Clinical Diagnosis

FBLN5-related cutis laxa is diagnosed in individuals with the following:

• Cutis laxa. Furrowing of the skin of the whole body that is particularly obvious in 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. Pulmonary emphysema is usually seen at an early age, including the neonatal period.
• Arterial involvement. Peripheral pulmonary artery stenosis seems to be specific for this disorder. Some affected individuals also display supravalvular aortic stenosis.
• Other evidence of a generalized connective disorder
  • Inguinal hernias
  • Hollow viscus diverticula (e.g., intestine, bladder)
  • Pyloric stenosis

Testing

Skin biopsy with orcein staining on paraffin-embedded samples

• Light microscopy. Normal or mild fragmentation and paucity/absence of elastic fibers
• Electron microscopy (EM). 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.
  
  Note: EM studies require a high level of expertise and are only available in specialized centers.

Testing Strategy

To confirm/establish the diagnosis in a proband

• The diagnosis of FBLN5-related cutis laxa is established in individuals who meet clinical diagnostic criteria and have mutations identified in FBLN5.
• Molecular genetic testing begins with sequence analysis.
• If a mutation is not identified (or in the case of autosomal recessive FBLN5-related cutis laxa, if no or only one mutation is identified), deletion/duplication analysis is considered.

Carrier testing for relatives at risk for the autosomal recessive form 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 mutation(s) in the family.

Genetically Related (Allelic) Disorders

The only other phenotype known to be associated with mutations in FBLN5 is age-related macular degeneration (AMD) [Stone et al 2004].

Natural History

In addition to cutis laxa, the most common finding in FBLN5-related cutis laxa, most affected individuals have early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder including inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). Occasionally, supravalvular aortic stenosis is observed. Intrafamilial variability in age of onset is observed.

Infections (such as pyelonephritis) secondary to vesicoureteral reflux are observed. In one individual, the bladder was described on voiding cystouretrogram as having an unusual “cauliflower” shape secondary to the presence of multiple diverticula; a similar bladder appearance has been observed in individuals with Menkes disease.

Pulmonary artery stenosis, congenital heart disease, and/or hollow viscus diverticula are likely to cause early death. Peripheral pulmonary artery stenoses lead to ventricular dilatation and contribute to progressive heart failure. Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is 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].

Autosomal recessive FBLN5-related cutis laxa. To date, five 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]. A listing of cases reported in the literature and fulfilling clinical criteria for FBLN5-related cutis laxa can be found in Appendix 1 of Van Maldergem et al [2008].

In the first family described, all six affected individuals had severe congenital cutis laxa and all but one had severe, variable pulmonary emphysema; the sixth was said to have normal chest x-rays. Ages of death ranged from six months to 21 years. Of note, the initial description of this family was expanded to include two relatives living in Western Europe and then a relative living in Turkey, who had initially been described as having Debré-type cutis laxa [Karakurt et al 2001]. The disorder in the latter individual was reclassified clinically as “pulmonary emphysema-type cutis laxa” based on his facial appearance in published photographs and then molecularly confirmed with identification of homozygosity for the same FBLN5 base pair change (T998C) observed in the remainder of the family. Subsequent genealogic studies identified a common ancestor.

In the second family, two affected children from an apparently unrelated family from Iran shared a similar clinical presentation plus supravalvular aortic stenosis. The children died at ages two years and 14 years. No common ancestor was found with the first family reported; however, homozygosity for the same base pair change (T998C) in these two children suggested identity by descent, which was supported by haplotype studies using polymorphic markers [Elahi et al 2006].

In a third family in which two children had cutis laxa, emphysema, and inguinal hernias, both children were alive at ages five and eight years [Claus et al 2008].

Two additional unpublished families, each with three affected individuals, presented with similar phenotypes [B Loeys, personal communication].

Heterozygous carriers for autosomal recessive FBLN5-related cutis laxa. To date, no evidence has shown that heterozygous carriers in these families develop AMD.

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 seems milder in clinical presentation with less internal organ involvement than the autosomal recessive form [Markova et al 2003].

Genotype-Phenotype Correlations

Mutations in FBLN5 can cause either autosomal recessive or autosomal dominant cutis laxa resulting from alterations of the microfibrillar component of elastic fibers.

• Recessive mutations entail loss of function resulting from aberrant folding and intracellular retention [Loeys et al 2002].
• An affected individual from the only reported family with autosomal dominant inheritance had an elongated, stable protein that acted in a dominant-negative manner [Markova et al 2003].
• One other 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 mutations in the context of inflammatory destruction of elastic fibers in an acquired form of cutis laxa [Hu et al 2006].

Prevalence

The prevalence at birth for all types of cutis laxa is 1:4,000,000, according to the Rhône-Alpes Eurocat registry [E Robert, personal observation].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with FBLN5-related cutis laxa, the following evaluations are recommended:

• Chest roentgenogram
• Echocardiogram
• Kidney ultrasound examination
• Genetics consultation

If clinically indicated:

• Pulmonary vessel angiogram
• Barium enema
• Voiding cystouretrogram (VCUG)

Treatment of Manifestations

Appropriate treatment for:

• Inguinal hernias. Routine repair
• Cutis laxa. Repeat plastic surgery of the face and trunk as needed
• Pulmonary emphysema. Symptomatic treatment
• Arterial abnormalities. No treatment available

Prevention of Secondary Complications

The following are appropriate:

• Attention to respiratory function prior to surgery
• Prophylactic antibiotics (cotrimoxazole) in case of vesicoureteral reflux

Surveillance

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

Agents/Circumstances to Avoid

Smoking is contraindicated; however, the limited life span of affected individuals makes this recommendation mostly theoretical.

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 for this disorder.

Mode of Inheritance

FBLN5-related cutis laxa can be inherited in an autosomal recessive or autosomal dominant manner. Autosomal recessive inheritance is more common.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry 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. Individuals with autosomal recessive FBLN5-related cutis laxa have not been reported to reproduce. If they were to reproduce, their offspring would be obligate heterozygotes (carriers) for a disease-causing mutation.

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

Carrier Detection

Carrier testing of at-risk relatives is possible if the disease-causing FBLN5 mutations have been identified 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.
• A proband with autosomal dominant FBLN5-related cutis laxa may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a dermatologic examination and molecular genetic testing for the mutation identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of 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 genetic status of the proband’s parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent.

Offspring of a proband. Each child of an individual with autosomal dominant cutis laxa has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, 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, 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 mutation(s) in the family must have been 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 some families in which the disease-causing mutations have been identified.

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) which 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 mutations cause alterations that primarily affect the vasculature (supravalvular aortic stenosis) and only minimally affect the skin. In autosomal dominant cutis laxa, ELN mutations are mostly confined to the 3’ end of the gene [Metcalfe et al 2000]. These mutations result in secretion of abnormal tropoelastin molecules that interfere with elastic fiber assembly in a dominant-negative fashion [Zhang et al 1999].

Mutations in FBLN5 can cause either dominant or recessive cutis laxa resulting from alterations of the microfibrillar component of the elastic fibers. The dominant mutations 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 mutations 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 mutations 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 mutations 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.

Normal allelic variants. (See Table 3.) FBLN5 consists of 13 exons that are differentially combined in three major transcripts. The only annotated nonsynonymous coding normal variant in FBLN5 resides in exon 10 and leads to a p.Asp364Tyr change.

Pathologic allelic variants. (See Table 3.)

• Autosomal recessive FBLN5-related cutis laxa: p.Cys217Arg (in 2 families), p.Ser227Pro (in 2 likely related families), p.Gly202Arg, and p.Glu391* [Loeys, personal communication]
• Autosomal dominant FBLN5-related cutis laxa: a 22,729-bp duplication comprising all of exons 5 to 8 and the first 9 bp of exon 9 [Markova et al 2003]

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. The same applies to fibulin-4, encoded by FBLN4 (EFEMP2), except that fibulin-4 does not contain an RGD-motif.

Abnormal gene product. Autosomal recessive mutations in FBLN5 result in intracellular retention of the misfolded protein [Hu et al 2006], resulting in a loss of function. Autosomal dominant mutations lead to an elongation of the protein that is stable and can act in a dominant-negative manner [Markova et al 2003].

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Acknowledgments

We thank the families for their participation.

Revision History

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