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ELN-Related Cutis Laxa

Synonym: Autosomal Dominant Cutis Laxa Type 1 (ADCL1)

, MD, PhD and , PhD.

Author Information and Affiliations

Initial Posting: .

Estimated reading time: 25 minutes

Summary

Clinical characteristics.

ELN-related cutis laxa is characterized by generalized cutis laxa (ranging from generalized skin redundancy causing excessive skin folds to skin hyperextensibility without obvious skin folds) and distinctive facial features that may become more prominent with age. Other common findings are joint hyperlaxity in infancy and increasing risk of inguinal hernia at all ages. Progressive findings that may be present as early as childhood include ptosis, aortic root dilatation, and emphysema.

Diagnosis/testing.

The diagnosis of ELN-related cutis laxa is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ELN identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for ELN-related cutis laxa. Experience in treating individuals with ELN-related cutis laxa is very limited. Supportive care to improve quality of life, maximize function, and reduce complications is recommended and ideally involves multidisciplinary care by specialists in general surgery, cardiothoracic surgery, cardiology, pulmonology, urology, physical therapy, ophthalmology, and medical genetics.

Surveillance: Monitor for known problems (e.g., inguinal hernias, joint hypermobility and pain) and new issues that may require interventions (e.g., ptosis, aortic root dilatation, emphysema, bladder diverticula).

Agents/circumstances to avoid: Positive pressure ventilation unless needed for life-threatening conditions; contact with people with respiratory infections; tobacco smoking; isometric exercise (which causes an increase in blood pressure); contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain; sunbathing or tanning in order to preserve residual skin elasticity.

Pregnancy management: Perinatal complications for mothers with ELN-related cutis laxa or affected neonates have not been reported to date. Nonetheless, recommended evaluations for women with ELN-related cutis laxa before conception and during pregnancy are pulmonary function testing and cardiovascular assessment (including aortic root diameter). Continued cardiac surveillance for six months post partum is also recommended. Additionally, women taking a beta-blocker should continue it during pregnancy; however, some other classes of medications, such as angiotensin receptor-blocking agents, are teratogenic and should be discontinued or changed to beta-blocking agents, given the increased risk for teratogenicity typically related to second- and third-trimester exposure.

Genetic counseling.

ELN-related cutis laxa is inherited in an autosomal dominant manner. About one third of individuals diagnosed with ELN-related cutis laxa have an affected parent; about two thirds of affected individuals have the disorder as the result of a de novo ELN pathogenic variant. Each child of an individual with ELN-related cutis laxa has a 50% chance of inheriting the pathogenic variant. Once the ELN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for ELN-related cutis laxa have been published.

Suggestive Findings

ELN-related cutis laxa should be suspected in individuals with the following clinical findings and family history.

Clinical findings include generalized cutis laxa (ranging from generalized skin redundancy causing excessive skin folds to skin hyperextensibility without obvious skin folds) (Figure 1) with or without the following:

Figure 1.

Figure 1.

Findings in individuals with ELN-related cutis laxa A, B, C. Girl age six years with generalized cutis laxa and typical facial features (convex nasal ridge, sagging cheeks, large ears, long philtrum, and increased folds of the perioral skin). Posture (more...)

  • Present at birth
    • Inguinal hernia, with increased risk at all ages
    • Joint hyperlaxity
  • Progressive (may be present as early as childhood)
    • Aortic root dilatation
    • Emphysema
    • Ptosis (eyelid drooping that can be caused by skin laxity)
    • Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance (Figure 1)

Note: The skin is hyperextensible if it can be stretched more than a standardized cutoff in three of the following areas: 1.5 cm for the distal part of the forearms and the dorsum of the hands; 3 cm for neck, elbows, and knees.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of ELN-related cutis laxa is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ELN identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous ELN variant of uncertain significance does not establish or rule out a diagnosis.

Because the phenotype of ELN-related cutis laxa may be difficult to distinguish from many other inherited disorders with cutis laxa, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of ELN, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

  • A cutis laxa multigene panel that includes ELN and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in ELN-Related Cutis Laxa

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
ELN Sequence analysis 3~100% 4, 5
Gene-targeted deletion/duplication analysis 61 family reported 7
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Percentage should include deep intronic sequencing, as c.2272+20C>G has been reported, resulting in partial retention of the intron [Vodo et al 2015].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

In one family with a complex intragenic ELN duplication/triplication with a predicted extended open reading frame, affected individuals had severe emphysema with concomitant risk factors of tobacco use and an M/Z α1-anti-trypsin genotype [Urban et al 2005]. In retrospect, the presentation in this family is likely not different from that of other individuals with ELN-related cutis laxa [Author, unpublished data].

Clinical Characteristics

Clinical Description

ELN-related cutis laxa is characterized by generalized cutis laxa (ranging from generalized skin redundancy causing excessive skin folds to skin hyperextensibility without obvious skin folds) and distinctive facial features that may become more prominent with age. Other common findings are joint hyperlaxity in infancy and increasing risk of inguinal hernia at all ages. Progressive findings that may be present as early as childhood include ptosis, aortic root dilatation, and emphysema.

To date, more than 46 individuals from 23 families have been identified with a pathogenic variant in ELN [Tassabehji et al 1998, Zhang et al 1999, Rodriguez-Revenga et al 2004, Urban et al 2005, Szabo et al 2006, Callewaert et al 2011, Hadj-Rabia et al 2013, Vodo et al 2015, Duz et al 2017, Okuneva et al 2019, Xiao et al 2019]. The following description (Table 2) of the phenotypic features associated with ELN-related cutis laxa is based on these reports. The phenotype is present at birth and affects males and females equally.

Table 2.

ELN-Related Cutis Laxa: Frequency of Select Features

FeatureFrequency
In nearly allCommonInfrequent
Cutis laxaX
Craniofacial characteristicsX
Aged appearanceX
Hoarse voiceX
Joint hypermobilityX
Aortic root dilatationX
COPD & emphysemaX
Inguinal herniaX
Arterial tortuosityX
Bicuspid aortic valveX

COPD = chronic obstructive pulmonary disease

Findings in Nearly All Individuals

Skin features in ELN-related cutis laxa include generalized loose and redundant skin, most prominent in the lower face, axillar, and inguinal regions, usually present at birth [Callewaert et al 2011]. Milder skin manifestations have been reported in adults as skin hyperlaxity [Szabo et al 2006, Hadj-Rabia et al 2013].

Nevertheless, all affected individuals have an aged appearance (see Figure 1), often with sagging eyelids, a convex nasal ridge, a long philtrum, prominent nasolabial folds, and skin redundancy in the chin and neck area. The external ears tend to be large.

Voice. The voice usually sounds hoarse and lower than expected.

Common Findings

Joint hypermobility. Affected individuals may show remarkable joint hypermobility of the small and large joints.

Aortic root dilatation. It has been estimated that up to 55% of affected individuals may develop aortic root aneurysm, with the risk increasing with age [Beyens et al 2021a, Beyens et al 2021b]. Aortic root dilatation has been observed in the first decade [Callewaert et al 2011]. Large diameters of the aortic root (up to 85 mm) and ascending aorta have been described [Szabo et al 2006, Callewaert et al 2011, Hadj-Rabia et al 2013].

Aortic aneurysms are amenable to surgery and there is no evidence of vascular fragility during surgery [Szabo et al 2006, Hadj-Rabia et al 2013].

Aortic dissection has been reported in multiple families as early as in the third decade [Szabo et al 2006]. The risk for aortic dissection has not been established.

Chronic obstructive pulmonary disease (COPD) and emphysema. Up to 35% of all affected individuals develop obstructive lung disease and emphysema, predisposing to airway infections [Beyens et al 2021a, Beyens et al 2021b].

Severe emphysema requiring lung transplantation has been observed in the context of concomitant excessive use of tobacco [Urban et al 2005, Hadj-Rabia et al 2013].

Inguinal hernias may occur and are prone to recurrence after surgery. Wound healing is normal.

Infrequent Findings

Arterial tortuosity. Increased tortuosity of the arteries (mainly of the supra-aortic vasculature) has been incidentally noted but not systematically assessed [Zhang et al 1999].

Bicuspid aortic valve. Three individuals had a bicuspid aortic valve associated with aneurysm formation of the ascending aorta [Callewaert et al 2011].

Other Observations

A splice site variant was reported in exon 25 of ELN (c.1708C>T) in an individual with cutis laxa, congenital emphysema, and epilepsy [Graul-Neumann et al 2008]. The facial characteristics do not fit with typical ELN-related cutis laxa. The variant was also present in the unaffected father. The variant results in exclusion of exon 25, containing lysine residues important for elastin crosslinking. Alternatively, if exon 25 is not spliced out, the variant creates a stop codon at position 541. The authors hypothesized that differences in expression of the mutated gene accounted for the interfamilial clinical variability. Of note, the c.1708C>T variant has been reported multiple times in individuals with supravalvular aortic stenosis (SVAS) (see Genetically Related Disorders). It is unclear if the variant explains all or part of the phenotype observed in the proband.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified in individuals with ELN-related cutis laxa.

Penetrance

ELN-related cutis laxa has 100% penetrance on detailed clinical observation [Hadj-Rabia et al 2013].

Prevalence

ELN-related cutis laxa is extremely rare; fewer than 50 individuals with a molecularly confirmed diagnosis have been reported to date.

While affected individuals have been mostly of European descent, individuals of other ethnicities have been reported, and there is no evidence to suspect ethnic preponderance.

Differential Diagnosis

Table 3.

Disorders to Consider in the Differential Diagnosis of ELN-Related Cutis Laxa

GeneDisorderMOIClinical FindingsComment
Cutis
laxa
EmphysemaAneurysmsID/DDBladder
diverticula
ALDH18A1 De Barsy syndrome A (ARCL3A) (OMIM 219150)AR+++Translucent skin (See also Neurometabolic Cutis Laxa.)
ADCL3 (OMIM 616603)AD++
ATP6V1A ARCL2D (OMIM 617403)AR++++Facial appearance similar to ARCL2A; myopathy, lipodystrophy, marfanoid habitus, potentially lethal respiratory problems in infancy; no seizures; often no ID. Like ARCL2A, ARCL2D & ARCL2C are CDGs. (See also Neurometabolic Cutis Laxa.)
ATP6V1E1 ARCL2C (OMIM 617402)AR++++
ATP7A 1Occipital horn syndrome (OHS) / Menkes disease (See ATP7A Copper Transport Disorders.)XL++++++Bony exostoses, intracranial & retinal tortuosity (See also Neurometabolic Cutis Laxa.)
ATP6V0A2 ATP6V0A2-related cutis laxa (ARCL2A)AR++++See also Neurometabolic Cutis Laxa.
EFEMP1 2EFEMP1-related cutis laxaAR+Multiple hernias, marfanoid habitus
EFEMP2 EFEMP2-related cutis laxa (ARCL1B)AR+++++++Bone fragility, arachnodactyly, widespread arterial tortuosity
FBLN5 FBLN5-related cutis laxa (ARCL1A & ADCL2)AR
AD
++++++++SVAS
GORAB Gerodermia osteodysplastica (GO) (OMIM 231070)AR++See also Neurometabolic Cutis Laxa.
LOX 3LOX-related cutis laxaAR+++++
LTBP1 4LTBP1-related cutis laxa (ARCL2E)AR+Craniosynostosis, short stature, congenital cardiac defects
LTBP4 LTBP4-related cutis laxa (ARCL1C)AR++++++--++Pulmonary artery stenosis
NBAS Short stature, optic nerve atrophy, & Pelger-Huet anomaly (SOPH syndrome) (OMIM 614800)AR+++Hepatopathy, optic atrophy, hypogammaglobulinemia, liver failure during episodes of fever, Pelger-Huet anomaly (See also Neurometabolic Cutis Laxa.)
PTDSS1 Lenz-Majewski syndrome hyperostotic dwarfism (LMS) (OMIM 151050)AD++++UnknownEarly cutis laxa followed by progressive thinning of skin w/prominent veins; severe brachydactyly & unique facies w/prominent eyes distinguish LMS in early stages from other forms of cutis laxa. 5 (See also Neurometabolic Cutis Laxa.)
PYCR1 De Barsy syndrome B (ARCL3B) (OMIM 614438)AR++++Translucent skin; chorea-athetosis (See also Neurometabolic Cutis Laxa.)
ARCL2B (OMIM 612940)AR++++Translucent skin (See also Neurometabolic Cutis Laxa.)
RIN2 RIN2-related cutis laxa (MACS syndrome) (OMIM 613075)AR+±UnknownVery characteristic facial gestalt; 6 alopecia; mild cutis laxa, mostly manifest as redundant, hyperextensible facial skin (See also Neurometabolic Cutis Laxa.)
SLC2A10 Arterial tortuosity syndrome AR++May display droopy facial appearance similar to other forms of cutis laxa 7 & have a high palate w/dental crowding; widespread arterial tortuosity

ADCL = autosomal dominant cutis laxa; ARCL = autosomal recessive cutis laxa; CDG = congenital disorder of glycosylation; DD = developmental delay; ID = intellectual disability; MACS = macrocephaly, alopecia, cutis laxa, & scoliosis; MOI = mode of inheritance; SVAS = supravalvular aortic stenosis

1.
2.
3.
4.
5.
6.
7.

Neurometabolic Cutis Laxa

The term "neurometabolic cutis laxa" has been suggested for a group of diseases related to inborn errors of metabolism. These disorders combine cutis laxa and skeletal defects with neurometabolic findings and result from pathogenic variants causing aberrant intracellular processing of extracellular matrix proteins as well as other proteins necessary for neurometabolic homeostasis.

Known genetic defects involved in neurometabolic cutis laxa include:

  • Aberrant glycosylation due to reduced acidification of the secretory vesicles (caused by defects in subunits of the v-ATPase transporter, including ATP6V0A2, ATP6V1E1, ATP6V1A, and ATP6AP1 [OMIM 300972]);
  • Defects in transporters for cofactors necessary for enzymes in the glycosylation pathway (ATP7A, encoding a copper transporter);
  • Defects in proteins involved in retrograde Golgi-to-ER transport (COG7 [see Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview], GORAB, NBAS, RIN2);
  • Defects in enzymes involved in mitochondrial processes that include proline synthesis (PYCR1, encoding pyrroline-5-carboxylate reductase 1, and ALDH18A1, encoding delta-1-pyrroline-5-carboxylate synthase);
  • Defects in enzymes involved in the synthesis of reducing equivalents to protect the cell from reactive oxygen species (TALDO1 [OMIM 606003]);
  • Defects in phosphatidylserine synthesis (PTDSS1) and mitochondrial fatty acid beta-oxidation (ECHS1).

Note: For simplicity and clarity, not all of the growing list of genes involved in neurometabolic cutis laxa have been included in Table 3.

Management

No clinical practice guidelines for ELN-related cutis laxa have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ELN-related cutis laxa, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with ELN-Related Cutis Laxa

System/ConcernEvaluationComment
Cardiovascular EchocardiographyTo evaluate:
  • Aortic valve morphology
  • Diameter of aortic root & ascending aorta
MR angiography
  • To evaluate arterial tortuosity
  • To enable visualization of ascending aorta when echocardiography is inadequate
  • Baseline testing at age 15 yrs
Pulmonary Chest radiographyBaseline eval before puberty
High-resolution computed tomographyTo evaluate severity of emphysema in symptomatic persons
Peak flow measurementBaseline testing usually at age 5 yrs
Pulmonary function testsBaseline testing at age 7 yrs
Urogenital system Ultrasound examTo evaluate for bladder diverticula
Ophthalmologic Routine eye exam by ophthalmologistW/attn to whether ptosis is obscuring pupil & causing person to adopt head tilt to clear pupillary axis
Joint laxity/pain Physical therapy
  • To identify joint hyperlaxity & joint instability/subluxations
  • To evaluate general posture
Self-esteem Psychological screeningAssess for need for intervention for significant self-esteem issues requiring proactive psychological support.
Genetic
counseling
By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of ELN-related cutis laxa to facilitate medical & personal decision making
Family support
& resources
Assess need for:
1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

There is no cure for ELN-related cutis laxa.

Supportive treatment. Experience in treating individuals with ELN-related cutis laxa is very limited. Treatment is largely symptomatic and serves to improve quality of life, maximize function, and reduce complications. It ideally involves multidisciplinary care by specialists in relevant fields (Table 5).

Table 5.

Supportive Treatment of Manifestations in Individuals with ELN-Related Cutis Laxa

Manifestation/ConcernTreatmentConsiderations/Other
Inguinal hernia Repair w/mesh.↑ risk for recurrence
Aortic root dilatation Aortic root repair (Bentall or David procedure depending on aortic valve function)
  • Best thresholds for aortic repair are not established. In general, criteria for Marfan syndrome can be used.
  • 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.
  • For beta-blocking agents, caution is appropriate in persons w/ (reversible) obstructive airway disease, & cardio-selective beta-blocking agents may be preferred.
Emphysema Beta mimetics, anticholinergic agentsAvoid use of anticholinergic agents in persons w/bladder diverticula.
Bladder diverticula
  • Education on complete bladder emptying when voiding
  • Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections
  • PT to strengthen pelvic floor to help prevent prolapse of pelvic organs
  • Catheterization if significant urinary residual after voiding
Joint hypermobility PTEncourage non-weight-bearing exercise such as cycling & swimming.
Joint pain
  • PT
  • Pain medications in case of acute aggravation of pain
  • Lifestyle recommendations
  • Non-weight-bearing exercise such as cycling & swimming
Ptosis Eyelid surgerySurgery is recommended when eyelid obscures pupil &/or sagging results in recurrent conjunctival infection/irritation.
Skin Cosmetic surgery, lipofilling
  • Skin laxity often recurs.
  • Cosmetic interventions are currently not encouraged.
Self-esteem Psychological supportSuch as giving children age-appropriate language to describe their condition to help w/curious peers

PT = physical therapy

Surveillance

Table 6.

Recommended Surveillance for Individuals with ELN-Related Cutis Laxa

System/ConcernEvaluationFrequency
Cardiovascular EchocardiographyAnnually (or depending on measurements/progression)
Magnetic resonance angiographyPost puberty, frequency based on observations or every 5 yrs 1
Pulmonary Lung function tests
  • Baseline testing at age 7 yrs
  • Repeat if there is shortness of breath or decline in peak flow measurement.
Peak flow measurement
  • Baseline testing at age 5 yrs
  • Repeat every 6 mos.
Inguinal hernia Clinical eval (Valsalva maneuver)Annually
Joint pain Clinical eval
Ptosis
Bladder diverticula
  • Ultrasound of urinary tract
  • Voiding cystography
Whenever there is incomplete voiding or urinary tract infections
Family/Community Assess family need for social work support (e.g., other local resources) & follow-up genetic counseling if new questions arise (e.g., family planning).At each visit
1.

Although the risk for arterial aneurysms beyond the ascending aorta is likely low, given the small number of individuals reported with ELN-related cutis laxa and the known risks for arterial aneurysm in other connective tissue disorders, it is recommended that the potential risks and benefits of screening with MR angiography be discussed with the patient.

Agents/Circumstances to Avoid

Avoid the following:

  • 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.
  • Contracting respiratory infections
  • Tobacco smoking, which can result in rapid, severe loss of lung function in persons with ELN-related cutis laxa
  • Isometric exercise (which causes an increase in blood pressure)
  • Contact sports. The increased risk for joint injury or pain related to contact sports should be discussed. In case of arterial aneurysms reaching diameters necessitating surgery, blunt trauma should be prevented as much as possible (similar to Marfan syndrome guidelines).
  • Sunbathing or tanning, to preserve residual skin elasticity. Vitamin D supplementation should be considered in this context, and monitored annually.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

At least 21 pregnancies have been reported in affected females. No perinatal complications for the affected mother or the neonate were reported [Zhang et al 1999, Rodriguez-Revenga et al 2004, Urban et al 2005, Szabo et al 2006, Hadj-Rabia et al 2013, Vodo et al 2015, Okuneva et al 2019, Xiao et al 2019, Velandia-Piedrahita et al 2020].

Per guidelines used for women with Marfan syndrome who are planning a pregnancy, women with ELN-related cutis laxa require preconception cardiovascular evaluation, including assessment of the aortic root diameter, as well as increased surveillance throughout the pregnancy and six months post partum.

Additionally, pulmonary evaluation and follow up are warranted before and during pregnancy. Pregnancy may aggravate respiratory symptoms as a result of reduced lung volume, resulting in increased respiratory effort in the third trimester.

Uterine prolapse may occur [Urban et al 2005].

Affected women who anticipate pregnancy or become pregnant and are taking a beta-blocker should continue it during pregnancy; however, some other classes of medications, such as angiotensin receptor-blocking agents, are teratogenic and should be discontinued or changed to beta-blocking agents, given the increased risk for teratogenicity (i.e., increased risk for fetal loss, oligohydramnios, and abnormal fetal development) typically related to second- and third-trimester exposure. Women who are planning a pregnancy or who become pregnant while taking an angiotensin receptor blocker can be transitioned to a beta-blocker.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ELN-related cutis laxa is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • About one third of individuals diagnosed with ELN-related cutis laxa have an affected parent.
  • About two thirds of individuals diagnosed with ELN-related cutis laxa have the disorder as the result of a de novo ELN pathogenic variant.
  • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The family history of some individuals diagnosed with ELN-related cutis laxa may appear to be negative because of a milder personal appreciation of a phenotypic presentation in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • A sib who inherits a pathogenic variant is expected to have manifestations of the disorder; however, intrafamilial clinical variability is observed in ELN-related cutis laxa.
  • If the ELN pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents have not been tested for the ELN pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ELN-related cutis laxa because of the possibility of a mild presentation in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with ELN-related cutis laxa has a 50% chance of inheriting the ELN pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the ELN pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the ELN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

ELN-Related Cutis Laxa: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ELN 7q11​.23 Elastin ELN database ELN ELN

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for ELN-Related Cutis Laxa (View All in OMIM)

123700CUTIS LAXA, AUTOSOMAL DOMINANT 1; ADCL1
130160ELASTIN; ELN

Molecular Pathogenesis

ELN pathogenic variants causing ELN-related cutis laxa result in a shift in the reading frame in the last four exons of the ELN transcript, causing an elongated sequence at the C terminus of the protein tropoelastin. The altered tropoelastin is stable and secreted [Szabo et al 2006, Callewaert et al 2011]. When in the secretory pathway, the abnormal protein interacts with wild type tropoelastin increasing self-aggregation (coacervation) and clump formation that impedes proper crosslinking in elastic fibers by lysyl oxidases [Callewaert et al 2011]. As a result, electron microscopy of skin biopsies shows abnormal elastic fibers that appear as amorphic clumps without parallel directionality to the microfibrils [Callewaert et al 2011].

Mechanism of disease causation. ELN pathogenic variants that cause ELN-related cutis laxa result in an abnormal protein with an extended C terminal. The pathogenic variant may result in a frameshift with a readthrough in the 3' untranslated region or result in inclusion of noncoding sequences in the mature mRNA. Mutated tropoelastin has been shown to aggregate with wild type elastin. Hence, the likely mechanism is a dominant-negative effect [Callewaert et al 2011].

Although other mechanisms of ELN variants have been described, confirmation is necessary to establish a causal relationship with typical ELN-related cutis laxa [Graul-Neumann et al 2008, Velandia-Piedrahita et al 2020].

ELN-specific laboratory technical considerations. Most identified pathogenic variants in ELN-related cutis laxa cause an ELN frameshift affecting exons 30-34 and result in an extended open reading frame.

A more complex gene duplication/triplication was reported in one family by Urban et al [2005]. The predicted open reading frame similarly extended beyond the typical stop codon.

Molecular testing should include analysis for deep intronic variants. One reported intronic splice variant (c.2272+20), causing inclusion of a 19-base pair intronic sequence in the mature ELN mRNA resulting in a frameshift, was reported in a boy age five years with a phenotype indistinguishable from other individuals with ELN-related cutis laxa [Vodo et al 2015].

Table 7.

Notable ELN Pathogenic Variants

Reference SequencesDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeComment [Reference]
NM_001278939​.2
NP_001265868​.1
c.1708C>T 2
(1621C>T)
p.Arg570TerTypically assoc w/SVAS & reported in 1 family w/ELN-related cutis laxa [Graul-Neumann et al 2008]
c.2272+20C>G
(2086+20)
p.Val697ArgfsTer57Deep intronic variant [Vodo et al 2015]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

This nucleotide change affects the nucleotide immediately upstream of the donor splice site of intron 25 and is predicted to affect splicing.

Chapter Notes

Author Notes

Bert Callewaert is an Associate Professor at Ghent University and a pediatrician/clinical geneticist at the Center for Medical Genetics of the Ghent University Hospital. His research focuses on connective tissue disorders (including arterial tortuosity syndrome, cutis laxa syndromes, and familial thoracic aortic aneurysms). Both zebra fish and mouse models are used to gain insight into the pathogenesis of these disorders.

Dr Callewaert is actively involved in clinical research regarding individuals with ELN-related cutis laxa. He would be happy to communicate with persons who have any questions regarding diagnosis of ELN-related cutis laxa or other considerations.

Contact Dr Callewaert to inquire about the interpretation of ELN variants of uncertain significance.

Dr Callewaert is also interested in hearing from clinicians treating families affected by cutis laxa in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Email: eb.tnegu@treawellac.treb

Website: Center for Medical Genetics, Ghent University Hospital

Zsolt Urban is an Associate Professor of Human Genetics at the Graduate School of Public Health of the University of Pittsburgh. His research is focused on cutis laxa and related disorders. His research team pursues clinical, cell culture, and animal model studies to characterize the natural history of cutis laxa and identify the genetic causes and underlying molecular mechanisms responsible for this group of disorders.

For more information, go to the Cutis Laxa Research Study website or email ude.ttip@znabru.

Acknowledgments

Bert Callewaert is a Senior Clinical Investigator of the Fund for Scientific Research-Flanders. Zsolt Urban is funded by a National Institutes of Health grant HL090648.

Revision History

  • 29 September 2022 (bp) Review posted live
  • 25 January 2022 (bc) Original submission

References

Literature Cited

  • Basel-Vanagaite L, Sarig O, Hershkovitz D, Fuchs-Telem D, Rapaport D, Gat A, Isman G, Shirazi I, Shohat M, Enk CD, Birk E, Kohlhase J, Matysiak-Scholze U, Maya I, Knopf C, Peffekoven A, Hennies HC, Bergman R, Horowitz M, Ishida-Yamamoto A, Sprecher E. RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome. Am J Hum Genet. 2009;85:254–63. [PMC free article: PMC2725231] [PubMed: 19631308]
  • Beyens A, Boel A, Symoens S, Callewaert B. Cutis laxa: a comprehensive overview of clinical characteristics and pathophysiology. Clinical genetics. 2021a;99:53–66. [PubMed: 33058140]
  • Beyens A, Pottie L, Sips P, Callewaert B. Clinical and molecular delineation of cutis laxa syndromes: paradigms for homeostasis. Advances in experimental medicine and biology. 2021b;1348:273–309. [PubMed: 34807425]
  • Beyens A, Van Meensel K, Pottie L, De Rycke R, De Bruyne M, Baeke F, Hoebeke P, Plasschaert F, Loeys B, De Schepper S, Symoens S, Callewaert B. Defining the clinical, molecular and ultrastructural characteristics in occipital horn syndrome: two new cases and review of the literature. Genes. 2019;10:528. [PMC free article: PMC6678539] [PubMed: 31336972]
  • Callewaert B, Renard M, Hucthagowder V, Albrecht B, Hausser I, Blair E, Dias C, Albino A, Wachi H, Sato F, Mecham RP, Loeys B, Coucke PJ, De Paepe A, Urban Z. New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations. Hum Mutat. 2011;32:445–55. [PMC free article: PMC3383654] [PubMed: 21309044]
  • Callewaert BL, Willaert A, Kerstjens-Frederikse WS, De Backer J, Devriendt K, Albrecht B, Ramos-Arroyo MA, Doco-Fenzy M, Hennekam RC, Pyeritz RE, Krogmann ON, Gillessen-kaesbach G, Wakeling EL, Nik-zainal S, Francannet C, Mauran P, Booth C, Barrow M, Dekens R, Loeys BL, Coucke PJ, De Paepe AM. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008;29:150–8. [PubMed: 17935213]
  • Duz MB, Kirat E, Coucke PJ, Koparir E, Gezdirici A, Paepe A, Callewaert B, Seven M. A novel case of autosomal dominant cutis laxa in a consanguineous family: report and literature review. Clin Dysmorphol. 2017;26:142–7. [PubMed: 28383366]
  • Graul-Neumann LM, Hausser I, Essayie M, Rauch A, Kraus C. Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene. Am J Med Genet A. 2008;146A:977–83. [PubMed: 18348261]
  • Hadj-Rabia S, Callewaert BL, Bourrat E, Kempers M, Plomp AS, Layet V, Bartholdi D, Renard M, De Backer J, Malfait F, Vanakker OM, Coucke PJ, De Paepe AM, Bodemer C. Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity. Orphanet J Rare Dis. 2013;8:36. [PMC free article: PMC3599008] [PubMed: 23442826]
  • McKenzie F, Mina K, Callewaert B, Beyens A, Dickinson JE, Jevon G, Papadimitriou J, Diness BR, Steensberg JN, Ek J, Baynam G. Severe congenital cutis laxa: Identification of novel homozygous LOX gene variants in two families. Clin Genet. 2021;100:168–75. [PubMed: 33866545]
  • Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Raber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359:1685–99. [PMC free article: PMC2703742] [PubMed: 18784092]
  • Merla G, Brunetti-Pierri N, Piccolo P, Micale L, Loviglio MN. Supravalvular aortic stenosis: elastin arteriopathy. Circ Cardiovasc Genet. 2012;5:692–6. [PubMed: 23250899]
  • Okuneva EG, Kozina AA, Baryshnikova NV, Krasnenko AY, Tsukanov KY, Klimchuk OI, Surkova EI, Ilinsky VV. A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report. BMC dermatology. 2019;19:4. [PMC free article: PMC6357400] [PubMed: 30704477]
  • Piard J, Lespinasse J, Vlckova M, Mensah MA, Iurian S, Simandlova M, Malikova M, Bartsch O, Rossi M, Lenoir M, Nugues F, Mundlos S, Kornak U, Stanier P, Sousa SB, Van Maldergem L. Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1. Am J Med Genet A. 2018;176:668–75. [PMC free article: PMC5838527] [PubMed: 29341480]
  • Pottie L, Adamo CS, Beyens A, Lutke S, Tapaneeyaphan P, De Clercq A, Salmon PL, De Rycke R, Gezdirici A, Gulec EY, Khan N, Urquhart JE, Newman WG, Metcalfe K, Efthymiou S, Maroofian R, Anwar N, Maqbool S, Rahman F, Altweijri I, Alsaleh M, Abdullah SM, Al-Owain M, Hashem M, Houlden H, Alkuraya FS, Sips P, Sengle G, Callewaert B. Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome. Am J Hum Genet. 2021;108:1095–114. [PMC free article: PMC8206382] [PubMed: 33991472]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Rodriguez-Revenga L, Iranzo P, Badenas C, Puig S, Carrio A, Mila M. A novel elastin gene mutation resulting in an autosomal dominant form of cutis laxa. Arch Dermatol. 2004;140:1135–9. [PubMed: 15381555]
  • Sousa SB, Jenkins D, Chanudet E, Tasseva G, Ishida M, Anderson G, Docker J, Ryten M, Sa J, Saraiva JM, Barnicoat A, Scott R, Calder A, Wattanasirichaigoon D, Chrzanowska K, Simandlova M, Van Maldergem L, Stanier P, Beales PL, Vance JE, Moore GE. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nat Genet. 2014;46:70–6. [PubMed: 24241535]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • Szabo Z, Crepeau MW, Mitchell AL, Stephan MJ, Puntel RA, Yin Loke K, Kirk RC, Urban Z. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J Med Genet. 2006;43:255–8. [PMC free article: PMC2563239] [PubMed: 16085695]
  • Tassabehji M, Metcalfe K, Hurst J, Ashcroft GS, Kielty C, Wilmot C, Donnai D, Read AP, Jones CJ. An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa. Hum Mol Genet. 1998;7:1021–8. [PubMed: 9580666]
  • Urban Z, Gao J, Pope FM, Davis EC. Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin. J Invest Dermatol. 2005;124:1193–9. [PubMed: 15955094]
  • Velandia-Piedrahita CA, Morel A, Fonseca-Mendoza DJ, Huertas-Quinones VM, Castillo D, Bonilla JD, Hernandez-Toro CJ, Miranda-Fernandez MC, Restrepo CM, Cabrera R. A novel splice-site mutation in the ELN gene suggests an alternative mechanism for vascular elastinopathies. Appl Clin Genet. 2020;13:233–40. [PMC free article: PMC7751611] [PubMed: 33364810]
  • Verlee M, Beyens A, Gezdirici A, Gulec EY, Pottie L, De Feyter S, Vanhooydonck M, Tapaneeyaphan P, Symoens S, Callewaert B. Loss-of-function variants in EFEMP1 cause a recognizable connective tissue disorder characterized by cutis laxa and multiple herniations. Genes. 2021;13:12. [PMC free article: PMC8066907] [PubMed: 33807164]
  • Vodo D, Sarig O, Peled A, Frydman M, Greenberger S, Sprecher E. Autosomal-dominant cutis laxa resulting from an intronic mutation in ELN. Exp Dermatol. 2015;24:885–7. [PubMed: 26121527]
  • Xiao H, Zhang Z, Lyu X, Li T, Guo Q, Wang H, Zhang Q, Su J, Liao S. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019;36:785–8. [Analysis of ELN gene mutation in a pedigree affected with cutis laxa] [PubMed: 31400128]
  • Zhang MC, He L, Giro M, Yong SL, Tiller GE, Davidson JM. Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN). J Biol Chem. 1999;274:981–6. [PubMed: 9873040]
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