ELN – Autosomal dominant cutis laxa

Autosomal dominant cutis laxa (ADCL) is a rare connective tissue disorder characterized by loose, redundant skin folds, typical aged facial features, and multisystem involvement including cardiovascular and pulmonary complications. The condition follows an autosomal dominant inheritance pattern with most patients harboring heterozygous frameshift mutations in the last five exons of ELN, leading to C-terminal protein extensions and dominant-negative effects. Clinical manifestations include skin laxity, inguinal hernias, aortic root dilatation, emphysema, and occasional urogenital anomalies (HP:0000119).

Genetic evidence for ELN in ADCL is robust. A large case series and literature review identified 39 previously reported ADCL patients with frameshift mutations in exons 30–33 ([PMID:28383366]), while a targeted sequencing study in five probands revealed five de novo heterozygous ELN mutations, including c.2137delG (p.Ala713ProfsTer) ([PMID:21309044]). An Orphanet cohort of 20 patients from six families (including one sporadic case) confirmed a mutational hotspot in exon 32 (c.2262delA) and recurrence of C-terminal frameshifts ([PMID:23442826]). Together, these studies document over 60 independent probands across multiple families.

Segregation analyses across families demonstrate consistent co-segregation of ELN mutations with disease, with de novo occurrences and familial transmission. Mutation spectrum is dominated by frameshifts in exons 30–34; missense and splice variants are rare in ADCL, reinforcing a gain-of-function or dominant-negative mechanism rather than simple haploinsufficiency.

Functional studies corroborate the pathogenic mechanism. Electron microscopy of patient fibroblasts shows elastic fiber fragmentation and reduced dermal elastin deposition, while RT-PCR demonstrates stable mutant mRNA escaping nonsense-mediated decay and leading to C-terminally extended tropoelastin. In vitro assays reveal impaired tropoelastin deposition onto microfibrils, enhanced coacervation, increased endoplasmic reticulum stress, apoptosis, and upregulated TGF-β signaling in ADCL fibroblasts ([PMID:21309044]).

No significant conflicting data have been reported for ADCL, and all variants in the last five exons of ELN show concordant genetic and functional evidence. The disease mechanism appears distinct from ELN-related supravalvular aortic stenosis, which arises via haploinsufficiency of N-terminal variants.

Integration of genetic and experimental data yields a definitive association between ELN and ADCL. ELN mutation analysis should be included in diagnostic panels for cutis laxa and related connective tissue disorders. Key Take-home: ELN C-terminal frameshift mutations cause ADCL through dominant-negative tropoelastin extension, supporting targeted genetic testing and family counseling.

References

• Clinical dysmorphology • 2017 • A novel case of autosomal dominant cutis laxa in a consanguineous family: report and literature review. PMID:28383366
• Human mutation • 2011 • New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations. PMID:21309044
• Orphanet journal of rare diseases • 2013 • Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. PMID:23442826

Evidence Based Scoring (AI generated)