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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: .

Summary

Disease characteristics. EFEMP2-related cutis laxa (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. Mutations 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.

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

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 disease-causing mutations have been identified in the family.

Diagnosis

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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
EFEMP2Sequence analysisSequence variants 4>95%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

4. 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.

Clinical Description

Natural History

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. All features present in at least two affected individuals are shown in Table 2.

Table 2. Clinical Manifestations of Persons with EFEMP2-Related Cutis Laxa

FindingPatient
123456
Cutis laxa++++/- 1--
Retrognathia?+++--
Ocular hypertelorism???-++
Highly arched palate???++-
Dysplastic ears--+--+
Arterial tortuosity++++++
Aortic aneurysm++?+++
Pulmonary arterial hypoplasia-+?+--
Cardiac hypertrophy-++---
Bradycardia-++???
Cerebral atrophy, stroke??+??+
Developmental emphysema+?+---
Diaphragmatic hernia/hypoplasia+?+???
Oligohydramnios+-+???
Joint laxity+?+++-
Arachnodactyly+++--+
Pectus excavatum+??-+-
Fractures+-+---
Age at death (months)-10--18
ReferenceHucthagowder et al [2006]Dasouki et al [2007]Hoyer et al [2009]Renard et al [2010]Renard et al [2010]Renard et al [2010]

? = no information

1. Velvety skin

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].

Differential Diagnosis

Other disorders characterized by cutis laxa are summarized in Table 3.

FBLN5-related cutis laxa (ARCL1A) 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. Occasionally supravalvular aortic stenosis is observed. Rarely, diverticulae of hollow viscera have been described. 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. Inheritance is autosomal recessive.

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 associated with severe developmental and neurologic abnormalities including seizures. Clinical features of ARCL2A that are 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.

ELN-related cutis laxa (ADCL) was historically considered a strictly cutaneous disorder without systemic involvement; however, it is now known that persons with ELN mutations 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 ADCL: arterial tortuosity, infantile aneurysms, infantile developmental emphysema, death in infancy or early childhood, arachnodactyly, and retrognathia.

Gerodermia osteodysplastica (GO). 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. Mutations in SCYL1BP1 are causative [Hennies et al 2008]. Unlike EFEMP2-related cutis laxa, GO is generally not associated with cardiovascular and pulmonary manifestations.

De Barsy syndrome 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 causative gene is not known. Like GO, de Barsy syndrome is not associated with cardiovascular and pulmonary involvement.

Table 3. Disorders to Consider in the Differential Diagnosis of Cutis Laxa

Disease NameGene SymbolOMIM #InheritanceClinical Findings
Cutis Laxa EmphysemaAneurysmsIntellectual disabilityGI and GU Malformations
ARCL1A FBLN5219100AR ++++++--+
ARCL1BEFEMP2614437AR+++++++--
ARCL1C URDSLTBP4613177AR+++++--+++
ARCL2AATP6V0A2219200AR++--++-
ARCL2BPYCR1612940AR+++-++-
ADCLELN or FBLN5123700AD+++--
GOSCYL1BP1231070AR+ +----
De Barsy syndromeUnknown219150AR+--+++-

Management

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.

Evaluation 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.

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 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.

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 an option for families in which the disease-causing mutations 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.

No specific resources for EFEMP2-Related Cutis Laxa have been identified by GeneReviews staff.

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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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 Symbol.

Pathogenic allelic variants. See Table 4.

Table 4. Selected EFEMP2 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change Protein 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 author(s). 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. rs601314

2. rs61893867

3. Hucthagowder et al 2006]

4. Nampoothiri et al [2010]

5. Dasouki et al [2007]

6. Hoyer et al [2009]

7. Renard et al [2010]

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. Mutations in EFEMP2 (FBLN4) impair the stability and/or secretion of fibulin-4 [Hucthagowder et al 2006], similarly to previous findings for fibulin-5 mutations [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 mutations [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, as recently shown [Huang et al 2010].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. 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]
  2. Guerra D, Fornieri C, Bacchelli B, Lugli L, Torelli P, Balli F, Ferrari P. The De Barsy syndrome. J Cutan Pathol. 2004;31:616–24. [PubMed: 15330994]
  3. Hanada K, Vermeij M, Garinis GA, de Waard MC, Kunen MG, Myers L, Maas A, Duncker DJ, Meijers C, Dietz HC, Kanaar R, Essers J. Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice. Circ Res. 2007;100:738–46. [PubMed: 17293478]
  4. Hennies HC, Kornak U, Zhang H, Egerer J, Zhang X, Seifert W, Kühnisch J, Budde B, Nätebus M, Brancati F, Wilcox WR, Müller D, Kaplan PB, Rajab A, Zampino G, Fodale V, Dallapiccola B, Newman W, Metcalfe K, Clayton-Smith J, Tassabehji M, Steinmann B, Barr FA, Nürnberg P, Wieacker P, Mundlos S. Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin. Nat Genet. 2008;40:1410–2. [PMC free article: PMC3122266] [PubMed: 18997784]
  5. Horiguchi M, Inoue T, Ohbayashi T, Hirai M, Noda K, Marmorstein LY, Yabe D, Takagi K, Akama TO, Kita T, Kimura T, Nakamura T. Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. Proc Natl Acad Sci U S A. 2009;106:19029–34. [PMC free article: PMC2776456] [PubMed: 19855011]
  6. Hoyer J, Kraus C, Hammersen G, Geppert JP, Rauch A. Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin-4 gene mutation. Clin Genet. 2009;76:276–81. [PubMed: 19664000]
  7. Hu Q, Loeys BL, Coucke PJ, De Paepe A, Mecham RP, Choi J, Davis EC, Urban Z. Fibulin-5 mutations: mechanisms of impaired elastic fiber formation in recessive cutis laxa. Hum Mol Genet. 2006;15:3379–86. [PubMed: 17035250]
  8. Huang J, Davis EC, Chapman SL, Budatha M, Marmorstein LY, Word RA, Yanagisawa H. Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ Res. 2010;106:583–92. [PMC free article: PMC2826613] [PubMed: 20019329]
  9. Hucthagowder V, Sausgruber N, Kim KH, Angle B, Marmorstein LY, Urban Z. Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet. 2006;78:1075–80. [PMC free article: PMC1474103] [PubMed: 16685658]
  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.
  12. Ono RN, Sengle G, Charbonneau NL, Carlberg V, Bächinger HP, Sasaki T, Lee-Arteaga S, Zilberberg L, Rifkin DB, Ramirez F, Chu ML, Sakai LY. Latent transforming growth factor beta-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites. J Biol Chem. 2009;284:16872–81. [PMC free article: PMC2719323] [PubMed: 19349279]
  13. Renard M, Holm T, Veith R, Callewaert BL, Adès LC, Baspinar O, Pickart A, Dasouki M, Hoyer J, Rauch A, Trapane P, Earing MG, Coucke PJ, Sakai LY, Dietz HC, De Paepe AM, Loeys BL. Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. Eur J Hum Genet. 2010;18:895–901. [PMC free article: PMC2987390] [PubMed: 20389311]
  14. 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]
  15. 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]

Chapter Notes

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
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