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.

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).

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.

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.

Treatment of Manifestations

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.

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:

• If a parent of the proband is affected and/or is known to have an FBLN5 pathogenic variant, the risk to the sibs is 50%.
• If the FBLN5 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the FBLN5 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for FBLN5-related cutis laxa because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

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.

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]

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].

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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