Efemp2-Related Cutis Laxa

Clinical characteristics.

EFEMP2-related cutis laxa, or autosomal recessive cutis laxa type 1B (ARCL1B), is characterized by cutis laxa and systemic involvement, most commonly arterial tortuosity, aneurysms, and stenosis; retrognathia; joint laxity; and arachnodactyly. Severity ranges from perinatal lethality as a result of cardiopulmonary failure to manifestations limited to the vascular and craniofacial systems.

Diagnosis/testing.

The diagnosis of EFEMP2-related cutis laxa is established in a proband with suggestive findings and biallelic pathogenic variants in EFEMP2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment of aortic root dilatation with beta-blockers or angiotensin receptor inhibitors can be considered. Aortic aneurysm replacement has been performed successfully. Symptomatic treatment of pulmonary emphysema; muscle-reinforcing physical therapy for joint hypermobility; routine repair of hernias. Tracheostomy may be necessary when retrognathia leads to upper-airway obstruction.

Surveillance: Follow-up evaluations with a cardiologist and pulmonologist at least annually starting from the time of diagnosis. Annual MR angiography from head to pelvis.

Agents/circumstances to avoid: Sun tanning to avoid damaging the skin; cigarette smoking to avoid worsening of emphysema.

Genetic counseling.

EFEMP2-related cutis laxa is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EFEMP2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the EFEMP2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

The diagnosis of EFEMP2-related cutis laxa should be considered in individuals with the following clinical characteristics:

• Vascular involvement
  • Arterial and aortic tortuosity
  • Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated.
  • Aortic stenosis.The isthmus aorta in particular is often stenotic.
  • Stenosis and dilatation of pulmonary arteries
  • Pulmonary hypertension
  • Hemorrhagic stroke
• Cutis laxa. Furrowing of the skin of the whole body that can be displaced more than normal skin and shows abnormal recoil; the skin has a "doughy" consistency. It does not display redundancy as in the Ehlers-Danlos syndromes.
• Respiratory involvement. Diaphragmatic hernia or hypoplasia
• Craniofacial involvement
  • Retrognathia
  • Widely spaced eyes
  • High palate
  • Long philtrum
  • Sagging cheeks
  • Dysplastic ears
• Other evidence of a generalized connective disorder
  • Joint laxity or contractures
  • Arachnodactyly
  • Pectus excavatum
  • Inguinal hernias
  • Hypotonia
  • Bone fragility

Establishing the Diagnosis

The diagnosis of EFEMP2-related cutis laxa is established in a proband with suggestive findings and biallelic pathogenic variants in EFEMP2 identified by molecular genetic testing (see Table 1).

Note: Identification of biallelic EFEMP2 variants of uncertain significance (or identification of one known EFEMP2 pathogenic variant and one EFEMP2 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Because the phenotype of EFEMP2-related cutis laxa is indistinguishable from many other inherited disorders with cutis laxa and/or arterial abnormalities (tortuosity, aneurysm, and/or stenosis), recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of EFEMP2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A cutis laxa or arteriopathy multigene panel that includes EFEMP2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost 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.
  If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of this disorder.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EFEMP2-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

Surveillance

Agents/Circumstances to Avoid

Avoid the following:

• Sun tanning, which can damage skin
• Cigarette smoking, which can worsen emphysema

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of older and younger sibs of an affected individual in order to identify as early as possible those who should undergo regular cardiovascular and pulmonary surveillance to allow prompt initiation of treatment and preventive measures.

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

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.