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The CL syndromes are multisystem disorders that share loose redundant skin folds as a common hallmark clinical feature. Currently, the classification of cutis laxa disorders is based on the constellation of extradermal features and the mode of inheritance. On examination with light microscopy, skin biopsies are characterized by severe elastic fiber fragmentation. The underlying molecular defects in these heterogeneous disorders involve all steps in elastic fiber assembly and therefore provide a basis for elucidating this complex process.
The aims of this project are:
- The clinical characterization of the different cutis laxa disorders
- The molecular characterization of the different cutis laxa disorders
- The identification of novel genes in cutis laxa disorders
- The functional evaluation of known and novel genes underlying cutis laxa disorders using patient materials and animal models.
As a reference center for the molecular diagnosis of cutis laxa disorders, we have gathered large cohorts of patients affected by these very rare entities.
Molecular analysis in cutis laxa syndromes is done by PCR-based next generation sequencing of all known cutis laxa genes (turn-around time 3 months). In the absence of causal mutations, exome sequencing is carried out.
Further functional analysis includes experimentation on cellular cultures, serum analysis, light and electron microscopy of relevant tissues and zebrafish modeling using CrisprCas9 technology.
We are happy to include novel patients provided sufficient clinical information and DNA samples of both affected and non-affected family members are available. For further contact information, see LINK
As such, we could characterize the clinical and molecular features of autosomal dominant and type 1 recessive cutis laxa. In autosomal dominant cutis laxa we made the important observation, in contrast to previous reports, that patients are at risk for severe complications including pulmonary emphysema and aortic root dilatation.
At the molecular level we confirmed the homogeneity of ADCL showing that all mutations reside at the 3’ end of the ELN gene, encoding elastin. These mutations cause a frameshift and result in a stable and partially secreted elastin protein that interferes with normal elastin deposition. It enhances the naturally occurring self-assembly of elastin molecules, a process called coacervation. Increased coacervation interferes with correct deposition of elastin on the microfibrils prohibiting correct crosslinking.
We further delineated the clinical and molecular findings in autosomal recessive cutis laxa type 1 that typically shows severe cardiopulmonary complications as the main systemic manifestations. Types 1a (ARCLt1a) and 1c (ARCLt1c, also known as Urban-Rifkin-Davis syndrome) are very similar disorders and result in life-threatening emphysematous lung changes and mechanical insufficiency of the gastrointestinal and genitourinary tract wall. Studying FBLN4, FBLN5 and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in 2 probands, whereas 9 probands harbored biallelic mutations in LTBP4. No mutations were identified in FBLN4. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor beta (TGFβ) signaling. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.R1377fsX27) caused altered binding to fibrillin-1 and loss of binding to fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ signaling. ARCL type 1b (ARCLt1b) is typically characterized by elongation, tortuosity and aneurysm formation of the large and middle-sized arteries. Typically, most patients have a focal stenosis at the aortic isthmus. Again clinical variability is wide and though patients may die in the neonatal period, others have survived in their twenties. ARCL type 1b is caused by mutations in FBLN4 and result in increased TGFβ signaling similarly to other aneurysm disorders.
In ARCL type 2 and 3, the systemic involvement typically includes central nervous and skeletal abnormalities. Type 3 ARCL further shows ocular manifestations that are generally not present in type 2 cutis laxa. ARCL type 2 comprises the historically denominated ‘Debré-type’ cutis laxa and the milder wrinkly skin syndrome within the same spectrum. Patients present with an elongated face, slight hypertelorism, downslanting palpebral fissures, a beaked nose, and a rather long philtrum. Cutis laxa manifests as a wrinkled skin on the dorsum of hands and feet, but may be more generalized and with more sagging skin, especially with increasing age. Delayed neuromotor development is common but not invariably present. Epilepsy occurs and often associates with brain malformations including cobblestone brain dysgenesis (slight degree of lissencephaly). Skeletal involvement may result in short stature, congenital dislocation of the hips, joint hypermobility, and a risk for bony exostoses and extraskeletal bone formation in older individuals. Mutations are found in ATP6V0A2, encoding a component of the lysosomal ATPase. These patients invariably have N- and /or O-glycosylation defects. Some individuals have been described to harbor mutations in PYCR1, but may lean closer to type 3 ARCL, though ocular involvement was absent.
The syndromic constellation in type 3 recessive cutis laxa includes craniofacial characteristics with a typical triangular face, skeletal involvement with short stature, congenital dislocation of the hips and joint hypermobility and neuromotor delay. Epilepsy can occur. The skin shows wrinkles of the hands and feet, rather than prominent cutis laxa. Brain malformations include corpus callosum hypoplasia or agenesis, and polymicrogyria. The most prominent ocular manifestation is corneal clouding due to rupture of Descemet’s membrane. Cataract can occur. Patients may harbor mutations in PYCR1 or ALDH18A1. The latter often have a more severe involvement with severely delayed neuromotor development, more severe brain malformations, and tortuosity of the brain arteries. These patients may have abnormal levels of serum amino acids.
X-linked cutis laxa, formerly also called occipital horn syndrome and Ehlers-Danlos syndrome type 9, is situated within the spectrum of Menkes disease. Main abnormalities include cutis laxa, urogenital tract diverticula and skeletal exostoses. The cutis laxa can be generalized, but mostly shows wrinkles of the dorsum of hands and feet and of the belly. The facial skin can be sagging and may lead to a coarse appearance. Diverticula of the urogenital tract, especially of the bladder, can be impressive and an underlying reason of pollakisuria (due to inadequate voiding) and recurrent urinary tract infections. The most typical skeletal manifestation includes the formation of a bony ‘horn’ or exostosis, at the insertion of the trapezius muscle. Exostoses can occur at any muscle insertion and may limit joint movements. Joint hypermobility, especially of the small joints is usually present. A highly indicative sign is the presence of pili torti (twisted hair shafts) that can be readily seen on a microscopic evaluation of the scalp hair. Furthermore, tortuosity of the intracranial and retinal arteries completes the tableau. Neuromotor delay, when present, is often mild. In contrast, Menkes disease, at the more severe end of the spectrum, shows severe neuromotor delay and a metaphyseal skeletal dysplasia with growth retardation in addition to these characteristics. The disorder is caused by hemizygous mutations in the ATP7A gene. Recently, our group found, in an international collaboration, that deep intronic mutations can be at the molecular basis of X-linked cutis laxa.
Last updated: 17 July 2018 - 17:00
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