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FBLN5-Related Cutis Laxa

, MD, PhD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: August 16, 2018.

Summary

Clinical characteristics.

FBLN5-related cutis laxa 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.

Diagnosis/testing.

The diagnosis of FBLN5-related cutis laxa is established in a proband with the characteristic clinical features and identification of biallelic pathogenic variants in FBLN5 (autosomal recessive FBLN5-related cutis laxa) or a heterozygous pathogenic variant in FBLN5 (autosomal dominant FBLN5-related cutis laxa) by molecular genetic testing.

Management.

Treatment of manifestations: Symptomatic treatment of pulmonary emphysema; antibiotics for urinary tract infections; routine repair of inguinal hernias; repeat plastic surgery of the face and trunk as needed.

Prevention of secondary complications: Attention to respiratory function prior to surgery; prophylactic antibiotics as needed for vesicoureteral reflux; immunizations against respiratory viruses.

Surveillance: Routine surveillance of the urinary tract for evidence of bladder diverticula and/or vesicoureteral reflux.

Agents/circumstances to avoid: Smoking; positive pressure ventilation unless needed to treat life-threatening conditions; isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain; exposure to respiratory infections.

Genetic counseling.

FBLN5-related cutis laxa can be inherited in an autosomal recessive or (less commonly) autosomal dominant manner.

Autosomal recessive inheritance: 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.

Autosomal dominant inheritance: Each child of an individual with autosomal dominant cutis laxa has a 50% chance of inheriting the pathogenic variant.

Prenatal testing is possible for pregnancies at increased risk in families in which the pathogenic variant(s) have been identified.

Diagnosis

Suggestive Findings

FBLN5-related cutis laxa should be suspected in individuals with the following clinical features:

  • Cutis laxa
  • Pulmonary emphysema
  • Arterial involvement (e.g., peripheral pulmonary artery stenosis, supravalvular aortic stenosis)
  • Inguinal hernias
  • Hollow viscus diverticula (e.g., intestine, bladder)
  • Pyloric stenosis

Establishing the Diagnosis

The diagnosis of FBLN5-related cutis laxa is established in a proband with the above Suggestive Findings and by identification of biallelic pathogenic variants in FBLN5 (autosomal recessive FBLN5-related cutis laxa) or a heterozygous pathogenic variant in FBLN5 (autosomal dominant FBLN5-related cutis laxa) on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FBLN5-related cutis laxa is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of FBLN5-related cutis laxa has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of FBLN5-related cutis laxa molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of FBLN5 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
    Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • A multigene panel that includes FBLN5 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.

Option 2

When the diagnosis of FBLN5-related cutis laxa is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. 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.

Table 1.

Molecular Genetic Testing Used in FBLN5-Related Cutis Laxa

Gene 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
FBLN5Sequence analysis 36 families 4
Gene-targeted deletion/duplication analysis 5See footnote 6
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.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used 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.

6.

Duplication reported in one individual with autosomal dominant inheritance [Markova et al 2003]; see Table 5. No exon or whole-gene deletions or duplications are known to cause the autosomal recessive form of the disease.

Clinical Characteristics

Clinical Description

Autosomal recessive FBLN5-related cutis laxa. To date, six families with autosomal recessive FBLN5-related cutis laxa have been described [Van Maldergem et al 1988, Karakurt et al 2001, Loeys et al 2002, Pour-Jafari & Sahiri 2004, Claus et al 2008, Callewaert et al 2013, Kantaputra et al 2014]. Intrafamilial variability in age of onset is observed.

Cutis laxa. The most common finding in FBLN5-related cutis laxa is described as furrowing of the skin of the whole body that is particularly obvious in the neck, axillae, and groin. The face has a "droopy" appearance with eyelid ptosis and drooping cheeks. When one tries to extend the skin, it does not display hyperelasticity as in the Ehlers-Danlos syndromes, but rather keeps its consistency.

Pulmonary emphysema. Most affected individuals have early childhood-onset pulmonary emphysema, and some individuals have presented with emphysema during the neonatal period. Two affected siblings reported by Van Maldergem et al [1988] had recurrent pneumonias.

Arterial involvement. Peripheral pulmonary artery stenosis appears to be specific for this disorder. Peripheral pulmonary artery stenosis leads to ventricular dilatation and contributes to progressive heart failure. Supravalvular aortic stenosis was reported in two related children from Iran who died at ages two years and 14 years [Elahi et al 2006]. Aortic valve dysplasia (stenosis and regurgitation) was reported in one affected child of Lebanese ancestry [Callewaert et al 2013].

Other evidence of a generalized connective disorder including inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). In one individual, the bladder was described on voiding cystoureterogram as having an unusual "cauliflower" shape secondary to the presence of multiple diverticula. In a Lebanese family, all three affected siblings homozygous for missense variant c.649T>C underwent surgery in the first months of life for pyloric stenosis [Callewaert et al 2013].

Infections secondary to vesicoureteral reflux (e.g., pyelonephritis) are observed. Urinary tract candidiasis with "fungus balls" have been observed on renal ultrasound [Author, personal communication].

Prognosis. Pulmonary artery stenosis, congenital heart disease, and/or hollow viscus diverticula are likely to cause early death, with cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) being the most common cause of death. For those who survive early childhood, pulmonary emphysema, cor pulmonale, and multiple surgeries are the rule. Prolonged survival is exceptional; the oldest known person with this disorder was a high-functioning young woman who died at age 21 years from cor pulmonale.

Hip dislocation is not observed in FBLN5-related cutis laxa.

Intelligence is normal [Van Maldergem et al 1988].

Note: To date, no heterozygous carriers for autosomal recessive FBLN5-related cutis laxa have developed age-related macular degeneration.

Skin histology. Skin biopsy with orcein staining on paraffin-embedded samples on light microscopy shows normal or mild fragmentation and paucity/absence of elastic fibers.

Electron microscopy (EM) shows paucity of elastic fibers with accumulation of elastin (ELN) globules, reflecting lack of assembly of the primary components of elastic fibers [Ledoux-Corbusier 1983]. These findings are in contrast to those of Debré-type cutis laxa (see ATP6V0A2-Related Cutis Laxa) and De Barsy syndrome (see Differential Diagnosis), in which a sparse elastic network, but not defective assembly of ELN fibers, is observed. Because deficiency of other proteins or cofactors involved in the process of elastic fiber assembly could potentially give the same ultrastructural picture, it is not known whether this feature is specific for FBLN5-related cutis laxa. EM studies require a high level of expertise and are only available in specialized centers.

Autosomal dominant FBLN5-related cutis laxa. Based on the description of the only family reported to date to have demonstrated autosomal dominant inheritance, this form appears to be milder in clinical presentation with less internal organ involvement than the autosomal recessive form [Markova et al 2003].

Genotype-Phenotype Correlations

Due to the small number of individuals with FBLN5-related cutis laxa reported in the literature, reliable data on genotype-phenotype correlations are lacking.

Of note, one individual who was heterozygous for an inherited FBLN5 allele (p.Gly202Arg) and compound heterozygous for ELN alleles has been reported. It was hypothesized that the FBLN5 allele modified the phenotype caused by the ELN pathogenic variants in the context of inflammatory destruction of elastic fibers in an acquired form of cutis laxa [Hu et al 2006].

Prevalence

The prevalence is unknown, with only six families reported to date.

Differential Diagnosis

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

EFEMP2-related cutis laxa (ARCL1B). EFEMP2-related cutis laxa 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. The cutis laxa and emphysema are similar in FBLN4- or FBLN5-related cutis laxa; however, to date, the diaphragmatic changes and arterial aneurysms seem more predominant 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 fontanelle 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 that distinguish FBLN5-related cutis laxa from ARCL2A are absence of intellectual disability, hip dislocation, and delayed closure of the fontanelle. In individuals with ARCL2A, EM findings of skin biopsy, rarefaction of ELN fibers composed of ELN and elastofibrils, and abnormal serum transferrin isoelectrofocusing may help confirm the diagnosis.

ELN-related cutis laxa (ADCL1) 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 (so-called cystic media degeneration) is indistinguishable from that of Marfan syndrome. It remains to be seen whether pathogenic variants in ELN are associated with heritable thoracic aortic disease (HTAD).

Gerodermia osteodysplastica (GO). Onset occurs in infancy or early childhood [Nanda et al 2008]. Children appear older than their age as a result of sagging cheeks and jaw hypoplasia. Skin wrinkling is less severe 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. 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. Mental development is in the normal range. In contrast to Debré-type cutis laxa, fontanelle size and closure are normal, positioning of the palpebral fissures is normal, and disease manifestations do not become milder with age. Pathogenic variants in GORAB are causative [Hennies et al 2008].

Cutis laxa, autosomal recessive, type IIIA (or de Barsy syndrome A) 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, pseudoathetoid movements, and hyperreflexia are observed. Inheritance is autosomal recessive, with the exception of PYCR1 (pathogenic variants in which account for a small percentage of this syndrome). Further molecular characterization is needed.

LTBP4-related cutis laxa is characterized by a cutaneous phenotype similar to that of FBLN5-related cutis laxa and by severe multiple malformations including congenital heart disease, pulmonary arterial stenosis, and, interestingly, pulmonary hypertension. The latter appears to be a distinctive feature as it was observed in two individuals in the authors' series. Bladder diverticulae, noticeably absent in the other entities discussed in this section, have also been described.

Table 2.

Disorders to Consider in the Differential Diagnosis of Cutis Laxa

Disease NameGeneMOIClinical Findings
Cutis
laxa
EmphysemaAneurysmsIDGI & GU
malformations
ARCL1A 1FBLN5AR+++++++
ARCL1BEFEMP2AR+++++++
LTBP4-related cutis laxaLTBP4AR++++++++
ARCL2AATP6V0A2AR++++
ARCL2B (OMIM 612940, 614438)PYCR1AR+++++
ADCL1 (OMIM 123700)ELNAD+++
GO (OMIM 231070)GORABAR++
Cutis laxa, autosomal recessive, type IIIA (de Barsy syndrome A) (OMIM 219150)PYCR1 2AR++++

ID = intellectual disability

1.

i.e., autosomal recessive FBLN5-related cutis laxa

2.

Pathogenic variants in PYCR1 account for a small percentage of De Barsy syndrome.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FBLN5-related cutis laxa, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with FBLN5-Related Cutis Laxa

Organ SystemEvaluationComment
Pulmonary
  • Chest roentgenogram
  • Chest CT examination
To evaluate for pulmonary emphysema
  • Pulmonary function testing
  • Evaluation w/pulmonologist
If the individual has clinical signs/symptoms of pulmonary disease
CardiovascularEchocardiogramConsider pulmonary vessel angiogram if clinically indicated.
RenalKidney ultrasound examinationConsider voiding cystoureterogram, given the potential presence of urethral diverticula; catheterization should be done carefully. Intravenous pyelogram may be an alternative.
GastrointestinalExamination for inguinal herniaBarium enema if clinically indicated
OtherConsultation w/clinical geneticist &/or genetic counselor

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with FBLN5-Related Cutis Laxa

ManifestationTreatment
Pulmonary emphysema
  • Symptomatic treatment w/inhaled corticosteroids, atropine, & selective β2-adrenergic bronchodilation
  • Oxygen supplementation if necessary
Arterial abnormalitiesNo treatment available
Urinary tract infectionsAntibiotic therapy
Inguinal herniasSurgical repair
Cutis laxaRepeat plastic surgery of the face and trunk as needed

Prevention of Secondary Complications

The following are appropriate:

  • Attention to respiratory function prior to surgery
  • Prophylactic antibiotics (cotrimoxazole) in individuals with vesicoureteral reflux
  • Immunization against respiratory infections (influenza, Streptococcus pneumonia, Haemophilus influenza)
  • Consideration of passive immunization for respiratory syncytial virus (RSV) with palivizumab during the RSV season

Surveillance

Routine surveillance of the urinary tract for evidence of bladder diverticula and/or vesicoureteral reflux is indicated.

Agents/Circumstances to Avoid

Avoid the following:

  • Smoking; however, the limited life span of affected individuals makes this recommendation mostly theoretic.
  • Positive pressure ventilation unless needed to treat life-threatening conditions
  • Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
  • People with respiratory infections

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 in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for 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

FBLN5-related cutis laxa can be inherited in an autosomal recessive or (less commonly) autosomal dominant manner.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one FBLN5 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with autosomal recessive FBLN5-related cutis laxa are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an FBLN5 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the FBLN5 pathogenic variants in the family.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • Rare individuals diagnosed with autosomal dominant FBLN5-related cutis laxa have an affected parent.
  • An individual diagnosed with autosomal dominant FBLN5-related cutis laxa may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown but is presumed to be high.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include a dermatologic examination and molecular genetic testing for the pathogenic variant identified in the proband.
  • The family history of some individuals diagnosed with autosomal dominant FBLN5-related cutis laxa may appear to be negative because of reduced penetrance or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with autosomal dominant cutis laxa has a 50% chance of inheriting the 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 FBLN5 pathogenic variant, his or her family members may be at risk.

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

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the FBLN5 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for FBLN5-related cutis laxa are possible.

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.

FBLN5-Related Cutis Laxa: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FBLN514q32​.12Fibulin-5FBLN5 databaseFBLN5FBLN5

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

Table B.

OMIM Entries for FBLN5-Related Cutis Laxa (View All in OMIM)

219100CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IA; ARCL1A
604580FIBULIN 5; FBLN5
614434CUTIS LAXA, AUTOSOMAL DOMINANT 2; ADCL2

Molecular Genetic Pathogenesis

Independent of the underlying molecular pathophysiology, all types of cutis laxa are characterized by alterations of elastic fibers, not collagen. In ultrastructural investigations elastic fibers are reduced in number and often appear fragmented.

The assembly of elastic fibers, a complex mechanism, takes place in the extracellular space. According to the currently accepted model, microfibrillar proteins like the fibrillins first form a lattice with fibulins into which secreted tropoelastin is deposited and then further processed [Kielty 2006]. Enzymes necessary for the conversion of tropoelastin into ELN are the lysyl oxidases, a group of copper-dependent enzymes (deficient in secondary cutis laxa associated with treatment with copper chelators like penicillamine) that form covalent crosslinks between ELN molecules. Elastic fibers not only increase the elasticity of the extracellular matrix, but also influence its architecture and regulate TGFβ-signaling.

When tropoelastin expression is insufficient, the generation of elastic fibers is disturbed. This explains why heterozygous loss-of-function ELN pathogenic variants cause alterations that primarily affect the vasculature (supravalvular aortic stenosis) and only minimally affect the skin. In autosomal dominant cutis laxa, ELN pathogenic variants are mostly confined to the 3' end of the gene [Metcalfe et al 2000]. These variants result in secretion of abnormal tropoelastin molecules that interfere with elastic fiber assembly in a dominant-negative fashion [Zhang et al 1999].

Pathogenic variants in FBLN5 can cause either dominant or recessive cutis laxa resulting from alterations of the microfibrillar component of the elastic fibers. The dominant pathogenic variants lead to an elongation of the protein that is stable and can act in a dominant-negative manner [Markova et al 2003], whereas the recessive pathogenic variants entail loss of function as a result of aberrant folding and intracellular retention [Loeys et al 2002, Hu et al 2006]. The same applies to recessive pathogenic variants in FBLN4 (EFEMP2) [Hucthagowder et al 2006] (see EFEMP2-Related Cutis Laxa).

A more complex mechanism underlies autosomal recessive cutis laxa, Debré type (ARCL2A) (see ATP6V0A2-Related Cutis Laxa). Here, the loss-of-function variants do not affect an extracellular matrix protein, but a subunit of a v-type H+-ATPase that resides in endosomes as well as in the Golgi compartment [Hurtado-Lorenzo et al 2006, Pietrement et al 2006]. Proton pumps are universally expressed and allow pH regulation in the extracellular space and in many subcellular compartments [Forgac 2007]. In addition, there are indications that a subunit of the proton pump complex is directly involved in vesicle fusion [Peters et al 2001]. The following two lines of evidence suggest that a defect of the secretory pathway is the basis of the elastic fiber defect in ARCL2A:

  • Patients show a glycosylation defect, which can be detected by isoelectrofocusing (IEF) of serum transferrins [Morava et al 2005, Kornak et al 2008, Van Maldergem et al 2008].
  • Patient cells display a delay of Golgi-to-ER trafficking. It is unknown whether the glycosylation defect impairs the function of a protein involved in the formation of elastic fibers or if it is just an epiphenomenon caused by a secretion defect also involving elastic fiber components.

Gene structure. FBLN5 consists of 13 exons that are differentially combined in three major transcripts. The primary transcript is NM_006329.3. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. See Table 5. The only annotated nonsynonymous coding normal variant in FBLN5 resides in exon 10 and leads to a p.Asp364Tyr change.

Pathogenic variants. See Table 5.

  • Autosomal recessive FBLN5-related cutis laxa: p.Cys144Trp, p.Cys217Arg (in 2 families), p.Ser227Pro (in 2 likely related families), and p.Glu391Ter
  • Autosomal dominant FBLN5-related cutis laxa: a 22,729-bp duplication (c.380-9061_873dup) spanning exons 5 to 8 and the first 9 bp of exon 9 [Markova et al 2003]

Table 5.

FBLN5 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide Change (Alias 1)Predicted Protein ChangeReference Sequences
Benignc.1090G>T 2p.Asp364Tyr 2NM_006329​.3
NP_006320​.2
Pathogenicc.432C>Gp.Cys144Trp
c.604G>A 3p.Gly202Arg 3
c.649T>Cp.Cys217Arg
c.679T>C 4
(T998C)
p.Ser227Pro
c.1171G>Tp.Glu391Ter
c​.380-9061_873dup
(380-9063_872dup22729) 5
See footnote 6

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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.
3.

One of three variant alleles of different genes thought to result in an acquired form of cutis laxa [Hu et al 2006] (see Genotype/Phenotype Correlations)

4.

Variant nomenclature described in Elahi et al [2006]

5.

Duplication of 22,729 nucleotides from intron 4 to exon 9 [Markova et al 2003]. The genomic coordinates are NG_008254​.1:g.48570_71295dup22726.

6.

Duplication results in a larger transcript with a tandem duplication of 483 nucleotides that translates to a tandem duplication of four cbEGF motifs in the protein product [Markova et al 2003]. This is the only pathogenic variant known to cause the autosomal dominant form of the disease.

Normal gene product. Fibulin-5, the protein encoded by FBLN5, is an extracellular matrix protein involved in the formation of the microfibrillar scaffold of the elastic fibers. It contains calcium-binding EGF-like repeats and an RGD-motif and is approximately 55 kd in size.

Abnormal gene product. Autosomal recessive variants in FBLN5 result in intracellular retention of the misfolded protein [Hu et al 2006] and matrix deposition. Additionally, these pathogenic variants show decreased affinity for tropoelastin [Hu et al 2006]. The single known autosomal dominant variant leads to an elongation of the protein that is stable and can act in a dominant-negative manner [Markova et al 2003].

References

Literature Cited

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  • Claus S, Fischer J, Mégarbané H, Mégarbané A, Jobard F, Debret R, Peyrol S, Saker S, Devillers M, Sommer P, Damour O. A p.C217R mutation in fibulin-5 from cutis laxa patients is associated with incomplete extracellular matrix formation in a skin equivalent model. J Invest Dermatol. 2008;128:1442–50. [PubMed: 18185537]
  • Elahi E, Kalhor R, Banihosseini SS, Torabi N, Pour-Jafari H, Houshmand M, Amini SS, Ramezani A, Loeys B. Homozygous missense mutation in fibulin-5 in an Iranian autosomal recessive cutis laxa pedigree and associated haplotype. J Invest Dermatol. 2006;126:1506–9. [PubMed: 16691202]
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Chapter Notes

Acknowledgments

We thank the families for their participation.

Revision History

  • 16 August 2018 (sw) Comprehensive update posted live
  • 13 March 2014 (me) Comprehensive update posted live
  • 13 October 2011 (me) Comprehensive update posted live
  • 19 March 2009 (et) Review posted live
  • 10 September 2008 (lvm) Original submission
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