Clinical Diagnosis

EFEMP2-related cutis laxa is characterized by cutis laxa and systemic involvement.

Major clinical characteristics:

• Cutis laxa. Furrowing of the skin of the whole body that is particularly obvious in face, torso, and limbs. The face can have a “droopy” appearance with eyelid ptosis and sagging cheeks. When extended the skin 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. The skin can also be normal.

• Arterial involvement. Arterial tortuosity with aortic and arterial aneurysms and stenosis (the isthmus aorta in particular is often stenotic); pulmonary hypertension, stenosis and dilatation of pulmonary arteries; hemorrhagic stroke

• Respiratory involvement. Emphysema, diaphragmatic hernia or hypoplasia

• Craniofacial involvement. Midface hypoplasia, retrognathia, ocular hypertelorism, highly arched palate

• Other evidence of a generalized connective disorder

  • Joint laxity or contractures

  • Arachnodactyly

  • Pectus excavatum

  • Inguinal hernias

  • Hypotonia

  • Bone fragility

Molecular Genetic Testing

Gene. EFEMP2 (previously known as FBLN4) is the only gene in which mutations cause EFEMP2-related cutis laxa.

Clinical testing

• Sequence analysis. No large cohorts in which molecular genetic testing has been performed have been published; however, in persons with a typical clinical presentation, including congenital cutis laxa and arterial involvement, the probability of identifying two causative EFEMP2 mutations is high.

Table 1. Summary of Molecular Genetic Testing Used in EFEMP2-Related Cutis Laxa

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
EFEMP2	Sequence analysis	Sequence variants 2	>95%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of EFEMP2-related cutis laxa is established in individuals who meet clinical diagnostic criteria and have two mutations identified in EFEMP2.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in EFEMP2 (FBLN4).

Individuals without cutis laxa ascertained based on the presence of arterial tortuosity, stenosis, and aneurysms can have mutations in EFEMP2 [Renard et al 2010]. This is considered to be a variant of the EFEMP2-related cutis laxa phenotypic spectrum with variable expression or reduced penetrance of cutis laxa rather than a distinct disorder. (See Clinical Description.)

Natural History

EFEMP2-related cutis laxa (autosomal recessive cutis laxa type 1A, ARCL1A) is a highly variable disorder ranging from perinatal lethality caused by cardiopulmonary failure [Hoyer et al 2009] to manifestations limited to the vascular and craniofacial systems [Renard et al 2010]. The most common shared features besides cutis laxa include arterial tortuosity, aneurysms and stenosis; retrognathia; joint laxity; and arachnodactyly. All features present in at least two affected individuals are shown in Table 2.

Of note, several features not included in Table 2 were found in only one affected individual, highlighting the pleiotropic and variable nature of EFEMP2-related phenotypes. Unique features by patient:

• Patient 1. Transparent skin, low muscle tone, and inguinal hernia

• Patient 2. Pneumonia, pulmonary hypertension, right ventricular hypertrophy, tricuspid insufficiency, renal tubular damage

• Patient 3. Long birth length, absolute microcephaly, contractures, spina bifida, small palpebral fissures, soft cranial bones, bowing and elongation of the long bones, flaring of the metaphyses, soft tissue bleeding

• Patient 5. Flat facies

In a cohort of 16 affected individuals from India almost all died from cardiopulmonary failure [Nampoothiri et al 2010]. Major clinical characteristics included marked aortic dilatation, aortic and arterial tortuosity, isthmic aortic narrowing, and dilatation/stenosis of the pulmonary arteries. Aberrant branching of the right pulmonary artery was also a frequent finding. Recurrent additional features included long philtrum with thin upper lip, prominent eyes with ocular hypertelorism, and hypotonia.

Genotype-Phenotype Correlations

No clinically significant genotype-phenotype correlations have emerged.

Prevalence

Very few reliable estimates of prevalence of cutis laxa exist. A prevalence at birth for all types of cutis laxa is 1:4,000,000 according to the Rhone-Alps Eurocat Registry [E Robert, personal observation].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with EFEMP2 -related cutis laxa, the following evaluations are recommended:

• Chest roentgenogram

• Echocardiography

• 3D-CT scan

• Lung function test

• MR angiography

Treatment of Manifestations

Hernia. Routine repair is appropriate.

Pulmonary emphysema is treated symptomatically. Tracheostomy may be necessary when retrognathia leads to upper airway obstruction.

Arterial abnormalities. No definitive treatment is available. Based on experience in other related disorders (e.g., Marfan syndrome), treatment with beta-blockers or angiotensin receptor blockers can be considered when aortic root dilatation is present. However, the efficacy of these interventions in EFEMP2- related disorders has not been proven.

Surveillance

Regular cardiovascular and pulmonary follow-up starting at birth or at the time of diagnosis is appropriate.

Agents/Circumstances to Avoid

Cigarette smoking can worsen emphysema and should be avoided

To protect skin, sun tanning should be avoided.

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials related to this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

EFEMP2-related cutis laxa is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has 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 an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with EFEMP2-related cutis laxa are obligate heterozygotes (carriers) for a disease-causing mutation in EFEMP2.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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10. Kobayashi N, Kostka G, Garbe JH, Keene DR, Bächinger HP, Hanisch FG, Markova D, Tsuda T, Timpl R, Chu ML, Sasaki T. A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization. J Biol Chem. 2007;282:11805–16. [PubMed: 17324935]
11. Nampoothiri S, Kappanayil M, De Paepe A, Loeys B, Van Laer L, Kannan R, Faiyaz-Ul-Haque M, Krishna Kumar R. Lethal vascular syndrome from South India due to a novel mutation in fibulin 4. Abstract c16.3. Gothenburg, Sweden: European Society of Human Genetics Conference. 2010.
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Author Notes

Bart Loeys, MD, PhD
Web: www.genetica-antwerpen.be

Anne De Paepe, MD, PhD
Web: medgen.ugent.be

Zsolt Urban, PhD
Web: www.hgen.pitt.edu

Acknowledgments

This work was funded in part by a March of Dimes grant (1-FY09-556 to ZU) and an NIH/NHLBI grant (HL090648 to ZU), a ‘Methusalem grant’ from the Flemish government and Ghent University (08/01M01108 to ADP), and an EC-FP7 project (FAD). BL is a senior clinical investigator of the fund for scientific research Flanders.

Revision History

• 12 May 2011 (me) Review posted live

• 9 July 2010 (bl) Original submission