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EFEMP2-Related Cutis Laxa

Synonyms: Autosomal Recessive Cutis Laxa Type 1B, ARCL1B

, MD, PhD, , MD, PhD, and , PhD.

Author Information
, MD, PhD
Center for Medical Genetics
Antwerp University Hospital
Antwerp, Belgium
, MD, PhD
Center for Medical Genetics
Ghent University Hospital
Ghent, Belgium
, PhD
Department of Human Genetics
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, Pennsylvania

Initial Posting: ; Last Update: July 23, 2015.

Summary

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 by clinical diagnostic criteria. Pathogenic variants in EFEMP2 (also known as FBLN4) are causative.

Management.

Treatment of manifestations: Routine repair of hernias; symptomatic treatment of pulmonary emphysema. Treatment of aortic root dilatation with beta-blockers and angiotensin-receptor inhibitors can be considered. Aortic aneurysm replacement has been performed successfully. Joint hypermobility can be supported by muscle-reinforcing physical therapy.

Surveillance: Regular cardiovascular and pulmonary follow up starting at birth or at the time of diagnosis. Annual MR angiography from head to pelvis.

Agents/circumstances to avoid: Cigarette smoking to avoid worsening of emphysema, sun tanning to protect skin.

Genetic counseling.

EFEMP2-related cutis laxa is inherited in an autosomal recessive manner. 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. Carrier testing and prenatal diagnosis of EFEMP2-related cutis laxa are possible once the pathogenic variants have been identified in the family.

Diagnosis

Suggestive Findings

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

  • 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.
  • 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 retrusion, retrognathia, widely spaced eyes, high palate
  • 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 the identification of biallelic pathogenic variants in EFEMP2 (also known as FBLN4). See Table 1.

Molecular testing approaches can include single-gene testing and use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of EFEMP2 is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multi-gene panel that includes EFEMP2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

Table 1.

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

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by this Method
EFEMP2Sequence analysis 3>95%
Gene-targeted deletion/duplication analysis 4None reported
Unknown 5NA
1.
2.

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

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.

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

5.

Cutis laxa is genetically heterogeneous and currently known genes do not account for all patients [Callewaert et al 2013, Urban & Davis 2014].

Clinical Characteristics

Clinical Description

EFEMP2-related cutis laxa (autosomal recessive cutis laxa type 1B, ARCL1B) 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. Features present in the currently known affected individuals are summarized below [Hucthagowder et al 2006, Dasouki et al 2007, Hoyer et al 2009, Renard et al 2010, Kappanayil et al 2012, Sawyer et al 2013, Hebson et al 2014]

Cardiovascular. The most typical cardiovascular findings are 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. Additional cardiovascular findings that have been described occasionally include cardiac hypertrophy, bradycardia [Dasouki et al 2007, Hoyer et al 2009], pulmonary hypertension, and tricuspid insufficiency [Dasouki et al 2007]. In a cohort of 16 affected individuals from India almost all died from cardiopulmonary failure in the neonatal period [Nampoothiri et al 2010]. Other patients underwent successful aortic surgery and survived [Sawyer et al 2013, Hebson et al 2014].

Skin. Although EFEMP2-related cutis laxa is classified within the cutis laxa group, skin findings can be minor or even normal. If present, pertinent skin findings include cutis laxa and thin translucent or velvety skin.

Craniofacial. Most recurrent characteristics are retrognathia, widely spaced eyes, high palate, and dysplastic ears. Additional features include long philtrum with thin vermillion of the upper lip and prominent eyes.

Lung. Developmental emphysema has been described in one patient [Hoyer et al 2009] but emphysema is more typical for FBLN5-associated cutis laxa (type 1B). In the reported patient, lung problems may also be related to diaphragmatic hypoplasia.

Musculoskeletal. Individuals with EFEMP2-related cutis laxa usually present with muscle hypotonia. Other common findings are arachnodactyly, joint laxity, and pectus deformities. Fractures also appear to be common [Hoyer et al 2009]. Additional skeletal observations were soft cranial bones, bowing and elongation of the long bones, and flaring of the metaphyses.

Other. Inguinal hernias may be present.

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].

Differential Diagnosis

Other disorders characterized by cutis laxa are summarized in Table 2.

FBLN5-related cutis laxa (ARCL1A and ADCL2) is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder such as inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). Occasionally, supravalvular aortic stenosis is observed. Intrafamilial variability in age of onset is observed. Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is the most common cause of death. FBLN5-related cutis laxa can be inherited in an autosomal recessive or autosomal dominant manner. Autosomal recessive inheritance is more common.

LTBP4-related cutis laxa (ARCL1C, cutis laxa with severe pulmonary, gastrointestinal and urinary abnormalities, Urban-Rifkin-Davis syndrome [URDS]) is characterized by abnormal pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All affected individuals had severe respiratory distress with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Cardiovascular lesions were mild and limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis and enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide anterior fontanels. The craniofacial and pulmonary phenotype of URDS is similar to EFEMP2-related cutis laxa. Differences include relatively mild cardiovascular involvement in URDS and the presence of severe gastrointestinal and urinary complications, which have not been described to date in EFEMP2-related cutis laxa.

ATP6V0A2-related cutis laxa (ARCL2A) spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end. Affected individuals have furrowing of the skin of the whole body that improves with time. They may have other evidence of a generalized connective disorder, including enlarged anterior fontanel in infancy, congenital dislocation of the hips, inguinal hernias, and high myopia. In most (but not all) affected individuals, cortical and cerebellar malformations are present and are associated with severe developmental delays, seizures, and neurologic regression. Clinical features of ARCL2A not observed in EFEMP2-related cutis laxa are: intellectual disability, hip dislocation, and delayed closure of the fontanel. Secondary effects of strokes (developmental delay, structural brain defects) [Hoyer et al 2009, Renard et al 2010] may complicate the distinction between ARCL2A and ARCL1B. In ARCL2A, abnormal serum transferrin (N-glycosylation test) and apolipoprotein CIII (O-glycosylation test) isoelectric focusing (IEF) may help confirm the diagnosis. ATP6V0A2-related cutis laxa is inherited in an autosomal recessive manner.

ELN-related cutis laxa (ADCL1) (OMIM 123700) was historically considered a strictly cutaneous disorder without systemic involvement; however, it is now known that persons with ELN pathogenic variants can also have aortic aneurysms that require aortic root replacement or lead to aortic rupture in early adulthood. The aortic pathology of these aneurysms is indistinguishable from that of Marfan syndrome. It remains to be seen whether ELN is mutated in persons with thoracic aortic aneurysms and aortic dissections (TAAD) [Szabo et al 2006] (see Thoracic Aortic Aneurysms and Aortic Dissections). Adult-onset emphysema has also been reported in ADCL [Urban et al 2005]. The following manifestations distinguish EFEMP2 -related cutis laxa from ADCL1: arterial tortuosity, infantile aneurysms, infantile developmental emphysema, death in infancy or early childhood, arachnodactyly, and retrognathia. ELN-related cutis laxa is inherited in an autosomal dominant manner.

Gerodermia osteodysplastica (GO) (OMIM 231070). Onset occurs in infancy or early childhood (for review, see Nanda et al [2008]). Children appear older than their age as a result of sagging cheeks and jaw hypoplasia. Skin wrinkling is less severe than in persons with cutis laxa and is confined to the dorsum of the hands and feet and to the abdomen when in the sitting position. A generalized connective tissue weakness leads to frequent hip dislocation and hernias; however, GO can be distinguished from other types of cutis laxa by the presence of osteopenia/osteoporosis and fractures, most commonly vertebral compression fractures, but also fractures of the long bones. However, fractures have also been described in EFEMP2 -related cutis laxa [Hucthagowder et al 2006, Hoyer et al 2009]. Intellectual development is in the normal range. In contrast to ARCL2A, fontanel size and closure are normal; positioning of the palpebral fissures is normal; and disease manifestations do not become milder with age. Unlike EFEMP2-related cutis laxa, GO is generally not associated with cardiovascular and pulmonary manifestations. Pathogenic variants in GORAB are causative [Hennies et al 2008]. GO is inherited in an autosomal recessive manner.

De Barsy syndrome (ARCL3A and ARCL3B) (OMIM 219150, OMIM 614438) is characterized by a progeroid appearance, pre- and postnatal growth retardation, moderate to severe intellectual disability, corneal clouding or cataracts, and generalized cutis laxa [Guerra et al 2004]. The progeroid appearance is not caused by skin sagging, but rather by a hypoplasia of the dermis. Joint hyperlaxity, pseudo-athetoid movements, and hyperreflexia are observed. Inheritance is autosomal recessive; the gene in which mutation is causative is not known. Like GO, de Barsy syndrome is not associated with cardiovascular and pulmonary involvement. De Barsy syndrome is inherited in an autosomal recessive manner.

Table 2.

Disorders to Consider in the Differential Diagnosis of Cutis Laxa

Disease NameGeneOMIMMOIClinical Findings
CLEmphysemaAneurysmIDGI & GU
Malformation
ARCL1AFBLN5219100AR++++++--+
ARCL1BEFEMP2614437AR++++++--
ARCL1C (URDS)LTBP4613177AR+++++--+++
ARCL2AATP6V0A2219200AR++--++-
ARCL2BPYCR1612940AR+++-++-
ADCL1ELN123700AD+++--
ADCL2FBLN5614434AD+++--
GOGORAB231070AR+ +----
De Barsy syndrome
(ARCL3)
ALDH18A1, PYCR1219150,
614438
AR+--+++-

CL = cutis laxa

ID = intellectural disability

URDS = Urban-Rifkin-Davis syndrome

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 (MRA) from head to pelvis
  • Consultation with a medical geneticist and/or genetic counselor

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. Surgical repair of large aortic aneurysms (at risk for dissection) should be considered. Aortic aneurysm replacement has been performed successfully
  • Joint hypermobility can be supported by muscle reinforcing physical therapy.

Surveillance

The following are appropriate:

  • Regular cardiovascular and pulmonary follow up starting at birth or at the time of diagnosis
  • Annual MRA from head to pelvis

Agents/Circumstances to Avoid

Avoid the following:

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

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the EFEMP2 pathogenic variants in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

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

Pregnancy Management

No experience with pregnancy in an affected proband has been reported.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 EFEMP2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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 of an EFEMP2 pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an EFEMP2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the EFEMP2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the EFEMP2 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the EFEMP2 pathogenic variants have been identified.

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.

EFEMP2-Related Cutis Laxa: Genes and Databases

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

Table B.

OMIM Entries for EFEMP2-Related Cutis Laxa (View All in OMIM)

604633EGF-CONTAINING FIBULIN-LIKE EXTRACELLULAR MATRIX PROTEIN 2; EFEMP2
614437CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IB; ARCL1B

Gene structure. EFEMP2 has 11 exons and produces a 2002-bp long transcript, which in turn encodes a protein of 443 amino acid residues. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. See Table 3.

Pathogenic allelic variants. See Table 3.

Table 3.

Selected EFEMP2 Allelic Variants

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.775G>A 1p.Val259Ile 1NM_016938​.4
NP_058634​.4
c.1126G>A 2p.Arg409Gln 2
Pathogenicc.169G>A 3p.Glu57Lys 3
c.608A>C 4p.Asp203Ala
c.835C>T 5p.Arg279Cys 5
c.1070_1073dupCCGC 5p.Asp359fsTer360 5
c.800G>A 6p.Cys267Tyr 6
c.376G>A 7p.Glu126Lys 7
c.1189G>A 7p.Ala397Thr 7
c.377A>T 7p.Glu126Val 7
c.577delC 7p.Gln193fsTer204 7

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

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

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

Normal gene product. Fibulin-4 is a member of the fibulin family of extracellular matrix proteins. Fibulin-4 is known to associate with tropoelastin, possibly connecting elastin to microfibrils to form elastic fibers [Kobayashi et al 2007]. Fibulin-4 also binds strongly to the N-terminal region of fibrillin-1 in the presence of Ca2+ [Ono et al 2009]. Fibulin-4 can bind lysyl oxidase, an enzyme responsible for the crosslinking of elastin and collagen required for the integrity of the extracellular matrix [Horiguchi et al 2009].

Abnormal gene product. Pathogenic variants in EFEMP2 (FBLN4) impair the stability and/or secretion of fibulin-4 [Hucthagowder et al 2006], similarly to previous findings for fibulin-5 pathogenic variants [Hu et al 2006]. The resulting decrease of protein in the extracellular matrix may lead to altered interactions with fibulin-4 binding partners and, subsequently, to impaired elastogenesis. Fibulin-4 also competes with latent transforming growth factor-β (TGFβ)-binding proteins (LTBPs) for binding to fibrillin-1 [Ono et al 2009]. As such, this fibulin protein may modulate the sequestration of latent TGFβ in the extracellular matrix. Consistent with this notion, increased TGFβ signaling was found in tissues from persons with EFEMP2 pathogenic variants [Renard et al 2010] and in a murine model of fibulin-4 deficiency [Hanada et al 2007]. In addition, the resulting decrease of mutant fibulin-4 protein in the extracellular matrix may lead to defective terminal differentiation of vascular smooth muscle [Huang et al 2010].

References

Literature Cited

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  2. Dasouki M, Markova D, Garola R, Sasaki T, Charbonneau NL, Sakai LY, Chu ML. Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa. Am J Med Genet A. 2007;143A:2635–41. [PubMed: 17937443]
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Chapter Notes

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

  • 23 July 2015 (me) Comprehensive update posted live
  • 12 May 2011 (me) Review posted live
  • 9 July 2010 (bl) Original submission
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