Elastin gene (ELN) mutations have been associated with various skin, cardiovascular and pulmonary phenotypes. Microdeletions of the region on 7q11, encompassing the ELN gene, result in Williams-Beuren syndrome (WBS, OMIM #194050) 1 . This recognizable entity combines mental retardation with a happy demeanor, typical facial gestalt, a soft, slightly elastic and doughy skin, hypercalcaemia, and arterial stenoses, mainly of the supravalvular aorta. A related disorder is the supravalvular aortic stenosis (SVAS, OMIM #185500) phenotype. These patients present without the mental and dysmorphic features encountered in the WBS, but do show arterial stenoses. SVAS is caused by missense and premature truncation mutations that are dispersed throughout the ELN gene 2 .

In contrast, frameshift mutations at the 3’ terminus that result in a C-terminally elongated and secreted elastin protein 3 4 5 6 7 8 have been identified in autosomal dominant cutis laxa (ADCL, OMIM #123700). This disorder comprises generalized skin redundancy, pulmonary emphysema and aortic root dilatation (ARD).

Different mechanisms underlying the perturbations subsequent to elastin mutations have been identified. In general, reduced elastin secretion and deposition, resulting in increased vascular smooth muscle cell proliferation and a higher number of smaller elastic lamellae, induces a phenotype dominated by arterial stenoses 9 , while aberrant elastin protein production infers to elastic fiber fragmentation with manifest cutis laxa, arterial dilatation and/or emphysema 3 .

To date, frameshift mutations in the 3’UTR of the elastin gene have been identified in 11 probands with ADCL, but it remains a matter of debate whether other molecular mechanisms could be involved. Indeed, two reports indicated a different molecular basis including a heterozygous mutation in exon 25 of the elastin gene 10 , and a tandem duplication in the fibulin-5 gene 11 , respectively. Moreover, in the absence of large patient cohorts, the ADCL phenotype is still insufficiently characterized and not always easy to discern from related forms of cutis laxa. Furthermore, the identification of an ELN variant in exon 34 (c.2318G>A; p.(G773D)) complicated genotype-phenotype correlations in the ELN gene. This variant was associated with pulmonary emphysema 12 and, in conjunction with a p.G202R alteration in the fibulin-5 protein, with acquired cutis laxa following a parasitic infection 13 . Finally, a case report mentions causal involvement of the ELN gene in a recessive form of cutis laxa due to a p.(P211S) alteration 14 .

We report on six novel ADCL families, comprising 19 patients, and one sporadic patient, with a review of the literature. Our data favor homogeneity both at the clinical and molecular level.

We present the largest patient cohort with ADCL thus far. The phenotype is homogeneous and comprises generalized skin involvement, inguinal and umbilical hernias, ARD and emphysema. The disorder shows full penetrance, but with variable expression. The aspect and topography of the skin lesions is highly variable but the skin changes are most pronounced on the axillar, inguinal, neck and lower facial regions. In congruence with earlier reports 5 8 , skin manifestations improve with aging and the phenotype may be unrecognized in older patients. Although ADCL is often considered ‘benign’, systemic involvement, although variable, is frequently present. Both lung (present in 35% of patients) and aortic involvement (present in 57% of patients) have led to premature death 5 7 . Patient management therefore warrants close monitoring of pulmonary function and aortic root diameters. No current treatment guidelines are available for ADCL patients. Because earlier reports indicated increased TGFβ signaling in the pathogenesis 3 , thresholds for aortic surgery could be based on similar parameters as in elastinopathies/TGFβ signalopathies associated with ARD (actual aortic diameter, rate of aortic growth, family history, the patient’s estimation of the risk, and pregnancy wish) 15 . Moreover, this mechanism might reveal a role for treatment with losartan, an angiotensin II type 1 receptor blocker with TGFβ antagonistic effect. Surgery for skin manifestations and hernias is disappointing and should be discouraged if done purely for aesthetic reasons.

The phenotype can be distinguished from autosomal recessive types of cutis laxa (ARCL) based on facial gestalt, the absence of skeletal, ocular, and central nervous involvement (type 2 and 3 ARCL) 16 17 , and the absence of severe early onset emphysema and gastrointestinal and genitourinary diverticula (type 1a/c ARCL 18 ) or arterial involvement (type 1b related cutis laxa) 19 (Table 4). The small number of patients described to date does not allow drawing straight-forward genotype-phenotype correlations, although a tendency for a milder vascular phenotype exists in exon 32 mutations. Mutations in this exon might be partially rescued by enhanced splicing of this exon 3 .

ARD, aortic root dilatation; SVAS, supravalvular aortic root stenosis; PPAS, peripheral pulmonary artery stenosis; CPAS, common pulmonary artery stenosis; AD, autosomal dominant; AR, autosomal recessive. References: 3 4 5 6 7 8 18 19 20 21 22 .

The clinical homogeneity of the phenotype corresponds to a striking molecular homogeneity with mutations found in the 3’terminus of the ELN gene. All mutations reside in exons 30, 32, 33, and 34 and result in a missense and elongated sequence at the C-terminus of the elastin protein 3 4 5 6 7 8 . Mutation analysis should focus firstly on these exons, although splice site mutations elsewhere in the ELN gene could also result in a C-terminal extension of the protein. Frameshift mutations resulting in C-terminal protein extensions have been identified in a variety of other diseases resulting in mislocalization, altered secretion, increased or decreased stability, resistance to proteases, loss-of-function, gain-of-function, and novel functions of the affected protein 23 24 25 26 27 28 . Extended proteins may also result from impaired processing of propeptides. A well-known example within the field of connective tissue disorders is the Ehlers-Danlos syndrome type VII that results from mutations in the substrate collagen type 1 or in its type 1 procollagen N-proteinase (type VIIC). In both cases the N-terminus of the procollagen type 1 is not removed and the mutant collagen is deposited into the extracellular matrix with severe dermal and internal organ consequences 29 30 . In ADCL it was shown that the altered and extended C-terminus resulted in increased endoplasmatic reticulum stress (due to protein misfolding), increased coacervation and elastin globule formation leading to lower amounts of insoluble, mature elastin. Enhanced TGFβ signaling is probably secondary to altered elastic fiber anatomy 3 .

Two reports indicated molecular heterogeneity in ADCL. In a single ADCL patient, a tandem duplication in the FBLN5 gene was shown to result in secretion of mutant protein, suggesting a dominant negative effect 11 . However, mutant protein integration in the extracellular matrix has been shown in FBLN5 related ARCL type 1 31 and carriers of these mutations do not have a cutis laxa phenotype. A second report showed a mutation in exon 25 of the ELN gene which encodes a conserved cross-linking domain important for insoluble elastin formation 10 . This patient also presented with severe neurological involvement, which was not attributed to his cutis laxa syndrome. His father carried the same alteration, but did not exhibit any phenotype. Future confirmation of these two defects may shed further insights on the molecular heterogeneity of ADCL. Until then, ADCL can be considered as a phenotypically and genetically homogeneous disorder in which analysis of exon 30-34 of the ELN gene is indicated in first instance.

This cohort of patients further indicates that ADCL is a systemic disorder with a risk for major complications including aortic root dilatation and pulmonary emphysema, warranting regular follow-up. The molecular data favor a single mutational mechanism resulting in a stable C-terminal extension of the elastin protein.

ADCL: Autosomal dominant Cutis Laxa; ARCL: Autosomal recessive cutis laxa; ARD: Aortic rooth dilatation; ELN: Elastin; SVAS: Supravalvular aortic stenosis; WBS: Williams-Beuren syndrome; TGFβ: Transforming Growth Factor β

The authors declare no competing interests.

SHR and BLC reviewed patients, designed the study and drafted the manuscript. EB, MK, ASP, VL and DB reviewed patients. MR and PJC performed and supervised the molecular analyses. JDB, FM, OMV and ADP contributed to clinical assessment, sample collection and drafting of the manuscript. CB reviewed patients, and contributed in the design of the study. All authors have read and approved the final manuscript.