Autosomal Dominant Cutis Laxa 1: Disease Characteristics Report

Executive summary and scope

Autosomal dominant cutis laxa 1 (ADCL1) is an exceptionally rare, germline ELN-related elastinopathy. Its defining manifestation is congenital or early-onset loose, redundant, poorly elastic skin, but it is a systemic disorder because aortic-root dilatation, valvular disease, pulmonary emphysema, and hernias can occur. The best quantitative evidence remains a 2013 cohort of only 20 clinically evaluated patients; accordingly, frequencies below are estimates from selected families rather than population-level rates. Recent ADCL1-specific research in 2023–2024 was extremely limited, and contemporary work has not displaced the mechanistic model established by human fibroblast, ultrastructural, and transgenic-mouse studies. (hadjrabia2013twentypatientsincluding pages 1-2, callewaert2011newinsightsinto pages 10-12)

A compact knowledge-base representation is provided here, followed by detailed interpretation.

Table: Compact evidence table for ELN-related autosomal dominant cutis laxa 1, covering phenotype frequencies, variants, mechanism, diagnosis, surveillance, treatment, and evidence gaps. It explicitly distinguishes ADCL1 from predominantly recessive FBLN5-related cutis laxa.

1. Disease information

Definition. ADCL1 is a Mendelian connective-tissue disorder in which heterozygous pathogenic variants—usually frameshifts near the 3′ end of ELN—produce abnormal tropoelastin and defective elastic fibers. Unlike ordinary skin hyperextensibility, cutis laxa denotes skin that is loose, hangs in folds, and returns slowly after stretching. Internal elastic-fiber-rich organs may also be affected. (callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 1-2, lasio2018elastindrivengeneticdiseases pages 4-6)

Identifiers and nomenclature. The securely supported identifier is OMIM/MIM 123700. Common names are autosomal dominant cutis laxa, autosomal dominant cutis laxa type 1, ADCL, ADCL1, ELN-related cutis laxa, and dominant cutis laxa. ELN itself is OMIM 130160. A subtype-specific MONDO identifier could not be verified from the retrieved evidence; similarly, Orphanet, MeSH, ICD-10, and ICD-11 appear to classify cutis laxa more broadly rather than providing a reliably verified ADCL1-specific code. These fields should therefore be resolved directly against current ontology releases rather than inferred. (hadjrabia2013twentypatientsincluding pages 1-2, lasio2018elastindrivengeneticdiseases pages 2-4)

Critical disease boundary. ADCL1 should not be mislabeled as FBLN5-related disease. Classical ADCL1 is ELN-related, whereas biallelic FBLN5 variants predominantly cause autosomal-recessive cutis laxa type 1A. Reports suggesting dominant FBLN5 cutis laxa have not established FBLN5 as the routine cause of ADCL1. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 6-7)

Evidence provenance. Available information is aggregated from disease-level resources, multigenerational pedigrees, small cohorts, case reports, patient-derived fibroblasts, biopsies, and engineered mice. It is not based on a representative EHR population.

2. Etiology, risk, and protective factors

Causal factors

ADCL1 is caused by a heterozygous constitutional ELN pathogenic variant. Most established alleles are frameshifts in exons 30–34 that escape complete nonsense-mediated decay and encode tropoelastin with a missense-altered, extended C terminus. Splice-altering variants can converge on the same abnormal reading frame. This differs from ELN haploinsufficiency, which more characteristically causes supravalvular aortic stenosis, and from a 7q11.23 deletion including ELN, which causes Williams–Beuren syndrome. (akcay2020consequencesofelastinb pages 1-3, hadjrabia2013twentypatientsincluding pages 1-2, lasio2018elastindrivengeneticdiseases pages 4-6)

Genetic risk and modifiers

A pathogenic ELN allele is the primary risk factor; an affected heterozygous parent confers a theoretical 50% risk per pregnancy. Both vertical transmission and de novo occurrence are documented. Alternative ELN splicing is a demonstrated biological modifier: exon 32 was absent from about 70% of control transcripts in one study, potentially reducing the burden of variants located in that exon. Tissue-specific incorporation of mutant protein also modifies organ involvement. Firm modifier genes, founder alleles, or polygenic risk scores have not been established. (callewaert2011newinsightsinto pages 1-2, callewaert2011newinsightsinto pages 7-9, lasio2018elastindrivengeneticdiseases pages 4-6)

Environmental and protective factors

No environmental, infectious, dietary, occupational, or lifestyle exposure causes inherited ADCL1, and no protective allele or intervention has been demonstrated. Avoiding tobacco smoke and inhaled pollutants is prudent because emphysema is an important complication, but this is extrapolated respiratory-risk reduction—not proof of an ADCL1-specific gene–environment interaction. Alpha-1-antitrypsin deficiency was excluded in two severely affected patients, indicating that their emphysema was not explained by that common genetic risk factor. (callewaert2011newinsightsinto pages 7-9)

3. Phenotypes

The strongest frequency estimates come from 20 clinically evaluated individuals aged 1–84 years. Because ascertainment was syndromic and familial, confidence intervals and generalizability are limited. (hadjrabia2013twentypatientsincluding pages 1-2)

• Cutis laxa—clinical sign/physical manifestation: present in 100%; approximately 75% had extensive/generalized laxity and 25% localized redundancy involving the face, neck, axillae, or groin. Onset is usually congenital or in infancy. Severity ranges from mild regional redundancy to severe neonatal disease; skin conspicuousness may lessen with age. Suggested HPO labels: Cutis laxa, redundant skin, generalized skin laxity, and abnormality of dermal elastic fibers. (hadjrabia2013twentypatientsincluding pages 1-2, kun2022congenitalcutislaxa pages 2-4)
• Characteristic face—physical manifestation: long or coarse prematurely aged face, large pliant ears, long philtrum, beaked nose, ptosis, and blepharochalasis. Facial gestalt was reported in all patients in one analysis, while the long-face/large-ear/long-philtrum/beaked-nose constellation occurred in about 70%. Suggested HPO labels: Long face, long philtrum, beaked nose, large ears, ptosis, blepharochalasis, and prematurely aged appearance. (hadjrabia2013twentypatientsincluding pages 5-6, hadjrabia2013twentypatientsincluding pages 1-2)
• Hernia—clinical sign: inguinal hernia occurred in approximately 50–51%; umbilical hernia is also reported. Hernias can arise in infancy and recur because the underlying matrix defect persists. Suggested HPO: Inguinal hernia and umbilical hernia. (hadjrabia2013twentypatientsincluding pages 5-6, graul‐neumann2008highlyvariablecutis pages 1-2, callewaert2011newinsightsinto pages 6-7)
• Aortic disease—imaging/clinical sign: aortic-root dilatation occurred in 55–57% and may progress during childhood or adolescence. In one adolescent, the root increased from 41 mm to 45 mm by age 17. Suggested HPO: Aortic root dilatation and ascending aortic dilatation. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 6-7)
• Valvular disease—clinical/imaging sign: other valve anomalies were reported in 38%, with bicuspid aortic valve in 5%; mitral-valve prolapse also occurs. Bicuspid valve may accompany both root and ascending-aortic enlargement. Suggested HPO: Bicuspid aortic valve and mitral valve prolapse. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 10-12)
• Pulmonary emphysema/obstruction—clinical and functional abnormality: emphysema occurred in 35–37% and can be severe in childhood. One 12-year-old had FEV1/FVC 42.9% and residual volume 209%. A severe congenital case had repeated pneumothoraces and required respiratory support through day 69. Suggested HPO: Pulmonary emphysema, obstructive lung disease, pneumothorax, and dyspnea. (hadjrabia2013twentypatientsincluding pages 1-2, graul‐neumann2008highlyvariablecutis pages 1-2, callewaert2011newinsightsinto pages 6-7)
• Additional variable findings: joint hypermobility, vocal-cord laxity/hoarse voice, diaphragmatic eventration, gastrointestinal or genitourinary diverticula, and feeding difficulty have been reported, but reliable ADCL1-specific frequencies are unavailable. (hadjrabia2013twentypatientsincluding pages 6-7, graul‐neumann2008highlyvariablecutis pages 1-2, callewaert2011newinsightsinto pages 6-7)

Formal EQ-5D, SF-36, PROMIS, disability, or behavioral data were not found. Cosmetic distress, exertional limitation, repeated surgery, and lifelong cardiopulmonary surveillance are clinically plausible burdens but remain unquantified.

4. Genetic and molecular information

Causal gene. ELN, encoding tropoelastin/elastin, lies in the 7q11 region. The retrieved literature describes ELN as a 34-exon gene spanning approximately 45 kb and elastin as the major mass component of mature elastic fibers. Exact current HGNC and genomic-transcript identifiers should be taken from HGNC/NCBI rather than assigned from the retrieved articles. (akcay2020consequencesofelastin pages 1-3)

Representative pathogenic variants. Reported heterozygous germline alleles include c.2262delA—a recurrent exon-32 hotspot—c.2365delC, c.2189delG, c.2142delG, c.2296_2299dupGCAG, c.2333delC, c.2137delG, c.2124del25, c.2323delG (p.Ala775fs), and c.1985delG (p.Gly662Alafs*25). Historical transcript differences can alter residue numbering, so clinical reinterpretation should normalize every allele to a current MANE transcript. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 1-2, kun2022congenitalcutislaxa pages 2-4, okuneva2019anovelelastin pages 2-4)

Variant classification and population frequency. Variants producing the characteristic terminal frameshift may be pathogenic or likely pathogenic under ACMG/AMP criteria when supported by phenotype, segregation/de novo status, extreme rarity, and functional evidence. A 2019 c.2323delG allele was absent from ExAC's 60,706 individuals, 1000 Genomes' 2,535 individuals, and a 2,000-person local database; variants from another cohort were absent from 100 controls. These observations support rarity but are not allele-frequency estimates for ADCL1 overall. Missense or noncanonical splice variants require careful assessment; a VUS should not be used for predictive testing without further evidence. (okuneva2019anovelelastin pages 2-4, hadjrabia2013twentypatientsincluding pages 2-4)

Origin and consequences. Established variants are germline, not somatic. The dominant mechanism is best described as dominant-negative with possible toxic gain of function, rather than simple loss of function: stable mutant tropoelastin is secreted or retained, self-associates abnormally, and interferes with extracellular elastic-fiber assembly. Predicted abnormal C-terminal extensions of approximately 49, 53, or 86 residues were analyzed experimentally. (callewaert2011newinsightsinto pages 10-12, akcay2020consequencesofelastinb pages 1-3, lasio2018elastindrivengeneticdiseases pages 4-6)

No ADCL1-specific DNA-methylation signature, chromatin abnormality, recurrent CNV, aneuploidy, translocation, validated modifier gene, or somatic mosaic mechanism was identified. Large 7q11.23 deletions belong to the Williams–Beuren differential rather than typical ADCL1.

5. Environmental information

No toxin, radiation exposure, pollution source, occupation, diet, alcohol exposure, or infectious agent is established as causal or triggering. Standard avoidance of smoking, vaping, and avoidable pulmonary irritants is reasonable tertiary prevention for any patient at risk of emphysema, but no study quantified its effect in ADCL1. There is no zoonotic or transmissible component.

6. Mechanism and pathophysiology

Ordered causal chain

1. A heterozygous 3′ ELN frameshift or functionally equivalent splice defect leads to stable mutant transcripts encoding tropoelastin with an abnormal extended C terminus. (hadjrabia2013twentypatientsincluding pages 1-2, lasio2018elastindrivengeneticdiseases pages 4-6)
2. The altered C-terminal assembly domain leads to increased self-association, lower coacervation temperature, and abnormal elastin globules. (callewaert2011newinsightsinto pages 10-12)
3. Abnormal tropoelastin binding to fibrillin-1/fibulin-5 microfibrils results in poor elastin–microfibril integration and reduced mature insoluble elastin deposition. (callewaert2011newinsightsinto pages 10-12, merla2012supravalvularaorticstenosis pages 2-3)
4. Incorporation of mutant protein into fibers leads to a dominant-negative disruption of elastic-fiber architecture; intracellular retention can additionally result in ER stress, unfolded-protein-response activation, and apoptosis in an allele-dependent manner. (callewaert2011newinsightsinto pages 1-2, callewaert2011newinsightsinto pages 10-12)
5. Reduced and fragmented elastic fibers result in loss of recoil in dermis, aortic wall, valves, lung parenchyma, and hernia-prone connective tissue. (callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 1-2)
6. Loss of dermal recoil causes loose redundant skin and the characteristic aged facial appearance; loss of connective-tissue support causes hernias and possibly diverticula. (hadjrabia2013twentypatientsincluding pages 6-7, hadjrabia2013twentypatientsincluding pages 1-2)
7. Loss of pulmonary elastic recoil causes air-space enlargement, obstruction, emphysema, and occasionally pneumothorax. (graul‐neumann2008highlyvariablecutis pages 1-2, callewaert2011newinsightsinto pages 6-7)
8. Loss of arterial/valvular matrix integrity leads to aortic-root dilatation and valve abnormalities. Increased pSMAD2/TGF-β signaling may amplify remodeling, but this downstream contribution remains mechanistically inferred rather than proven as a treatment-responsive driver in humans. (callewaert2011newinsightsinto pages 10-12)
9. Modifier branch: alternative exon splicing and tissue-specific mutant-protein incorporation alter mutant dosage and therefore organ severity; this explains some inter- and intrafamilial variability. (callewaert2011newinsightsinto pages 7-9, lasio2018elastindrivengeneticdiseases pages 4-6)

Cells and processes. Dermal fibroblasts are directly supported by patient-cell studies; vascular smooth-muscle cells and pulmonary matrix-producing cells are biologically relevant but less directly profiled in human ADCL1. Suggested GO biological-process labels include elastic fiber assembly, extracellular matrix organization, protein folding, response to endoplasmic-reticulum stress, unfolded protein response, apoptotic process, TGF-beta receptor signaling, and alternative mRNA splicing. Suggested Cell Ontology labels are fibroblast, dermal fibroblast, vascular smooth-muscle cell, and pulmonary fibroblast.

Molecular profiling. Human biopsy electron microscopy demonstrated reduced, fragmented, branched, or disorganized elastic fibers and abnormal globules. Patient fibroblasts showed defective deposition, reduced insoluble elastin, allele-specific BiP, phosphorylated eIF2α and caspase-3 responses, and increased pSMAD2. These are targeted cellular/protein assays, not unbiased transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial, or multi-omic profiles. No ADCL1-specific omics signature or CRISPR screen was found. (callewaert2011newinsightsinto pages 1-2, callewaert2011newinsightsinto pages 7-9, callewaert2011newinsightsinto pages 10-12)

A useful direct abstract statement from the humanized-mouse study is: “Mutant transcripts incorporate into elastic fibers of skin and lung with adverse effects but not aorta.” This supports tissue-specific assembly as a biological modifier rather than assuming equal effects in all elastic tissues.

7. Anatomical structures affected

• Primary: skin/dermis, particularly face, neck, axillae, groin, and generalized integument; suggested UBERON labels: skin of body, dermis, skin of face.
• Cardiovascular: aortic root, ascending aorta, arterial elastic lamellae, aortic and mitral valves; suggested UBERON: aortic root, ascending aorta, aortic valve, mitral valve.
• Respiratory: lung parenchyma/alveolar elastic matrix and, variably, vocal cords; suggested UBERON: lung, pulmonary alveolus, vocal fold.
• Supportive connective tissues: inguinal and umbilical regions, diaphragm, and hollow-viscus walls.
• Subcellular/extracellular: ER, secretory pathway, extracellular matrix, microfibrils, and elastic fibers; suggested GO cellular components: endoplasmic reticulum, extracellular matrix, and elastic fiber.

Disease is generally bilateral/generalized rather than lateralized. Regional skin severity can nevertheless be asymmetric after growth or surgery.

8. Temporal development

Onset is usually congenital or during infancy and is chronic/lifelong. Skin folds may become less prominent with growth, but this is not molecular remission. Cardiovascular and pulmonary complications can emerge or progress during childhood, adolescence, or adulthood even when the skin phenotype appears mild. Severe neonatal respiratory presentations are possible but uncommon. (graul‐neumann2008highlyvariablecutis pages 1-2, kun2022congenitalcutislaxa pages 2-4, hadjrabia2013twentypatientsincluding pages 1-2, callewaert2011newinsightsinto pages 6-7)

There is no validated staging system. A practical course model is: (1) congenital/early cutaneous recognition; (2) ascertainment of hernia and baseline cardiopulmonary involvement; (3) longitudinal monitoring for aortic enlargement, valve disease, and airflow obstruction; and (4) complication-directed intervention. No spontaneous genetic remission occurs. Critical opportunities are early molecular diagnosis, baseline cardiovascular/pulmonary assessment, and continued surveillance through growth and pregnancy planning.

9. Inheritance and population

Inheritance is autosomal dominant, with marked variable expressivity. Phenotypic transmission occurred in 20 of 22 observed meioses in the principal cohort, and five de novo variants were reported in another series. Cutaneous penetrance appears high in documented pedigrees, while penetrance of aortic and pulmonary complications is incomplete or age dependent. Genetic anticipation is not established. Germline mosaicism is theoretically possible after an apparently de novo case but was not demonstrated in the retrieved evidence. Consanguinity does not cause this dominant disorder, although it may complicate differential diagnosis with recessive cutis-laxa syndromes. (callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 2-4, hadjrabia2013twentypatientsincluding pages 1-2)

No reliable incidence, prevalence per 100,000, carrier frequency, sex ratio, ethnic enrichment, founder effect, or geographic gradient is available. The largest cited cohort contained only 20 evaluated patients from six families plus one sporadic case. Both sexes and multiple geographic populations have been reported, without evidence of sex-linked risk. (hadjrabia2013twentypatientsincluding pages 1-2)

10. Diagnostics

Clinical and laboratory evaluation

Diagnosis begins with congenital/early loose inelastic skin, characteristic facial morphology, hernias, and family history, followed by cardiovascular and respiratory assessment. Baseline evaluation should include echocardiography of the aortic root, ascending aorta, and valves; ECG as clinically indicated; spirometry and lung volumes; and chest CT or MR/CT angiography when symptoms or initial findings justify radiation/cross-sectional imaging. There is no validated circulating biomarker or enzyme assay. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 6-7, hadjrabia2013twentypatientsincluding pages 1-2)

Skin biopsy with an elastic-fiber stain or electron microscopy is supportive: fibers may be absent, reduced, fragmented, branched, or poorly deposited. It is not definitive, because a severely affected neonate showed only mild elastic-fiber rarefaction. (graul‐neumann2008highlyvariablecutis pages 1-2, kun2022congenitalcutislaxa pages 2-4, callewaert2011newinsightsinto pages 1-2)

Genetic testing

1. Use an ELN-inclusive cutis-laxa/connective-tissue panel when the phenotype is recognizable but genetically heterogeneous.
2. Single-gene ELN sequencing may initially prioritize exons 30–34, but full coding/splice-region analysis is preferable because pathogenic splice variants can occur elsewhere.
3. Include deletion/duplication analysis where the assay does not detect CNVs.
4. Use WES or WGS when panel testing is negative, phenotype is atypical, or dual diagnoses are suspected; confirm clinically actionable variants by an orthogonal method and perform parental/segregation testing.
5. RNA studies from fibroblasts can resolve splice variants or transcript escape but are specialist functional tests, not routine first-line diagnostics. (graul‐neumann2008highlyvariablecutis pages 1-2, hadjrabia2013twentypatientsincluding pages 5-6, okuneva2019anovelelastin pages 2-4)

CMA, karyotyping, and FISH are not first-line tests for typical ADCL1 but may identify a 7q11.23 deletion in the Williams–Beuren differential. Mitochondrial-DNA and repeat-expansion testing are not applicable. No validated RNA-seq, proteomic, metabolomic, epigenomic, or liquid-biopsy diagnostic exists.

Differential diagnosis

Consider FBLN5-, EFEMP2/FBLN4-, LTBP4-, ATP6V0A2-, PYCR1-, and other recessive cutis-laxa syndromes; arterial-tortuosity syndrome; occipital-horn syndrome; Ehlers–Danlos syndromes; acquired inflammatory cutis laxa; progeroid disorders; isolated ELN-related supravalvular aortic stenosis; and Williams–Beuren syndrome. Severe developmental, neurologic, ocular, skeletal, metabolic, gastrointestinal, or diffuse arterial abnormalities should trigger reassessment for another subtype. Ehlers–Danlos skin is typically hyperextensible and associated with tissue fragility/abnormal collagen, whereas cutis-laxa skin is redundant and returns slowly. (callewaert2011newinsightsinto pages 1-2, kun2022congenitalcutislaxa pages 2-4, hadjrabia2013twentypatientsincluding pages 5-6)

No population or newborn screening program exists. Once a familial pathogenic variant is known, targeted cascade testing is appropriate.

11. Outcome and prognosis

Prognosis is variable and primarily determined by aortic and pulmonary involvement rather than cutaneous severity. Skin appearance may improve, while aortic-root dilatation or emphysema progresses. Patients in the principal cohort ranged up to 84 years, but that observation is not a life-expectancy estimate. No valid 5-year/10-year survival, mortality rate, disability rate, or prognostic-biomarker model is available. (hadjrabia2013twentypatientsincluding pages 1-2, callewaert2011newinsightsinto pages 6-7)

Potential major morbidity includes progressive aneurysmal aortic disease, valve dysfunction, severe COPD/emphysema, pneumothorax, recurrent hernias, hoarseness, exercise limitation, and recurrent cosmetic laxity after surgery. Variant position and exon skipping may influence severity, but current cohorts are too small for dependable genotype-based prognosis. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 7-9, lasio2018elastindrivengeneticdiseases pages 4-6)

12. Treatment and current applications

There is no approved therapy that corrects ELN or regenerates normal elastic fibers, and no ADCL1-specific gene, cell, RNA, CRISPR, targeted, or immunotherapy was identified. A ClinicalTrials.gov search found no relevant interventional ADCL1 trial; retrieved “skin laxity” trials addressed cosmetic/acquired laxity and should not be annotated as ADCL1 studies.

Current real-world care is multidisciplinary and complication directed:

• Cardiovascular: serial echocardiography, cross-sectional imaging when indicated, blood-pressure management, and referral to an inherited-aortopathy team. Aortic surgery must be individualized using diameter, growth rate, body size, valve anatomy, family history, pregnancy plans, and operative risk; ADCL1-specific thresholds have not been validated. Losartan has been proposed because of increased TGF-β signaling, but there is no ADCL1-specific efficacy trial. Suggested NCIT labels: Echocardiography, antihypertensive therapy, and cardiovascular surgery. (hadjrabia2013twentypatientsincluding pages 5-6)
• Pulmonary: smoking avoidance, vaccination according to routine respiratory guidance, bronchodilator/other COPD therapy when clinically indicated, pulmonary rehabilitation, prompt treatment of infections, and pneumothorax management. These are standard-care extrapolations, not genotype-specific treatments. Suggested NCIT: Supportive care and pulmonary rehabilitation.
• Hernias: repair when symptomatic or at risk of complications. Suggested NCIT: Hernia repair.
• Cutaneous/cosmetic: rhytidectomy or staged excision may temporarily improve appearance. Evidence is weak: among seven surgical patients summarized in a 2022 review, five had recurrence within months and two required more than two procedures; one recent patient remained recurrence-free at only five months. Suggested NCIT: Rhytidectomy and reconstructive surgery. (kun2022congenitalcutislaxa pages 2-4, kun2022congenitalcutislaxa pages 1-2)
• Genetic counseling and psychosocial care: explain recurrence risk, variable expressivity, and limitations of predicting systemic severity; offer appearance-related and chronic-disease support.

No disease-specific pharmacogenomic guidance, combination regimen, response rate, or adverse-event dataset exists.

13. Prevention

Primary prevention by lifestyle or vaccination is impossible for a constitutional pathogenic allele. Reproductive options after identifying the familial variant include preimplantation genetic testing, prenatal diagnosis, donor gametes, or natural conception with testing, guided by nondirective counseling. Predictive cascade testing of at-risk relatives is the principal secondary-prevention strategy because it enables cardiopulmonary surveillance before symptoms. Tertiary prevention includes blood-pressure control, avoidance of smoking and pulmonary irritants, respiratory vaccination under standard schedules, prompt hernia management, and specialist surveillance for aortic growth and lung disease. No public-health screening, prophylactic medication, or immunization specifically prevents ADCL1.

14. Other species and natural disease

The causal biology is evolutionarily conserved because elastin is essential to vertebrate elastic tissues. Nevertheless, no well-established, naturally occurring veterinary syndrome precisely homologous to human ELN-terminal-frameshift ADCL1 was identified in the retrieved evidence. Therefore, breed/VBO identifiers, natural incidence, veterinary burden, cross-species transmission, and zoonotic potential are not applicable or unavailable. Relevant experimental taxonomy is Mus musculus (NCBI Taxonomy 10090); the human taxon is Homo sapiens (9606).

15. Model organisms and experimental systems

Patient-derived fibroblasts and skin biopsy provide the most direct human mechanistic models. They reproduce abnormal tropoelastin coacervation and deposition, reduced insoluble elastin, microfibril-binding defects, allele-specific ER stress/apoptosis, and increased pSMAD2. Their limitation is that cultured dermal fibroblasts do not reproduce whole-organ mechanics or age-dependent aortic and pulmonary disease. (callewaert2011newinsightsinto pages 10-12)

Humanized transgenic mice carrying a human ADCL ELN frameshift incorporated mutant protein into skin and lung elastic fibers and developed adverse lung effects/emphysema. Mutant incorporation into aortic elastin was low, illustrating tissue-specific assembly. A related transgenic model showed intracellular retention, apoptosis, reduced lung stiffness, increased stretch, and increased TGF-β signaling. These mice are useful for elastogenesis, pulmonary mechanics, tissue-specific splicing, and proof-of-mechanism studies, but primate-specific ELN splicing and structural differences limit direct genotype–phenotype translation. (callewaert2011newinsightsinto pages 10-12)

By contrast, ELN-null mice die neonatally from vascular obstruction and ELN-heterozygous mice develop hypertension and altered arterial lamellae; these are valuable elastin-dosage models but do not reproduce the dominant-negative terminal-frameshift mechanism of ADCL1. (akcay2020consequencesofelastina pages 1-3)

Recent developments, expert interpretation, and research priorities

No 2023–2024 primary study retrieved here materially revised ADCL1 natural history or treatment. The most recent directly relevant clinical report in the search space described severe coronary disease in a young adult with an intronic ELN variant, but full text was unavailable and it was therefore not used as evidence. A 2024 bioinformatic study nominated oxidative-stress/SOD3-correlated genes across rare disorders, including dominant cutis laxa, but this is computational hypothesis generation rather than an ADCL1 biomarker or therapeutic validation.

The authoritative interpretation remains that ADCL1 is not merely cosmetic: the 2013 cohort concluded that “regular cardiovascular and pulmonary evaluations are imperative.” The central translational gap is the absence of prospective registries linking normalized ELN variants, transcript processing, organ imaging, pulmonary function, pregnancy outcomes, and patient-reported quality of life. Priority research needs are an international natural-history registry; standardized aortic and pulmonary surveillance intervals; longitudinal pregnancy data; updated gnomAD-normalized variant curation; patient-specific iPSC/organoid systems; single-cell and spatial profiling of aortic, pulmonary, and dermal matrix-producing cells; and preclinical tests of allele-specific RNA suppression or correction.

Evidence limitations and key references

The field relies heavily on small, nonrepresentative cohorts and older mechanistic studies. Percentages must not be interpreted as population prevalence, absence of reported findings is not proof of absence, and proposed TGF-β-directed treatment remains unvalidated.

Key accessible publications include:

1. Hadj-Rabia S, et al. Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. Orphanet Journal of Rare Diseases. Published February 2013;8:36. DOI/URL: https://doi.org/10.1186/1750-1172-8-36. (hadjrabia2013twentypatientsincluding pages 1-2)
2. Callewaert B, et al. New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations. Human Mutation. Published April 2011;32:445–455. DOI/URL: https://doi.org/10.1002/humu.21462. (callewaert2011newinsightsinto pages 1-2)
3. Sugitani H, et al. Alternative splicing and tissue-specific elastin misassembly act as biological modifiers of human elastin gene frameshift mutations associated with dominant cutis laxa. Journal of Biological Chemistry. Published June 2012;287:22055–22067. DOI/URL: https://doi.org/10.1074/jbc.M111.327940. (callewaert2011newinsightsinto pages 10-12)
4. Graul-Neumann LM, et al. Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene. American Journal of Medical Genetics Part A. Published April 2008;146A:977–983. DOI/URL: https://doi.org/10.1002/ajmg.a.32242. (graul‐neumann2008highlyvariablecutis pages 1-2)
5. Okuneva EG, et al. A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report. BMC Dermatology. Published January 2019. DOI/URL: https://doi.org/10.1186/s12895-019-0084-6. (okuneva2019anovelelastin pages 2-4)
6. Kun Y, et al. Congenital Cutis Laxa: A Case Report and Literature Review. Frontiers in Surgery. Published March 2022;9:814897. DOI/URL: https://doi.org/10.3389/fsurg.2022.814897. (kun2022congenitalcutislaxa pages 2-4)

PMIDs were not exposed in the retrieved full-text metadata and are therefore not supplied from memory; DOI links are provided to avoid introducing unverified identifiers.

References

1. (hadjrabia2013twentypatientsincluding pages 1-2): Smail Hadj-Rabia, Bert L Callewaert, Emmanuelle Bourrat, Marlies Kempers, Astrid S Plomp, Valerie Layet, Deborah Bartholdi, Marjolijn Renard, Julie De Backer, Fransiska Malfait, Olivier M Vanakker, Paul J Coucke, Anne M De Paepe, and Christine Bodemer. Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. Orphanet Journal of Rare Diseases, 8:36-36, Feb 2013. URL: https://doi.org/10.1186/1750-1172-8-36, doi:10.1186/1750-1172-8-36. This article has 59 citations and is from a peer-reviewed journal.

2. (callewaert2011newinsightsinto pages 10-12): Bert Callewaert, Marjolijn Renard, Vishwanathan Hucthagowder, Beate Albrecht, Ingrid Hausser, Edward Blair, Cristina Dias, Alice Albino, Hiroshi Wachi, Fumiaki Sato, Robert P. Mecham, Bart Loeys, Paul J. Coucke, Anne De Paepe, and Zsolt Urban. New insights into the pathogenesis of autosomal‐dominant cutis laxa with report of five eln mutations. Human Mutation, 32:445-455, Apr 2011. URL: https://doi.org/10.1002/humu.21462, doi:10.1002/humu.21462. This article has 179 citations and is from a domain leading peer-reviewed journal.

3. (hadjrabia2013twentypatientsincluding pages 6-7): Smail Hadj-Rabia, Bert L Callewaert, Emmanuelle Bourrat, Marlies Kempers, Astrid S Plomp, Valerie Layet, Deborah Bartholdi, Marjolijn Renard, Julie De Backer, Fransiska Malfait, Olivier M Vanakker, Paul J Coucke, Anne M De Paepe, and Christine Bodemer. Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. Orphanet Journal of Rare Diseases, 8:36-36, Feb 2013. URL: https://doi.org/10.1186/1750-1172-8-36, doi:10.1186/1750-1172-8-36. This article has 59 citations and is from a peer-reviewed journal.

4. (lasio2018elastindrivengeneticdiseases pages 2-4): Maria Laura Duque Lasio and Beth A. Kozel. Elastin-driven genetic diseases. Oct 2018. URL: https://doi.org/10.1016/j.matbio.2018.02.021, doi:10.1016/j.matbio.2018.02.021. This article has 122 citations and is from a domain leading peer-reviewed journal.

5. (hadjrabia2013twentypatientsincluding pages 5-6): Smail Hadj-Rabia, Bert L Callewaert, Emmanuelle Bourrat, Marlies Kempers, Astrid S Plomp, Valerie Layet, Deborah Bartholdi, Marjolijn Renard, Julie De Backer, Fransiska Malfait, Olivier M Vanakker, Paul J Coucke, Anne M De Paepe, and Christine Bodemer. Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. Orphanet Journal of Rare Diseases, 8:36-36, Feb 2013. URL: https://doi.org/10.1186/1750-1172-8-36, doi:10.1186/1750-1172-8-36. This article has 59 citations and is from a peer-reviewed journal.

6. (callewaert2011newinsightsinto pages 1-2): Bert Callewaert, Marjolijn Renard, Vishwanathan Hucthagowder, Beate Albrecht, Ingrid Hausser, Edward Blair, Cristina Dias, Alice Albino, Hiroshi Wachi, Fumiaki Sato, Robert P. Mecham, Bart Loeys, Paul J. Coucke, Anne De Paepe, and Zsolt Urban. New insights into the pathogenesis of autosomal‐dominant cutis laxa with report of five eln mutations. Human Mutation, 32:445-455, Apr 2011. URL: https://doi.org/10.1002/humu.21462, doi:10.1002/humu.21462. This article has 179 citations and is from a domain leading peer-reviewed journal.

7. (kun2022congenitalcutislaxa pages 2-4): Yang Kun, Shi Mengdong, Fu Cong, and Huo Ran. Congenital cutis laxa: a case report and literature review. Frontiers in Surgery, Mar 2022. URL: https://doi.org/10.3389/fsurg.2022.814897, doi:10.3389/fsurg.2022.814897. This article has 10 citations.

8. (kun2022congenitalcutislaxa pages 1-2): Yang Kun, Shi Mengdong, Fu Cong, and Huo Ran. Congenital cutis laxa: a case report and literature review. Frontiers in Surgery, Mar 2022. URL: https://doi.org/10.3389/fsurg.2022.814897, doi:10.3389/fsurg.2022.814897. This article has 10 citations.

9. (graul‐neumann2008highlyvariablecutis pages 1-2): Luitgard M. Graul‐Neumann, Ingrid Hausser, Maximilian Essayie, Anita Rauch, and Cornelia Kraus. Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene. American Journal of Medical Genetics Part A, 146A:977-983, Apr 2008. URL: https://doi.org/10.1002/ajmg.a.32242, doi:10.1002/ajmg.a.32242. This article has 92 citations.

10. (callewaert2011newinsightsinto pages 6-7): Bert Callewaert, Marjolijn Renard, Vishwanathan Hucthagowder, Beate Albrecht, Ingrid Hausser, Edward Blair, Cristina Dias, Alice Albino, Hiroshi Wachi, Fumiaki Sato, Robert P. Mecham, Bart Loeys, Paul J. Coucke, Anne De Paepe, and Zsolt Urban. New insights into the pathogenesis of autosomal‐dominant cutis laxa with report of five eln mutations. Human Mutation, 32:445-455, Apr 2011. URL: https://doi.org/10.1002/humu.21462, doi:10.1002/humu.21462. This article has 179 citations and is from a domain leading peer-reviewed journal.

11. (lasio2018elastindrivengeneticdiseases pages 4-6): Maria Laura Duque Lasio and Beth A. Kozel. Elastin-driven genetic diseases. Oct 2018. URL: https://doi.org/10.1016/j.matbio.2018.02.021, doi:10.1016/j.matbio.2018.02.021. This article has 122 citations and is from a domain leading peer-reviewed journal.

12. (okuneva2019anovelelastin pages 2-4): E. G. Okuneva, A. A. Kozina, N. V. Baryshnikova, A. Yu Krasnenko, K. Yu Tsukanov, O. I. Klimchuk, E. I. Surkova, and V. V. Ilinsky. A novel elastin gene frameshift mutation in a russian family with cutis laxa: a case report. BMC Dermatology, Jan 2019. URL: https://doi.org/10.1186/s12895-019-0084-6, doi:10.1186/s12895-019-0084-6. This article has 10 citations and is from a peer-reviewed journal.

13. (hadjrabia2013twentypatientsincluding pages 2-4): Smail Hadj-Rabia, Bert L Callewaert, Emmanuelle Bourrat, Marlies Kempers, Astrid S Plomp, Valerie Layet, Deborah Bartholdi, Marjolijn Renard, Julie De Backer, Fransiska Malfait, Olivier M Vanakker, Paul J Coucke, Anne M De Paepe, and Christine Bodemer. Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. Orphanet Journal of Rare Diseases, 8:36-36, Feb 2013. URL: https://doi.org/10.1186/1750-1172-8-36, doi:10.1186/1750-1172-8-36. This article has 59 citations and is from a peer-reviewed journal.

14. (callewaert2011newinsightsinto pages 7-9): Bert Callewaert, Marjolijn Renard, Vishwanathan Hucthagowder, Beate Albrecht, Ingrid Hausser, Edward Blair, Cristina Dias, Alice Albino, Hiroshi Wachi, Fumiaki Sato, Robert P. Mecham, Bart Loeys, Paul J. Coucke, Anne De Paepe, and Zsolt Urban. New insights into the pathogenesis of autosomal‐dominant cutis laxa with report of five eln mutations. Human Mutation, 32:445-455, Apr 2011. URL: https://doi.org/10.1002/humu.21462, doi:10.1002/humu.21462. This article has 179 citations and is from a domain leading peer-reviewed journal.

15. (akcay2020consequencesofelastin pages 1-3): S Akcay. Consequences of elastin gene mutations in autosomal dominant cutis laxa and supravalvular aortic stenosis. Unknown journal, 2020.

16. (akcay2020consequencesofelastinb pages 1-3): S Akcay. Consequences of elastin gene mutations in autosomal dominant cutis laxa and supravalvular aortic stenosis. Unknown journal, 2020.

17. (merla2012supravalvularaorticstenosis pages 2-3): Giuseppe Merla, Nicola Brunetti-Pierri, Pasquale Piccolo, Lucia Micale, and Maria Nicla Loviglio. Supravalvular aortic stenosis: elastin arteriopathy. Circulation: Cardiovascular Genetics, 5:692–696, Dec 2012. URL: https://doi.org/10.1161/circgenetics.112.962860, doi:10.1161/circgenetics.112.962860. This article has 144 citations.

18. (akcay2020consequencesofelastina pages 1-3): S Akcay. Consequences of elastin gene mutations in autosomal dominant cutis laxa and supravalvular aortic stenosis. Unknown journal, 2020.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

No ontology term identifiers were found in this report.