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Cutis laxa type 2B (de Barsy)
Cutis laxa type 2B is a rare inherited disorder primarily affecting connective tissue, leading to saggy skin. It also involves developmental delays and neurological concerns, presenting from birth and significantly impacting an individual's development.
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Overview
Cutis laxa type 2B, or de Barsy syndrome, is a very rare genetic condition that primarily affects the body's connective tissues. Connective tissue provides structural support and strength to many parts of the body, including the skin, blood vessels, and internal organs. In individuals with cutis laxa type 2B, this connective tissue is abnormally elastic and fragile [PMID:20464639]. This typically results in characteristic loose, inelastic skin that may appear wrinkled or aged.
Beyond the skin, cutis laxa type 2B can also affect other body systems, leading to a variety of symptoms. These often include distinctive facial features, problems with eyes, developmental delays, and sometimes neurological issues. The condition is usually apparent at birth or in early infancy, and its severity can vary among affected individuals.
Symptoms & clinical features
The main symptom of cutis laxa type 2B is loose, sagging, and inelastic skin, particularly noticeable around the face, neck, and joints. This can give a prematurely aged appearance. Additionally, individuals may have unusual facial features, such as hypertelorism (widely spaced eyes), a short nose with a broad tip, and a small jaw [PMID:19421297]. Eye abnormalities are common and can include corneal clouding, microcornea (unusually small cornea), and strabismus (misalignment of the eyes).
Other symptoms often associated with cutis laxa type 2B include developmental delays, affecting both motor skills (like sitting and walking) and cognitive abilities. Muscle weakness (hypotonia) is frequently observed, contributing to motor challenges. Some individuals may experience growth challenges, intellectual disabilities, and neurological issues such as seizures or movement disorders [PMID:20464639].
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Affected organs
Cutis laxa type 2B affects several organ systems, primarily those rich in connective tissue. The most noticeable impact is on the skin, which loses its elasticity and appears loose and wrinkled. The eyes are frequently involved, with potential issues ranging from corneal abnormalities to problems with eye movement. The skeletal system can also be affected, sometimes leading to joint hypermobility or bone abnormalities.
The central nervous system is another key area of involvement, contributing to developmental delay, intellectual disability, and in some cases, neurological signs like hypotonia (low muscle tone) and seizures. Growth can also be affected, leading to short stature. While less common, cardiac and gastrointestinal involvement have also been reported in some forms of cutis laxa, though this is less typical for type 2B specifically.
Risks & severity
Cutis laxa type 2B is considered a rare condition, and its exact prevalence is not well established. The severity of symptoms can vary considerably between individuals, even within the same family. Some people may have milder skin and developmental issues, while others experience more significant challenges affecting their motor skills, cognition, and overall health.
The condition typically presents at birth or in early infancy. Life-limiting complications primarily arise from neurological involvement or significant developmental challenges, although these are not universal. Regular monitoring by healthcare professionals is important to manage symptoms and address any emerging complications, potentially improving long-term outcomes.
Genetic causes
Cutis laxa type 2B is caused by pathogenic variants in the PYCR1 gene [PMID:19421297]. The PYCR1 gene provides instructions for making an enzyme called pyrroline-5-carboxylate reductase 1. This enzyme plays a crucial role in the production of proline, an amino acid that is a vital component of collagen. Collagen is a major protein found in connective tissues throughout the body, providing strength and elasticity.
When there are pathogenic changes in the PYCR1 gene, the PYCR1 enzyme cannot function correctly. This disruption leads to problems with collagen formation and turnover, particularly in elastic fibres which give skin its elasticity. The resulting faulty connective tissue structure is what causes the characteristic loose skin and other symptoms seen in cutis laxa type 2B [PMID:20464639].
- PYCR1 pyrroline-5-carboxylate reductase 1The PYCR1 gene provides instructions for making an enzyme crucial for proline synthesis, a process important for protein production and cellular energy transfer.
Inheritance pattern
Cutis laxa type 2B is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the PYCR1 gene - one from each parent - to develop the condition. People who have only one altered copy of the PYCR1 gene are called carriers. Carriers typically do not show any symptoms of the condition themselves because their other unaffected copy of the gene can compensate.
If both parents are carriers of a pathogenic variant in the PYCR1 gene, their children have a 25% (1 in 4) chance of inheriting two altered copies and developing cutis laxa type 2B with each pregnancy. There is a 50% chance their children will be carriers like them, and a 25% chance their children will inherit two normal copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosing cutis laxa type 2B typically begins with a clinical evaluation based on the characteristic physical features, particularly the loose skin, distinctive facial features, and developmental delays. If cutis laxa type 2B is suspected, genetic testing is the primary method to confirm the diagnosis. This involves analysing the PYCR1 gene to identify specific pathogenic variants.
In the UK, genetic testing for suspected cutis laxa type 2B would usually be initiated following a referral to a clinical genetics service by a GP or specialist. Clinical geneticists may consider requesting tests under the NHS Genomic Medicine Service (GMS) pathways. Relevant R-codes for such testing would be determined by the clinical geneticist based on the patient's specific presentation, likely falling under broad categories for connective tissue disorders or inherited metabolic conditions.
Management & lifestyle
There is currently no cure for cutis laxa type 2B, so management focuses on addressing specific symptoms and providing supportive care to improve quality of life. A multidisciplinary team of healthcare professionals is often involved, including paediatricians, dermatologists, ophthalmologists, neurologists, and physiotherapists.
Surveillance may involve regular developmental assessments, eye examinations, and monitoring for any neurological symptoms. Physiotherapy and occupational therapy can help address muscle weakness and developmental delays. Educational support services are also crucial. While the cosmetic aspects of the loose skin might be a concern, surgical interventions are generally not recommended due to the underlying connective tissue fragility. Genetic counsellors can provide essential information and support regarding the inheritance pattern and family planning.
UK care pathway
In the UK, individuals with suspected genetic conditions like cutis laxa type 2B are typically referred to a Clinical Genetics service. This referral can come from a GP or another specialist. Clinical geneticists and genetic counsellors at these centres provide expert diagnosis, genetic testing (often via the NHS Genomic Medicine Service with specific R-codes for relevant gene panels), and support to individuals and families impacted by rare conditions.
Frequently asked questions
Is cutis laxa type 2B a progressive condition?
The skin laxity and distinctive features of cutis laxa type 2B are typically present from birth. While developmental challenges may become more apparent over time, the fundamental changes in connective tissue do not generally worsen progressively in the same way some neurodegenerative conditions do.
Can cutis laxa type 2B be diagnosed before birth?
Yes, if there is a known family history of cutis laxa type 2B and the specific genetic variant in the PYCR1 gene has been identified in previous family members, prenatal diagnosis is possible through procedures like chorionic villus sampling or amniocentesis. This would be discussed with a clinical genetics team.
Is there any specific treatment for the loose skin?
Currently, there is no specific treatment to repair the underlying connective tissue defect. While cosmetic surgery might seem like an option for the loose skin, it is generally not recommended for cutis laxa type 2B due to the fragility and poor healing properties of the affected skin, which can lead to unsatisfactory results or complications.
What kind of support is available for families affected by cutis laxa type 2B?
Families can receive support from various healthcare professionals, including paediatricians, genetic counsellors, and therapists (physiotherapists, occupational therapists, speech and language therapists). Patient support groups and rare disease organisations can also offer valuable resources, information, and peer support.
How common is cutis laxa type 2B?
Cutis laxa type 2B is considered a very rare condition. The exact number of affected individuals is not precisely known, but it is one of the less common forms of cutis laxa reported worldwide.