Autosomal Dominant Cutis Laxa 1

Mendelian MONDO:0007411 Pathograph 53 Show in embeddings browser Connective Tissue Disease Cutis Laxa Elastinopathy

ELN-related autosomal dominant cutis laxa is a heritable connective-tissue disorder with variably redundant, inelastic skin and characteristic facial features. Heterozygous variants often alter the tropoelastin carboxy terminus, impairing elastic-fiber assembly and function through allele-dependent effects. Inguinal hernias, joint laxity, hoarse voice, aortic-root disease and pulmonary complications can occur. Skin severity does not reliably predict internal-organ involvement, and aortic dissection or severe lung disease can be consequential even when skin findings are mild. Experimental studies support dominant interference with elastic tissue mechanics, but transcript processing, intracellular stress and signaling effects vary; their respective contributions to human organ disease remain incompletely resolved.

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Classifications

Harrison's Part

👪

Inheritance

Autosomal dominant inheritance HP:0000006

An affected heterozygous parent has a 50% chance of transmitting the pathogenic allele in each pregnancy. Expressivity varies within families. Reported probands include inherited and de novo variants; an apparently negative family history is not proof of a de novo event. Parental testing refines recurrence counseling, and negative leukocyte testing cannot exclude gonadal mosaicism.

Autosomal dominant inheritance

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"-related cutis laxa has a 50% chance of inheriting the"

The offspring section specifies allele-transmission risk; it does not predict individual organ severity.

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Direct sequencing of the probands’ DNA revealed 5 different de novo frameshift mutations"

The five probands in this selected series had reported de novo variants; the identical twins share one proband-level event.

Discussions and Knowledge Gaps

Does increased SMAD2 phosphorylation mediate organ injury or accompany the elastic-tissue abnormality?

KNOWLEDGE GAP OPEN adcl1_tgfbeta_treatment_target

Attached to

pathophysiology#Increased SMAD2 Phosphorylation

Patient fibroblast and mouse-lung signaling readouts are present, but the reviewed studies do not directly measure matrix-mediated active-ligand release or show selective TGF-beta pathway rescue of structural organ disease. Beta-blocker or ARB care is extrapolated from other aortopathies, not an ADCL1 efficacy result.

Show evidence (1 reference)

PMID:21309044 SUPPORT INDIRECT BACKGROUND In Vitro

"We speculate that due to failure of proper elastic fiber organization in ADCL, a more compliant ECM results in higher amounts of released TGFβ."

The authors explicitly identify ligand release as speculation.

Which expression, splicing and tissue-assembly differences explain the organ-specific phenotypes of the two transgenic designs?

HUMAN MODEL MISMATCH OPEN adcl1_mouse_skin_and_aorta_mismatch

Attached to

pathophysiology#Reduced Tissue Elastic Recoil pathophysiology#Aortic Medial Disorganization

The cDNA minigene model has prominent lung findings without consistent skin or vascular disease. The separate BAC model has measured skin laxity, background-dependent pulmonary effects and little aortic matrix incorporation. Added transgene expression, mouse/human elastin backgrounds, splice processing and local assembly are candidate explanations, not proven alternatives. Mouse aortic sparing does not establish minor human vascular risk.

Show evidence (2 references)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"No consistent dermatological or cardiovascular pathologies were observed."

This negative observation pertains to the minigene design.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"only about half as much force was required to displace skin"

In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.

Which allele, tissue and environmental factors predict organ involvement in ELN-related cutis laxa?

KNOWLEDGE GAP OPEN adcl1_organ_involvement_variability

Attached to

pathophysiology#C-Terminally Altered Tropoelastin pathophysiology#Endoplasmic Reticulum Stress Response

Splicing and transcript stability vary by allele and model. Earlier exon 32 attenuation proposals are not established clinical genotype-risk rules. Selected fibroblast ER-stress differences do not explain all pulmonary and aortic variability, and the reported cohorts are too small and related to estimate population penetrance or validate an exon-specific surveillance exemption.

Show evidence (2 references)

PMID:21309044 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"However, the observed allele-specific differences in the extent of ER stress alone do not explain the observed clinical variability in pulmonary and aortic involvement among patients."

The paper explicitly limits the explanatory scope of its cultured-cell finding.

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"ADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account."

The selected clinical cohort documents organ variability rather than a validated molecular predictor.

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Pathophysiology

Heterozygous ELN Pathogenic Variant

Heterozygous ELN variants causing this phenotype usually alter the carboxy-terminal coding sequence. Frameshifts predominate, while splice-altering intronic variants and an intragenic duplication are also reported. This is not a claim that every ELN loss-of-function allele causes cutis laxa; dosage-reducing alleles more often cause supravalvular aortic stenosis.

ELN hgnc:3327

Downstream

C-Terminally Altered Tropoelastin The tested frameshift alleles change the translated carboxy terminus; intervening transcript processing determines which protein isoforms are produced.

Small Airway Dysfunction The single molecularly diagnosed case establishes a clinical association; the route from altered elastin to small-airway dysfunction remains unresolved.

Bicuspid aortic valve This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Arterial tortuosity This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Mitral valve prolapse This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Mitral regurgitation This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Bronchiectasis This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Pectus excavatum This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Gastroesophageal reflux This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Irrespective of the location or type, each mutation was predicted to result in the replacement of the normal C-terminus of TE with a missense peptide sequence"

All five sequence changes in the selected 2011 probands were predicted to replace the normal C terminus; the statement does not generalize to all ELN variation.

C-Terminally Altered Tropoelastin

Affected alleles can produce tropoelastin with a replaced and often extended carboxy terminus. Protein is demonstrable in selected patient cultures, but transcript abundance, exon skipping and partial nonsense-mediated decay depend on allele and isoform. Splicing can produce truncated, extended or mutation-skipping products; universal escape from RNA decay is not established.

skin fibroblast CL:0002620

ELN hgnc:3327

Downstream

Increased Tropoelastin Self-Association The tested altered protein changes temperature-dependent self-association in a purified-protein assay.

Reduced Tropoelastin Binding to Fibrillin-1 Changing the tested carboxy-terminal sequence reduces measured binding to the fibrillin fragment.

Reduced Tropoelastin Binding to Fibulin-5 Changing the tested carboxy-terminal sequence reduces measured binding to fibulin-5.

Intracellular Mutant Tropoelastin Retention The tested abnormal proteins show incomplete secretion with intracellular retention; other alleles need not share the same degree.

Increased Apoptotic Readouts Mutant-expression and control comparisons support an allele/model-associated increase in apoptotic readouts; the intervening stress or signaling mediator remains unresolved.

Increased SMAD2 Phosphorylation Expression-associated comparisons support an altered signaling readout, while matrix-mediated ligand release and intracellular contributions remain unresolved.

Show evidence (2 references)

PMID:9580666 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"mRNA and immunoprecipitation studies show that the mutant allele is expressed."

The original exon-32 case demonstrates expression, without proving that all pathogenic alleles escape RNA decay.

PMID:15955094 SUPPORT DIRECT PRIMARY RESULT In Vitro

"an abnormal, 120 kDa polypeptide was detected in the proband and her affected daughter"

Patient dermal fibroblasts from the duplication family produced an abnormal protein in addition to normal tropoelastin.

Increased Tropoelastin Self-Association

A purified exon-32 frameshift tropoelastin construct coacervates at a lower temperature than its normal comparator. An equimolar mixture retains the mutant-like shift, supporting a dominant biophysical effect for this construct. This assay does not establish identical behavior for every ELN allele.

Experimental models

Purified frameshift tropoelastin coacervation assay OTHER The purified mixture measures altered temperature-dependent self-association.

Downstream

Impaired Elastic Fiber Assembly Abnormal self-association is proposed to interfere with later assembly. The study associates globules with poor fibrillar deposition but does not selectively normalize coacervation while holding other mutant effects constant.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation"

The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.

Reduced Tropoelastin Binding to Fibrillin-1

The exon-32 frameshift recombinant tropoelastin binds less strongly to a recombinant amino-terminal fibrillin-1 PET fragment in a solid-phase assay. This measures one molecular interaction; it is not loss of the fibrillin scaffold or proof of the same defect in every tissue.

Experimental models

Recombinant tropoelastin binding and ARPE-19 matrix assembly CELL LINE The specified recombinant binding or deposition measurement supports this component.

Downstream

Impaired Elastic Fiber Assembly Reduced scaffold-protein interaction is a proposed contributor to poor deposition; binding and assembly assays do not isolate that interaction as the sole necessary mediator.

Show evidence (1 reference)

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"the binding of nTE to PET was also increased 30% above fmTE binding."

Normal and mutant recombinant proteins were compared against the fibrillin-1 PET fragment, not full-length fibrillin in a patient tissue.

Reduced Tropoelastin Binding to Fibulin-5

The same recombinant frameshift protein shows lower association with fibulin-5 in solid-phase binding and solution co-immunoprecipitation assays. Conditioned-medium recombinant fibulin-5 and purified tropoelastin define the tested system.

Experimental models

Recombinant tropoelastin binding and ARPE-19 matrix assembly CELL LINE The specified recombinant binding or deposition measurement supports this component.

Downstream

Show evidence (1 reference)

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"At all concentrations used there was a significantly lower molecular interac- tion with fmTE compared to nTE."

Solution co-immunoprecipitation supports reduced association under the tested recombinant-protein conditions.

Impaired Elastic Fiber Assembly

Selected patient fibroblasts deposit less insoluble elastin and show abnormal extracellular globules and fibrillar deposition. Recombinant mutant protein also yields less matrix-associated elastin in ARPE-19 culture. Total desmosine per culture protein is lower in that assay, but this does not establish a universal reduction in crosslinks per elastin molecule: crosslinked elastin is increased in some transgenic tissues.

skin fibroblast CL:0002620

elastic fiber assembly GO:0048251 ↓ DECREASED

Experimental models

Selected ADCL1 patient dermal fibroblast cultures PRIMARY CELL CULTURE The patient-culture readout supports this component, with allele-specific differences.

Recombinant tropoelastin binding and ARPE-19 matrix assembly CELL LINE The specified recombinant binding or deposition measurement supports this component.

Downstream

Abnormal Elastic Fiber Architecture Poor assembly provides a mechanistic explanation for abnormal dermal fibers; culture and biopsy observations support the route without a longitudinal tissue rescue.

Show evidence (2 references)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found significantly lower amounts of insoluble elastin in ADCL cells compared to controls on day 4 and 8"

Cultured patient fibroblasts have reduced mature insoluble elastin deposition relative to the normalization used in the study.

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"Cells treated with fmTE also increased desmosine concentration but significantly less than with the addition of nTE (Fig. 3)."

Desmosine was lower than with normal added tropoelastin but was still produced; it was normalized to total culture protein, not incorporated elastin mass.

Abnormal Elastic Fiber Architecture

Human dermal biopsies show reduced and disorganized elastin deposition, fragmentation and poor association with microfibrils. Aortic elastic lamellae are disorganized in a surgically sampled affected person. Findings differ across tissues and models; mutant protein can be incorporated into mechanically abnormal fibers without a reduced total desmosine content.

dermis UBERON:0002067

Animal models

Human ELN BAC frameshift transgenic mouse Mouse partially recapitulates Mutant elastin entered skin and lung fibers with tissue-specific functional abnormalities.

Downstream

Reduced Tissue Elastic Recoil Abnormal elastic material is associated with impaired organ mechanics. Transgenic comparisons support a functional effect, while other matrix and cellular changes preclude a single-fiber mediator claim.

Alveolar Airspace Enlargement An abnormal elastic network is a plausible contributor to airspace enlargement, supported by mutant-expression models without a selective matrix or apoptosis rescue.

Aortic Medial Disorganization The qualitative elastic-fiber defect is consistent with medial disorganization in the sampled aorta, but tissue-specific deposition and cellular mechanisms remain incompletely resolved.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The amorphous component of the elastic fibers showed extensive branching and fragmentation and was not properly associated with the microfibrils."

Direct ultrastructural findings were obtained from dermal biopsies, not lung or aorta in every patient.

Reduced Tissue Elastic Recoil

Abnormal elastic networks can impair tissue mechanics. Mutant BAC mouse skin requires less suction force to displace, and the separate minigene model has reduced lung recoil and tissue stiffness. Extension to hernia, joint, bladder and vocal-fold support is a tissue-level explanation, not direct biomechanical testing of each organ in every patient.

skin of body UBERON:0002097 lung UBERON:0002048

Animal models

Human ELN cutis-laxa cDNA minigene mouse Mouse partially recapitulates The functional model reproduces reduced lung recoil and stiffness.

Human ELN BAC frameshift transgenic mouse Mouse partially recapitulates Skin suction testing found reduced force required for displacement.

Downstream

Cutis laxa This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Prematurely aged appearance This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Coarse facial features This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Long face This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Long philtrum This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Large ears This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Ptosis This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Convex nasal ridge This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Inguinal hernia This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Umbilical hernia This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Joint hypermobility This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Hoarse voice This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Bladder diverticulum This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Uterine prolapse This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Show evidence (2 references)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Expiratory static pressure-volume curves of CL lungs were shifted to the left compared with NTg controls, indicating that lung elastic recoil pressure in CL mice was reduced"

The minigene line-60 lung shows reduced recoil; this is an organ-level mechanical measurement.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"only about half as much force was required to displace skin"

In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.

Intracellular Mutant Tropoelastin Retention

Some abnormal tropoelastin remains intracellular while another fraction is secreted. This has been demonstrated in the duplication-family fibroblasts and selected frameshift cultures or transgenic lung. Retention is not assumed universal or complete.

skin fibroblast CL:0002620

Experimental models

Intragenic ELN duplication family fibroblasts PRIMARY CELL CULTURE Mutant-specific immunostaining and immunoprecipitation support intracellular retention alongside secretion.

Downstream

Endoplasmic Reticulum Stress Response Colocalization of retained tropoelastin with stress markers supports the proposed trigger, without selective removal of retention or proof of necessity.

Show evidence (1 reference)

PMID:15955094 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Immunoprecipitation experiments showed that the mutant TE was partially secreted and partially retained intracellularly."

This is a direct protein-processing observation in patient-derived fibroblasts from the duplication family.

Endoplasmic Reticulum Stress Response

Selected patient fibroblasts show elevated BiP or phosphorylated eIF2alpha, with different results by cell line. The exon-30 line CL-3 has the clearest combined stress readout; CL-1 lacks a significant BiP increase. Transgenic lung also shows increased phosphorylated eIF2alpha. These assays do not establish a required serial pathway to organ disease.

skin fibroblast CL:0002620

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED

Experimental models

Selected ADCL1 patient dermal fibroblast cultures PRIMARY CELL CULTURE The patient-culture readout supports this component, with allele-specific differences.

Animal models

Human ELN cutis-laxa cDNA minigene mouse Mouse partially recapitulates The stated molecular or histological readout was elevated in mutant lung.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"phosphorylated eukaryotic translation initiation factor (peIF2α), a marker for ER stress, which was only significantly upregulated in patient CL-3"

Stress-marker changes were not uniform across the three tested patient fibroblast lines.

Increased Apoptotic Readouts

Caspase-3 staining rises in the selected CL-3 fibroblast line and the minigene mouse lung has a small increased TUNEL-positive fraction. Stress and SMAD2 readouts were measured alongside apoptosis. Neither pathway was selectively inhibited to establish an obligatory death mechanism, and apoptosis was not shown to mediate human emphysema.

apoptotic process GO:0006915 ↑ INCREASED

Experimental models

Selected ADCL1 patient dermal fibroblast cultures PRIMARY CELL CULTURE The patient-culture readout supports this component, with allele-specific differences.

Animal models

Human ELN cutis-laxa cDNA minigene mouse Mouse partially recapitulates The stated molecular or histological readout was elevated in mutant lung.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice"

The minigene model supports increased TUNEL staining with a low absolute index, not extensive universal tissue loss.

Increased SMAD2 Phosphorylation

Increased phosphorylated SMAD2 in the three studied patient fibroblast cultures and minigene lung is consistent with enhanced TGF-beta-pathway signaling. Release of latent matrix TGF-beta was not directly measured, and there is no selective pathway rescue establishing mediation of aortic or lung disease.

skin fibroblast CL:0002620

Experimental models

Selected ADCL1 patient dermal fibroblast cultures PRIMARY CELL CULTURE The patient-culture readout supports this component, with allele-specific differences.

Animal models

Human ELN cutis-laxa cDNA minigene mouse Mouse partially recapitulates The stated molecular or histological readout was elevated in mutant lung.

Show evidence (2 references)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Staining for pSMAD2 in fibroblast cultures of all patients showed significant upregulation of the TGFβ signaling pathway"

The measured endpoint was phosphorylated SMAD2 in the three available patient cultures, rather than direct active-ligand release.

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantitative evaluation of pSMAD2-positive nuclei showed a highly significant increase in the lungs of CL mice, whereas WT mice showed no difference compared to NTg"

The transgenic lung result supports altered pathway readout with an expression comparator.

Alveolar Airspace Enlargement

Mutant minigene mice show enlarged pulmonary airspaces across three founder lines, with different severity. Human ELN-related disease can include severe emphysema, but this is not obligatory and the separate BAC model has weaker lung findings. Airspace morphology does not by itself identify whether abnormal development, mechanical failure or cell injury is the necessary mediator.

alveolus of lung UBERON:0002299

Animal models

Human ELN cutis-laxa cDNA minigene mouse Mouse partially recapitulates Airspace enlargement occurred in all three founder lines, with variable severity.

Downstream

Emphysema This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantitative morphometry confirmed significant airspace enlargement in all CL lines and normal alveolar sizes in WT transgenic mice"

The three founder lines showed variable pulmonary severity; subsequent functional work used line 60.

Small Airway Dysfunction

A never-smoking adult with an ELN frameshift had severe obstruction, air trapping and abnormal small-airway indices over eight years without visually apparent CT emphysema. Quantitative low-attenuation measures and visual CT were discordant. The specific microscopic or extracellular-matrix mediator was not established in this single case.

lung UBERON:0002048

Downstream

Airway obstruction This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Show evidence (1 reference)

PMID:39354494 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Computed tomography (CT) revealed the lack of normal increase in lung attenuation on expiratory CT scan, with no discernible emphysematous changes."

The case supports small-airway dysfunction without visually discernible emphysema; no lung histology established the exact tissue lesion.

Aortic Medial Disorganization

A surgically sampled adult with a familial ELN frameshift and aortic aneurysm had thinning and disorganization of the medial elastic lamellae and reduced smooth-muscle density. This direct aortic observation is distinct from skin electron microscopy in another family member. TGF-beta mediation and generalized vascular fragility were not established.

vascular associated smooth muscle cell CL:0000359

aorta tunica media UBERON:0003618

Downstream

Aortic root dilatation This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Aortic dissection This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Aortic rupture This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Aortic regurgitation This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The aortic pathology associated with this condition is medial degeneration, characterised by dramatic loss of elastic lamellae and smooth muscle cells and a lack of atherosclerotic and inflammatory lesions."

The source reports aortic pathological changes in the aneurysm case; detailed anatomy and sampling limits are retained.

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Pathograph

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Phenotypes

Cardiovascular 8

Aortic root dilatation Aortic root aneurysm HP:0002616

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Vascular involvement included ARD in eight patients, and a dilatation of the aortic arch in one"

The body separates root and arch involvement rather than combining them into one root-dilation count.

Aortic dissection HP:0002647

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Aortic dissection has been reported in multiple families as early as in the third decade"

The synthesis supports the clinically important vascular risk without a reliable incidence estimate.

Aortic rupture HP:0031649

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"aortic lesions ranging from mild dilatation to severe aneurysm and rupture of the aortic root"

The primary family report and sporadic case establish the vascular complication spectrum.

Bicuspid aortic valve HP:0001647

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the prevalence in our group of ADCL patients is 2/6."

The denominator is six selected individuals, not six independent probands.

Arterial tortuosity HP:0005116

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Increased tortuosity of the arteries (mainly of the supra-aortic vasculature) has been incidentally noted but not systematically assessed"

The synthesis explicitly limits ascertainment.

Aortic regurgitation HP:0001659

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"patients had aortic valve regurgitation"

The Results describe four affected members; this fragment is interpreted within that explicit clinical context.

Mitral valve prolapse HP:0001634

Show evidence (1 reference)

PMID:30704477 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"evaluation by echocardiography revealed mitral valve prolapse and diffuse changes in myocardium."

The reported mother had echocardiographic mitral prolapse; incidental cardiac rhythm findings in the family are not assigned to ELN here.

Mitral regurgitation HP:0001653

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"patients F1:II-4 and F6-20 had mitral valve regurgitation."

The body reports this valve manifestation in selected patients.

Digestive 3

Inguinal hernia HP:0000023

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Inguinal hernias were frequent, appearing congenitally (F1:II-2, F1:II-3, F1:III-1, F2:II-1) or throughout life (F1: I-2 at age 80 and F1:III-4 at 18 years old) and often re- occurred after surgery"

The clinical cohort documents variable age of onset and postoperative recurrence; no population frequency is assigned.

Umbilical hernia HP:0001537

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient F1:II-4 also had an umbilical hernia."

This is an individual observation within the cohort.

Gastroesophageal reflux HP:0002020

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other manifestations included gastro- oesophageal reflux (F1:II-7 and F1:III-4)"

The source assigns reflux to two related individuals rather than a general prevalence.

Ear 1

Large ears Macrotia HP:0000400

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum."

The clinical figure caption documents the individual facial features in this selected cohort.

Eye 1

Ptosis HP:0000508

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum."

The clinical figure caption documents the individual facial features in this selected cohort.

Genitourinary 2

Bladder diverticulum HP:0000015

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"ptosis, aortic root dilatation, emphysema, bladder diverticula"

The chapter identifies bladder diverticula among recognized manifestations requiring surveillance.

Uterine prolapse HP:0000139

Show evidence (2 references)

PMID:29501665 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Genital prolapse has been described in at least 2 individuals with ADCL caused by ELN variants"

This review reports genital prolapse; the full GeneReviews pregnancy section specifically identifies uterine prolapse.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Uterine prolapse may occur [Urban et al 2005]."

The full GeneReviews pregnancy section explicitly names the uterine manifestation; the additional synthesis quotation establishes reported genital prolapse cases.

Head and Neck 4

Coarse facial features HP:0000280

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum."

The clinical figure caption documents the individual facial features in this selected cohort.

Long face HP:0000276

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum."

The clinical figure caption documents the individual facial features in this selected cohort.

Long philtrum HP:0000343

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance"

GeneReviews explicitly describes a long philtrum, without inferring length from the less specific word large.

Convex nasal ridge HP:0000444

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance"

GeneReviews specifically describes convex nasal shape.

Integument 2

Cutis laxa HP:0000973

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"generalized cutis laxa (ranging from generalized skin redundancy causing excessive skin folds to skin hyperextensibility without obvious skin folds)"

The full chapter describes the broad cutaneous spectrum.

Prematurely aged appearance HP:0007495

Show evidence (1 reference)

PMID:15381555 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A 45-year-old woman and her 19-year-old son presented with inelastic, loose-hanging, and wrinkled skin that appeared prematurely aged"

The familial report describes an appearance phenotype, not a molecular aging syndrome.

Musculoskeletal 2

Joint hypermobility HP:0001382

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Other common findings are joint hyperlaxity in infancy and increasing risk of inguinal hernia at all ages."

The synthesis identifies joint hyperlaxity with an age qualifier.

Pectus excavatum HP:0000767

Show evidence (1 reference)

PMID:39354494 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the chest CT scan revealed the presence of pectus excavatum."

A direct CT observation in one case, without a frequency estimate.

Respiratory 3

Emphysema HP:0002097

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Chronic obstructive pulmonary disease was diag- nosed in eight patients, seven of whom had emphysema and one had asthma."

The full Results distinguish emphysema from asthma rather than treating all eight diagnoses as emphysema.

Airway obstruction HP:0006536

Show evidence (1 reference)

PMID:39354494 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in pulmonary function tests"

This was one adult with severe physiological obstruction despite little subjective limitation.

Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:15955094 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a CL family characterized by hernias and unusually severe and early-onset pulmonary disease including bronchiectasis and pulmonary emphysema."

The finding is scoped to the duplication family; infection and airway remodeling intermediates are not established for all alleles.

Voice 1

Hoarse voice HP:0001609

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a long philtrum, large ears, a husky voice and often a beaked nose."

The selected cohort directly documents the voice finding.

🧬

Genetic Associations

ELN variants and allele-specific transcript processing (Heterozygous pathogenic variants causing ELN-related cutis laxa)

Gene: ELN hgnc:3327

Show evidence (3 references)

PMID:9873040 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Transcripts from both alleles in each kindred were unstable and responsive to transforming growth factor-beta."

The older selected fibroblast strains show why a universal RNA-stability claim is inappropriate.

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"There are no obvious genotype-phenotype correlations when comparing patients with mutations in different exons"

The new cohort explicitly avoids an established exon-level severity rule.

PMID:15955094 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"affected individuals in this family carried a partial tandem duplication in the elastin locus."

The duplication family broadens the established variant spectrum beyond point frameshifts.

💊

Medical Actions

Multidisciplinary supportive care

Category: Therapeutic Action: Supportive Care NCIT:C15747

Platform: Other

Management is largely symptomatic and individualized. Coordinate relevant cardiology, pulmonology, surgery, urology, ophthalmology, physical therapy and genetics input. The 2022 GeneReviews chapter reports no disease-specific clinical practice guideline and limited treatment experience; these recommendations are expert synthesis, not comparative ADCL1 trials.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Supportive care to improve quality of life, maximize function, and reduce complications is recommended"

The full chapter recommends supportive management across manifestations.

Aortic and valvular surveillance

Category: Monitoring Action: Echocardiography Test NCIT:C16525

Platform: Other

GeneReviews recommends echocardiography annually or according to dimensions and progression. Discuss MR angiography after puberty and subsequent intervals based on findings, commonly every 5 years. Screening recommendations are not proof that a specific schedule reduces mortality. Mild skin findings or an exon 32 allele do not identify a group exempt from vascular surveillance.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Annually (or depending on measurements/progression)"

The cardiovascular-surveillance table individualizes the echocardiography interval.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"the potential risks and benefits of screening with MR angiography be discussed with the patient."

The chapter recommends discussion of screening uncertainty rather than indiscriminate fixed imaging.

Pulmonary surveillance

Category: Monitoring Action: Spirometry NCIT:C85397

Platform: Other

Establish age-appropriate baseline lung function; the chapter suggests peak flow from age 5 every 6 months and formal pulmonary-function testing from age 7, repeated with breathlessness or a fall in peak flow. Interpret results with symptoms and imaging. The single detailed small-airway case supports attention to physiology even without visible CT emphysema.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Repeat if there is shortness of breath or decline in peak flow measurement."

The pulmonary-function surveillance recommendation uses clinical and peak-flow triggers.

PMID:39354494 SUPPORT DIRECT REVIEW SYNTHESIS Other

"We advocate for meticulous monitoring with pulmonary function tests and CT scans, even in cases of cutis laxa with minimal CT evidence of emphysematous changes."

This is the case authors’ recommendation rather than a tested screening schedule.

Aortic aneurysm repair

Category: Therapeutic Action: Thoracic Aortic Aneurysm Open Repair NCIT:C158011

Platform: Surgery

Specialist aortic-root repair may be required, with valve-sparing or composite procedures chosen according to anatomy and valve function. Disease-specific size thresholds are not established; expert guidance extrapolates from other heritable aortopathies and considers growth, family history and pregnancy plans. Reported surgery does not establish unusual universal operative tissue fragility.

Mechanism Target:

BYPASSES Aortic root dilatation — The intervention addresses this clinical manifestation; the evidence does not demonstrate repair of the inherited ELN lesion.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Aortic root repair (Bentall or David procedure depending on aortic valve function)"

The full treatment table recommends phenotype-directed aortic repair.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Best thresholds for aortic repair are not established."

The recommendation explicitly acknowledges threshold uncertainty.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Aortic root repair (Bentall or David procedure depending on aortic valve function)"

The full treatment table recommends phenotype-directed aortic repair.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Best thresholds for aortic repair are not established."

The recommendation explicitly acknowledges threshold uncertainty.

Individualized medical aortic protection

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576 angiotensin II receptor antagonist NCIT:C66930

Platform: Small molecule

Beta blockers or angiotensin-receptor blockers may be considered by the treating specialist by extrapolation from other connective-tissue aortopathies. Their effectiveness in ELN-related cutis laxa has not been evaluated. Do not interpret pSMAD2 findings as a demonstrated human losartan rescue. Reversible airway obstruction influences beta-blocker choice, and pregnancy requires medication review.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Effectiveness of beta-blocking agents or angiotensin receptor antagonists in slowing aortic root dilatation has not been evaluated, but (as w/other connective tissue disorders) these are likely beneficial."

This is explicitly extrapolative expert guidance with no ADCL1 efficacy trial.

Symptom-directed pulmonary treatment

Category: Therapeutic Action: Respiratory Therapy NCIT:C15322

Platform: Other

Treat clinically significant obstructive symptoms with specialist-directed conventional respiratory care. GeneReviews lists beta-mimetic and anticholinergic agents, but cautions against anticholinergics in people with bladder diverticula. A reported asymptomatic adult with severe functional obstruction received no drug because evidence was lacking. These observations do not establish a mandatory regimen for all patients.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Avoid use of anticholinergic agents in persons w/bladder diverticula."

The full treatment table qualifies its bronchodilator options for associated urologic disease.

PMID:39354494 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Pharmacological intervention was withheld due to the absence of respiratory manifestations and the lack of evidence."

This reflects one asymptomatic case, not a general recommendation to withhold treatment.

Inguinal hernia repair

Category: Therapeutic Action: Herniorrhaphy NCIT:C168249

Platform: Surgery

Hernia repair is considered for clinical indications, with mesh repair listed in GeneReviews and counseling about recurrence. The recommendation is not cosmetic skin tightening, and observed recurrence does not establish that clinically indicated repair is futile.

Mechanism Target:

BYPASSES Inguinal hernia — The intervention addresses this clinical manifestation; the evidence does not demonstrate repair of the inherited ELN lesion.

Show evidence (2 references)

PMID:35372488 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"The patient had been operated on the inguinal hernia at the age of 6 years old, and post-operative scar was not obvious."

The primary case documents performed hernia repair, while full GeneReviews provides the management recommendation.

PMID:23442826 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Inguinal hernias were frequent, appearing congenitally (F1:II-2, F1:II-3, F1:III-1, F2:II-1) or throughout life (F1: I-2 at age 80 and F1:III-4 at 18 years old) and often re- occurred after surgery"

The cohort documents recurrence after prior repair, not a comparative surgical trial.

Show evidence (2 references)

PMID:35372488 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient had been operated on the inguinal hernia at the age of 6 years old, and post-operative scar was not obvious."

The primary case documents performed hernia repair, while full GeneReviews provides the management recommendation.

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Inguinal hernias were frequent, appearing congenitally (F1:II-2, F1:II-3, F1:III-1, F2:II-1) or throughout life (F1: I-2 at age 80 and F1:III-4 at 18 years old) and often re- occurred after surgery"

The cohort documents recurrence after prior repair, not a comparative surgical trial.

Joint stability and pain support

Category: Therapeutic Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy and non-weight-bearing activities such as cycling or swimming can support joint function and stability. Treat episodes of pain as clinically appropriate; avoid activities that provoke instability or injury. This is supportive guidance rather than correction of elastic-fiber assembly.

Mechanism Target:

MODULATES Joint hypermobility — The intervention addresses this clinical manifestation; the evidence does not demonstrate repair of the inherited ELN lesion.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Encourage non-weight-bearing exercise such as cycling"

The joint-hypermobility treatment section recommends adapted activity.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Pain medications in case of acute aggravation of pain"

The joint-pain section provides symptom-directed care.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Encourage non-weight-bearing exercise such as cycling"

The joint-hypermobility treatment section recommends adapted activity.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Pain medications in case of acute aggravation of pain"

The joint-pain section provides symptom-directed care.

Management of bladder diverticula and impaired emptying

Category: Therapeutic Action: Supportive Care NCIT:C15747

Platform: Other

Teach complete bladder emptying; assess residual urine and recurrent urinary infections. The chapter recommends catheterization for significant residual volume, selected antibiotic prophylaxis when incomplete voiding coexists with recurrent infections, and pelvic-floor therapy for prolapse support. These options are conditional and are not prescribed to every person with a diverticulum.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Education on complete bladder emptying when voiding"

The full table recommends a specific functional management action.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Catheterization if significant urinary residual after voiding"

Catheterization is conditional on clinically important residual urine.

Functional ptosis surgery

Category: Therapeutic Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Consider eyelid surgery when drooping obscures the visual axis or causes recurrent conjunctival irritation/infection. Distinguish a functional indication from elective cosmetic skin reduction, and counsel about laxity recurrence.

Mechanism Target:

BYPASSES Ptosis — The intervention addresses this clinical manifestation; the evidence does not demonstrate repair of the inherited ELN lesion.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Surgery is recommended when eyelid obscures pupil"

The table supports a functional ocular indication for surgery.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Surgery is recommended when eyelid obscures pupil"

The table supports a functional ocular indication for surgery.

Cosmetic skin procedures with recurrence counseling

Category: Therapeutic Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Elective skin tightening or lipofilling is not routinely encouraged by GeneReviews because skin laxity often recurs. A 2022 uncontrolled case reported satisfaction without recurrence five months after a combined surgical and postoperative regimen; this does not establish lasting efficacy, superiority, or a standard recommendation. Discuss expectations, risks and psychosocial goals individually.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Cosmetic interventions are currently not encouraged."

The chapter’s cautious recommendation takes priority over an unsupported general claim that most patients should undergo surgery.

PMID:35372488 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient is content with the effect of treatment, and there are no signs of recurrence after 5 months"

The observation is limited to one case and short follow-up with cointerventions.

Psychological and family support

Category: Therapeutic Action: Psychotherapy NCIT:C15308

Platform: Behavioral / lifestyle

Assess self-esteem and family support needs and offer age-appropriate psychological support. Appearance-related distress and recurrent procedures may matter even when organ function is preserved.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Assess for need for intervention for significant self-esteem issues requiring proactive psychological support."

The chapter recommends needs-based psychological support.

Avoidance of aggravating exposures and mechanical stress

Category: Therapeutic Action: Supportive Care NCIT:C15747

Platform: Other

Avoid tobacco and minimize respiratory infections. Individualize advice about isometric exercise and contact sports according to vascular and joint risk. GeneReviews advises avoiding positive-pressure ventilation unless lifesaving and close follow-up if CPAP is required because its specific risk is unknown. Avoid excessive ultraviolet exposure; consider vitamin-D status when sun exposure is restricted.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Positive pressure ventilation unless needed to treat life-threatening conditions. No data exist on the potential risk of continuous positive airway pressure (CPAP) for the treatment of sleep apnea. Close follow up is warranted when CPAP is started."

The guidance preserves the lifesaving exception and the uncertainty around CPAP.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Sunbathing or tanning, to preserve residual skin elasticity. Vitamin D supplementation should be considered in this context, and monitored annually."

The recommendation balances UV avoidance with vitamin-D monitoring.

Pregnancy planning and surveillance

Category: Monitoring Action: Supportive Care NCIT:C15747

Platform: Other

Arrange preconception cardiovascular and pulmonary evaluation and closer follow-up during pregnancy and for six months postpartum. Absence of reported perinatal complications in the small published experience does not prove safety. Review medications before conception: expert guidance continues appropriate beta blockers and replaces angiotensin-receptor blockers because of fetal risk.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"as well as increased surveillance throughout the pregnancy and six months post partum."

The full chapter recommends increased pregnancy and postpartum vascular surveillance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"Women who are planning a pregnancy or who become pregnant while taking an angiotensin receptor blocker can be transitioned to a beta-blocker."

This is specialist medication guidance, not an ADCL-specific comparative treatment result.

Genetic counseling and family evaluation

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Platform: Other

Discuss autosomal-dominant transmission, variable expression, parental testing and residual uncertainty after a negative result. Offer evaluation to relatives at risk so organ complications can be recognized. Once the familial pathogenic variant is established, prenatal and preimplantation testing may be discussed according to individual preferences.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"has a 50% chance of inheriting the pathogenic variant."

The offspring section states the allele-transmission probability for each child of an affected person.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"is recommended for the parents of the proband to evaluate their genetic status and inform"

The full counseling section recommends parental molecular testing to refine recurrence assessment.

🔬

Diagnosis

Phenotype-guided molecular diagnosis

Suggestive skin and facial findings, family history and systemic assessment guide molecular testing. A heterozygous pathogenic or likely pathogenic ELN variant with compatible findings establishes the diagnosis; an ELN variant of uncertain significance alone neither confirms nor excludes it. Current GeneReviews favors a cutis-laxa multigene panel or genomic testing over a restricted terminal-exon-only strategy because of overlapping disorders and less usual variant classes.

No diagnosis_term is bound because this entry combines physical examination, family history, systemic assessment, and molecular variant interpretation rather than a single NCIT diagnostic procedure.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"does not establish or rule out the diagnosis."

The explicit GeneReviews statement concerns an ELN variant of uncertain significance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"is rarely useful and typically NOT recommended."

In context, GeneReviews applies this limitation to sequential single-gene ELN testing, favoring panel or genomic approaches.

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We clinically and molecularly characterized the thus far largest cohort of ADCL patients"

The primary study combines phenotype and molecular evaluation; it does not make its historical exon 28–34 screen a complete modern diagnostic algorithm.

Variant interpretation and assay coverage

Use transcript-specific nomenclature and assess segregation and structural or splice variation when appropriate. Terminal frameshifts, intragenic rearrangements and deep intronic splice variants require attention to assay coverage. Negative coding sequencing alone does not exclude every ELN mechanism or other cutis-laxa disorders. Genetic counseling should distinguish transmission risk, variable expression and an unresolved result.

No diagnosis_term is bound because this is an interpretation and assay-coverage qualifier layered onto molecular testing, not a separate clinical procedure in NCIT.

Show evidence (2 references)

PMID:15955094 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"affected individuals in this family carried a partial tandem duplication in the elastin locus."

A structural variant was identified after point-mutation testing was negative.

PMID:30704477 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We did not test DNA from maternal grandparents due to the unavail- ability of the material."

Missing grandparent testing prevents calling the mother’s variant definitively de novo.

Baseline cardiovascular assessment

Perform echocardiography to assess valve morphology and aortic-root and ascending-aortic dimensions. GeneReviews recommends discussion of baseline MR angiography around age 15, particularly for tortuosity or when the ascending aorta is not adequately visualized. Symptoms or suspected acute aortic complications require appropriate urgent clinical assessment.

Echocardiography Test NCIT:C16525

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"To enable visualization of ascending aorta when echocardiography is inadequate"

The full initial-evaluation table provides the MR-angiography indication.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"These findings emphasise the importance of cardiovascular monitoring to prevent fatal rupture of the aortic root in cutis laxa patients."

The primary report explains why apparently mild skin disease does not remove the need for vascular evaluation.

Baseline pulmonary assessment

Assess symptoms and age-appropriate lung function. GeneReviews suggests baseline chest radiography before puberty, peak flow around age 5 and pulmonary-function testing around age 7; HRCT is directed to symptomatic emphysema assessment. A normal visual emphysema assessment does not exclude marked small-airway dysfunction. Quantitative CT findings from one case do not establish a universal PRM testing protocol.

Spirometry NCIT:C85397

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"To evaluate severity of emphysema in symptomatic persons"

The initial-evaluation table makes HRCT assessment symptom-directed.

PMID:39354494 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Neither emphysema nor bronchial wall thickening, which is characteristic of bronchiolitis obliterans syndrome was present."

Visual CT can appear free of these features despite significant functional obstruction in the reported case.

Skin biopsy and other baseline organ assessment

Dermal histology can demonstrate sparse, fragmented or poorly organized elastic fibers but does not distinguish every genetic cause. Molecular testing establishes the etiologic diagnosis. Assess ptosis and visual-axis obstruction, joint stability and pain, bladder diverticula or voiding problems, and psychosocial needs according to the phenotype.

No diagnosis_term is bound because this bundles dermal histology, ophthalmologic, musculoskeletal, urinary, and psychosocial assessment rather than one NCIT diagnostic procedure.

Show evidence (2 references)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The amorphous component of the elastic fibers showed extensive branching and fragmentation and was not properly associated with the microfibrils."

Dermal ultrastructure supports an elastic-fiber disorder but does not by itself identify the causal gene.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Other

"To evaluate for bladder diverticula"

GeneReviews includes urinary ultrasound in baseline evaluation.

📈

Progression

Variable lifelong course

Skin laxity is usually apparent at birth or early childhood and may become less conspicuous with age, although progression also occurs. Facial appearance and skin findings vary considerably within families. Aortic and pulmonary disease can emerge or progress despite mild external skin changes. Neuromotor development and cognition are usually preserved in reported typical cases; this is not a standardized lifelong guarantee.

Show evidence (3 references)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Growth and psychomotor development were appropriate in all patients."

This observation concerns the selected cohort, not comprehensive lifetime cognitive testing.

PMID:30704477 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Skin laxity was first noticed at the age of 1 year."

The son in the reported family illustrates early-childhood recognition rather than obligatory diagnosis at birth.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Aortic dissection has been reported in multiple families as early as in the third decade"

The synthesis records serious vascular events in young adults.

🌍

Epidemiology

Rare reported-case evidence

Population prevalence is not established by the available selected families. The 2022 GeneReviews chapter summarized more than 46 molecularly identified individuals from 23 families; this is a dated literature count, not the number living with the disorder or a population prevalence. The 2013 study examined 20 people (19 from six families plus one sporadic patient). Its abstract, pooled table and discussion contain inconsistent organ-frequency percentages, so these are not converted into disease-wide frequency bands.

Show evidence (1 reference)

PMID:23442826 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"METHODS: We clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient."

The denominator is a selected clinical cohort of related individuals, not a population survey.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Cutis Laxa 1:

Other autosomal recessive cutis laxa syndromes

Overlapping Features EFEMP2, LTBP4, ATP6V0A2, PYCR1 and other disorders can combine loose skin with vascular, pulmonary, neurological, skeletal or glycosylation findings. The substantial clinical overlap requires molecular clarification. The uncertain exon 25 ELN family does not supply reliable typical ADCL1 pulmonary-artery or seizure frequencies.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Clinical overlap and related, unclassified disorders illustrate many shortcomings of this classification, as illustrated by the fact that 4 out of 5 probands were initially diagnosed with recessive cutis laxa."

These selected probands illustrate diagnostic overlap; the fraction is not diagnostic sensitivity or specificity.

Acquired cutis laxa

Overlapping Features Adult or post-inflammatory onset and associated systemic conditions may suggest acquired elastolysis. An absent family history does not distinguish acquired disease from a de novo genetic disorder; clinical history, tissue findings and appropriate molecular assessment are considered together.

🧫

Experimental Models

Selected ADCL1 patient dermal fibroblast cultures PRIMARY_CELL_CULTURE

Nonisogenic patient fibroblasts and age/sex/passage-matched controls were compared for elastin deposition, splicing and signaling. Reduced insoluble elastin and abnormal deposition accompanied allele-dependent intracellular effects. CL 1 lacked the measured stress response; CL 4 mainly increased BiP; CL 3 showed BiP, phospho-eIF2alpha and cleaved-caspase3 changes. Increased pSMAD2 was observed across all three tested patient cultures.

Cell source

Cultures from CL 1, CL 3 and CL 4 among six individuals/five probands in the 2011 series

Publication

PMID:21309044

Pathograph links

Impaired Elastic Fiber Assembly partially recapitulates fidelity: moderate observes: cellular The patient-culture readout supports this component, with allele-specific differences.

Limitations: Nonisogenic comparisons and no pathway-specific rescue limit causal attribution.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found significantly lower amounts of insoluble elastin in ADCL cells compared to controls on day 4 and 8"

Cultured patient fibroblasts have reduced mature insoluble elastin deposition relative to the normalization used in the study.

Endoplasmic Reticulum Stress Response partially recapitulates fidelity: moderate observes: cellular The patient-culture readout supports this component, with allele-specific differences.

Limitations: Nonisogenic comparisons and no pathway-specific rescue limit causal attribution.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"phosphorylated eukaryotic translation initiation factor (peIF2α), a marker for ER stress, which was only significantly upregulated in patient CL-3"

Stress-marker changes were not uniform across the three tested patient fibroblast lines.

Increased Apoptotic Readouts partially recapitulates fidelity: moderate observes: cellular The patient-culture readout supports this component, with allele-specific differences.

Limitations: Nonisogenic comparisons and no pathway-specific rescue limit causal attribution.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice"

The minigene model supports increased TUNEL staining with a low absolute index, not extensive universal tissue loss.

Increased SMAD2 Phosphorylation partially recapitulates fidelity: moderate observes: cellular The patient-culture readout supports this component, with allele-specific differences.

Limitations: Nonisogenic comparisons and no pathway-specific rescue limit causal attribution.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Staining for pSMAD2 in fibroblast cultures of all patients showed significant upregulation of the TGFβ signaling pathway"

The measured endpoint was phosphorylated SMAD2 in the three available patient cultures, rather than direct active-ligand release.

Not all six clinical participants supplied the mechanistic cultures. Biopsy sites differ, there is no allele correction or selective stress/TGF-beta rescue, and measured insoluble elastin does not establish crosslink density per molecule. Co-occurrence does not prove an obligatory retention→ER stress→apoptosis chain.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found significantly lower amounts of insoluble elastin in ADCL cells compared to controls on day 4 and 8"

The available patient cultures had reduced deposited mature insoluble elastin.

Purified frameshift tropoelastin coacervation assay OTHER

Purified normal tropoelastin, a single exon 32 c.2262delA frameshift construct and an equimolar mixture were compared during temperature-dependent coacervation. The mixture retained the lower transition temperature of mutant protein.

Publication

PMID:21309044

Pathograph links

Increased Tropoelastin Self-Association measures fidelity: moderate observes: molecular The purified mixture measures altered temperature-dependent self-association.

Limitations: No selective normalization of this property tests its necessity for disease.

Readouts

Coacervation propensity

Direction: INCREASED

Interpretation: The purified mixture measures altered temperature-dependent self-association.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation"

The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation"

The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.

This is an isolated-protein biophysical assay, not a patient organ or an allele-wide panel. It establishes a dominant shift in the tested mixture, not mediation of all downstream tissue damage.

Show evidence (1 reference)

PMID:21309044 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation"

The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.

Recombinant tropoelastin binding and ARPE-19 matrix assembly CELL_LINE

Over eight days, mutant added tropoelastin yielded less matrix-associated elastin and lower desmosine per total culture protein than normal protein, but assembly still occurred. Solid-phase assays tested a fibrillin1 amino-terminal PET fragment and recombinant fibulin5; solution co-immunoprecipitation independently tested fibulin5 association.

Cell source

ARPE-19 retinal pigment epithelial cell line supplied with purified normal or exon 32 frameshift tropoelastin; separate recombinant protein-binding assays

Publication

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf

Pathograph links

Reduced Tropoelastin Binding to Fibrillin-1 measures fidelity: moderate observes: molecular The specified recombinant binding or deposition measurement supports this component.

Limitations: Binding and deposition were separate assays without selective mediator rescue.

Show evidence (1 reference)

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"the binding of nTE to PET was also increased 30% above fmTE binding."

Normal and mutant recombinant proteins were compared against the fibrillin-1 PET fragment, not full-length fibrillin in a patient tissue.

Reduced Tropoelastin Binding to Fibulin-5 measures fidelity: moderate observes: molecular The specified recombinant binding or deposition measurement supports this component.

Limitations: Binding and deposition were separate assays without selective mediator rescue.

Show evidence (1 reference)

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"At all concentrations used there was a significantly lower molecular interac- tion with fmTE compared to nTE."

Solution co-immunoprecipitation supports reduced association under the tested recombinant-protein conditions.

Impaired Elastic Fiber Assembly measures fidelity: moderate observes: cellular The specified recombinant binding or deposition measurement supports this component.

Limitations: Binding and deposition were separate assays without selective mediator rescue.

Show evidence (1 reference)

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"Cells treated with fmTE also increased desmosine concentration but significantly less than with the addition of nTE (Fig. 3)."

Desmosine was lower than with normal added tropoelastin but was still produced; it was normalized to total culture protein, not incorporated elastin mass.

This is not endogenous expression in patient cells. CHO-conditioned medium supplied scaffold proteins; the fibrillin reagent is a fragment rather than full-length protein. No normal/mutant mixture, lysyl-oxidase activity or binding-restoration rescue was tested. Lower desmosine per total culture protein cannot establish fewer crosslinks per incorporated elastin molecule.

Show evidence (1 reference)

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"Cells treated with fmTE also increased desmosine concentration but significantly less than with the addition of nTE (Fig. 3)."

Desmosine was lower than with normal added tropoelastin but was still produced; it was normalized to total culture protein, not incorporated elastin mass.

Intragenic ELN duplication family fibroblasts PRIMARY_CELL_CULTURE

Metabolic labeling and immunoprecipitation identified normal68 kDa tropoelastin plus an abnormal120 kDa protein. Mutant protein was partly secreted and partly retained, with both intracellular and matrix immunostaining.

Cell source

Dermal fibroblasts from the proband and affected daughter

Publication

PMID:15955094

Pathograph links

Intracellular Mutant Tropoelastin Retention partially recapitulates fidelity: moderate observes: cellular Mutant-specific immunostaining and immunoprecipitation support intracellular retention alongside secretion.

Limitations: Abstract-only available source; no intervention resolves the contribution to clinical injury.

Show evidence (1 reference)

PMID:15955094 SUPPORT DIRECT PRIMARY RESULT In Vitro

"A polyclonal antibody raised against a unique peptide in the mutant TE molecule showed both intracellular and matrix staining."

The mutant-specific antibody detects both compartments.

The regenerated reference provides the abstract only; complete methods, sample-replication details and quantitative secretion fractions were unavailable. These findings do not prove which retained or matrix protein fraction causes severe lung disease.

Show evidence (1 reference)

PMID:15955094 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Immunoprecipitation experiments showed that the mutant TE was partially secreted and partially retained intracellularly."

The abstract directly describes mixed secretion and retention.

🐁

Animal Models

Human ELN cutis-laxa cDNA minigene mouse

Human mutant or wild-type elastin cDNA minigenes were introduced by pronuclear injection. All three mutant founders had enlarged pulmonary airspaces; severe line 2 could not be maintained and its early mortality is not the outcome of the line 60 functional experiments. Lung-strip stiffness and elastic recoil were reduced in line 60. Crosslinked elastin measured by desmosine increased in both wild-type and mutant transgenic lungs. Human and mouse elastin colocalized in a shared network; that does not resolve covalent copolymer composition molecule by molecule.

Species

Mouse

Genotype

CMV enhancer/chicken beta-actin-driven human ELN c.2114_2138del cDNA with exon 32 skipped, on intact endogenous Eln background

Background

C57BL/6J; three founder lines, detailed functional work principally line 60

Publication

PMID:20600892

Pathograph links

Alveolar Airspace Enlargement partially recapitulates fidelity: moderate observes: tissue Airspace enlargement occurred in all three founder lines, with variable severity.

Limitations: Detailed mechanical results principally concern line 60, not the severely affected line 2.

Readouts

Pulmonary airspace enlargement

Direction: INCREASED

Interpretation: Airspace enlargement occurred in all three founder lines, with variable severity.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantitative morphometry confirmed significant airspace enlargement in all CL lines and normal alveolar sizes in WT transgenic mice"

The three founder lines showed variable pulmonary severity; subsequent functional work used line 60.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantitative morphometry confirmed significant airspace enlargement in all CL lines and normal alveolar sizes in WT transgenic mice"

The three founder lines showed variable pulmonary severity; subsequent functional work used line 60.

Reduced Tissue Elastic Recoil partially recapitulates fidelity: moderate observes: tissue The functional model reproduces reduced lung recoil and stiffness.

Limitations: This does not demonstrate the same mechanical phenotype in skin or aorta.

Readouts

Lung elastic recoil

Direction: DECREASED

Interpretation: The functional model reproduces reduced lung recoil and stiffness.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Expiratory static pressure-volume curves of CL lungs were shifted to the left compared with NTg controls, indicating that lung elastic recoil pressure in CL mice was reduced"

The minigene line-60 lung shows reduced recoil; this is an organ-level mechanical measurement.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Expiratory static pressure-volume curves of CL lungs were shifted to the left compared with NTg controls, indicating that lung elastic recoil pressure in CL mice was reduced"

The minigene line-60 lung shows reduced recoil; this is an organ-level mechanical measurement.

Increased SMAD2 Phosphorylation partially recapitulates fidelity: moderate observes: cellular The stated molecular or histological readout was elevated in mutant lung.

Limitations: No selective rescue establishes that this readout causes airspace enlargement; TUNEL remained low in absolute fraction.

Readouts

pSMAD2-positive lung nuclei

Direction: INCREASED

Interpretation: The stated molecular or histological readout was elevated in mutant lung.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantitative evaluation of pSMAD2-positive nuclei showed a highly significant increase in the lungs of CL mice, whereas WT mice showed no difference compared to NTg"

The measurement is an in-vivo lung endpoint in the minigene model.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantitative evaluation of pSMAD2-positive nuclei showed a highly significant increase in the lungs of CL mice, whereas WT mice showed no difference compared to NTg"

The measurement is an in-vivo lung endpoint in the minigene model.

Endoplasmic Reticulum Stress Response partially recapitulates fidelity: moderate observes: cellular The stated molecular or histological readout was elevated in mutant lung.

Limitations: No selective rescue establishes that this readout causes airspace enlargement; TUNEL remained low in absolute fraction.

Readouts

Phospho-eIF2alpha staining with mutant elastin

Direction: INCREASED

Interpretation: The stated molecular or histological readout was elevated in mutant lung.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In CL lungs, the frequency of peIF2a positive cells was significantly elevated (Fig. 5D). Importantly, 80% of the peIF2a positive cells were also positive for CL elastin"

The measurement is an in-vivo lung endpoint in the minigene model.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In CL lungs, the frequency of peIF2a positive cells was significantly elevated (Fig. 5D). Importantly, 80% of the peIF2a positive cells were also positive for CL elastin"

The measurement is an in-vivo lung endpoint in the minigene model.

Increased Apoptotic Readouts partially recapitulates fidelity: moderate observes: cellular The stated molecular or histological readout was elevated in mutant lung.

Limitations: No selective rescue establishes that this readout causes airspace enlargement; TUNEL remained low in absolute fraction.

Readouts

Lung TUNEL index

Direction: INCREASED

Interpretation: The stated molecular or histological readout was elevated in mutant lung.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice"

The measurement is an in-vivo lung endpoint in the minigene model.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice"

The measurement is an in-vivo lung endpoint in the minigene model.

Notes

This is added cDNA expression, not a BAC or endogenous heterozygous knock-in. Genomic copy number and insertion-site matching were not reported. No consistent skin or cardiovascular pathology was observed. Elevated pSMAD2, phospho-eIF2alpha and TUNEL are parallel observations; no selective pathway blockade, active-TGF-beta release assay or therapeutic rescue establishes mediation. Histology/signaling used four mice per group and fields are nested within mice.

Show evidence (1 reference)

PMID:20600892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Transgenic mice were generated using pronuclear injection of minigenes containing either a human elastin cDNA with a cutis laxa mutation 2114_2138del (CL) or a wild-type human elastin cDNA (WT)."

The full methods establish minigene design and comparator.

Human ELN BAC frameshift transgenic mouse

A human genomic BAC preserves introns and alternative splicing; three founders were identified and line 1 was used subsequently. Mutant elastin incorporated into skin and lung, with little aortic matrix incorporation despite aortic protein production. Skin required about half the displacement force of controls. Aortic desmosine and mechanics were unchanged; skin desmosine increased. Mutant-BAC-only lung compliance trends on Eln+/+ and Eln+/- were not statistically significant; adverse effects were clearer in the human-WT-BAC rescue background. The mutant BAC did not rescue Eln-null viability and impaired rescue by the wild-type human BAC.

Species

Mouse

Genotype

Human ELN BAC carrying the paper’s 2012deltaG exon 30 deletion, tested on Eln+/+, Eln+/- and human-WT-BAC rescue backgrounds

Publication

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/

Pathograph links

Reduced Tissue Elastic Recoil partially recapitulates fidelity: moderate observes: tissue Skin suction testing found reduced force required for displacement.

Limitations: Pulmonary effects depend on the combined human/mouse elastin background, and no comparable aortic mechanical deficit was demonstrated.

Readouts

Skin displacement resistance

Direction: DECREASED

Interpretation: Skin suction testing found reduced force required for displacement.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"only about half as much force was required to displace skin"

In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"only about half as much force was required to displace skin"

In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.

Abnormal Elastic Fiber Architecture partially recapitulates fidelity: moderate observes: tissue Mutant elastin entered skin and lung fibers with tissue-specific functional abnormalities.

Limitations: Aortic protein production did not translate into substantial matrix incorporation; the model does not reproduce human aortopathy consistently.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"When expressed as a transgene in mice, mutant elastin was incorporated into elastic fibers in the skin and lung with adverse effects on tissue function."

This describes the affected compartments; full results qualify the lung-background dependence.

Notes

An added BAC is not the endogenous heterozygous patient genotype. Human and mouse elastin backgrounds alter expression and tissue responses. Translation-inhibitor RNA experiments were performed in cultured mouse fibroblasts, not measured as an in-vivo RNA-decay rate. Exon32 inclusion promotes partial decay, not universal elimination; adult splice ratios alone did not explain tissue-specific matrix incorporation. The article contains inconsistent printed significance thresholds, so no repaired numeric threshold is asserted here.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"To investigate the pathophysiology underlying a class of elastin gene mutations leading to autosomal dominant cutis laxa, we engineered a cutis laxa mutation (single base deletion) into the human elastin gene contained in a bacterial artificial chromosome."

This establishes the genomic human transgene design.

Eln hemizygous mouse as an allelic dosage comparator

This model addresses reduced elastin dosage rather than an ADCL1 mutant protein. Reduced RNA and thin lamellae accompany an adaptive increase in arterial lamellar units. Arterial extensibility is near normal around physiological pressure but lower at higher pressure; mice do not develop the focal human supravalvular hourglass lesion. The human histology comparison included only two SVAS cases and three controls.

Species

Mouse

Genotype

Eln+/- with promoter and exon 1 deletion

Publication

PMID:9819363

Retained as differential allelic context, with no claim that it tests or refutes a dominant-negative ADCL1 mechanism. Reduced quantity and altered protein cannot be assumed to be molecular opposites at every tissue endpoint.

Show evidence (1 reference)

PMID:9819363 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at physiologic pressures was nearly normal."

The abstract summarizes the dosage model; the full body provides pressure-dependent limitations.

{ }

Source YAML

click to show

name: Autosomal Dominant Cutis Laxa 1
creation_date: '2026-09-04T23:23:40Z'
category: Mendelian
description: ELN-related autosomal dominant cutis laxa is a heritable connective-tissue disorder with variably redundant, inelastic skin and characteristic facial features. Heterozygous variants often alter the tropoelastin carboxy terminus, impairing elastic-fiber assembly and function through allele-dependent effects. Inguinal hernias, joint laxity, hoarse voice, aortic-root disease and pulmonary complications can occur. Skin severity does not reliably predict internal-organ involvement, and aortic dissection or severe lung disease can be consequential even when skin findings are mild. Experimental studies support dominant interference with elastic tissue mechanics, but transcript processing, intracellular stress and signaling effects vary; their respective contributions to human organ disease remain incompletely resolved.
disease_term:
  preferred_term: Autosomal Dominant Cutis Laxa 1
  term:
    id: MONDO:0007411
    label: cutis laxa, autosomal dominant 1
synonyms:
- ADCL1
- ELN-related cutis laxa
- ELN autosomal dominant cutis laxa
- Cutis laxa, autosomal dominant type 1
- Autosomal dominant cutis laxa caused by mutation in ELN
- Cutis laxa, autosomal dominant
parents:
- Connective Tissue Disease
- Cutis Laxa
- Elastinopathy
notes: This entry covers ELN-related cutis laxa (ADCL1). FBLN5-related and ALDH18A1-related dominant cutis laxa, recessive cutis laxa syndromes, and ELN haploinsufficiency-associated supravalvular aortic stenosis remain differential or allelic disorders. They can share matrix or cellular processes without being interchangeable diagnoses. The atypical exon-25 family is discussed with its unresolved diagnostic attribution rather than supplying typical ADCL1 frequencies. Aortic TGF-beta module conformance is not asserted because elevated SMAD2 phosphorylation does not demonstrate matrix-mediated ligand release or required signaling mediation. Excluding alpha-1-antitrypsin deficiency in two patients does not exclude all proteolytic or inflammatory contributions to lung disease.
references:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
  title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
  findings:
  - statement: Complete GeneReviews chapter read across phenotype, genetics, diagnosis and care, including tables and limitations. Updated2022; care is expert synthesis, with no ADCL1 comparative efficacy trial.
- reference: PMID:23442826
  title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
  findings:
  - statement: Full main text, Methods, Results, Discussion and Tables1–4 independently audited. Abstract and pooled-table percentages disagree; no pooled frequency band is assigned.
- reference: PMID:21309044
  title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
  findings:
  - statement: Complete available main Methods, Results and Discussion read; separate figure legends and supplementary files are absent from this cache.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
  title: Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC
  findings:
  - statement: PMID22573328; complete recovered main body and available figure captions read. Supplemental objects not independently read. Main-body genotype and significance caveats take priority over the broad abstract.
- reference: PMID:20600892
  title: Mechanisms of emphysema in autosomal dominant cutis laxa.
  findings:
  - statement: Complete available main Methods, Results and Discussion independently audited; separate figure legends and supplements were unavailable.
- reference: PMID:15955094
  title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
  findings:
  - statement: Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/
  title: Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene - PMC
  findings:
  - statement: PMID16085695; complete recovered main body, Table 1 and Figures1–3 read. Aortic pathology and skin electron microscopy involve different sampled relatives.
- reference: PMID:9580666
  title: An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa.
  findings:
  - statement: Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.
- reference: PMID:9873040
  title: Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN).
  findings:
  - statement: Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.
- reference: PMID:15381555
  title: A novel elastin gene mutation resulting in an autosomal dominant form of cutis laxa.
  findings:
  - statement: Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.
- reference: PMID:18348261
  title: Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene.
  findings:
  - statement: Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.
- reference: PMID:9819363
  title: Novel arterial pathology in mice and humans hemizygous for elastin.
  findings:
  - statement: Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.
- reference: PMID:23250899
  title: 'Supravalvular aortic stenosis: elastin arteriopathy.'
  findings:
  - statement: Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.
- reference: PMID:29501665
  title: Elastin-driven genetic diseases.
  findings:
  - statement: Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.
- reference: PMID:30704477
  title: 'A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report.'
  findings:
  - statement: Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.
- reference: PMID:35372488
  title: 'Congenital Cutis Laxa: A Case Report and Literature Review.'
  findings:
  - statement: Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.
- reference: PMID:39354494
  title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
  findings:
  - statement: Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.
- reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
  title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
  findings:
  - statement: Sato2006, J Health Sci52:259–267; complete primary PDF Methods, Results, Discussion and Figures1–5 read. Purified protein/ARPE-19 system, not patient tissue.
inheritance:
- name: Autosomal dominant inheritance
  description: An affected heterozygous parent has a 50% chance of transmitting the pathogenic allele in each pregnancy. Expressivity varies within families. Reported probands include inherited and de novo variants; an apparently negative family history is not proof of a de novo event. Parental testing refines recurrence counseling, and negative leukocyte testing cannot exclude gonadal mosaicism.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: -related cutis laxa has a 50% chance of inheriting the
    explanation: The offspring section specifies allele-transmission risk; it does not predict individual organ severity.
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Direct sequencing of the probands’ DNA revealed 5 different de novo frameshift mutations
    explanation: The five probands in this selected series had reported de novo variants; the identical twins share one proband-level event.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Irrespective of the location or type, each mutation was predicted to result in the replacement of the normal C-terminus of TE with a missense peptide sequence
      explanation: The monogenic ELN etiology supports the genetics category.
  - classification_value: DERMATOLOGY
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Autosomal dominant cutis laxa (ADCL) is a rare disorder that presents with lax skin, typical facial characteristics, inguinal hernias, aortic root dilatation and pulmonary emphysema.
      explanation: Lax skin is the defining and universal presentation, which places the primary clinical home in dermatology.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - classification_value: CARDIOVASCULAR
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/
      reference_title: Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: ELN mutations may cause severe aortic disease in patients with cutis laxa. Thus regular cardiac monitoring is necessary in this disease to avert fatal aortic rupture.
      explanation: The aortic aneurysmal phenotype is the life-limiting arm of the disease and is managed as a heritable aortopathy.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
pathophysiology:
- name: Heterozygous ELN Pathogenic Variant
  biological_scale: MOLECULAR
  description: Heterozygous ELN variants causing this phenotype usually alter the carboxy-terminal coding sequence. Frameshifts predominate, while splice-altering intronic variants and an intragenic duplication are also reported. This is not a claim that every ELN loss-of-function allele causes cutis laxa; dosage-reducing alleles more often cause supravalvular aortic stenosis.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Irrespective of the location or type, each mutation was predicted to result in the replacement of the normal C-terminus of TE with a missense peptide sequence
    explanation: All five sequence changes in the selected 2011 probands were predicted to replace the normal C terminus; the statement does not generalize to all ELN variation.
  role: trigger
  genes:
  - &id001
    preferred_term: ELN
    term:
      id: hgnc:3327
      label: ELN
  downstream:
  - target: C-Terminally Altered Tropoelastin
    description: The tested frameshift alleles change the translated carboxy terminus; intervening transcript processing determines which protein isoforms are produced.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Irrespective of the location or type, each mutation was predicted to result in the replacement of the normal C-terminus of TE with a missense peptide sequence
      explanation: All five sequence changes in the selected 2011 probands were predicted to replace the normal C terminus; the statement does not generalize to all ELN variation.
  - target: Small Airway Dysfunction
    description: The single molecularly diagnosed case establishes a clinical association; the route from altered elastin to small-airway dysfunction remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39354494
      reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Computed tomography (CT) revealed the lack of normal increase in lung attenuation on expiratory CT scan, with no discernible emphysematous changes.
      explanation: The case supports small-airway dysfunction without visually discernible emphysema; no lung histology established the exact tissue lesion.
  - target: Bicuspid aortic valve
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: the prevalence in our group of ADCL patients is 2/6.
      explanation: The denominator is six selected individuals, not six independent probands.
  - target: Arterial tortuosity
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Increased tortuosity of the arteries (mainly of the supra-aortic vasculature) has been incidentally noted but not systematically assessed
      explanation: The synthesis explicitly limits ascertainment.
  - target: Mitral valve prolapse
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30704477
      reference_title: 'A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: evaluation by echocardiography revealed mitral valve prolapse and diffuse changes in myocardium.
      explanation: The reported mother had echocardiographic mitral prolapse; incidental cardiac rhythm findings in the family are not assigned to ELN here.
  - target: Mitral regurgitation
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: patients F1:II-4 and F6-20 had mitral valve regurgitation.
      explanation: The body reports this valve manifestation in selected patients.
  - target: Bronchiectasis
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15955094
      reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: a CL family characterized by hernias and unusually severe and early-onset pulmonary disease including bronchiectasis and pulmonary emphysema.
      explanation: The finding is scoped to the duplication family; infection and airway remodeling intermediates are not established for all alleles.
  - target: Pectus excavatum
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39354494
      reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: the chest CT scan revealed the presence of pectus excavatum.
      explanation: A direct CT observation in one case, without a frequency estimate.
  - target: Gastroesophageal reflux
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Other manifestations included gastro- oesophageal reflux (F1:II-7 and F1:III-4)
      explanation: The source assigns reflux to two related individuals rather than a general prevalence.
- name: C-Terminally Altered Tropoelastin
  biological_scale: MOLECULAR
  description: Affected alleles can produce tropoelastin with a replaced and often extended carboxy terminus. Protein is demonstrable in selected patient cultures, but transcript abundance, exon skipping and partial nonsense-mediated decay depend on allele and isoform. Splicing can produce truncated, extended or mutation-skipping products; universal escape from RNA decay is not established.
  evidence:
  - reference: PMID:9580666
    reference_title: An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: mRNA and immunoprecipitation studies show that the mutant allele is expressed.
    explanation: The original exon-32 case demonstrates expression, without proving that all pathogenic alleles escape RNA decay.
  - reference: PMID:15955094
    reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: an abnormal, 120 kDa polypeptide was detected in the proband and her affected daughter
    explanation: Patient dermal fibroblasts from the duplication family produced an abnormal protein in addition to normal tropoelastin.
  genes:
  - *id001
  cell_types:
  - &id002
    preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  downstream:
  - target: Increased Tropoelastin Self-Association
    description: The tested altered protein changes temperature-dependent self-association in a purified-protein assay.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation
      explanation: The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.
  - target: Reduced Tropoelastin Binding to Fibrillin-1
    description: Changing the tested carboxy-terminal sequence reduces measured binding to the fibrillin fragment.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
      reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the binding of nTE to PET was also increased 30% above fmTE binding.
      explanation: Normal and mutant recombinant proteins were compared against the fibrillin-1 PET fragment, not full-length fibrillin in a patient tissue.
  - target: Reduced Tropoelastin Binding to Fibulin-5
    description: Changing the tested carboxy-terminal sequence reduces measured binding to fibulin-5.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
      reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: At all concentrations used there was a significantly lower molecular interac- tion with fmTE compared to nTE.
      explanation: Solution co-immunoprecipitation supports reduced association under the tested recombinant-protein conditions.
  - target: Intracellular Mutant Tropoelastin Retention
    description: The tested abnormal proteins show incomplete secretion with intracellular retention; other alleles need not share the same degree.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15955094
      reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Immunoprecipitation experiments showed that the mutant TE was partially secreted and partially retained intracellularly.
      explanation: This is a direct protein-processing observation in patient-derived fibroblasts from the duplication family.
  - target: Increased Apoptotic Readouts
    description: Mutant-expression and control comparisons support an allele/model-associated increase in apoptotic readouts; the intervening stress or signaling mediator remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice
      explanation: The minigene model supports increased TUNEL staining with a low absolute index, not extensive universal tissue loss.
  - target: Increased SMAD2 Phosphorylation
    description: Expression-associated comparisons support an altered signaling readout, while matrix-mediated ligand release and intracellular contributions remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Staining for pSMAD2 in fibroblast cultures of all patients showed significant upregulation of the TGFβ signaling pathway
      explanation: The measured endpoint was phosphorylated SMAD2 in the three available patient cultures, rather than direct active-ligand release.
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Quantitative evaluation of pSMAD2-positive nuclei showed a highly significant increase in the lungs of CL mice, whereas WT mice showed no difference compared to NTg
      explanation: The transgenic lung result supports altered pathway readout with an expression comparator.
- name: Increased Tropoelastin Self-Association
  biological_scale: MOLECULAR
  description: A purified exon-32 frameshift tropoelastin construct coacervates at a lower temperature than its normal comparator. An equimolar mixture retains the mutant-like shift, supporting a dominant biophysical effect for this construct. This assay does not establish identical behavior for every ELN allele.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation
    explanation: The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.
  downstream:
  - target: Impaired Elastic Fiber Assembly
    description: Abnormal self-association is proposed to interfere with later assembly. The study associates globules with poor fibrillar deposition but does not selectively normalize coacervation while holding other mutant effects constant.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: We observe an accumulation of globular elastin aggregates in fibroblast cultures from patients with ADCL, suggesting that fmTE disrupts later stages of the elastin assembly process.
      explanation: The source itself frames the assembly-stage interpretation as a suggestion.
- name: Reduced Tropoelastin Binding to Fibrillin-1
  biological_scale: MOLECULAR
  description: The exon-32 frameshift recombinant tropoelastin binds less strongly to a recombinant amino-terminal fibrillin-1 PET fragment in a solid-phase assay. This measures one molecular interaction; it is not loss of the fibrillin scaffold or proof of the same defect in every tissue.
  evidence:
  - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
    reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the binding of nTE to PET was also increased 30% above fmTE binding.
    explanation: Normal and mutant recombinant proteins were compared against the fibrillin-1 PET fragment, not full-length fibrillin in a patient tissue.
  downstream:
  - target: Impaired Elastic Fiber Assembly
    description: Reduced scaffold-protein interaction is a proposed contributor to poor deposition; binding and assembly assays do not isolate that interaction as the sole necessary mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
      reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Our results suggest that the defect of fmTE fiber assembly is due, at least in part, to decreased molecular interactions between tropoelastin and the microfibrillar components fibulin-5 and fibrillin.
      explanation: The authors propose partial mediation by altered molecular interactions, not a selective binding-rescue result.
- name: Reduced Tropoelastin Binding to Fibulin-5
  biological_scale: MOLECULAR
  description: The same recombinant frameshift protein shows lower association with fibulin-5 in solid-phase binding and solution co-immunoprecipitation assays. Conditioned-medium recombinant fibulin-5 and purified tropoelastin define the tested system.
  evidence:
  - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
    reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: At all concentrations used there was a significantly lower molecular interac- tion with fmTE compared to nTE.
    explanation: Solution co-immunoprecipitation supports reduced association under the tested recombinant-protein conditions.
  downstream:
  - target: Impaired Elastic Fiber Assembly
    description: Reduced scaffold-protein interaction is a proposed contributor to poor deposition; binding and assembly assays do not isolate that interaction as the sole necessary mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
      reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Our results suggest that the defect of fmTE fiber assembly is due, at least in part, to decreased molecular interactions between tropoelastin and the microfibrillar components fibulin-5 and fibrillin.
      explanation: The authors propose partial mediation by altered molecular interactions, not a selective binding-rescue result.
- name: Impaired Elastic Fiber Assembly
  biological_scale: CELLULAR
  description: 'Selected patient fibroblasts deposit less insoluble elastin and show abnormal extracellular globules and fibrillar deposition. Recombinant mutant protein also yields less matrix-associated elastin in ARPE-19 culture. Total desmosine per culture protein is lower in that assay, but this does not establish a universal reduction in crosslinks per elastin molecule: crosslinked elastin is increased in some transgenic tissues.'
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We found significantly lower amounts of insoluble elastin in ADCL cells compared to controls on day 4 and 8
    explanation: Cultured patient fibroblasts have reduced mature insoluble elastin deposition relative to the normalization used in the study.
  - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
    reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cells treated with fmTE also increased desmosine concentration but significantly less than with the addition of nTE (Fig. 3).
    explanation: Desmosine was lower than with normal added tropoelastin but was still produced; it was normalized to total culture protein, not incorporated elastin mass.
  cell_types:
  - *id002
  biological_processes:
  - preferred_term: elastic fiber assembly
    term:
      id: GO:0048251
      label: elastic fiber assembly
    modifier: DECREASED
  downstream:
  - target: Abnormal Elastic Fiber Architecture
    description: Poor assembly provides a mechanistic explanation for abnormal dermal fibers; culture and biopsy observations support the route without a longitudinal tissue rescue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: our electron microscopic results demonstrate the abnormal elastin assembly, characterized by poor integration of elastin with microfibrils.
      explanation: The article integrates culture assembly findings with dermal ultrastructure; tissue architecture is not inferred from protein amount alone.
- name: Abnormal Elastic Fiber Architecture
  biological_scale: TISSUE
  description: Human dermal biopsies show reduced and disorganized elastin deposition, fragmentation and poor association with microfibrils. Aortic elastic lamellae are disorganized in a surgically sampled affected person. Findings differ across tissues and models; mutant protein can be incorporated into mechanically abnormal fibers without a reduced total desmosine content.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The amorphous component of the elastic fibers showed extensive branching and fragmentation and was not properly associated with the microfibrils.
    explanation: Direct ultrastructural findings were obtained from dermal biopsies, not lung or aorta in every patient.
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  downstream:
  - target: Reduced Tissue Elastic Recoil
    description: Abnormal elastic material is associated with impaired organ mechanics. Transgenic comparisons support a functional effect, while other matrix and cellular changes preclude a single-fiber mediator claim.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Expiratory static pressure-volume curves of CL lungs were shifted to the left compared with NTg controls, indicating that lung elastic recoil pressure in CL mice was reduced
      explanation: The minigene line-60 lung shows reduced recoil; this is an organ-level mechanical measurement.
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
      reference_title: Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: only about half as much force was required to displace skin
      explanation: In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.
  - target: Alveolar Airspace Enlargement
    description: An abnormal elastic network is a plausible contributor to airspace enlargement, supported by mutant-expression models without a selective matrix or apoptosis rescue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Quantitative morphometry confirmed significant airspace enlargement in all CL lines and normal alveolar sizes in WT transgenic mice
      explanation: The three founder lines showed variable pulmonary severity; subsequent functional work used line 60.
  - target: Aortic Medial Disorganization
    description: The qualitative elastic-fiber defect is consistent with medial disorganization in the sampled aorta, but tissue-specific deposition and cellular mechanisms remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/
      reference_title: Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The aortic pathology associated with this condition is medial degeneration, characterised by dramatic loss of elastic lamellae and smooth muscle cells and a lack of atherosclerotic and inflammatory lesions.
      explanation: The source reports aortic pathological changes in the aneurysm case; detailed anatomy and sampling limits are retained.
- name: Reduced Tissue Elastic Recoil
  biological_scale: TISSUE
  description: Abnormal elastic networks can impair tissue mechanics. Mutant BAC mouse skin requires less suction force to displace, and the separate minigene model has reduced lung recoil and tissue stiffness. Extension to hernia, joint, bladder and vocal-fold support is a tissue-level explanation, not direct biomechanical testing of each organ in every patient.
  evidence:
  - reference: PMID:20600892
    reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Expiratory static pressure-volume curves of CL lungs were shifted to the left compared with NTg controls, indicating that lung elastic recoil pressure in CL mice was reduced
    explanation: The minigene line-60 lung shows reduced recoil; this is an organ-level mechanical measurement.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
    reference_title: Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: only about half as much force was required to displace skin
    explanation: In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  downstream:
  - target: Cutis laxa
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: generalized cutis laxa (ranging from generalized skin redundancy causing excessive skin folds to skin hyperextensibility without obvious skin folds)
      explanation: The full chapter describes the broad cutaneous spectrum.
  - target: Prematurely aged appearance
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15381555
      reference_title: A novel elastin gene mutation resulting in an autosomal dominant form of cutis laxa.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: A 45-year-old woman and her 19-year-old son presented with inelastic, loose-hanging, and wrinkled skin that appeared prematurely aged
      explanation: The familial report describes an appearance phenotype, not a molecular aging syndrome.
  - target: Coarse facial features
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum.
      explanation: The clinical figure caption documents the individual facial features in this selected cohort.
  - target: Long face
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum.
      explanation: The clinical figure caption documents the individual facial features in this selected cohort.
  - target: Long philtrum
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: 'Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance'
      explanation: GeneReviews explicitly describes a long philtrum, without inferring length from the less specific word large.
  - target: Large ears
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum.
      explanation: The clinical figure caption documents the individual facial features in this selected cohort.
  - target: Ptosis
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum.
      explanation: The clinical figure caption documents the individual facial features in this selected cohort.
  - target: Convex nasal ridge
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: 'Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance'
      explanation: GeneReviews specifically describes convex nasal shape.
  - target: Inguinal hernia
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: 'Inguinal hernias were frequent, appearing congenitally (F1:II-2, F1:II-3, F1:III-1, F2:II-1) or throughout life (F1: I-2 at age 80 and F1:III-4 at 18 years old) and often re- occurred after surgery'
      explanation: The clinical cohort documents variable age of onset and postoperative recurrence; no population frequency is assigned.
  - target: Umbilical hernia
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Patient F1:II-4 also had an umbilical hernia.
      explanation: This is an individual observation within the cohort.
  - target: Joint hypermobility
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Other common findings are joint hyperlaxity in infancy and increasing risk of inguinal hernia at all ages.
      explanation: The synthesis identifies joint hyperlaxity with an age qualifier.
  - target: Hoarse voice
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: a long philtrum, large ears, a husky voice and often a beaked nose.
      explanation: The selected cohort directly documents the voice finding.
  - target: Bladder diverticulum
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: ptosis, aortic root dilatation, emphysema, bladder diverticula
      explanation: The chapter identifies bladder diverticula among recognized manifestations requiring surveillance.
  - target: Uterine prolapse
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29501665
      reference_title: Elastin-driven genetic diseases.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Genital prolapse has been described in at least 2 individuals with ADCL caused by ELN variants
      explanation: This review reports genital prolapse; the full GeneReviews pregnancy section specifically identifies uterine prolapse.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Uterine prolapse may occur [Urban et al 2005].
      explanation: The full GeneReviews pregnancy section explicitly names the uterine manifestation; the additional synthesis quotation establishes reported genital prolapse cases.
- name: Intracellular Mutant Tropoelastin Retention
  biological_scale: CELLULAR
  description: Some abnormal tropoelastin remains intracellular while another fraction is secreted. This has been demonstrated in the duplication-family fibroblasts and selected frameshift cultures or transgenic lung. Retention is not assumed universal or complete.
  evidence:
  - reference: PMID:15955094
    reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Immunoprecipitation experiments showed that the mutant TE was partially secreted and partially retained intracellularly.
    explanation: This is a direct protein-processing observation in patient-derived fibroblasts from the duplication family.
  cell_types:
  - *id002
  downstream:
  - target: Endoplasmic Reticulum Stress Response
    description: Colocalization of retained tropoelastin with stress markers supports the proposed trigger, without selective removal of retention or proof of necessity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: BiP co-localized with TE in the ER, indicating misfolding
      explanation: Colocalization supports an ER-processing hypothesis; it is not an isolated folding assay or intervention establishing mediation.
- name: Endoplasmic Reticulum Stress Response
  biological_scale: CELLULAR
  description: Selected patient fibroblasts show elevated BiP or phosphorylated eIF2alpha, with different results by cell line. The exon-30 line CL-3 has the clearest combined stress readout; CL-1 lacks a significant BiP increase. Transgenic lung also shows increased phosphorylated eIF2alpha. These assays do not establish a required serial pathway to organ disease.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: phosphorylated eukaryotic translation initiation factor (peIF2α), a marker for ER stress, which was only significantly upregulated in patient CL-3
    explanation: Stress-marker changes were not uniform across the three tested patient fibroblast lines.
  cell_types:
  - *id002
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
- name: Increased Apoptotic Readouts
  biological_scale: CELLULAR
  description: Caspase-3 staining rises in the selected CL-3 fibroblast line and the minigene mouse lung has a small increased TUNEL-positive fraction. Stress and SMAD2 readouts were measured alongside apoptosis. Neither pathway was selectively inhibited to establish an obligatory death mechanism, and apoptosis was not shown to mediate human emphysema.
  evidence:
  - reference: PMID:20600892
    reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice
    explanation: The minigene model supports increased TUNEL staining with a low absolute index, not extensive universal tissue loss.
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
- name: Increased SMAD2 Phosphorylation
  biological_scale: CELLULAR
  description: Increased phosphorylated SMAD2 in the three studied patient fibroblast cultures and minigene lung is consistent with enhanced TGF-beta-pathway signaling. Release of latent matrix TGF-beta was not directly measured, and there is no selective pathway rescue establishing mediation of aortic or lung disease.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Staining for pSMAD2 in fibroblast cultures of all patients showed significant upregulation of the TGFβ signaling pathway
    explanation: The measured endpoint was phosphorylated SMAD2 in the three available patient cultures, rather than direct active-ligand release.
  - reference: PMID:20600892
    reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Quantitative evaluation of pSMAD2-positive nuclei showed a highly significant increase in the lungs of CL mice, whereas WT mice showed no difference compared to NTg
    explanation: The transgenic lung result supports altered pathway readout with an expression comparator.
  cell_types:
  - *id002
- name: Alveolar Airspace Enlargement
  biological_scale: TISSUE
  description: Mutant minigene mice show enlarged pulmonary airspaces across three founder lines, with different severity. Human ELN-related disease can include severe emphysema, but this is not obligatory and the separate BAC model has weaker lung findings. Airspace morphology does not by itself identify whether abnormal development, mechanical failure or cell injury is the necessary mediator.
  evidence:
  - reference: PMID:20600892
    reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Quantitative morphometry confirmed significant airspace enlargement in all CL lines and normal alveolar sizes in WT transgenic mice
    explanation: The three founder lines showed variable pulmonary severity; subsequent functional work used line 60.
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  downstream:
  - target: Emphysema
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Chronic obstructive pulmonary disease was diag- nosed in eight patients, seven of whom had emphysema and one had asthma.
      explanation: The full Results distinguish emphysema from asthma rather than treating all eight diagnoses as emphysema.
- name: Small Airway Dysfunction
  biological_scale: TISSUE
  description: A never-smoking adult with an ELN frameshift had severe obstruction, air trapping and abnormal small-airway indices over eight years without visually apparent CT emphysema. Quantitative low-attenuation measures and visual CT were discordant. The specific microscopic or extracellular-matrix mediator was not established in this single case.
  evidence:
  - reference: PMID:39354494
    reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Computed tomography (CT) revealed the lack of normal increase in lung attenuation on expiratory CT scan, with no discernible emphysematous changes.
    explanation: The case supports small-airway dysfunction without visually discernible emphysema; no lung histology established the exact tissue lesion.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  downstream:
  - target: Airway obstruction
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39354494
      reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in pulmonary function tests
      explanation: This was one adult with severe physiological obstruction despite little subjective limitation.
- name: Aortic Medial Disorganization
  biological_scale: TISSUE
  description: A surgically sampled adult with a familial ELN frameshift and aortic aneurysm had thinning and disorganization of the medial elastic lamellae and reduced smooth-muscle density. This direct aortic observation is distinct from skin electron microscopy in another family member. TGF-beta mediation and generalized vascular fragility were not established.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/
    reference_title: Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The aortic pathology associated with this condition is medial degeneration, characterised by dramatic loss of elastic lamellae and smooth muscle cells and a lack of atherosclerotic and inflammatory lesions.
    explanation: The source reports aortic pathological changes in the aneurysm case; detailed anatomy and sampling limits are retained.
  locations:
  - preferred_term: aorta tunica media
    term:
      id: UBERON:0003618
      label: aorta tunica media
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  downstream:
  - target: Aortic root dilatation
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Vascular involvement included ARD in eight patients, and a dilatation of the aortic arch in one
      explanation: The body separates root and arch involvement rather than combining them into one root-dilation count.
  - target: Aortic dissection
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Aortic dissection has been reported in multiple families as early as in the third decade
      explanation: The synthesis supports the clinically important vascular risk without a reliable incidence estimate.
  - target: Aortic rupture
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/
      reference_title: Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: aortic lesions ranging from mild dilatation to severe aneurysm and rupture of the aortic root
      explanation: The primary family report and sporadic case establish the vascular complication spectrum.
  - target: Aortic regurgitation
    description: This tissue-level route is a proposed explanation for the observed clinical manifestation; the cited clinical observation does not directly measure every intervening step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: patients had aortic valve regurgitation
      explanation: The Results describe four affected members; this fragment is interpreted within that explicit clinical context.
phenotypes:
- name: Cutis laxa
  category: Integument
  description: Skin can be generalized and redundant or more mildly hyperextensible, with poor recoil. Severity varies with age and within families; mild skin involvement does not exclude consequential organ disease.
  phenotype_term:
    preferred_term: Cutis laxa
    term:
      id: HP:0000973
      label: Cutis laxa
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: generalized cutis laxa (ranging from generalized skin redundancy causing excessive skin folds to skin hyperextensibility without obvious skin folds)
    explanation: The full chapter describes the broad cutaneous spectrum.
- name: Prematurely aged appearance
  category: Integument
  description: An aged facial appearance reflects variable sagging and redundant skin; it does not imply accelerated systemic aging.
  phenotype_term:
    preferred_term: Prematurely aged appearance
    term:
      id: HP:0007495
      label: Prematurely aged appearance
  evidence:
  - reference: PMID:15381555
    reference_title: A novel elastin gene mutation resulting in an autosomal dominant form of cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A 45-year-old woman and her 19-year-old son presented with inelastic, loose-hanging, and wrinkled skin that appeared prematurely aged
    explanation: The familial report describes an appearance phenotype, not a molecular aging syndrome.
- name: Coarse facial features
  category: Craniofacial
  description: A coarse facial appearance is one end of the reported facial spectrum.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum.
    explanation: The clinical figure caption documents the individual facial features in this selected cohort.
- name: Long face
  category: Craniofacial
  description: An elongated facial appearance is reported in the 2013 cohort.
  phenotype_term:
    preferred_term: Long face
    term:
      id: HP:0000276
      label: Long face
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum.
    explanation: The clinical figure caption documents the individual facial features in this selected cohort.
- name: Long philtrum
  category: Craniofacial
  description: A long philtrum is part of the characteristic facial appearance.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance'
    explanation: GeneReviews explicitly describes a long philtrum, without inferring length from the less specific word large.
- name: Large ears
  category: Craniofacial
  description: The external ears are often large and pliant.
  phenotype_term:
    preferred_term: Large ears
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum.
    explanation: The clinical figure caption documents the individual facial features in this selected cohort.
- name: Ptosis
  category: Craniofacial
  description: Upper-lid drooping and lax redundant eyelid tissue can be functionally important when the pupil is obscured.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum.
    explanation: The clinical figure caption documents the individual facial features in this selected cohort.
- name: Convex nasal ridge
  category: Craniofacial
  description: A convex or beaked nasal profile is characteristic in some affected individuals.
  phenotype_term:
    preferred_term: Convex nasal ridge
    term:
      id: HP:0000444
      label: Convex nasal ridge
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance'
    explanation: GeneReviews specifically describes convex nasal shape.
- name: Inguinal hernia
  category: Abdominal
  description: Hernias may present at birth or later in life and may recur after repair.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Inguinal hernias were frequent, appearing congenitally (F1:II-2, F1:II-3, F1:III-1, F2:II-1) or throughout life (F1: I-2 at age 80 and F1:III-4 at 18 years old) and often re- occurred after surgery'
    explanation: The clinical cohort documents variable age of onset and postoperative recurrence; no population frequency is assigned.
- name: Umbilical hernia
  category: Abdominal
  description: An umbilical hernia was documented in one member of the 2013 series.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patient F1:II-4 also had an umbilical hernia.
    explanation: This is an individual observation within the cohort.
- name: Joint hypermobility
  category: Musculoskeletal
  description: Joint laxity is particularly noted in infancy and can contribute to instability or pain.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Other common findings are joint hyperlaxity in infancy and increasing risk of inguinal hernia at all ages.
    explanation: The synthesis identifies joint hyperlaxity with an age qualifier.
- name: Hoarse voice
  category: Otolaryngologic
  description: A husky or hoarse voice is reported; laryngoscopy demonstrated slack vocal cords in one molecularly characterized patient.
  phenotype_term:
    preferred_term: Hoarse voice
    term:
      id: HP:0001609
      label: Hoarse voice
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a long philtrum, large ears, a husky voice and often a beaked nose.
    explanation: The selected cohort directly documents the voice finding.
- name: Bladder diverticulum
  category: Genitourinary
  description: Bladder outpouchings may contribute to incomplete emptying and recurrent urinary infection; they are not universal.
  phenotype_term:
    preferred_term: Bladder diverticulum
    term:
      id: HP:0000015
      label: Bladder diverticulum
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: ptosis, aortic root dilatation, emphysema, bladder diverticula
    explanation: The chapter identifies bladder diverticula among recognized manifestations requiring surveillance.
- name: Uterine prolapse
  category: Genitourinary
  description: Uterine prolapse has been reported in affected women, including in the pregnancy discussion; its frequency is unknown.
  phenotype_term:
    preferred_term: Uterine prolapse
    term:
      id: HP:0000139
      label: Uterine prolapse
  evidence:
  - reference: PMID:29501665
    reference_title: Elastin-driven genetic diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Genital prolapse has been described in at least 2 individuals with ADCL caused by ELN variants
    explanation: This review reports genital prolapse; the full GeneReviews pregnancy section specifically identifies uterine prolapse.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Uterine prolapse may occur [Urban et al 2005].
    explanation: The full GeneReviews pregnancy section explicitly names the uterine manifestation; the additional synthesis quotation establishes reported genital prolapse cases.
- name: Aortic root dilatation
  category: Cardiovascular
  description: Root enlargement ranges from mild dilation to severe aneurysm. In the 2013 newly examined cohort it was described in eight patients; a separate patient had arch dilation. The report’s abstract and pooled-table percentages differ.
  phenotype_term:
    preferred_term: Aortic root dilatation
    term:
      id: HP:0002616
      label: Aortic root aneurysm
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Vascular involvement included ARD in eight patients, and a dilatation of the aortic arch in one
    explanation: The body separates root and arch involvement rather than combining them into one root-dilation count.
- name: Aortic dissection
  category: Cardiovascular
  description: Dissection can occur in young adulthood. The 2006 family included a relative who died at age 26, but that deceased relative was not among the available genotyped family members.
  phenotype_term:
    preferred_term: Aortic dissection
    term:
      id: HP:0002647
      label: Aortic dissection
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Aortic dissection has been reported in multiple families as early as in the third decade
    explanation: The synthesis supports the clinically important vascular risk without a reliable incidence estimate.
- name: Aortic rupture
  category: Cardiovascular
  description: Severe aortic disease can culminate in rupture; a disease-wide risk estimate is not established.
  phenotype_term:
    preferred_term: Aortic rupture
    term:
      id: HP:0031649
      label: Aortic rupture
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/
    reference_title: Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: aortic lesions ranging from mild dilatation to severe aneurysm and rupture of the aortic root
    explanation: The primary family report and sporadic case establish the vascular complication spectrum.
- name: Bicuspid aortic valve
  category: Cardiovascular
  description: A congenital bicuspid valve was present in two of six individuals in the 2011 series, including the shared-proband twins elsewhere in that denominator. Association with more extensive ascending-aortic dilation in that small series is not a validated predictor.
  phenotype_term:
    preferred_term: Bicuspid aortic valve
    term:
      id: HP:0001647
      label: Bicuspid aortic valve
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the prevalence in our group of ADCL patients is 2/6.
    explanation: The denominator is six selected individuals, not six independent probands.
- name: Arterial tortuosity
  category: Cardiovascular
  description: Increased arterial tortuosity, especially in supra-aortic vessels, has been incidentally noted and not systematically assessed.
  phenotype_term:
    preferred_term: Arterial tortuosity
    term:
      id: HP:0005116
      label: Arterial tortuosity
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Increased tortuosity of the arteries (mainly of the supra-aortic vasculature) has been incidentally noted but not systematically assessed
    explanation: The synthesis explicitly limits ascertainment.
- name: Aortic regurgitation
  category: Cardiovascular
  description: Aortic-valve regurgitation occurs variably and may accompany aortic-root disease.
  phenotype_term:
    preferred_term: Aortic regurgitation
    term:
      id: HP:0001659
      label: Aortic regurgitation
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: patients had aortic valve regurgitation
    explanation: The Results describe four affected members; this fragment is interpreted within that explicit clinical context.
- name: Mitral valve prolapse
  category: Cardiovascular
  description: Mitral prolapse has been reported in individual molecularly diagnosed patients and is not obligatory.
  phenotype_term:
    preferred_term: Mitral valve prolapse
    term:
      id: HP:0001634
      label: Mitral valve prolapse
  evidence:
  - reference: PMID:30704477
    reference_title: 'A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: evaluation by echocardiography revealed mitral valve prolapse and diffuse changes in myocardium.
    explanation: The reported mother had echocardiographic mitral prolapse; incidental cardiac rhythm findings in the family are not assigned to ELN here.
- name: Mitral regurgitation
  category: Cardiovascular
  description: Mitral regurgitation was documented in the 2013 cohort.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: patients F1:II-4 and F6-20 had mitral valve regurgitation.
    explanation: The body reports this valve manifestation in selected patients.
- name: Emphysema
  category: Respiratory
  description: Pulmonary emphysema can be early and severe but is variable. Seven of the eight obstructive pulmonary diagnoses in the 2013 new cohort were emphysema; one was asthma. Tobacco exposure can worsen disease.
  phenotype_term:
    preferred_term: Emphysema
    term:
      id: HP:0002097
      label: Emphysema
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Chronic obstructive pulmonary disease was diag- nosed in eight patients, seven of whom had emphysema and one had asthma.
    explanation: The full Results distinguish emphysema from asthma rather than treating all eight diagnoses as emphysema.
- name: Airway obstruction
  category: Respiratory
  description: Marked obstruction can occur even without visually apparent emphysema on CT. The detailed 2024 case was asymptomatic in ordinary daily activity despite severe functional impairment.
  phenotype_term:
    preferred_term: Airway obstruction
    term:
      id: HP:0006536
      label: Airway obstruction
  evidence:
  - reference: PMID:39354494
    reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in pulmonary function tests
    explanation: This was one adult with severe physiological obstruction despite little subjective limitation.
- name: Bronchiectasis
  category: Respiratory
  description: Bronchiectasis was reported in the family with an intragenic ELN duplication and severe early pulmonary involvement.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:15955094
    reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a CL family characterized by hernias and unusually severe and early-onset pulmonary disease including bronchiectasis and pulmonary emphysema.
    explanation: The finding is scoped to the duplication family; infection and airway remodeling intermediates are not established for all alleles.
- name: Pectus excavatum
  category: Musculoskeletal
  description: Pectus excavatum was present in the 2024 airway case and did not visibly worsen during follow-up; the authors judged it unlikely to explain the declining respiratory function.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:39354494
    reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the chest CT scan revealed the presence of pectus excavatum.
    explanation: A direct CT observation in one case, without a frequency estimate.
- name: Gastroesophageal reflux
  category: Gastrointestinal
  description: Reflux was reported in selected cohort members; it is not a defining manifestation.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Other manifestations included gastro- oesophageal reflux (F1:II-7 and F1:III-4)
    explanation: The source assigns reflux to two related individuals rather than a general prevalence.
genetic:
- name: ELN variants and allele-specific transcript processing
  gene_term:
    preferred_term: ELN
    term:
      id: hgnc:3327
      label: ELN
  association: Heterozygous pathogenic variants causing ELN-related cutis laxa
  notes: 'Most established alleles are carboxy-terminal frameshifts, but an intragenic tandem duplication and a deep intronic splice allele are reported. GeneReviews describes c.2272+20C>G with19-nucleotide intronic retention; historic transcripts use different numbering. Mutation location, normal and mutation-induced exon skipping, and partial transcript decay alter expressed isoforms. Stable mutant RNA in selected 2011 cultures is not universal: the earlier 1999 fibroblast study found instability of both alleles, and the human BAC model shows partial decay of the exon 32-in product. Exon-level clinical severity correlations and splicing as a surveillance predictor remain unconfirmed. The unrelated exon 25 atypical family does not establish the usual ADCL1 spectrum.'
  evidence:
  - reference: PMID:9873040
    reference_title: Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN).
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Transcripts from both alleles in each kindred were unstable and responsive to transforming growth factor-beta.
    explanation: The older selected fibroblast strains show why a universal RNA-stability claim is inappropriate.
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: There are no obvious genotype-phenotype correlations when comparing patients with mutations in different exons
    explanation: The new cohort explicitly avoids an established exon-level severity rule.
  - reference: PMID:15955094
    reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: affected individuals in this family carried a partial tandem duplication in the elastin locus.
    explanation: The duplication family broadens the established variant spectrum beyond point frameshifts.
diagnosis:
- name: Phenotype-guided molecular diagnosis
  description: Suggestive skin and facial findings, family history and systemic assessment guide molecular testing. A heterozygous pathogenic or likely pathogenic ELN variant with compatible findings establishes the diagnosis; an ELN variant of uncertain significance alone neither confirms nor excludes it. Current GeneReviews favors a cutis-laxa multigene panel or genomic testing over a restricted terminal-exon-only strategy because of overlapping disorders and less usual variant classes.
  notes: No diagnosis_term is bound because this entry combines physical examination, family history, systemic assessment, and molecular variant interpretation rather than a single NCIT diagnostic procedure.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: does not establish or rule out the diagnosis.
    explanation: The explicit GeneReviews statement concerns an ELN variant of uncertain significance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: is rarely useful and typically NOT recommended.
    explanation: In context, GeneReviews applies this limitation to sequential single-gene ELN testing, favoring panel or genomic approaches.
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We clinically and molecularly characterized the thus far largest cohort of ADCL patients
    explanation: The primary study combines phenotype and molecular evaluation; it does not make its historical exon 28–34 screen a complete modern diagnostic algorithm.
- name: Variant interpretation and assay coverage
  description: Use transcript-specific nomenclature and assess segregation and structural or splice variation when appropriate. Terminal frameshifts, intragenic rearrangements and deep intronic splice variants require attention to assay coverage. Negative coding sequencing alone does not exclude every ELN mechanism or other cutis-laxa disorders. Genetic counseling should distinguish transmission risk, variable expression and an unresolved result.
  notes: No diagnosis_term is bound because this is an interpretation and assay-coverage qualifier layered onto molecular testing, not a separate clinical procedure in NCIT.
  evidence:
  - reference: PMID:15955094
    reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: affected individuals in this family carried a partial tandem duplication in the elastin locus.
    explanation: A structural variant was identified after point-mutation testing was negative.
  - reference: PMID:30704477
    reference_title: 'A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We did not test DNA from maternal grandparents due to the unavail- ability of the material.
    explanation: Missing grandparent testing prevents calling the mother’s variant definitively de novo.
- name: Baseline cardiovascular assessment
  diagnosis_term:
    preferred_term: Echocardiography Test
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: Perform echocardiography to assess valve morphology and aortic-root and ascending-aortic dimensions. GeneReviews recommends discussion of baseline MR angiography around age 15, particularly for tortuosity or when the ascending aorta is not adequately visualized. Symptoms or suspected acute aortic complications require appropriate urgent clinical assessment.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: To enable visualization of ascending aorta when echocardiography is inadequate
    explanation: The full initial-evaluation table provides the MR-angiography indication.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/
    reference_title: Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These findings emphasise the importance of cardiovascular monitoring to prevent fatal rupture of the aortic root in cutis laxa patients.
    explanation: The primary report explains why apparently mild skin disease does not remove the need for vascular evaluation.
- name: Baseline pulmonary assessment
  diagnosis_term:
    preferred_term: Spirometry
    term:
      id: NCIT:C85397
      label: Spirometry
  description: Assess symptoms and age-appropriate lung function. GeneReviews suggests baseline chest radiography before puberty, peak flow around age 5 and pulmonary-function testing around age 7; HRCT is directed to symptomatic emphysema assessment. A normal visual emphysema assessment does not exclude marked small-airway dysfunction. Quantitative CT findings from one case do not establish a universal PRM testing protocol.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: To evaluate severity of emphysema in symptomatic persons
    explanation: The initial-evaluation table makes HRCT assessment symptom-directed.
  - reference: PMID:39354494
    reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neither emphysema nor bronchial wall thickening, which is characteristic of bronchiolitis obliterans syndrome was present.
    explanation: Visual CT can appear free of these features despite significant functional obstruction in the reported case.
- name: Skin biopsy and other baseline organ assessment
  description: Dermal histology can demonstrate sparse, fragmented or poorly organized elastic fibers but does not distinguish every genetic cause. Molecular testing establishes the etiologic diagnosis. Assess ptosis and visual-axis obstruction, joint stability and pain, bladder diverticula or voiding problems, and psychosocial needs according to the phenotype.
  notes: No diagnosis_term is bound because this bundles dermal histology, ophthalmologic, musculoskeletal, urinary, and psychosocial assessment rather than one NCIT diagnostic procedure.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The amorphous component of the elastic fibers showed extensive branching and fragmentation and was not properly associated with the microfibrils.
    explanation: Dermal ultrastructure supports an elastic-fiber disorder but does not by itself identify the causal gene.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: To evaluate for bladder diverticula
    explanation: GeneReviews includes urinary ultrasound in baseline evaluation.
treatments:
- name: Multidisciplinary supportive care
  description: Management is largely symptomatic and individualized. Coordinate relevant cardiology, pulmonology, surgery, urology, ophthalmology, physical therapy and genetics input. The 2022 GeneReviews chapter reports no disease-specific clinical practice guideline and limited treatment experience; these recommendations are expert synthesis, not comparative ADCL1 trials.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Supportive care to improve quality of life, maximize function, and reduce complications is recommended
    explanation: The full chapter recommends supportive management across manifestations.
- name: Aortic and valvular surveillance
  description: GeneReviews recommends echocardiography annually or according to dimensions and progression. Discuss MR angiography after puberty and subsequent intervals based on findings, commonly every 5 years. Screening recommendations are not proof that a specific schedule reduces mortality. Mild skin findings or an exon 32 allele do not identify a group exempt from vascular surveillance.
  action_category: MONITORING
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Echocardiography Test
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Annually (or depending on measurements/progression)
    explanation: The cardiovascular-surveillance table individualizes the echocardiography interval.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: the potential risks and benefits of screening with MR angiography be discussed with the patient.
    explanation: The chapter recommends discussion of screening uncertainty rather than indiscriminate fixed imaging.
- name: Pulmonary surveillance
  description: Establish age-appropriate baseline lung function; the chapter suggests peak flow from age 5 every 6 months and formal pulmonary-function testing from age 7, repeated with breathlessness or a fall in peak flow. Interpret results with symptoms and imaging. The single detailed small-airway case supports attention to physiology even without visible CT emphysema.
  action_category: MONITORING
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Spirometry
    term:
      id: NCIT:C85397
      label: Spirometry
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Repeat if there is shortness of breath or decline in peak flow measurement.
    explanation: The pulmonary-function surveillance recommendation uses clinical and peak-flow triggers.
  - reference: PMID:39354494
    reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: We advocate for meticulous monitoring with pulmonary function tests and CT scans, even in cases of cutis laxa with minimal CT evidence of emphysematous changes.
    explanation: This is the case authors’ recommendation rather than a tested screening schedule.
- name: Aortic aneurysm repair
  description: Specialist aortic-root repair may be required, with valve-sparing or composite procedures chosen according to anatomy and valve function. Disease-specific size thresholds are not established; expert guidance extrapolates from other heritable aortopathies and considers growth, family history and pregnancy plans. Reported surgery does not establish unusual universal operative tissue fragility.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Thoracic Aortic Aneurysm Open Repair
    term:
      id: NCIT:C158011
      label: Thoracic Aortic Aneurysm Open Repair
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Aortic root repair (Bentall or David procedure depending on aortic valve function)
    explanation: The full treatment table recommends phenotype-directed aortic repair.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Best thresholds for aortic repair are not established.
    explanation: The recommendation explicitly acknowledges threshold uncertainty.
  target_mechanisms:
  - target: Aortic root dilatation
    treatment_effect: BYPASSES
    description: The intervention addresses this clinical manifestation; the evidence does not demonstrate repair of the inherited ELN lesion.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Aortic root repair (Bentall or David procedure depending on aortic valve function)
      explanation: The full treatment table recommends phenotype-directed aortic repair.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Best thresholds for aortic repair are not established.
      explanation: The recommendation explicitly acknowledges threshold uncertainty.
- name: Individualized medical aortic protection
  description: Beta blockers or angiotensin-receptor blockers may be considered by the treating specialist by extrapolation from other connective-tissue aortopathies. Their effectiveness in ELN-related cutis laxa has not been evaluated. Do not interpret pSMAD2 findings as a demonstrated human losartan rescue. Reversible airway obstruction influences beta-blocker choice, and pregnancy requires medication review.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: angiotensin II receptor antagonist
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Effectiveness of beta-blocking agents or angiotensin receptor antagonists in slowing aortic root dilatation has not been evaluated, but (as w/other connective tissue disorders) these are likely beneficial.
    explanation: This is explicitly extrapolative expert guidance with no ADCL1 efficacy trial.
- name: Symptom-directed pulmonary treatment
  description: Treat clinically significant obstructive symptoms with specialist-directed conventional respiratory care. GeneReviews lists beta-mimetic and anticholinergic agents, but cautions against anticholinergics in people with bladder diverticula. A reported asymptomatic adult with severe functional obstruction received no drug because evidence was lacking. These observations do not establish a mandatory regimen for all patients.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Respiratory Therapy
    term:
      id: NCIT:C15322
      label: Respiratory Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Avoid use of anticholinergic agents in persons w/bladder diverticula.
    explanation: The full treatment table qualifies its bronchodilator options for associated urologic disease.
  - reference: PMID:39354494
    reference_title: The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Pharmacological intervention was withheld due to the absence of respiratory manifestations and the lack of evidence.
    explanation: This reflects one asymptomatic case, not a general recommendation to withhold treatment.
- name: Inguinal hernia repair
  description: Hernia repair is considered for clinical indications, with mesh repair listed in GeneReviews and counseling about recurrence. The recommendation is not cosmetic skin tightening, and observed recurrence does not establish that clinically indicated repair is futile.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Herniorrhaphy
    term:
      id: NCIT:C168249
      label: Herniorrhaphy
  evidence:
  - reference: PMID:35372488
    reference_title: 'Congenital Cutis Laxa: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient had been operated on the inguinal hernia at the age of 6 years old, and post-operative scar was not obvious.
    explanation: The primary case documents performed hernia repair, while full GeneReviews provides the management recommendation.
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Inguinal hernias were frequent, appearing congenitally (F1:II-2, F1:II-3, F1:III-1, F2:II-1) or throughout life (F1: I-2 at age 80 and F1:III-4 at 18 years old) and often re- occurred after surgery'
    explanation: The cohort documents recurrence after prior repair, not a comparative surgical trial.
  target_mechanisms:
  - target: Inguinal hernia
    treatment_effect: BYPASSES
    description: The intervention addresses this clinical manifestation; the evidence does not demonstrate repair of the inherited ELN lesion.
    evidence:
    - reference: PMID:35372488
      reference_title: 'Congenital Cutis Laxa: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The patient had been operated on the inguinal hernia at the age of 6 years old, and post-operative scar was not obvious.
      explanation: The primary case documents performed hernia repair, while full GeneReviews provides the management recommendation.
    - reference: PMID:23442826
      reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: 'Inguinal hernias were frequent, appearing congenitally (F1:II-2, F1:II-3, F1:III-1, F2:II-1) or throughout life (F1: I-2 at age 80 and F1:III-4 at 18 years old) and often re- occurred after surgery'
      explanation: The cohort documents recurrence after prior repair, not a comparative surgical trial.
- name: Joint stability and pain support
  description: Physical therapy and non-weight-bearing activities such as cycling or swimming can support joint function and stability. Treat episodes of pain as clinically appropriate; avoid activities that provoke instability or injury. This is supportive guidance rather than correction of elastic-fiber assembly.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Encourage non-weight-bearing exercise such as cycling
    explanation: The joint-hypermobility treatment section recommends adapted activity.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Pain medications in case of acute aggravation of pain
    explanation: The joint-pain section provides symptom-directed care.
  target_mechanisms:
  - target: Joint hypermobility
    treatment_effect: MODULATES
    description: The intervention addresses this clinical manifestation; the evidence does not demonstrate repair of the inherited ELN lesion.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Encourage non-weight-bearing exercise such as cycling
      explanation: The joint-hypermobility treatment section recommends adapted activity.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Pain medications in case of acute aggravation of pain
      explanation: The joint-pain section provides symptom-directed care.
- name: Management of bladder diverticula and impaired emptying
  description: Teach complete bladder emptying; assess residual urine and recurrent urinary infections. The chapter recommends catheterization for significant residual volume, selected antibiotic prophylaxis when incomplete voiding coexists with recurrent infections, and pelvic-floor therapy for prolapse support. These options are conditional and are not prescribed to every person with a diverticulum.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Education on complete bladder emptying when voiding
    explanation: The full table recommends a specific functional management action.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Catheterization if significant urinary residual after voiding
    explanation: Catheterization is conditional on clinically important residual urine.
- name: Functional ptosis surgery
  description: Consider eyelid surgery when drooping obscures the visual axis or causes recurrent conjunctival irritation/infection. Distinguish a functional indication from elective cosmetic skin reduction, and counsel about laxity recurrence.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Surgery is recommended when eyelid obscures pupil
    explanation: The table supports a functional ocular indication for surgery.
  target_mechanisms:
  - target: Ptosis
    treatment_effect: BYPASSES
    description: The intervention addresses this clinical manifestation; the evidence does not demonstrate repair of the inherited ELN lesion.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
      reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Surgery is recommended when eyelid obscures pupil
      explanation: The table supports a functional ocular indication for surgery.
- name: Cosmetic skin procedures with recurrence counseling
  description: Elective skin tightening or lipofilling is not routinely encouraged by GeneReviews because skin laxity often recurs. A 2022 uncontrolled case reported satisfaction without recurrence five months after a combined surgical and postoperative regimen; this does not establish lasting efficacy, superiority, or a standard recommendation. Discuss expectations, risks and psychosocial goals individually.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Cosmetic interventions are currently not encouraged.
    explanation: The chapter’s cautious recommendation takes priority over an unsupported general claim that most patients should undergo surgery.
  - reference: PMID:35372488
    reference_title: 'Congenital Cutis Laxa: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient is content with the effect of treatment, and there are no signs of recurrence after 5 months
    explanation: The observation is limited to one case and short follow-up with cointerventions.
- name: Psychological and family support
  description: Assess self-esteem and family support needs and offer age-appropriate psychological support. Appearance-related distress and recurrent procedures may matter even when organ function is preserved.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Psychotherapy
    term:
      id: NCIT:C15308
      label: Psychotherapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Assess for need for intervention for significant self-esteem issues requiring proactive psychological support.
    explanation: The chapter recommends needs-based psychological support.
- name: Avoidance of aggravating exposures and mechanical stress
  description: Avoid tobacco and minimize respiratory infections. Individualize advice about isometric exercise and contact sports according to vascular and joint risk. GeneReviews advises avoiding positive-pressure ventilation unless lifesaving and close follow-up if CPAP is required because its specific risk is unknown. Avoid excessive ultraviolet exposure; consider vitamin-D status when sun exposure is restricted.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Positive pressure ventilation unless needed to treat life-threatening conditions. No data exist on the potential risk of continuous positive airway pressure (CPAP) for the treatment of sleep apnea. Close follow up is warranted when CPAP is started.
    explanation: The guidance preserves the lifesaving exception and the uncertainty around CPAP.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Sunbathing or tanning, to preserve residual skin elasticity. Vitamin D supplementation should be considered in this context, and monitored annually.
    explanation: The recommendation balances UV avoidance with vitamin-D monitoring.
- name: Pregnancy planning and surveillance
  description: 'Arrange preconception cardiovascular and pulmonary evaluation and closer follow-up during pregnancy and for six months postpartum. Absence of reported perinatal complications in the small published experience does not prove safety. Review medications before conception: expert guidance continues appropriate beta blockers and replaces angiotensin-receptor blockers because of fetal risk.'
  action_category: MONITORING
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: as well as increased surveillance throughout the pregnancy and six months post partum.
    explanation: The full chapter recommends increased pregnancy and postpartum vascular surveillance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Women who are planning a pregnancy or who become pregnant while taking an angiotensin receptor blocker can be transitioned to a beta-blocker.
    explanation: This is specialist medication guidance, not an ADCL-specific comparative treatment result.
- name: Genetic counseling and family evaluation
  description: Discuss autosomal-dominant transmission, variable expression, parental testing and residual uncertainty after a negative result. Offer evaluation to relatives at risk so organ complications can be recognized. Once the familial pathogenic variant is established, prenatal and preimplantation testing may be discussed according to individual preferences.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: has a 50% chance of inheriting the pathogenic variant.
    explanation: The offspring section states the allele-transmission probability for each child of an affected person.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: is recommended for the parents of the proband to evaluate their genetic status and inform
    explanation: The full counseling section recommends parental molecular testing to refine recurrence assessment.
animal_models:
- name: Human ELN cutis-laxa cDNA minigene mouse
  species: Mouse
  genotype: CMV enhancer/chicken beta-actin-driven human ELN c.2114_2138del cDNA with exon 32 skipped, on intact endogenous Eln background
  background: C57BL/6J; three founder lines, detailed functional work principally line 60
  publication: PMID:20600892
  description: Human mutant or wild-type elastin cDNA minigenes were introduced by pronuclear injection. All three mutant founders had enlarged pulmonary airspaces; severe line 2 could not be maintained and its early mortality is not the outcome of the line 60 functional experiments. Lung-strip stiffness and elastic recoil were reduced in line 60. Crosslinked elastin measured by desmosine increased in both wild-type and mutant transgenic lungs. Human and mouse elastin colocalized in a shared network; that does not resolve covalent copolymer composition molecule by molecule.
  notes: This is added cDNA expression, not a BAC or endogenous heterozygous knock-in. Genomic copy number and insertion-site matching were not reported. No consistent skin or cardiovascular pathology was observed. Elevated pSMAD2, phospho-eIF2alpha and TUNEL are parallel observations; no selective pathway blockade, active-TGF-beta release assay or therapeutic rescue establishes mediation. Histology/signaling used four mice per group and fields are nested within mice.
  evidence:
  - reference: PMID:20600892
    reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Transgenic mice were generated using pronuclear injection of minigenes containing either a human elastin cDNA with a cutis laxa mutation 2114_2138del (CL) or a wild-type human elastin cDNA (WT).
    explanation: The full methods establish minigene design and comparator.
  modeled_mechanisms:
  - target: Alveolar Airspace Enlargement
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Airspace enlargement occurred in all three founder lines, with variable severity.
    limitations: Detailed mechanical results principally concern line 60, not the severely affected line 2.
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Quantitative morphometry confirmed significant airspace enlargement in all CL lines and normal alveolar sizes in WT transgenic mice
      explanation: The three founder lines showed variable pulmonary severity; subsequent functional work used line 60.
    readouts:
    - name: Pulmonary airspace enlargement
      target: Alveolar Airspace Enlargement
      direction: INCREASED
      interpretation: Airspace enlargement occurred in all three founder lines, with variable severity.
      evidence:
      - reference: PMID:20600892
        reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Quantitative morphometry confirmed significant airspace enlargement in all CL lines and normal alveolar sizes in WT transgenic mice
        explanation: The three founder lines showed variable pulmonary severity; subsequent functional work used line 60.
  - target: Reduced Tissue Elastic Recoil
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The functional model reproduces reduced lung recoil and stiffness.
    limitations: This does not demonstrate the same mechanical phenotype in skin or aorta.
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Expiratory static pressure-volume curves of CL lungs were shifted to the left compared with NTg controls, indicating that lung elastic recoil pressure in CL mice was reduced
      explanation: The minigene line-60 lung shows reduced recoil; this is an organ-level mechanical measurement.
    readouts:
    - name: Lung elastic recoil
      target: Reduced Tissue Elastic Recoil
      direction: DECREASED
      interpretation: The functional model reproduces reduced lung recoil and stiffness.
      evidence:
      - reference: PMID:20600892
        reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Expiratory static pressure-volume curves of CL lungs were shifted to the left compared with NTg controls, indicating that lung elastic recoil pressure in CL mice was reduced
        explanation: The minigene line-60 lung shows reduced recoil; this is an organ-level mechanical measurement.
  - target: Increased SMAD2 Phosphorylation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The stated molecular or histological readout was elevated in mutant lung.
    limitations: No selective rescue establishes that this readout causes airspace enlargement; TUNEL remained low in absolute fraction.
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Quantitative evaluation of pSMAD2-positive nuclei showed a highly significant increase in the lungs of CL mice, whereas WT mice showed no difference compared to NTg
      explanation: The measurement is an in-vivo lung endpoint in the minigene model.
    readouts:
    - name: pSMAD2-positive lung nuclei
      target: Increased SMAD2 Phosphorylation
      direction: INCREASED
      interpretation: The stated molecular or histological readout was elevated in mutant lung.
      evidence:
      - reference: PMID:20600892
        reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Quantitative evaluation of pSMAD2-positive nuclei showed a highly significant increase in the lungs of CL mice, whereas WT mice showed no difference compared to NTg
        explanation: The measurement is an in-vivo lung endpoint in the minigene model.
  - target: Endoplasmic Reticulum Stress Response
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The stated molecular or histological readout was elevated in mutant lung.
    limitations: No selective rescue establishes that this readout causes airspace enlargement; TUNEL remained low in absolute fraction.
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In CL lungs, the frequency of peIF2a positive cells was significantly elevated (Fig. 5D). Importantly, 80% of the peIF2a positive cells were also positive for CL elastin
      explanation: The measurement is an in-vivo lung endpoint in the minigene model.
    readouts:
    - name: Phospho-eIF2alpha staining with mutant elastin
      target: Endoplasmic Reticulum Stress Response
      direction: INCREASED
      interpretation: The stated molecular or histological readout was elevated in mutant lung.
      evidence:
      - reference: PMID:20600892
        reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: In CL lungs, the frequency of peIF2a positive cells was significantly elevated (Fig. 5D). Importantly, 80% of the peIF2a positive cells were also positive for CL elastin
        explanation: The measurement is an in-vivo lung endpoint in the minigene model.
  - target: Increased Apoptotic Readouts
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The stated molecular or histological readout was elevated in mutant lung.
    limitations: No selective rescue establishes that this readout causes airspace enlargement; TUNEL remained low in absolute fraction.
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice
      explanation: The measurement is an in-vivo lung endpoint in the minigene model.
    readouts:
    - name: Lung TUNEL index
      target: Increased Apoptotic Readouts
      direction: INCREASED
      interpretation: The stated molecular or histological readout was elevated in mutant lung.
      evidence:
      - reference: PMID:20600892
        reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice
        explanation: The measurement is an in-vivo lung endpoint in the minigene model.
- name: Human ELN BAC frameshift transgenic mouse
  species: Mouse
  genotype: Human ELN BAC carrying the paper’s 2012deltaG exon 30 deletion, tested on Eln+/+, Eln+/- and human-WT-BAC rescue backgrounds
  publication: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
  description: A human genomic BAC preserves introns and alternative splicing; three founders were identified and line 1 was used subsequently. Mutant elastin incorporated into skin and lung, with little aortic matrix incorporation despite aortic protein production. Skin required about half the displacement force of controls. Aortic desmosine and mechanics were unchanged; skin desmosine increased. Mutant-BAC-only lung compliance trends on Eln+/+ and Eln+/- were not statistically significant; adverse effects were clearer in the human-WT-BAC rescue background. The mutant BAC did not rescue Eln-null viability and impaired rescue by the wild-type human BAC.
  notes: An added BAC is not the endogenous heterozygous patient genotype. Human and mouse elastin backgrounds alter expression and tissue responses. Translation-inhibitor RNA experiments were performed in cultured mouse fibroblasts, not measured as an in-vivo RNA-decay rate. Exon32 inclusion promotes partial decay, not universal elimination; adult splice ratios alone did not explain tissue-specific matrix incorporation. The article contains inconsistent printed significance thresholds, so no repaired numeric threshold is asserted here.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
    reference_title: Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To investigate the pathophysiology underlying a class of elastin gene mutations leading to autosomal dominant cutis laxa, we engineered a cutis laxa mutation (single base deletion) into the human elastin gene contained in a bacterial artificial chromosome.
    explanation: This establishes the genomic human transgene design.
  modeled_mechanisms:
  - target: Reduced Tissue Elastic Recoil
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Skin suction testing found reduced force required for displacement.
    limitations: Pulmonary effects depend on the combined human/mouse elastin background, and no comparable aortic mechanical deficit was demonstrated.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
      reference_title: Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: only about half as much force was required to displace skin
      explanation: In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.
    readouts:
    - name: Skin displacement resistance
      target: Reduced Tissue Elastic Recoil
      direction: DECREASED
      interpretation: Skin suction testing found reduced force required for displacement.
      evidence:
      - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
        reference_title: Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: only about half as much force was required to displace skin
        explanation: In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.
  - target: Abnormal Elastic Fiber Architecture
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Mutant elastin entered skin and lung fibers with tissue-specific functional abnormalities.
    limitations: Aortic protein production did not translate into substantial matrix incorporation; the model does not reproduce human aortopathy consistently.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
      reference_title: Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: When expressed as a transgene in mice, mutant elastin was incorporated into elastic fibers in the skin and lung with adverse effects on tissue function.
      explanation: This describes the affected compartments; full results qualify the lung-background dependence.
- name: Eln hemizygous mouse as an allelic dosage comparator
  species: Mouse
  genotype: Eln+/- with promoter and exon 1 deletion
  publication: PMID:9819363
  description: This model addresses reduced elastin dosage rather than an ADCL1 mutant protein. Reduced RNA and thin lamellae accompany an adaptive increase in arterial lamellar units. Arterial extensibility is near normal around physiological pressure but lower at higher pressure; mice do not develop the focal human supravalvular hourglass lesion. The human histology comparison included only two SVAS cases and three controls.
  notes: Retained as differential allelic context, with no claim that it tests or refutes a dominant-negative ADCL1 mechanism. Reduced quantity and altered protein cannot be assumed to be molecular opposites at every tissue endpoint.
  evidence:
  - reference: PMID:9819363
    reference_title: Novel arterial pathology in mice and humans hemizygous for elastin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at physiologic pressures was nearly normal.
    explanation: The abstract summarizes the dosage model; the full body provides pressure-dependent limitations.
differential_diagnoses:
- name: ELN-related supravalvular aortic stenosis and Williams syndrome
  description: 'ELN haploinsufficiency, either from intragenic variants or the broader Williams-region deletion, usually produces an obstructive arteriopathy. Soft or hyperextensible skin can occur, so normal skin is not required. Variant position alone is insufficient: transcript effects, phenotype and the broader deletion context distinguish allelic disease from ELN-related cutis laxa.'
  evidence:
  - reference: PMID:23250899
    reference_title: 'Supravalvular aortic stenosis: elastin arteriopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: ELN arteriopathy is genetically heterogeneous and occurs as a consequence of haploinsufficiency of the ELN gene on chromosome 7q11.23, owing to either microdeletion of the entire chromosomal region or ELN point mutations.
    explanation: The review describes the dosage-loss allelic disease.
- name: FBLN5-related dominant and recessive cutis laxa
  description: FBLN5-related disease can overlap with ELN-related skin laxity and elastic-fiber pathology. Inheritance, systemic evaluation and molecular testing distinguish these disorders; clinical appearance alone may be insufficient.
  evidence:
  - reference: PMID:15955094
    reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Cutis laxa (CL) is a heterogeneous group of genetic and acquired disorders with at least two autosomal dominant forms caused by mutations in the elastin and fibulin-5 genes, respectively.
    explanation: This introductory synthesis establishes genetic heterogeneity, not a new FBLN5 cohort.
- name: ALDH18A1-related cutis laxa
  description: ALDH18A1-related dominant or recessive syndromes can add progeroid features, growth restriction and neurological or ocular involvement. Developmental findings help guide the differential but are not an absolute bedside exclusion rule for ELN-related disease. Use phenotype-guided multigene or genomic testing.
- name: Other autosomal recessive cutis laxa syndromes
  description: EFEMP2, LTBP4, ATP6V0A2, PYCR1 and other disorders can combine loose skin with vascular, pulmonary, neurological, skeletal or glycosylation findings. The substantial clinical overlap requires molecular clarification. The uncertain exon 25 ELN family does not supply reliable typical ADCL1 pulmonary-artery or seizure frequencies.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Clinical overlap and related, unclassified disorders illustrate many shortcomings of this classification, as illustrated by the fact that 4 out of 5 probands were initially diagnosed with recessive cutis laxa.
    explanation: These selected probands illustrate diagnostic overlap; the fraction is not diagnostic sensitivity or specificity.
- name: Ehlers-Danlos syndromes and related connective-tissue disorders
  description: Hyperextensible skin, joint laxity, scarring and tissue fragility can overlap. Redundant skin with poor recoil favors cutis laxa, whereas subtype-specific collagen or other matrix findings guide Ehlers-Danlos assessment. Normal healing is common in ELN-related disease but delayed healing has also been reported, so an absolute fragility rule is inappropriate.
- name: Acquired cutis laxa
  description: Adult or post-inflammatory onset and associated systemic conditions may suggest acquired elastolysis. An absent family history does not distinguish acquired disease from a de novo genetic disorder; clinical history, tissue findings and appropriate molecular assessment are considered together.
discussions:
- discussion_id: adcl1_tgfbeta_treatment_target
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does increased SMAD2 phosphorylation mediate organ injury or accompany the elastic-tissue abnormality?
  attaches_to:
  - pathophysiology#Increased SMAD2 Phosphorylation
  rationale: Patient fibroblast and mouse-lung signaling readouts are present, but the reviewed studies do not directly measure matrix-mediated active-ligand release or show selective TGF-beta pathway rescue of structural organ disease. Beta-blocker or ARB care is extrapolated from other aortopathies, not an ADCL1 efficacy result.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: We speculate that due to failure of proper elastic fiber organization in ADCL, a more compliant ECM results in higher amounts of released TGFβ.
    explanation: The authors explicitly identify ligand release as speculation.
- discussion_id: adcl1_mouse_skin_and_aorta_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Which expression, splicing and tissue-assembly differences explain the organ-specific phenotypes of the two transgenic designs?
  attaches_to:
  - pathophysiology#Reduced Tissue Elastic Recoil
  - pathophysiology#Aortic Medial Disorganization
  rationale: The cDNA minigene model has prominent lung findings without consistent skin or vascular disease. The separate BAC model has measured skin laxity, background-dependent pulmonary effects and little aortic matrix incorporation. Added transgene expression, mouse/human elastin backgrounds, splice processing and local assembly are candidate explanations, not proven alternatives. Mouse aortic sparing does not establish minor human vascular risk.
  evidence:
  - reference: PMID:20600892
    reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: No consistent dermatological or cardiovascular pathologies were observed.
    explanation: This negative observation pertains to the minigene design.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/
    reference_title: Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: only about half as much force was required to displace skin
    explanation: In the full sentence, this lower displacement force applies to both mutant-BAC backgrounds compared with mWT and mHet controls; the contiguous excerpt stops before an HTML genotype tag.
- discussion_id: adcl1_organ_involvement_variability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which allele, tissue and environmental factors predict organ involvement in ELN-related cutis laxa?
  attaches_to:
  - pathophysiology#C-Terminally Altered Tropoelastin
  - pathophysiology#Endoplasmic Reticulum Stress Response
  rationale: Splicing and transcript stability vary by allele and model. Earlier exon 32 attenuation proposals are not established clinical genotype-risk rules. Selected fibroblast ER-stress differences do not explain all pulmonary and aortic variability, and the reported cohorts are too small and related to estimate population penetrance or validate an exon-specific surveillance exemption.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: However, the observed allele-specific differences in the extent of ER stress alone do not explain the observed clinical variability in pulmonary and aortic involvement among patients.
    explanation: The paper explicitly limits the explanatory scope of its cultured-cell finding.
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: ADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account.
    explanation: The selected clinical cohort documents organ variability rather than a validated molecular predictor.
epidemiology:
- name: Rare reported-case evidence
  description: Population prevalence is not established by the available selected families. The 2022 GeneReviews chapter summarized more than 46 molecularly identified individuals from 23 families; this is a dated literature count, not the number living with the disorder or a population prevalence. The 2013 study examined 20 people (19 from six families plus one sporadic patient). Its abstract, pooled table and discussion contain inconsistent organ-frequency percentages, so these are not converted into disease-wide frequency bands.
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'METHODS: We clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient.'
    explanation: The denominator is a selected clinical cohort of related individuals, not a population survey.
progression:
- phase: Variable lifelong course
  evidence:
  - reference: PMID:23442826
    reference_title: Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Growth and psychomotor development were appropriate in all patients.
    explanation: This observation concerns the selected cohort, not comprehensive lifetime cognitive testing.
  - reference: PMID:30704477
    reference_title: 'A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Skin laxity was first noticed at the age of 1 year.
    explanation: The son in the reported family illustrates early-childhood recognition rather than obligatory diagnosis at birth.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/
    reference_title: ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Aortic dissection has been reported in multiple families as early as in the third decade
    explanation: The synthesis records serious vascular events in young adults.
  notes: Skin laxity is usually apparent at birth or early childhood and may become less conspicuous with age, although progression also occurs. Facial appearance and skin findings vary considerably within families. Aortic and pulmonary disease can emerge or progress despite mild external skin changes. Neuromotor development and cognition are usually preserved in reported typical cases; this is not a standardized lifelong guarantee.
experimental_models:
- name: Selected ADCL1 patient dermal fibroblast cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Cultures from CL 1, CL 3 and CL 4 among six individuals/five probands in the 2011 series
  cell_types:
  - &id003
    preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  publication: PMID:21309044
  description: Nonisogenic patient fibroblasts and age/sex/passage-matched controls were compared for elastin deposition, splicing and signaling. Reduced insoluble elastin and abnormal deposition accompanied allele-dependent intracellular effects. CL 1 lacked the measured stress response; CL 4 mainly increased BiP; CL 3 showed BiP, phospho-eIF2alpha and cleaved-caspase3 changes. Increased pSMAD2 was observed across all three tested patient cultures.
  notes: Not all six clinical participants supplied the mechanistic cultures. Biopsy sites differ, there is no allele correction or selective stress/TGF-beta rescue, and measured insoluble elastin does not establish crosslink density per molecule. Co-occurrence does not prove an obligatory retention→ER stress→apoptosis chain.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We found significantly lower amounts of insoluble elastin in ADCL cells compared to controls on day 4 and 8
    explanation: The available patient cultures had reduced deposited mature insoluble elastin.
  modeled_mechanisms:
  - target: Impaired Elastic Fiber Assembly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The patient-culture readout supports this component, with allele-specific differences.
    limitations: Nonisogenic comparisons and no pathway-specific rescue limit causal attribution.
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We found significantly lower amounts of insoluble elastin in ADCL cells compared to controls on day 4 and 8
      explanation: Cultured patient fibroblasts have reduced mature insoluble elastin deposition relative to the normalization used in the study.
  - target: Endoplasmic Reticulum Stress Response
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The patient-culture readout supports this component, with allele-specific differences.
    limitations: Nonisogenic comparisons and no pathway-specific rescue limit causal attribution.
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: phosphorylated eukaryotic translation initiation factor (peIF2α), a marker for ER stress, which was only significantly upregulated in patient CL-3
      explanation: Stress-marker changes were not uniform across the three tested patient fibroblast lines.
  - target: Increased Apoptotic Readouts
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The patient-culture readout supports this component, with allele-specific differences.
    limitations: Nonisogenic comparisons and no pathway-specific rescue limit causal attribution.
    evidence:
    - reference: PMID:20600892
      reference_title: Mechanisms of emphysema in autosomal dominant cutis laxa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The apoptosis index in CL mouse lungs remained low in absolute terms (0.005) but was significantly elevated compared to NTg mice
      explanation: The minigene model supports increased TUNEL staining with a low absolute index, not extensive universal tissue loss.
  - target: Increased SMAD2 Phosphorylation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The patient-culture readout supports this component, with allele-specific differences.
    limitations: Nonisogenic comparisons and no pathway-specific rescue limit causal attribution.
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Staining for pSMAD2 in fibroblast cultures of all patients showed significant upregulation of the TGFβ signaling pathway
      explanation: The measured endpoint was phosphorylated SMAD2 in the three available patient cultures, rather than direct active-ligand release.
- name: Purified frameshift tropoelastin coacervation assay
  experimental_model_type: OTHER
  publication: PMID:21309044
  description: Purified normal tropoelastin, a single exon 32 c.2262delA frameshift construct and an equimolar mixture were compared during temperature-dependent coacervation. The mixture retained the lower transition temperature of mutant protein.
  notes: This is an isolated-protein biophysical assay, not a patient organ or an allele-wide panel. It establishes a dominant shift in the tested mixture, not mediation of all downstream tissue damage.
  evidence:
  - reference: PMID:21309044
    reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation
    explanation: The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.
  modeled_mechanisms:
  - target: Increased Tropoelastin Self-Association
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: The purified mixture measures altered temperature-dependent self-association.
    limitations: No selective normalization of this property tests its necessity for disease.
    evidence:
    - reference: PMID:21309044
      reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation
      explanation: The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.
    readouts:
    - name: Coacervation propensity
      target: Increased Tropoelastin Self-Association
      direction: INCREASED
      interpretation: The purified mixture measures altered temperature-dependent self-association.
      evidence:
      - reference: PMID:21309044
        reference_title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Moreover, the coacervation temperature of an equimolar mixture of TE and fmTE were close to fmTE alone, showing a dominant effect of fmTE on TE coacervation
        explanation: The purified-protein mixture demonstrates the direction of this allele-scoped coacervation effect.
- name: Recombinant tropoelastin binding and ARPE-19 matrix assembly
  experimental_model_type: CELL_LINE
  cell_source: ARPE-19 retinal pigment epithelial cell line supplied with purified normal or exon 32 frameshift tropoelastin; separate recombinant protein-binding assays
  publication: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
  description: Over eight days, mutant added tropoelastin yielded less matrix-associated elastin and lower desmosine per total culture protein than normal protein, but assembly still occurred. Solid-phase assays tested a fibrillin1 amino-terminal PET fragment and recombinant fibulin5; solution co-immunoprecipitation independently tested fibulin5 association.
  notes: This is not endogenous expression in patient cells. CHO-conditioned medium supplied scaffold proteins; the fibrillin reagent is a fragment rather than full-length protein. No normal/mutant mixture, lysyl-oxidase activity or binding-restoration rescue was tested. Lower desmosine per total culture protein cannot establish fewer crosslinks per incorporated elastin molecule.
  evidence:
  - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
    reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cells treated with fmTE also increased desmosine concentration but significantly less than with the addition of nTE (Fig. 3).
    explanation: Desmosine was lower than with normal added tropoelastin but was still produced; it was normalized to total culture protein, not incorporated elastin mass.
  modeled_mechanisms:
  - target: Reduced Tropoelastin Binding to Fibrillin-1
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: The specified recombinant binding or deposition measurement supports this component.
    limitations: Binding and deposition were separate assays without selective mediator rescue.
    evidence:
    - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
      reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the binding of nTE to PET was also increased 30% above fmTE binding.
      explanation: Normal and mutant recombinant proteins were compared against the fibrillin-1 PET fragment, not full-length fibrillin in a patient tissue.
  - target: Reduced Tropoelastin Binding to Fibulin-5
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: The specified recombinant binding or deposition measurement supports this component.
    limitations: Binding and deposition were separate assays without selective mediator rescue.
    evidence:
    - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
      reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: At all concentrations used there was a significantly lower molecular interac- tion with fmTE compared to nTE.
      explanation: Solution co-immunoprecipitation supports reduced association under the tested recombinant-protein conditions.
  - target: Impaired Elastic Fiber Assembly
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The specified recombinant binding or deposition measurement supports this component.
    limitations: Binding and deposition were separate assays without selective mediator rescue.
    evidence:
    - reference: url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf
      reference_title: Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Cells treated with fmTE also increased desmosine concentration but significantly less than with the addition of nTE (Fig. 3).
      explanation: Desmosine was lower than with normal added tropoelastin but was still produced; it was normalized to total culture protein, not incorporated elastin mass.
- name: Intragenic ELN duplication family fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Dermal fibroblasts from the proband and affected daughter
  cell_types:
  - *id003
  publication: PMID:15955094
  description: Metabolic labeling and immunoprecipitation identified normal68 kDa tropoelastin plus an abnormal120 kDa protein. Mutant protein was partly secreted and partly retained, with both intracellular and matrix immunostaining.
  notes: The regenerated reference provides the abstract only; complete methods, sample-replication details and quantitative secretion fractions were unavailable. These findings do not prove which retained or matrix protein fraction causes severe lung disease.
  evidence:
  - reference: PMID:15955094
    reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Immunoprecipitation experiments showed that the mutant TE was partially secreted and partially retained intracellularly.
    explanation: The abstract directly describes mixed secretion and retention.
  modeled_mechanisms:
  - target: Intracellular Mutant Tropoelastin Retention
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Mutant-specific immunostaining and immunoprecipitation support intracellular retention alongside secretion.
    limitations: Abstract-only available source; no intervention resolves the contribution to clinical injury.
    evidence:
    - reference: PMID:15955094
      reference_title: 'Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: A polyclonal antibody raised against a unique peptide in the mutant TE molecule showed both intracellular and matrix staining.
      explanation: The mutant-specific antibody detects both compartments.

📚

References & Deep Research

References

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK584550/

ELN-Related Cutis Laxa - GeneReviews® - NCBI Bookshelf

1 finding

Complete GeneReviews chapter read across phenotype, genetics, diagnosis and care, including tables and limitations. Updated2022; care is expert synthesis, with no ADCL1 comparative efficacy trial.

PMID:23442826

Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity.

1 finding

Full main text, Methods, Results, Discussion and Tables1–4 independently audited. Abstract and pooled-table percentages disagree; no pooled frequency band is assigned.

PMID:21309044

New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.

1 finding

Complete available main Methods, Results and Discussion read; separate figure legends and supplementary files are absent from this cache.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381164/

Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa - PMC

1 finding

PMID22573328; complete recovered main body and available figure captions read. Supplemental objects not independently read. Main-body genotype and significance caveats take priority over the broad abstract.

PMID:20600892

Mechanisms of emphysema in autosomal dominant cutis laxa.

1 finding

Complete available main Methods, Results and Discussion independently audited; separate figure legends and supplements were unavailable.

PMID:15955094

Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.

1 finding

Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563239/

Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene - PMC

1 finding

PMID16085695; complete recovered main body, Table 1 and Figures1–3 read. Aortic pathology and skin electron microscopy involve different sampled relatives.

PMID:9580666

An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa.

1 finding

Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.

PMID:9873040

Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN).

1 finding

Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.

PMID:15381555

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

1 finding

Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.

PMID:18348261

Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene.

1 finding

Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.

PMID:9819363

Novel arterial pathology in mice and humans hemizygous for elastin.

1 finding

Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.

PMID:23250899

Supravalvular aortic stenosis: elastin arteriopathy.

1 finding

Regenerated abstract only; complete primary methods and results could not be recovered, so use is restricted to the available abstract.

PMID:29501665

Elastin-driven genetic diseases.

1 finding

Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.

PMID:30704477

A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report.

1 finding

Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.

PMID:35372488

Congenital Cutis Laxa: A Case Report and Literature Review.

1 finding

Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.

PMID:39354494

The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.

1 finding

Complete available scientific main body, Methods, Results, Discussion and available tables/figure captions read; separately linked supplements were not independently audited.

url:https://www.jstage.jst.go.jp/article/jhs/52/3/52_3_259/_pdf

Biochemical Analysis of Elastic Fiber Formation with a Frameshift-Mutated Tropoelastin (fmTE) at the C-Terminus of Tropoelastin

1 finding

Sato2006, J Health Sci52:259–267; complete primary PDF Methods, Results, Discussion and Figures1–5 read. Purified protein/ARPE-19 system, not patient tissue.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Autosomal Dominant Cutis Laxa 1 (MONDO:0007411) · 2026-09-18T14:28:15Z · View source

New entry curated from the Edison Falcon deep-research report research/Autosomal_Dominant_Cutis_Laxa_1-deep-research-falcon.md with report DOIs resolved to PMIDs through PubMed and all snippets quoted from cached abstracts; the GeneReviews chapter PMID:36173875 (ELN-Related Cutis Laxa) is tagged and every finding in its clinical characteristics is curated. Ten-node pathograph: heterozygous 3-prime ELN frameshift, stable mutant transcript escaping nonsense-mediated decay, synthesis and secretion of C-terminally altered tropoelastin, dominant-negative disruption of elastic fibre assembly, endoplasmic reticulum stress and apoptosis from retained mutant tropoelastin, fragmented sparse elastic fibres in dermis, lung and arterial media, increased TGF-beta signalling from a compliant matrix, loss of elastic recoil in skin, emphysematous airspace enlargement, and aortic medial degeneration with root dilatation. Lump/split: the ELN form only; ADCL2 (FBLN5) and ADCL3 (ALDH18A1, already curated) are separate entries. The allelic haploinsufficiency disease (supravalvular aortic stenosis, Williams syndrome) is described as the mirror-image mechanism and the Eln+/- mouse is recorded as a model of that allelic disease that fails to recapitulate ADCL1. The aortic arm conforms to aortopathy_tgfbeta_dysregulation at three nodes with mutant tropoelastin as the disorder-specific ECM substitution; emphysema_protease_antiprotease_imbalance was rejected because the emphysema here is a primary elastin assembly defect. Genetic block records DOMINANT_NEGATIVE functional impact and the 3-prime clustering of variants. Validated: just validate passed; count-verified-snippets 130/130; validate-terms, check-entity-refs, check-causal-targets, check-enum-values and check-duplicate-keys passed; pytest -k Autosomal_Dominant_Cutis_Laxa_1 passed. A first attempt at this curation was cut off by a session limit before writing; this record describes the completed second pass.

Falcon ▸

Autosomal Dominant Cutis Laxa 1: Disease Characteristics Report

Edison Scientific Literature 30 citations 2026-09-04T23:37:15.377869

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.

Domain	Evidence-backed findings	Quantitative data / representative variants	Suggested ontology terms
Disease identity	Autosomal dominant cutis laxa 1 (ADCL1) is an ELN-related systemic elastinopathy characterized by loose, inelastic skin and variable cardiovascular and pulmonary disease. Evidence is primarily aggregated from cohorts, families, and case reports rather than EHR-derived datasets. OMIM: 123700; MONDO, Orphanet, MeSH, and disease-specific ICD identifiers require direct database verification. (hadjrabia2013twentypatientsincluding pages 1-2, hadjrabia2013twentypatientsincluding pages 6-7, lasio2018elastindrivengeneticdiseases pages 2-4)	Largest cited cohort: 20 clinically evaluated individuals, ages 1–84 years. (hadjrabia2013twentypatientsincluding pages 1-2)	Autosomal dominant cutis laxa; cutis laxa; elastinopathy; MONDO term to verify
Disease boundary	ADCL1 is principally caused by ELN variants. It must not be conflated with FBLN5-related cutis laxa, which is predominantly autosomal recessive cutis laxa type 1A; FBLN5 is not the established primary cause of ELN-related ADCL1. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 6-7)	ELN gene OMIM: 130160.	ELN; elastic-fiber disorder; autosomal recessive cutis laxa type 1A
Cutaneous phenotype	Congenital or early-childhood loose, redundant, poorly elastic skin is defining. Disease may be localized or generalized and can become less conspicuous with age. Dermal elastic fibers are reduced, fragmented, branching, or disorganized. (hadjrabia2013twentypatientsincluding pages 1-2, kun2022congenitalcutislaxa pages 2-4, callewaert2011newinsightsinto pages 1-2)	Skin laxity 100%; generalized/extensive involvement 75%; localized redundancy 25% in the 20-person cohort. (hadjrabia2013twentypatientsincluding pages 1-2)	HPO: Cutis laxa; redundant skin; generalized skin laxity; abnormality of dermal elastic fibers
Craniofacial phenotype	Features include a long or coarse prematurely aged face, large pliant ears, long philtrum, beaked nose, ptosis, and blepharochalasis. (hadjrabia2013twentypatientsincluding pages 5-6, kun2022congenitalcutislaxa pages 1-2)	Facial gestalt reported in 100% in one cohort analysis; the long-face, large-ear, long-philtrum, and beaked-nose combination occurred in approximately 70%. (hadjrabia2013twentypatientsincluding pages 5-6, hadjrabia2013twentypatientsincluding pages 1-2)	HPO: Long face; long philtrum; beaked nose; large ears; ptosis; blepharochalasis; prematurely aged appearance
Hernias	Inguinal and less frequently umbilical hernias reflect impaired connective-tissue elasticity. (graul‐neumann2008highlyvariablecutis pages 1-2, callewaert2011newinsightsinto pages 6-7)	Inguinal hernia approximately 50–51%. (hadjrabia2013twentypatientsincluding pages 5-6, hadjrabia2013twentypatientsincluding pages 1-2)	HPO: Inguinal hernia; umbilical hernia
Cardiovascular phenotype	Aortic-root dilatation is a major complication and may progress during childhood or adolescence. Associated abnormalities include bicuspid aortic valve, mitral-valve prolapse, and other valve defects. (callewaert2011newinsightsinto pages 10-12, callewaert2011newinsightsinto pages 6-7)	Aortic-root dilatation 55–57%; other valve anomalies 38%; bicuspid aortic valve 5%. One patient's aortic root progressed from 41 to 45 mm by age 17. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 6-7)	HPO: Aortic-root dilatation; ascending-aortic dilatation; bicuspid aortic valve; mitral-valve prolapse
Pulmonary phenotype	Pulmonary emphysema and obstructive lung disease can be early and severe. Rare congenital presentations include recurrent pneumothorax and prolonged respiratory support. (graul‐neumann2008highlyvariablecutis pages 1-2, callewaert2011newinsightsinto pages 6-7)	Emphysema 35–37%. One child had FEV1/FVC 42.9% and residual volume 209% at age 12. (hadjrabia2013twentypatientsincluding pages 1-2, callewaert2011newinsightsinto pages 6-7)	HPO: Pulmonary emphysema; obstructive lung disease; pneumothorax; dyspnea
Causal variants	Causal variants are heterozygous germline ELN alterations, most commonly 3-prime frameshifts in exons 30–34 that produce stable tropoelastin with an abnormal extended C terminus. Splice variants may generate the same downstream frameshift. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 1-2, lasio2018elastindrivengeneticdiseases pages 4-6)	Representative variants: c.2262delA 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). (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 1-2, kun2022congenitalcutislaxa pages 2-4, okuneva2019anovelelastin pages 2-4)	ELN; germline pathogenic variant; frameshift variant; splice-altering variant; abnormal protein C terminus
Allele rarity	Pathogenic alleles are very rare or absent from population reference datasets. Classification should follow ACMG/AMP criteria using phenotype, segregation, population frequency, predicted C-terminal extension, and functional evidence. (kun2022congenitalcutislaxa pages 2-4, okuneva2019anovelelastin pages 2-4)	c.2323delG was absent from ExAC (60,706 individuals), 1000 Genomes (2,535), and a local database (2,000); cohort variants were absent from 100 controls. (okuneva2019anovelelastin pages 2-4, hadjrabia2013twentypatientsincluding pages 2-4)	Pathogenic variant; likely pathogenic variant; variant of uncertain significance; ACMG/AMP classification
Molecular mechanism	Mutant tropoelastin has increased self-association and globule formation, impaired binding to fibrillin-1 and fibulin-5-containing microfibrils, and reduced deposition of mature insoluble elastin. Incorporation of abnormal protein disrupts elastic-fiber assembly, supporting a dominant-negative mechanism with possible toxic gain of function. (callewaert2011newinsightsinto pages 10-12, lasio2018elastindrivengeneticdiseases pages 4-6)	Representative frameshifts generated predicted extensions of approximately 49, 53, or 86 amino acids. (callewaert2011newinsightsinto pages 10-12)	GO: Elastic-fiber assembly; extracellular-matrix organization; protein self-association; tropoelastin coacervation
Downstream biology	Allele-dependent misfolding can cause endoplasmic-reticulum stress, unfolded-protein-response activation, and apoptosis. Increased pSMAD2 suggests enhanced TGF-beta signaling, hypothesized rather than conclusively proven to contribute to emphysema and aortic-root dilation. (callewaert2011newinsightsinto pages 10-12)	Exon 30 alleles increased BiP, phosphorylated eIF2-alpha, and caspase-3; exon 32 alleles produced less extensive UPR activation. (callewaert2011newinsightsinto pages 10-12)	GO: Response to endoplasmic-reticulum stress; unfolded protein response; apoptotic process; TGF-beta receptor signaling; SMAD signal transduction
Biological modifiers	Alternative ELN splicing and tissue-specific mutant-protein incorporation modify severity. Exon 32 skipping may reduce mutant burden, but exon-specific genotype–phenotype associations remain provisional. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 7-9, lasio2018elastindrivengeneticdiseases pages 4-6)	Exon 32 was absent from approximately 70% of control transcripts in one study. (callewaert2011newinsightsinto pages 7-9)	GO: Alternative mRNA splicing; nonsense-mediated mRNA decay; tissue-specific gene expression
Anatomy and cells	Elastic-fiber-rich skin, aortic wall, cardiac valves, lung parenchyma, and hernia-prone connective tissues are affected. Relevant cells include dermal fibroblasts, vascular smooth-muscle cells, and pulmonary fibroblasts; compartments include the ER, extracellular matrix, microfibrils, and elastic fibers. (akcay2020consequencesofelastin pages 1-3, callewaert2011newinsightsinto pages 10-12)	Elastin constitutes approximately 90% of mature elastic fibers by mass in the cited review. (akcay2020consequencesofelastin pages 1-3)	CL: Fibroblast; vascular smooth-muscle cell; pulmonary fibroblast. UBERON: Skin; dermis; aortic wall; lung; cardiac valve. GO-CC: Endoplasmic reticulum; extracellular matrix; elastic fiber
Inheritance	Inheritance is autosomal dominant; familial vertical transmission and de novo variants are documented. Cutaneous penetrance appears high, while systemic manifestations show marked variable expressivity. Anticipation, founder effects, and germline mosaicism are not established. (callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 2-4, hadjrabia2013twentypatientsincluding pages 1-2)	Phenotype transmitted in 20/22 meioses; five probands in one study had de novo variants. (callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 1-2)	Autosomal dominant inheritance; variable expressivity; de novo variant; penetrance
Epidemiology	ADCL1 is exceptionally rare. No reliable population prevalence, incidence, carrier frequency, sex ratio, founder effect, or geographic gradient was identified; evidence consists mainly of small families and case reports.	Largest cited cohort had 20 clinically evaluated patients from six families plus one sporadic case. (hadjrabia2013twentypatientsincluding pages 1-2)	Rare genetic disease; orphan disease
Diagnosis	Diagnosis combines congenital or early skin laxity, characteristic facial appearance, family history, systemic assessment, and molecular confirmation. Testing may begin with ELN exons 30–34 but should expand to full ELN analysis or a connective-tissue/cutis-laxa panel; WES or WGS is useful when targeted testing is negative. Skin biopsy is supportive but not required and may correlate poorly with severity. (graul‐neumann2008highlyvariablecutis pages 1-2, kun2022congenitalcutislaxa pages 2-4, hadjrabia2013twentypatientsincluding pages 5-6, okuneva2019anovelelastin pages 2-4)	Histology may show absent, markedly reduced, broken, or disorganized dermal elastic fibers; a severe neonatal case showed only mild rarefaction. (graul‐neumann2008highlyvariablecutis pages 1-2, kun2022congenitalcutislaxa pages 2-4)	ELN sequencing; multigene panel; whole-exome sequencing; whole-genome sequencing; skin biopsy
Differential diagnosis	Differential diagnoses include FBLN5-, EFEMP2/FBLN4-, LTBP4-, ATP6V0A2-, and PYCR1-related recessive cutis laxa, Ehlers–Danlos syndromes, arterial-tortuosity syndrome, occipital-horn syndrome, acquired cutis laxa, and progeroid disorders. ELN haploinsufficiency more typically causes supravalvular aortic stenosis, while 7q11.23 deletion causes Williams–Beuren syndrome. (callewaert2011newinsightsinto pages 1-2, akcay2020consequencesofelastinb pages 1-3, kun2022congenitalcutislaxa pages 2-4, hadjrabia2013twentypatientsincluding pages 5-6)	Severe neurologic, ocular, skeletal, gastrointestinal, or generalized arterial disease should prompt reconsideration of the subtype. (callewaert2011newinsightsinto pages 1-2, hadjrabia2013twentypatientsincluding pages 6-7)	Ehlers–Danlos syndrome; arterial-tortuosity syndrome; supravalvular aortic stenosis; Williams syndrome; acquired cutis laxa
Surveillance	Baseline and lifelong cardiovascular and pulmonary evaluation are recommended. Assessments include echocardiography of the aortic root, ascending aorta, and valves; cross-sectional angiography when indicated; respiratory review; spirometry; lung volumes; and chest CT when clinically justified. Exact intervals are not standardized and require specialist individualization. (hadjrabia2013twentypatientsincluding pages 1-2, callewaert2011newinsightsinto pages 6-7)	Progressive childhood aortic disease and severe pediatric COPD have been documented. (callewaert2011newinsightsinto pages 6-7)	Echocardiography; magnetic-resonance angiography; computed tomography; spirometry; pulmonary-function testing
Treatment	No approved disease-modifying drug, gene therapy, RNA therapy, or genotype-directed treatment exists. Care is supportive and complication-specific. Aortic intervention should use individualized aneurysm risk assessment; emphysema is treated according to respiratory standards. Losartan has been proposed mechanistically but lacks ADCL1-specific efficacy evidence. (hadjrabia2013twentypatientsincluding pages 5-6, callewaert2011newinsightsinto pages 6-7)	No disease-specific response-rate data or randomized trials were identified.	NCIT labels: Supportive care; cardiovascular surgery; hernia repair; pulmonary rehabilitation; genetic counseling
Cutaneous surgery	Rhytidectomy or excision can improve appearance temporarily, but recurrence is common because the underlying elastic-fiber defect persists. Hernias may be repaired when clinically indicated. (kun2022congenitalcutislaxa pages 2-4, kun2022congenitalcutislaxa pages 1-2, callewaert2011newinsightsinto pages 6-7)	Review of 7 surgical patients found recurrence within months in 5; two required more than two operations. One recent case had no recurrence at five months. (kun2022congenitalcutislaxa pages 2-4)	NCIT labels: Rhytidectomy; reconstructive surgery; hernia repair
Prognosis and quality of life	Prognosis is highly variable. Skin laxity may improve with age, but aortic disease and emphysema can progress and dominate morbidity. Published survival, mortality, disability, and validated quality-of-life statistics are unavailable. Cosmetic distress, exertional dyspnea, recurrent surgery, and surveillance burden are plausible major impacts but are not quantified by disease-specific instruments. (kun2022congenitalcutislaxa pages 1-2, hadjrabia2013twentypatientsincluding pages 1-2, callewaert2011newinsightsinto pages 6-7)	Documented patient ages extend to 84 years, but this is not a life-expectancy estimate. (hadjrabia2013twentypatientsincluding pages 1-2)	Quality of life; chronic disease; exercise intolerance; facial appearance concern
Models	Human dermal fibroblasts and skin-equivalent systems reproduce abnormal tropoelastin deposition, ER stress, and elastic-fiber disorganization. A humanized transgenic mouse carrying an ADCL ELN frameshift incorporated mutant elastin into skin and lung fibers, developing adverse tissue effects and emphysema; mutant incorporation into aortic elastin was comparatively low, demonstrating tissue-specific assembly. (callewaert2011newinsightsinto pages 10-12)	Model findings include intracellular retention, apoptosis, emphysema, reduced lung stiffness, increased stretch, and increased TGF-beta signaling. (callewaert2011newinsightsinto pages 10-12)	Model organism: Mus musculus; transgenic model; humanized mouse; fibroblast culture; skin-equivalent model
Environmental and protective factors	ADCL1 is a monogenic disorder; no environmental cause or proven protective genetic, dietary, lifestyle, infectious, or occupational factor was identified. Avoidance of smoking and pulmonary irritants is clinically prudent for emphysema risk but is not proven to modify ADCL1 penetrance.	No ADCL1-specific gene–environment interaction statistics are available.	Tobacco-smoke exposure; air pollution exposure; environmental modifier
Evidence gaps	Major gaps include contemporary natural-history cohorts, 2023–2024 ADCL1-specific studies, validated prevalence, standardized surveillance intervals, prospective surgical outcomes, quality-of-life measures, prognostic biomarkers, modifier genes, epigenomics, single-cell or spatial profiling, and disease-modifying trials.	Available quantitative estimates rely heavily on a 20-person cohort and individual case reports. (hadjrabia2013twentypatientsincluding pages 1-2, hadjrabia2013twentypatientsincluding pages 5-6)	Natural history study; patient registry; multi-omics study; clinical trial

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

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)
The altered C-terminal assembly domain leads to increased self-association, lower coacervation temperature, and abnormal elastin globules. (callewaert2011newinsightsinto pages 10-12)
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)
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)
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)
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)
Loss of pulmonary elastic recoil causes air-space enlargement, obstruction, emphysema, and occasionally pneumothorax. (graul‐neumann2008highlyvariablecutis pages 1-2, callewaert2011newinsightsinto pages 6-7)
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)
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

Use an ELN-inclusive cutis-laxa/connective-tissue panel when the phenotype is recognizable but genetically heterogeneous.
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.
Include deletion/duplication analysis where the assay does not detect CNVs.
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.
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:

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)
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)
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)
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)
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)
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

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(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.
(akcay2020consequencesofelastin pages 1-3): S Akcay. Consequences of elastin gene mutations in autosomal dominant cutis laxa and supravalvular aortic stenosis. Unknown journal, 2020.
(akcay2020consequencesofelastinb pages 1-3): S Akcay. Consequences of elastin gene mutations in autosomal dominant cutis laxa and supravalvular aortic stenosis. Unknown journal, 2020.
(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.
(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.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	2
Off topic	0

All extracted references resolved successfully.

Term Validation

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Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Epidemiology

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Autosomal Dominant Cutis Laxa 1: Disease Characteristics Report

Executive summary and scope

1. Disease information

2. Etiology, risk, and protective factors

Causal factors

Genetic risk and modifiers

Environmental and protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and laboratory evaluation

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current applications

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Recent developments, expert interpretation, and research priorities

Evidence limitations and key references

Artifacts

Reference Validation

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