Cutis laxa of the autosomal recessive type in a consanguineous family

Cutis laxa comprises a group of uncommon disorders of elastin fibers first described by Graf in the early 19th century. The main characteristic is a redundant, loose skin with deep wrinkling or sagging combined with a variable systemic involvement. Histopathologic examination presents various abnormalities of the elastin fibers. We distinguish congenital as well as acquired forms of generalized or localized cutis laxa. The mode of inheritance shows great heterogeneity: autosomal dominant, autosomal recessive and X-linked recessive inheritance have all been described. We present a severe case of autosomal recessive type 1 cutis laxa in a female patient, born in a large, consanguineous Turkish family, where three other family members had already died of the disease. A missense mutation of fibulin-5 was identified in this patient.     

A novel elastin gene mutation resulting in an autosomal dominant form of cutis laxa

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.     

Healing slack skin

A non-lethal, murine knockout of fibulin-5 with features of autosomal recessive cutis laxa and marked defects in elastic fiber formation amplifies previous observations on the minimal role of the elastic component in acute, cutaneous wound healing. More demanding wound models or long-term studies may yet reveal how fibulin-5 and elastin impact the quality of repair.     

Autosomal recessive form of congenital cutis laxa: more than the clinical appearance

Congenital cutis laxa is an uncommon disorder of generalized elastolysis. The clinical picture is characterized by inelastic, loose, hanging skin that gives the appearance of premature aging. The disease is inherited most commonly in a severe autosomal recessive form, or as a relatively benign, autosomal dominant form. There is often systemic organ involvement in patients with the autosomal recessive form. Cardiopulmonary abnormalities are common and mainly determine the prognosis and life expectancy. Pulmonary emphysema, cor pulmonale, and right-sided heart failure generally caused by pulmonary disease are often seen in infancy. Various cardiovascular abnormalities including aortic aneurysm, pulmonary artery multiple branch stenosis have been reported in patients with this form of congenital cutis laxa. We report a 10-month-old boy with the autosomal recessive form of congenital cutis laxa who had pulmonary valve stenosis. To the best of our knowledge, this is the first case of this association to be reported in the English language literature. We also emphasize the systemic complications that may be associated with congenital cutis laxa.     

A 5-year Journey with Cutis Laxa in an Indian Child: The De Barsy Syndrome Revisited

De Barsy syndrome (DBS), synonymously known as autosomal recessive cutis laxa type III, is an extremely rare condition clinically characterized by cutis laxa, a progeroid appearance, and ophthalmologic abnormalities. We present here an account of 5-year follow-up since the birth of an Indian boy with DBS, who had a few rare and unusual manifestations. In addition, our case probably represents the first reported case of DBS from India.     

Congenital generalized cutis laxa: 5 cases]

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 Type II with Mutation in the Pyrroline‐5‐Carboxylate Reductase 1 Gene

A 14‐year‐old Iranian boy with congenital cutis laxa and several other typical autosomal recessive type II features was examined. Mutation analysis of the pyrroline‐5‐carboxylate reductase 1 gene revealed a single‐base deletion (c.345delC) in exon 4 leading to frame shift and premature termination of translation.     

Cutis laxa, congenital form with pulmonary emphysema: an ultrastructural study

A case of a congenital, autosomal recessive form of generalized cutis laxa with pulmonary emphysema was histologically and ultrastructurally investigated. The cutaneous abnormalities observed seem to result mainly from a developmental defect of the elastic network which is absent in the papillary dermis and blocked at an early state of its formation in the upper and mid-reticular dermis. The union between the two elastic fibre components appears to be defective; the vectorial synthesis is non-existent and the elastic fibres remain in the state of dystrophic elastic units. Evidence is given to suggest that cutis laxa, presenting several described structural patterns, should be considered as a syndrome.     

Generalized Cutis Laxa Associated with Heavy Chain Deposition Disease

BACKGROUND: Cutis laxa is a heterogeneous group of inherited and acquired disorders characterized clinically by loose skin and histologically by altered elastic tissue. Heavy chain deposition disease is a very rare monoclonal immunoglobulin disorder, distinct from multiple myeloma, in which there is production and deposition of defective immunoglobulin heavy chains without light chain deposition. OBJECTIVE: We describe a case of acquired cutis laxa associated with heavy chain deposition disease. RESULTS: A 50-year-old male presented with acute renal failure, IgG4 heavy chain deposition in the kidneys, and no evidence of multiple myeloma. Four years later, he developed generalized acquired cutis laxa, emphysema, and a peripheral polyneuropathy. On pathology, there was destruction of elastic fibers within the dermis. CONCLUSION: This case describes a previously unreported association between acquired cutis laxa and heavy chain deposition disease.     

Cutis laxa in hereditary gelsolin amyloidosis

BACKGROUND: Hereditary gelsolin amyloidosis (AGel amyloidosis) is an age-associated systemic disease with global distribution, caused by a G654A or G654T gelsolin gene mutation. Cutis laxa is a principal clinical manifestation of this disease. However, only few data on the dermatological involvement are available, and the pathogenesis of this amyloidosis-associated form of cutis laxa has remained unknown. OBJECTIVES: To elucidate the pathomechanism of this less well-known genodermatosis. METHODS: We performed systematic clinical, histological, immunohistochemical and ultrastructural skin biopsy studies in 12 patients with a G654A gelsolin gene mutation. For comparison, skin specimens from 10 control subjects were analysed. RESULTS: All patients had clinically characteristic cutis laxa, and frequently other signs of symptomatic skin disease such as increased fragility and risk for intracutaneous bleeding. All patients showed cutaneous deposition of gelsolin amyloid (AGel), mainly attached to basement membranes or basal laminae of various cutaneous structures, dermal nerves and blood vessel walls, and elastic fibres, particularly in the lower reticular dermis. AGel often encircled the elastic fibres, and colocalized with amyloid P component (AP), an elastic fibre microfibrillar sheath-associated protein. Fragmentation and loss of elastic fibres, epidermal atrophy, and reduction of dermal appendages were also common. Antibodies to wild-type gelsolin bound to S-100-positive epidermal dendritic cells, a previously unrecognized immunoreaction. Patients had fewer gelsolin-positive dendritic cells than controls. CONCLUSIONS: Widespread skin involvement with AGel deposition and elastic fibre involvement are essential pathological features in AGel amyloidosis, and contribute to the characteristic cutis laxa, dramatic in old age. Codistribution of AGel and AP, with demonstrated specific binding affinity for amyloid fibrils, suggests that elastic fibre-associated AP acts as a matrix for cutaneous amyloid deposition in AGel amyloidosis.     

Cutis laxa associated with central hypothyroidism owing to isolated thyrotropin deficiency in a newborn

Abstract:  Cutis laxa is an uncommon entity characterized by laxity of the skin, which hangs in loose folds, producing an appearance of premature aging. It can be subdivided into congenital and acquired forms. Genetic forms of cutis laxa include at least three forms of recessive disease, an X-linked form also termed occipital horn syndrome and an autosomal dominant form. Isolated pituitary hormone deficiency can be induced by many causes including mechanical destruction of the hypothalamo-pituitary axis, neoplasm, inflammation, and injury and genetic defects of pituitary hormone production and secretion. Isolated-thyrotropin deficiency has been considered to be a rare disease. We report a newborn with autosomal recessive form of congenital cutis laxa, who had congenital hypothyroidism owing to isolated thyrotropin deficiency. To the best of our knowledge, this is the first instance of this association to be reported in the literature.     

Postinflammatory elastolysis and cutis laxa. A case report

One of the rarest forms of cutis laxa is postinflammatory elastolysis and cutis laxa, a disease previously reported only in children in Africa and South America. This disease is characterized by an urticarial or papular eruption followed by acute destruction of elastic tissue that results in atrophy and severe disfigurement. It is distinguished from anetoderma and acquired cutis laxa by its clinical features, its occurrence in young children, and its relatively benign course. This article describes the first case of postinflammatory elastolysis and cutis laxa reported in a white child from North America.     

A Novel Elastin Gene Mutation in a Vietnamese Patient with Cutis Laxa

We report a 3‐year‐old girl from Vietnam with severe congenital cutis laxa; no cardiovascular, pulmonary, neurologic, or visceral involvement; and no family history of cutis laxa. Mutational analysis of the elastin gene identified heterozygosity for a previously unreported de novo c.2184delT mutation in exon 30 not present in either parent.     

Penicillamine-induced Elastosis Perforans Serpiginosa and Cutis Laxa in a Patient with Wilson's Disease

Elastosis perforans serpiginosa (EPS) is a rare reactive perforating dermatosis that is characterized by the transepidermal elimination of abnormal elastic fibers. Penicillamine, which is one of the clear triggers for EPS, is a heavy metal chelator that is primarily used for disorders such as cystinuria and Wilson''s disease. It may cause alterations in the dermal elastic tissue such as pseudo-pseudoxanthoma elasticum, acquired cutis laxa, EPS and anetoderma. Herein we present a case of cutis laxa and EPS in a 34-year-old man who was previously on a long-term, high-dose of penicillamine for Wilson''s disease. The combination of EPS and cutis laxa induced by penicillamine has rarely been reported and we report the first such case in Korea.     

Autosomal recessive cutis laxa in two siblings associated with blue sclera

Abstract:  Cutis laxa is a clinical entity found in a heterogeneous group of genetic and acquired disorders characterized by premature aging of the skin with normal wound healing. We report two siblings born of consanguineous parents who presented with growth retardation, delayed developmental milestones, and the classical phenotypic manifestations of type 2 recessive cutis laxa. They showed remarkable blue sclera, which to our knowledge has not been reported previously in cutis laxa.     

Cutis laxa: case report

Cutis laxa is a rare inherited or acquired disorder of elastic tissue characterized by inelastic and loose skin. Congenital cutis laxa may present with internal organ involvement, determining a worse prognosis. The authors present the case of a female patient with clinical manifestations suggestive of the hereditary form of the disease, with consanguineous parents (second-degree cousins) and a brother who died with a similar clinical presentation. The genetic study of the FBLN5 gene was important to confirm the diagnosis, define the prognosis, and provide genetic counseling to the family.     

Costello综合征合并皮肤松弛症一例基因突变检测

目的 报告1例并发皮肤松弛症的Costello综合征患者,并进行分子遗传学诊断.方法 收集1例合并有皮肤松弛症的Costello综合征患者临床资料,提取该患者皮肤组织和其父母及150例无关健康对照的外周血基因组DNA,对HRAS基因所有外显子和侧翼序列测序.结果 患儿女,13月龄,生长发育迟缓,重度营养不良,面容粗糙,四肢皮肤严重松弛,皮下脂肪减少甚至消失.患儿HRAS基因第2外显子出现突变c.34G＞ T(p.Gly 12Cys),但其父母及健康对照均未检测到该位点突变.结论 HRAS基因第2外显子c.34G＞ T(p.Gly12Cys)突变可能为该例Costello综合征的致病原因.     

Heterogeneity of elastin expression in cutis laxa fibroblast strains

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.     

Localized acquired cutis laxa associated with trachyonychia

Acquired cutis laxa is a rare disease of unknown cause, which affects elastin metabolism. Clinically, it is characterized by redundant skin and hyperelasticity, while the histological study shows a reduction in or absence of elastic fibers in the dermis. We present a case of localized acquired cutis laxa associated with trachyonychia.