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, supravalvar 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.
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.
Prenatal testing is possible for a pregnancy at increased risk in families in which the pathogenic variant(s) have been identified.
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).
EMILIN1-related cutis laxa is characterized by cutis laxa and systemic involvement, including arterial tortuosity, aneurysms, bone fragility, and congenital anomalies of kidney and urinary tract [Adamo et al 2022].
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 restriction, 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
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| Disease Name | Gene | MOI | Clinical Findings |
|---|
Cutis
laxa | Emphysema | Aneurysms | ID | GI & GU
malformations |
|---|
| ARCL1A 1 |
FBLN5
| AR | +++ | +++ | – | – | + |
|
ARCL1B
|
EFEMP2
| AR | ++ | ++ | +++ | – | – |
| EMILIN1-related cutis laxa 2 |
EMILIN1
| AR | + | – | +++ | – | + |
|
LTBP4-related cutis laxa
|
LTBP4
| AR | ++ | +++ | – | – | +++ |
|
ARCL2A
|
ATP6V0A2
| AR | ++ | – | – | ++ | – |
| ARCL2B (OMIM 612940, 614438) |
PYCR1
| AR | ++ | + | – | ++ | – |
|
ADCL1
|
ELN
| AD | + | + | + | – | – |
| Geroderma osteodysplasticum (OMIM 231070) |
GORAB
| AR | ++ | – | – | – | – |
| Cutis laxa, autosomal recessive, type IIIA (de Barsy syndrome A) (OMIM 219150) | PYCR1 3 | AR | + | – | – | +++ | – |
- 1.
The subject of this GeneReview chapter
- 2.
- 3.
Pathogenic variants in PYCR1 account for a small percentage of De Barsy syndrome.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Autosomal Recessive Inheritance – Risk to Family Members
Parents of a proband
Sibs of a proband
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 Detection
Carrier testing for at-risk relatives requires prior identification of the FBLN5 pathogenic variants in the family.
Autosomal Dominant Inheritance – Risk to Family Members
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.
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 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, the parent's family members may be at risk.
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
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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.
Molecular 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 (supravalvar 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]. See ELN-Related Cutis Laxa.
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:
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
Table 5.
FBLN5 Variants Discussed in This GeneReview
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| Variant Classification | DNA Nucleotide Change (Alias 1) | Predicted Protein Change | Reference Sequences |
|---|
|
Benign
| c.1090G>T 2 | p.Asp364Tyr 2 |
NM_006329.3
NP_006320.2
|
|
Pathogenic
| c.432C>G | p.Cys144Trp |
| c.604G>A 3 | p.Gly202Arg 3 |
| c.649T>C | p.Cys217Arg |
c.679T>C 4
(T998C) | p.Ser227Pro |
| c.1171G>T | p.Glu391Ter |
c.380-9061_873dup
(380-9063_872dup22729) 5 | See footnote 6. |
NM_006329.3
|
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
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.
- 4.
- 5.
- 6.
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].
