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.

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.

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.

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.

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.

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.

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.

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).

Surveillance

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.

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 proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Thus far, germline mosaicism has not been reported in ELN-related cutis laxa. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• 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.

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].

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: [email protected]

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

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