Fbln5-Related Cutis Laxa
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 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| FBLN5 | Sequence analysis 3 | 6 families 4 |
| Gene-targeted deletion/duplication analysis 5 | See footnote 6. |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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.
Loeys et al [2002], Claus et al [2008], Callewaert et al [2013], Kantaputra et al [2014]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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
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 Name | Gene | MOI | Clinical Findings | ||||
|---|---|---|---|---|---|---|---|
| Cutis laxa | Emphysema | Aneurysms | ID | GI & GU malformations | |||
| ARCL1A 1 | FBLN5 | AR | +++ | +++ | – | – | + |
| ARCL1B | EFEMP2 | AR | ++ | ++ | +++ | – | – |
| LTBP4-related cutis laxa | LTBP4 | AR | ++ | +++ | – | – | +++ |
| ARCL2A | ATP6V0A2 | AR | ++ | – | – | ++ | – |
| ARCL2B (OMIM 612940, 614438) | PYCR1 | AR | ++ | + | – | ++ | – |
| ADCL1 (OMIM 123700) | ELN | AD | + | + | + | – | – |
| GO (OMIM 231070) | GORAB | AR | ++ | – | – | – | – |
| Cutis laxa, autosomal recessive, type IIIA (de Barsy syndrome A) (OMIM 219150) | PYCR1 2 | AR | + | – | – | +++ | – |
AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance
- 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
| System/Concern | Evaluation | Comment |
|---|---|---|
| Pulmonary |
| To evaluate for pulmonary emphysema |
| If clinical signs/symptoms of pulmonary disease | |
| Cardiovascular | Echocardiogram | Consider pulmonary vessel angiogram if clinically indicated. |
| Renal | Kidney ultrasound exam | Consider voiding cystoureterogram, given potential presence of urethral diverticula; catheterization should be done carefully. IV pyelogram may be an alternative. |
| Gastrointestinal | Exam for inguinal hernia | Barium enema if clinically indicated |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
IV = intravenous
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with FBLN5-Related Cutis Laxa
| Manifestation/Concern | Treatment |
|---|---|
| Pulmonary emphysema |
|
| Arterial abnormalities | No treatment available |
| Urinary tract infections | Antibiotic therapy |
| Inguinal hernias | Surgical repair |
| Cutis laxa | Repeat 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 EU Clinical Trials Register 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.