calcitonin; Syndrome

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

Patients with the floppy eyelid syndrome have chronic papillary conjunctivitis with easily everted upper eyelids and a soft, pliant upper tarsus. The purpose of this study is to describe the clinical features and the histopathologic correlate in a group of patients with floppy eyelid syndrome.. The authors examined eight patients with floppy eyelid syndrome, four of whom underwent surgical management with horizontal eyelid shortening. Eyelid tissue from these patients was examined using light microscopy, electron microscopy, and immunohistochemistry and compared with controls with unrelated eyelid or orbital disorders.. Clinical findings included obesity or eye rubbing, lash ptosis, and, less commonly, blepharoptosis. Two patients had documented sleep apnea with abnormal sleep electroencephalogram. Light microscopy of the surgical specimens showed chronic conjunctival inflammation, papillary conjunctivitis, and meibomian gland abnormalities, including granuloma formation. Verhoeff's modified elastin stain demonstrated a marked decrease in the amount of elastin fibers in tarsus from patients with floppy eyelid syndrome compared with controls. Immunohistochemical staining for elastin also showed a marked decrease of tarsal elastin in floppy eyelid patients compared with controls. In contrast, immunohistochemical stains showed that the distribution of collagen types I and III was similar between patients with floppy eyelid syndrome and controls. Electron microscopy demonstrated that tarsal collagen was comparable in patients and controls, and that there was a reduced amount of tarsal elastin in floppy eyelid syndrome compared with controls.. These findings demonstrate that tarsal elastin is decreased in the floppy eyelid syndrome, which may contribute to the laxity of the tarsus in this disorder.

Topics: Adult; Aged; Collagen; Conjunctivitis, Allergic; Elastin; Eyelid Diseases; Eyelids; Female; Fluorescent Antibody Technique; Granuloma; Humans; Male; Meibomian Glands; Middle Aged; Syndrome

Williams syndrome (WS) is a developmental disorder affecting connective tissue and the central nervous system. A common feature of WS, supravalvular aortic stenosis, is also a distinct autosomal dominant disorder caused by mutations in the elastin gene. In this study, we identified hemizygosity at the elastin locus using genetic analyses in four familial and five sporadic cases of WS. Fluorescent in situ hybridization and quantitative Southern analyses confirmed these findings, demonstrating inherited and de novo deletions of the elastin gene. These data indicate that deletions involving one elastin allele cause WS and implicate elastin hemizygosity in the pathogenesis of the disease.

Topics: Adult; Alleles; Aortic Valve Stenosis; Arteries; Blotting, Southern; Child; Child, Preschool; Chromosomes, Human, Pair 7; Connective Tissue Diseases; Developmental Disabilities; Elastin; Genes; Genotype; Humans; In Situ Hybridization, Fluorescence; Intellectual Disability; Pedigree; Sequence Deletion; Syndrome

To identify genes involved in vascular disease, we investigated patients with supravalvular aortic stenosis (SVAS), an inherited vascular disorder that causes hemodynamically significant narrowing of large elastic arteries. Pulsed-field gel and Southern analyses showed that a translocation near the elastin gene cosegregated with SVAS in one family. DNA sequence analyses demonstrated that the translocation disrupted the elastin gene and localized the breakpoint to exon 28. Taken together with our previous study linking SVAS to the elastin gene in two additional families and existing knowledge of vascular biology, these data suggest that mutations in the elastin gene can cause SVAS.

Topics: Amino Acid Sequence; Aortic Valve Stenosis; Base Sequence; Chromosome Mapping; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 7; Elastin; Female; Genetic Linkage; Humans; Hybrid Cells; Male; Molecular Sequence Data; Pedigree; Polymorphism, Restriction Fragment Length; Syndrome; Translocation, Genetic

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

Supravalvular aortic stenosis (SVAS) is an autosomal dominant disorder characterized by abnormalities of development of the great vessels. SVAS is also commonly part of Williams syndrome. Linkage to the elastin gene on chromosome 7q11 has recently been reported in two kindreds with SVAS. Previous reports of patients with 7q11 deletions have noted great vessel abnormalities in some. We report on a family in which SVAS is cosegregating with a balanced reciprocal translocation, t(6:7) (p21.1;q11.23), providing further evidence that SVAS is the result of a mutation of elastin at 7q11.23 region. The propositus of the translocation family has some minor anomalies which occur in Williams syndrome, suggesting that elastin abnormalities may cause some of the abnormalities found in Williams syndrome.

Topics: Adult; Aged; Aged, 80 and over; Aortic Valve Stenosis; Child; Child, Preschool; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 7; Elastin; Female; Humans; Infant, Newborn; Karyotyping; Male; Pedigree; Syndrome; Translocation, Genetic; Ultrasonography

Buschke-Ollendorff syndrome (BOS; McKusick 16670) is an autosomal dominant connective-tissue disorder characterized by uneven osseous formation in bone (osteopoikilosis) and fibrous skin papules (dermatofibrosis lenticularis disseminata). We describe two patients in whom BOS occurred in an autosomal dominant inheritance pattern. The connective tissue of the skin lesions showed both collagen and elastin abnormalities by electron microscopy. Cultured fibroblasts from both patients produced 2-8 times more tropoelastin than normal skin fibroblasts in the presence of 10% calf serum. Involved skin fibroblasts of one patient produced up to eight times normal levels, whereas apparently uninvolved skin was also elevated more than threefold. In a second patient, whose involvement was nearly complete, elastin production was high in involved areas and less so in completely involved skin. Transforming growth factor-beta 1 (TGF beta 1), a powerful stimulus for elastin production, brought about similar relative increases in normal and BOS strains. Basic fibroblast growth factor, an antagonist of TGF beta 1-stimulated elastin production, was able to reduce elastin production in basal and TGF beta 1 stimulated BOS strains. Elastin mRNA levels were elevated in all patient strains, suggesting that Buschke-Ollendorff syndrome may result, at least in part, from abnormal regulation of extracellular matrix metabolism that leads to increased steady-state levels of elastin mRNA and elastin accumulation in the dermis.

Topics: Blotting, Southern; Cells, Cultured; Connective Tissue Diseases; Elastin; Female; Fibroblast Growth Factor 2; Fibroblasts; Humans; Male; Microscopy, Electron; Middle Aged; Nevus; Osteopoikilosis; Pedigree; Phenotype; RNA, Messenger; Skin; Skin Neoplasms; Syndrome; Transforming Growth Factor beta

The biopsy diagnosis of prolapsing rectal mucosa syndrome can be difficult. We present two newly described features--'diamond-shaped' crypts and mucosal elastin--which appear to be helpful in histological diagnosis. Of 32 biopsies of prolapsing rectal mucosa syndrome, all showed diamond-shaped crypts or mucosal elastin, and 28 contained both. Control biopsies comprised cases of normal or irritable bowel syndrome (46), irradiation colitis and ischaemic colitis (16), inflammatory bowel disease (26), and adenomas (30). Mucosal elastin and 'diamond-shaped' crypts with distinctive scalloped edges, which were never seen in prolapse, were observed in half the cases of irradiation and ischaemic colitis. Diamond-shaped crypts were seen in one case of inflammatory bowel disease. Diamond-shaped crypts and elastin were seen in the base of adenomas large enough to cause localized prolapse, and in four biopsies from patients with irritable bowel syndrome, all of whom had given a history of straining at stool.

Topics: Adenoma; Diagnosis, Differential; Elastic Tissue; Elastin; Humans; Intestinal Mucosa; Rectal Neoplasms; Rectal Prolapse; Syndrome

A patient with dermatofibrosis lenticularis disseminata (Buschke-Ollendorff syndrome) was found to have a distinctive abnormality of the cutaneous elastic tissue. This abnormality, studied by histochemical and ultrastructural techniques, was characterized by the presence of hyalinized, thick fibers that entrapped normal bundles of collagen. Histochemically, these fibers stained like elastin but showed certain tinctorial characteristics of pre-elastin. Ultrastructurally, this elastin-like substance was composed of large clumps of electron-dense material with a fine fibrillar coating. The changes were sufficiently distinctive to be diagnosed by light microscopy.

Topics: Collagen; Elastic Tissue; Elastin; Female; Fibroma; Humans; Microscopy, Electron; Middle Aged; Osteopoikilosis; Skin; Skin Neoplasms; Syndrome

The Buschke-Ollendorff syndrome is an association of cutaneous lesions, dermatofibrosis lenticularis disseminata, with osteopoikilosis. This condition is inherited in an autosomal dominant pattern. In order to clarify the biochemical nature of the skin lesions, we have examined 12 patients with the Buschke-Ollendorf syndrome, representing 2 unrelated kindreds. Histologically, the lesions were characterized by excessive amounts of unusually broad, interlacing elastic fibers in the dermis. Digestion of skin secretions with pancreatic elastase completely removed these fibers. Electron microscopy of the dermis further revealed markedly branched elastic fibers without fragmentation. The accumulation of elastin in the skin was also demonstrated by measurements of desmosine employing a radioimmunoassay. The desmosine content of the skin lesions increased 3- to 7-fold when compared to the skin either from healthy controls or from uninvolved skin adjacent to a lesion. The results indicate that the skin lesions of the Buschke-Ollendorff syndrome are connective tissue nevi of the elastin type. Cell cultures from these patients may provide a convenient model to study the control mechanisms involved in elastin metabolism.

Topics: Desmosine; Elastic Tissue; Elastin; Fibroma; Humans; Osteopoikilosis; Osteosclerosis; Skin; Skin Neoplasms; Syndrome

Topics: Angioid Streaks; Biopsy; Calcinosis; Calcium; Child; Elastin; Female; Histiocytes; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Phosphorus; Pseudoxanthoma Elasticum; Skin; Syndrome