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Cutis laxa is manifest histologically by fragmentation of elastic tissue throughout the body. The aorta and other systemic vessels show dilatation, elongation and even aneurysm formation. We report multiple pulmonary artery branch stenoses in a child who had cutis laxa. Pulmonary artery stenoses may be the cause of the pulmonary hypertension and right heart failure observed in patients with this condition.
Hereditary cutis laxa comprises a heterogeneous group of connective tissue disorders characterized by loose skin and variable systemic involvement. Autosomal dominant and recessive as well as X-linked forms have been described. Some dominant forms are caused by mutations in the elastine gene (ELN). The X-linked form is now classified in the group of copper transport diseases. The genetic defect underlying the autosomal recessive (AR) forms of cutis laxa is not known. The phenotypic abnormalities recently observed in a fibulin-5 knockout mouse model are reminiscent of human AR cutis laxa type I. Both share cutis laxa, lung emphysema and arterial involvement. Molecular study of the fibulin-5 (FBLN5) gene in a large consanguineous Turkish family with four patients affected by AR cutis laxa type I demonstrated the presence of a homozygous missense mutation (T998C) in the FBLN5 gene resulting in a serine-to-proline (S227P) substitution in the fourth calcium-binding epidermal growth factor-like domain of fibulin-5 protein. This amino acid substitution is predicted to have important structural and functional consequences for normal elastogenesis. As such, we provide evidence that a genetic defect in fibulin-5 (FBLN5, also known as EVEC or DANCE) is responsible for a recessive form of cutis laxa in humans.
BACKGROUND: Cutis laxa is an extremely rare disorder characterized by marked skin laxity. Few cases of cutis laxa have been described worldwide. Clinical presentation and mode of inheritance show considerable heterogeneity; autosomal dominant, autosomal recessive, and X-linked recessive forms have been reported. Only 3 mutations in the elastin gene have been described as the genetic cause of the autosomal dominant form of cutis laxa. OBSERVATIONS: A 45-year-old woman and her 19-year-old son presented with inelastic, loose-hanging, and wrinkled skin that appeared prematurely aged and were clinically diagnosed as having cutis laxa. Mutational analysis of the elastin gene evidenced a novel mutation (2292delC) that predicts a frameshift in the coding region and causes translation to proceed into the 3'-untranslated region. This would replace the C-terminal amino acid of the normal elastin protein with a novel sequence. CONCLUSION: This article is the fourth report of autosomal dominant cutis laxa to appear in the literature in which a mutation in the elastin gene has been correlated with the disease.
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Congenital cutis laxa is a rare disorder of the elastic tissue in which lax skin gives a premature senile appearance. We report a new case of this disease associated with craniosynostosis. In the literature, the genetics of cutis laxa are not clear. Fleischmajer and Matus (18) considers an inherited autosomal recessive or an incomplete autosomal dominant trait, Mehregan (33) reports an autosomal recessive mode of transmission and Byers (10) an X-linked form. Among these cases, the most serious visceral involvement is the development of pulmonary emphysema. However, in cutis laxa with development retardation, variety of minor injury of the skeleton, the prognosis seems appears to be better.
Cutis laxa is a condition characterized by redundant, pendulous, and inelastic skin. We identified a patient with recessive inheritance of a missense mutation (169G-->A; E57K) in the Fibulin-4 gene. She had multiple bone fractures at birth and was diagnosed with cutis laxa, vascular tortuosity, ascending aortic aneurysm, developmental emphysema, inguinal and diaphragmatic hernia, joint laxity, and pectus excavatum by age 2 years. Her skin showed markedly underdeveloped elastic fibers, and the extracellular matrix laid down by her skin fibroblasts contained dramatically reduced amounts of fibulin-4. We conclude that fibulin-4 is necessary for elastic fiber formation and connective tissue development.
Acquired cutis laxa is a rare disorder characterized by diffuse laxity of the skin and loss of connective tissue support with involvement of the lungs, gastrointestinal tract, pelvic organs, and aorta. The case report presented herein describes a forty-six year old woman with multiple myeloma and cutis laxa. Her history included several severe allergic reactions and the gradual development of lax skin, loss of connective tissue support throughout the body, and emphysema. At autopsy, multiple myeloma, diffuse laxity of the skin, and panacinar emphysema were found. The amount of elastic fiber in the skin, lungs, and aorta was decreased and showed abnormal fragmentation. Results of direct immunofluorescence study demonstrated IgG bound to dermal elastic fibers. Speculation regarding an immunologic etiology of the elastic tissue abnormality is presented herein.
Congenital cutis laxa is a genetically heterogeneous condition presenting with loose and redundant skin folds, decreased elasticity of the skin, connective tissue involvement and a highly variable spectrum of associated features. The most common forms are inherited in an autosomal recessive or dominant fashion. Fibulin 5 and elastin mutations were detected in a limited number of patients, but in most cases the etiology is not known. Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, we performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome, including a recently developed test for defective O-glycosylation. Here, we describe five patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay and neurological findings. Three of these five children have an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were found in the FBLN5 gene. In conclusion, we have identified a new combined glycosylation defect with a distinct clinical phenotype. Our results suggest that a combined defect of glycosylation might be a causative factor in congenital cutis laxa. This is the first report where abnormal N- and O-linked glycosylation is implicated in the etiology of cutis laxa syndrome.
Cutis laxa is a genetically heterogeneous connective tissue disease that occurs in both inherited and acquired forms. The most apparent defect is loose, redundant, nonresilient skin, but systemic connective tissue abnormalities exist, especially in conjunction with the early onset or autosomal recessive variety. The elastic fiber shows morphologic alterations. We studied dermal skin biopsies and cultured skin fibroblasts from 6 patients with congenital forms of cutis laxa in an effort to correlate alterations in elastin morphology and metabolism. In general, ultrastructural analysis revealed occasional variance in collagen fiber diameter, whereas elastic tissue varied in content, appearance, and the proportion and manner by which elastin and microfibrillar component associated. Fibroblast cell lines comprised of normal donors from a similar age group produced an average of 35 +/- 10 X 10(3) tropoelastin molecular equivalents per cell per hour, as measured by an ELISA. Three of six cutis laxa cell strains were markedly (5-20-fold) reduced in tropoelastin production. Two of these cell strains had specifically reduced levels of tropoelastin production relative to total protein synthesis. Analysis of elastin specific messenger RNA levels indicated this reduced expression of tropoelastin was regulated at a pretranslational level. In other strains, diminished production of elastin did not appear to be the primary defect, underscoring the heterogeneous nature of cutis laxa at both the biochemical and ultrastructural levels.
Cutis laxa (generalized elastolysis) is characterized by sagging folds of loose skin on the face and trunk. Although grouped with hyperelastic skin conditions such as Ehlers-Danlos syndrome, cutis laxa shows an almost total lack of skin elasticity. Because it is a generalized state, it may present as an abnormality in the connective tissue of more than one organ system. The authors report a patient who had end-stage renal failure related to heavy chain disease, a recognized association of cutis laxa. Although the patient's vascular abnormalities were significant, she died of respiratory failure at 41 years of age from cutis laxa-induced emphysema.
BACKGROUND: Acquired cutis laxa is a rare disease characterized by sagging skin, premature wrinkling and reduced skin elasticity. OBSERVATION: We report a 21-year-old woman, who presented with acquired cutis laxa on the face and the ear lobes. Urticarial papules had preceded for 6 years. There was no systemic involvement. Skin specimens were obtained from lax skin and urticarial papules, and from healthy controls. Histology showed only few perivascular lymphocytes in lax ear skin and a dense inflammatory infiltrate in urticarial skin. In both biopsies elastic fibres were decreased as demonstrated by computerized morphometric analyses. Elastase activities of fibroblasts in culture were evaluated. There was a 2- to 3-fold increase in elastase activity in urticarial skin fibroblasts, contrasting with a normal elastase activity in lax ear skin. CONCLUSION: Our findings suggest that the inflammatory cells could play a significant role in the destruction of elastic fibres.
A case of cutis laxa acquisita was studied with the aim of defining the molecular defects involved and comparing them with those of an inherited form of cutis laxa. In the acquisita form of cutis laxa ultrastructural and biochemical observations confirmed a dramatic reduction of dermal elastin, whereas collagen content was normal. Elastin mRNA expression as well as tropoelastin production by dermal fibroblasts, in vitro, were normal compared with control cells, as revealed by in situ hybridization and enzyme-linked immunosorbent assay, respectively. Lysyl oxidase activity, measured on cultured fibroblasts, was reduced to 60% compared with age-matched control subjects. Unlike control skin fibroblasts or fibroblasts from inherited cutis laxa, the affected skin cells from cutis laxa acquisita predominantly expressed an elastolytic activity identified as cathepsin G. Patient serum also has reduced elastase inhibitory capacity and reduced levels of alpha 1-antiproteinase inhibitor (alpha 1-antitrypsin). Although cutis laxa acquisita is a heterogeneous group of disorders, findings in this patient were consistent with excessive loss of cutaneous elastin due to the combined effects of several factors, such as low lysyl oxidase activity together with high levels of cathepsin G and reduction of circulating proteinase inhibitor(s).
Cutis laxa is an extremely rare genetic disorder of connective tissue. The striking dermatologic features are loose skin folds and skin laxity. Due to these folds the patients appear to be prematurely aged. Plastic surgery can improve these changes. This treatment is especially indicated in patients with the autosomal dominant type of cutis laxa where internal manifestations do not occur. We report the case of a seventeen years old boy with cutis laxa and surgical therapy.
Congenital cutis laxa is a rare generalized inherited elastosis, characterized by the appearance of premature aging and skin laxity with mild to severe systemic anomalies. Ocular manifestations include excess skin in the eyelids, ptosis and lower lid ectropion. Of the hyperelasticity syndromes - Ehlers Danlos, Pseudoxanthoma elasticum and cutis laxa - only cutis laxa has normal skin wound healing. The diagnosis must therefore be established before surgical options for treatment are considered. We report an unusual case of a 5-month-old male child with cutis laxa who presented with upper lid entropion secondary to severe redundant upper eyelid skin. An anterior lamellar repositioning procedure successfully corrected the lid margin malposition with complete relief of symptoms.
BACKGROUND: Congenital cutis laxa is an exceptional condition. No large scale series has been reported in the French literature. We report 5 cases observed between 1993 and 1997. PATIENTS AND METHODS: Five children with a morphotype compatible with congenital generalized cutis laxa were examined. A family study, complete visceral workup and skin biopsy with standard histology, orceine coloration and histomorphometric analysis of the collagen and elastic fibers of the dermis were performed. Karyotype and copper metabolism (cupremia and ceruloplasminemia) were available in 3 children. RESULTS: The diagnosis was clinical and proven histologically by orceine coloration of skin biopsies in all cases. There were discrete ultrastructure anomalies in the pure cutaneous form expressed in case n(o) 1 with possible autosomal dominant inheritance. Cupremia and ceruloplasminemia were normal in the 3 children explored; this corresponds to absence of the Elhers-Danlos type IX phenotype. The karyotype was normal in 3/3 children, in agreement with the absence in these three children of marfanoid cutis laxa phenotype. Patients n(o) 2, 3, 4 and 5 had common features: probable autosomal recessive inheritance and severe prognosis. Patient n(o) 2 died at the age of 3 weeks and had severe pulmonary emphysema. This child's sister also had cutis laxa but with no visceral component (autosomal recessive inheritance with variable expression). Patients n(o) 3, 4 and 5 had a severe multiple malformative syndrome with facial dysmorphism, growth retardation, unexplained digestive disorders and psychomotor retardation. DISCUSSION: Our series of 5 patients and data in the literature confirm that primary cutis laxa is a heterogeneous group of conditions both clinically and genetically. The anomalies associated in patients n(o) 3, 4 and 5 were not directly related to anomalous elastic tissue as was also the case for the craniostenosis in patient n(o) 3 reported in other cases in the literature.
Cutis laxa is a heterogeneous disease of elastic fibres, divided into three congenital and two acquired forms. Its aetiology is unknown except for the X-linked recessive form. A late form with slow progression in a 52-year-old woman and a probably postinflammatory form in a 29-year-old woman are reported. In both cases histological examination revealed severe damage of the elastic fibres of the skin, in the first one also calcium deposits and (electronmicroscopically) damage to collagen fibres. Treatment is entirely symptomatic, but in severe cases plastic surgery may help cosmetically.
Cutis laxa is a unusual disorder of the connective tissue. It may be hereditary or acquired and from the genetical viewpoint, can be either of the dominant or of the recessive type. The autosomic dominant type, less frequent, has a late beginning and the evolution is usually benign, and it seldom has cardiovascular anomalies. On the contrary, the recessive type usually has an early beginning having frequent cardiovascular anomalies, with the outcome of death early in infancy. We report two siblings with the recessive type of the illness, having peripheral arterial stenosis of pulmonary branches. We review the literature with special attention to the angiohemodynamic findings, as there are few bibliographic reports about this subject, as well as about the different hypothesis on the pathogenesis of this illness.
Cutis laxa is an uncommon condition characterized by loose and redundant skin. Biopsy results are positive for a reduction in or an absence of elastic fibers in the dermis. Cutis laxa is acquired or congenital. The acquired form is either a generalized insidious form (type I) or a form associated with prior inflammation (type II). Cardiovascular, pulmonary, gastrointestinal, and urologic complications may occur. In the past, cutis laxa was associated with plasma cell dyscrasia. We report on a characteristic cause of cutis laxa to alert clinicians to this uncommon manifestation of multiple myeloma.