Ltbp4-Related Cutis Laxa
Summary
Clinical characteristics.
LTBP4-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 visceral diverticula (e.g., intestine, bladder). Other manifestations can include diaphragmatic hernia, congenital heart disease, intestinal malrotation, and ectopic kidneys. Of the 17 affected individuals (from 13 families) reported to date, cutis laxa was evident from birth in most and pulmonary emphysema was present in all. Pulmonary emphysema is clinically evident during the first months of life, is often severe, and is the most common cause of death. Bladder diverticula and hydronephrosis are common.
Diagnosis/testing.
The diagnosis of LTBP4-related cutis laxa is established in a proband with cutis laxa and biallelic pathogenic variants in LTBP4.
Management.
Treatment of manifestations: Treatment is largely symptomatic and may include: routine treatment of pulmonary emphysema (inhaled corticosteroids, atropine, and selective β2-adrenergic bronchodilation, and supplemental oxygen as needed) and gastroesophageal reflux; education on complete bladder emptying when voiding; and treatment of clinically relevant pulmonary artery stenosis and pulmonary hypertension.
Prevention of secondary complications: Routine immunizations against respiratory infections.
Surveillance: Routine assessment of pulmonary function and oxygenation and repeat imaging of the GI tract, urinary tract, and cardiovascular system.
Agents/circumstances to avoid: 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 people with respiratory infections.
Genetic counseling.
LTBP4-related cutis laxa is inherited in an autosomal recessive manner. 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. Carrier testing for at-risk relatives and prenatal testing or preimplantation genetic testing for pregnancies at increased risk are possible if the LTBP4 pathogenic variants in the family are known.
Diagnosis
No formal clinical diagnostic criteria have been established for LTBP4-related cutis laxa.
Suggestive Findings
LTBP4-related cutis laxa should be suspected in individuals with loose redundant skin folds (cutis laxa) and various internal organ involvement including pulmonary emphysema and gastrointestinal and/or urinary tract diverticula.
The following major clinical findings and the rest of this GeneReview are based on the three reports published on LTBP4-related cutis laxa [Urban et al 2009, Callewaert et al 2013, Su et al 2015].
Skin
- Loose redundant skin folds, mainly on the trunk and limbs with variable involvement of the facial skin resulting in a droopy and puffy face giving a prematurely aged appearance. Rarely, the skin can be mainly hyperextensible instead of lax.
- Thin skin with prominent veins
Pulmonary
- Emphysema: variable but is mostly congenital or early-onset and progressive; may clinically manifest as respiratory distress or hypoxia; may be evident on routine x-rays or lung CT
- Laryngomalacia, tracheomalacia, bronchomalacia
- Bronchiolitis: may be severe and result in progression of emphysematous lesions
Gastrointestinal
- Diverticula throughout the gastrointestinal tract
- Gastrointestinal tract dilatations
- Elongated gastrointestinal tract resulting in tortuosity
- Perforation of the stomach or intestine
- Gastroesophageal reflux
- Rectal prolapse
- Pyloric stenosis
Genitourinary
- Bladder diverticula and rupture
- Hydronephrosis
- Urinary tract infections (secondary to anatomic abnormalities of the urinary tract)
Cardiovascular
- Peripheral pulmonary artery stenosis
- Atrial septal defects and atrial septal aneurysms
- Cardiac valve insufficiency (mitral, tricuspid, aortic)
- Pulmonary and aortic valve stenosis
- Pulmonary hypertension
Craniofacial
- Sagging skin with prominent sagging cheeks
- Sparse hair, especially temporally
- Sloping forehead
- Narrow forehead
- Periorbital fullness
- Epicanthus
- Depressed nasal bridge
- Anteverted nares
- Long philtrum
- Micrognathia
- Large ears
Other
- Inguinal and umbilical hernias
- Sliding and diaphragmatic hernias or diaphragmatic eventration
- Muscular hypotonia
- Joint laxity
Establishing the Diagnosis
The diagnosis of LTBP4-related cutis laxa is established in a proband with cutis laxa and biallelic pathogenic variants in LTBP4 (see Table 1).
It is appropriate to perform molecular analysis of LTBP4 in individuals with all of the following:
- Cutis laxa or hyperextensible skin
- Pulmonary emphysema
- Gastrointestinal and/or bladder diverticula
Molecular genetic testing approaches can include:
- Sequence analysis of LTBP4 followed by deletion/duplication analysis if only one or no pathogenic variant is found. Note: To date, no large intragenic deletions have been reported in affected individuals.
- Use of a multigene panel that includes LTBP4 and other genes of interest (see Differential Diagnosis). 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; thus, clinicians need to determine which multigene panel 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. (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.
Table 1.
Molecular Genetic Testing Used in LTBP4-Related Cutis Laxa
| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| LTBP4 | Sequence analysis 3 | 17/17 4 |
| Gene-targeted deletion/duplication analysis 4 | Unknown; none reported to date |
- 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. 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.
Urban et al [2009], Callewaert et al [2013], Su et al [2015]
- 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.
Clinical Characteristics
Differential Diagnosis
Disorders to consider in the differential diagnosis of LTBP4-related cutis laxa are summarized in Table 2 and discussed below.
Table 2.
Disorders to Consider in the Differential Diagnosis of LTBP4-Related Cutis Laxa
| Finding | Disorder | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| ARCL1A | ARCL1B | ARCL1C | ADCL | ARCL2A ARCL2B | ARCL3A ARCL3B | Progeroid ADCL | XLCL | ATS | |
| Gene(s) | FBLN5 | EFEMP2 | LTBP4 | ELN | ATP6V0A2 PYCR1 | ALDH18A1 PYCR1 | ALDH18A1 | ATP7A | SLC2A10 |
| Skin | Redundant | Hyper- extensible > redundant | Redundant | Redundant > hyper- extensible | Wrinkled > redundant | Wrinkled, thin | Wrinkled, thin | Wrinkled | Hyper- extensible > redundant |
| Emphysema | +++ | + | +++ | ++ | No | No | No | No | No |
| Cardiovascular | Arterial stenoses | Arterial tortuosity/ aneurysms | Arterial stenosis, septal defects | ARD | - | Arterial stenoses, ICA malformed | ICA tortuosity | ICA tortuosity | Arterial tortuosity |
| Hiatal/ diaphragmatic hernias | + | + | +++ | + | + | No | No | + | ++ |
| Bladder diverticula | ++ | + | +++ | + | + | No | No | +++ | + |
| GI diverticula | No | No | +++ | No | No | No | No | No | No |
| IUGR | No | No | + | No | ++ | +++ | ++ | No | No |
| Postnatal growth delay | + | ++ | ++ | No | +++ | +++ | ++ | + | No |
| Congenital hip dislocation | No | + | No | No | +++ | ++ | ++ | No | No |
| Osteoporosis, bone fragility | No | ++ | No | No | N/A | N/A | N/A | ++ | No |
| Scoliosis | No | + | No | No | ++ | ++ | ++ | ++ | ++ |
| Delayed anterior fontanelle closure | No | No | + | No | +++ | ++ | ++ | ++ | No |
| Microcephaly | No | No | No | No | +++ | +++ | ++ | + | No |
| Intellectual disability | No | No | No | No | ++ | +++ | ++ | ++ | No |
| Brain malformations | No | No | No | No | Cobblestone gyri (ATP6V0A2) CCA (PYCR1) | CCA | + | No | No |
| Athetoid movements | No | No | No | No | No | +++ | + | No | No |
| Corneal opacification / cataract | No | No | No | No | No | +++ | +++ | No | No |
| Other | Glycosylation defects | Brisk reflexes | Bony exostoses (>occipital) | ||||||
Features characteristic for the indicated disorder are shown underlined.
+ = rare case reports; ++ = multiple case reports; +++ = common finding; ADCL = autosomal dominant cutis laxa; ARCL = autosomal recessive cutis laxa; ARD = aortic root dilatation; ATS = arterial tortuosity syndrome; CCA = corpus callosum agenesis; CV = cardiovascular; ICA = intracranial arteries; IUGR = intrauterine growth restriction; No = not present; XLCL = X-linked cutis laxa
Autosomal recessive cutis laxa type 1A (ARCL1A, 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 visceral diverticula (e.g., intestine, bladder). Occasionally, supravalvular aortic stenosis is observed. Considerable overlap exists between FBLN5- and LTBP4-related cutis laxa and the two entities are difficult to distinguish from each other purely on a clinical basis. In FBLN5-related cutis laxa, the skin features may be more pronounced. In LTBP-related cutis laxa, supravalvular aortic stenosis has not yet been observed while bladder and gastrointestinal diverticula as well as rectal prolapse are more frequent.
Autosomal recessive cutis laxa type 1B (ARCL1B, EFEMP2 (FBLN4)-related cutis laxa) is characterized by cutis laxa and systemic involvement, most commonly arterial tortuosity, aneurysms and stenosis; retrognathia; joint laxity; and arachnodactyly. The severe arterial tortuosity seen in EFEMP2-related cutis laxa is absent in LTBP4-related cutis laxa.
Autosomal dominant cutis laxa type 1 (ADCL1) presents with generalized cutis laxa of variable severity. Aortic root dilatation and emphysema may occur and are currently only reported in adults, unlike the severe emphysema seen in LTBP4-related cutis laxa. ADCL1 is caused by ELN pathogenic variants that result in an elongated protein [Szabo et al 2006, Callewaert et al 2011, Hadj-Rabia et al 2013].
Autosomal recessive cutis laxa type 2A (ARCL2A, ATP6V0A2-related cutis laxa). The phenotypic spectrum of ATP6V0A2-related cutis laxa includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end. Affected individuals have furrowing and premature wrinkling of the skin of the entire body that improves with time. In most (not all) affected individuals, microcephaly and cortical and cerebellar malformations are present and are associated with variable developmental delay, seizures, and/or neurologic regression [Kornak et al 2008, Fischer et al 2012].
Autosomal recessive cutis laxa type 2B and 3B (ARCL2B and ARCL3B) (OMIM 612940, 614438). Although individuals with ARCL2B may have findings similar to ARCL2A, they often have a more progeroid appearance with a triangular face and corpus callosum agenesis. Patients who additionally have corneal clouding due to ruptures in Descemet’s membrane or cataracts are considered to have ARCL3B (de Barsy syndrome B) [Reversade et al 2009, Dimopoulou et al 2013]. ARCL2B and ARCL3B are caused by mutation of PYCR1.
Autosomal recessive cutis laxa type 3A (ARCL3A, de Barsy syndrome A) (OMIM 219150) is similar to ARCL3B, but is usually situated at the most severe end of the type 3 recessive cutis laxa spectrum with severe IUGR, a progeroid appearance with a thin skin and visible veins, adducted thumbs, and corneal clouding and/or cataract. In addition, patients with ARCL3A can show choreoathetoid movements and arterial involvement, including aortic stenosis and intracranial aneurysms [Zampatti et al 2012, Fischer et al 2014]. ARCL3A is caused by mutation of ALDH18A1.
Central nervous system and ocular anomalies in the absence of severe emphysema distinguish these disorders from LTBP4-related cutis laxa.
Geroderma osteodysplasticum (GO) (OMIM 231070), an autosomal recessive disorder that resembles ARCL2, has some distinct craniofacial characteristics and severe skeletal manifestations (osteopenia and fractures). Lipodystrophy and periodontal disease may occur. Emphysema is usually absent. Both mutation of GORAB [Hennies et al 2008] and PYCR1 [Yildirim et al 2011] have been described.
Occipital horn syndrome (OHS) (sometimes referred to as X-linked cutis laxa [XLCL]) is characterized by "occipital horns," distinctive wedge-shaped exostoses at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. Cutis laxa in OHS is often less severe and mostly involves wrinkling of the dorsum of the hands and feet. OHS is caused by mutation of ATP7A (encoding a copper transporter).
The skeletal abnormalities and abnormalities of the hair shaft (pili torti) seen in OHS and the absence of severe emphysema distinguish it from LTBP4-related cutis laxa.
Arterial tortuosity syndrome (ATS) is an autosomal recessive disorder characterized by:
- Severe and widespread arterial tortuosity of the aorta and middle-sized arteries (with an increased risk of aneurysms and dissections) and focal and widespread stenosis which can involve the aorta and/or pulmonary arteries. In addition, large veins may be dilated and valvular regurgitation and mitral valve prolapse can occur.
- Craniofacial involvement with characteristic facies and high palate with dental crowding;
- Soft/doughy skin and other evidence of a generalized connective tissue disorder including skeletal findings (scoliosis, pectus excavatum/carinatum, joint laxity, knee/elbow contractures, arachnodactyly, camptodactyly); inguinal/abdominal wall hernia; sliding hiatal or diaphragmatic hernia; hypotonia; and ocular involvement (myopia, keratoconus).
ATS is caused by mutation of SLC2A10. The absence of severe lung involvement and the presence of arterial tortuosity distinguish ATS from ARCL1C.
Macrocephaly, alopecia, cutis laxa, scoliosis (MACS) syndrome (also known as RIN2 syndrome) (OMIM 613075) is an autosomal recessive disorder that includes the eponymous clinical manifestations as well as progressive facial coarsening, gingival hyperplasia, and skin and joint laxity. The skin phenotype has been described variably as cutis laxa [Basel-Vanagaite et al 2009] or hyperextensible [Syx et al 2010]. RIN2 encodes a Ras and Rab interactor with guanine nucleotide exchange factor activity involved in endocytosis.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with LTBP4-related cutis laxa, the following evaluations are recommended:
- Assessment of lung function, including oxygen saturation, spirometry, lung volumes, and diffusion capacity
- Chest x-ray or high-resolution CT scan
- Ultrasound examination of the genitourinary tract
- Bladder ultrasound examination to diagnose multiple bladder diverticula
- Echocardiography
- Physiotherapeutic evaluation (hypotonia, hyperlaxity)
- Consultation with a clinical geneticist and/or genetic counselor
On clinical indication:
- Bronchoscopy
- Visualization of the gastrointestinal tract by gastrographin ingestion or enema
- Pulmonary vessel angiogram
- If necessary, bladder ultrasound can be complemented with a voiding cystoureterogram. Due to the potential presence of urethral diverticula, catheterization should be done carefully. Intravenous pyelogram may be an alternative.
Treatment of Manifestations
Experience in treating patients with LTBP4-related cutis laxa is very limited. Treatment is largely symptomatic. A reasonable approach to treatment could include the following.
Pulmonary
- Symptomatic treatment of pulmonary emphysema with inhaled corticosteroids, atropine, and selective β2-adrenergic bronchodilation
- Oxygen supplementation if necessary
Gastrointestinal
- Medical treatment of gastroesophageal reflux to reduce discomfort and reactive bronchospasms
- Feeding of mother’s milk in infants to maximize passive immunization
- Dietary advice, sufficient fluid intake and, if necessary, osmotic laxatives to avoid chronic constipation
Genitourinary
- Education on complete bladder emptying when voiding
- Antibiotic prophylaxis in case of incomplete voiding and recurrent urinary tract infections
- Pelvic floor strengthening by physical therapy may help to prevent prolapse of pelvic organs
- Consideration of artificial bladder implantation (performed in 1 patient)
Cardiovascular
- Care by a (pediatric) cardiologist with experience in connective tissue pathology
- Treatment of clinically relevant pulmonary artery stenosis (preferably by catheterization which is minimally invasive and needs a shorter period of anesthesia)
- Medical treatment of pulmonary hypertension (e.g., by sildenafil)
Other
- Surgical treatment of congenital diaphragmatic hernia or severe hiatal hernia
- Caution in surgical treatment of cutis laxa and inguinal or umbilical hernia, as the risk of recurrence is likely to be high (i.e., similar to that observed in other cutis laxa syndromes) and mechanical ventilation used during the procedure may aggravate pulmonary emphysema
- Physical therapy for muscle strength and joint stability
- Psychosocial support
Prevention of Secondary Complications
Immunize against respiratory infections (influenza, Streptococcus pneumonia, Haemophilus influenza).
Passive immunization for respiratory syncytial virus (RSV) with palivizumab may be considered during the RSV season.
Surveillance
The following are appropriate:
- Routine assessment of pulmonary function and oxygenation, at least yearly, or more frequently if indicated clinically
- Repeat imaging of:
- Gastrointestinal tract
- Urinary tract
- Cardiovascular system
Agents/Circumstances to Avoid
Avoid the following:
- 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
- Sunbathing or tanning in order to preserve any residual skin elasticity
- Smoking, which can result in rapid, severe loss of lung function in persons with LTBP4-related cutis laxa
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. In one family, recurrent spontaneous abortions have been noted.
Pregnancy Management
Affected mother. To date pregnancy has been observed in one affected female with an unaffected fetus. The pregnancy was uneventful, but delivery was induced because of elevated maternal blood pressure. Delivery was vaginal with normal healing and no signs of prolapse. Two years after delivery both the mother and her son were doing well.
Despite evidence for the possibility of relatively normal pregnancy, a risk of aggravation of cardiopulmonary manifestations, and increased risk of both uterine rupture and exacerbation of pelvic floor/organ insufficiency including uterine, bladder, and rectal prolapse cannot be excluded based on this single case. Therefore, it is recommended that follow up of pregnancy and the postnatal period be done in a high-risk obstetric care unit with experience in connective tissue disorders.
Affected fetus
- Major complications, such as preterm premature rupture of membranes, have not been reported during pregnancy with affected fetuses.
- Polyhydramnios has been described in two instances in association with esophageal tortuosity or diverticulosis [Callewaert et al 2013].
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.