What is de barsy syndrome (DBS)?

De Barsy syndrome (DBS) is a very rare inherited condition, first described in 1968.^1,2 It is considered a type of cutis laxa, a group of disorders that affect the connective tissue, the material that supports and gives structure to skin, muscles, joints, and organs.^1,2

Individuals with cutis laxa typically have skin that becomes wrinkled, loose and lacks elasticity, and when stretched, the skin returns to its normal position very slowly.^1,2

What are the signs and symptoms of DBS?

The signs and symptoms that affect individuals with this condition can vary from person to person.^1,2 Some of the core symptoms individuals with this syndrome have:^1,2

• Eye problems, such as clouding or cataracts
• Slow growth and physical development
• Loose, wrinkled, and sagging skin (called cutis laxa) that makes the person appear older than their age (progeroid appearance)
• Unique facial features and bone differences
• Intellectual disability and other neurological issues

Overall, the symptoms can be extremely varied between individuals

While researchers have identified several key features of DBS, much remains unknown.² Due to the limited number of reported cases and the scarcity of large-scale studies, there is still uncertainty about the full range of symptoms and the long-term outlook.²

Other genes may also influence the condition, which means that symptoms can vary greatly from one person to another.² Not every individual with DBS will show all the same signs, so it is important for parents and caregivers to work closely with their medical team to understand their child’s unique needs and care plan.²

Appearance and skin

One of the most noticeable signs is a prematurely aged appearance. This is caused by underdevelopment of facial bones (known as midface hypoplasia) and loose, sagging, inelastic skin—a key feature of a group of disorders called cutis laxa.² In some cases, the skin may be thin or translucent, making veins more visible, and there may be a reduction in the fat just beneath the skin, which can further contribute to the aged look.²

Facial and head features

Children with DBS may also have distinctive facial features, such as a prominent forehead, thin lips, wide-set eyes (hypertelorism), a small upturned nose, and large or unusually shaped ears.² The soft spot on the top of the head (fontanel) may take longer to close or be larger than usual.² In some cases, the head may also be smaller than expected for the child's age and sex, a condition known as microcephaly.²

Muscles, joints and bones

Muscle tone and joint stability can also be affected. Many children experience low muscle tone (hypotonia) and loose joints (hypermobility) due to weak ligaments and tendons.² Skeletal issues are common and may include frequent joint dislocations—especially of the hips—clenched hands with inward-turned thumbs (adducted thumbs), a sunken chest (pectus excavatum), and weak bones with low mineral density, which may lead to osteoporosis.²

Eyes and vision

This includes clouding of the lenses (cataracts) and the corneas (corneal opacification), which may or may not affect vision.² Less common eye features include blue-tinted sclera (the whites of the eyes), near-sightedness (myopia), and misaligned eyes (strabismus or crossed eyes).²

Development and neurological features

Developmentally, children with De Barsy syndrome may have varying levels of intellectual disability, ranging from moderate to severe.² They may also experience delays in reaching developmental milestones, such as sitting, walking, or speaking. Some may show stronger-than-normal reflexes (hyperreflexia), and as they get older, they may develop seizures or involuntary, slow, writhing movements of the limbs, known as athetoid movements.²

Growth

Growth issues are common.  Children often experience poor growth both before birth and during early childhood, and may struggle to gain weight or grow at the expected rate, a condition referred to as failure to thrive.  As a result , they may be shorter than average for their age.²

As DBS affects each person differently, individualised care is essential. A coordinated medical team, including geneticists, paediatricians, neurologists, and other specialists, can help manage symptoms and improve quality of life.²

Causes of DBS?

There are different types of cutis laxa.^1,2 These types are classified based on the specific gene mutation that causes them. ^1,2

For DBS, there are two known genetic causes:^1,2

• ALDH18A1 gene mutation (autosomal recessive cutis laxa type 3A)
• PYCR1 gene mutation (autosomal recessive cutis laxa type 3B)

Some individuals with De Barsy syndrome have changes (mutations) in the PYCR1 or ALDH18A1 genes, which affect how the body makes and uses certain proteins.^1,2 However, in some cases, the exact genetic cause is still unknown.^1,2

De Barsy syndrome is passed down in families in an autosomal recessive pattern.^1,2 This means an individual must inherit a copy of the mutated gene from both parents to have the condition.^1,2

De Barsy syndrome can also be caused by a problem in the body’s metabolism (the process that turns food into energy and helps remove harmful substances).² Normally, the body uses hormones and enzymes (proteins) to carry out this process in the right order.² This process gives our cells the energy they need and helps the body stay clean and balanced.²

In individuals with DBS, genetic changes can affect how these enzymes or hormones work.² When that happens, the body may not make enough energy, and it may not remove waste products or toxins properly.^1,2 This disruption in the metabolic process can affect many parts of the body and contribute to the symptoms of DBS.^1,2

Understanding the ALDH18A1 gene and its role in DBS

The ALDH18A1 gene gives the body instructions to make an important enzyme called P5CS.^3,4 This enzyme helps the body make certain building blocks called amino acids.^3,4 These amino acids are important for many body functions, like making collagen for healthy skin, helping cells manage stress, and keeping energy production working properly, especially in the mitochondria, which are the "powerhouses" inside our cells.^3,4

When there are mutations (changes) in the ALDH18A1 gene, the enzyme may not work correctly or may not be made at all.³ As a result, the body can’t make the amino acids properly, which can lead to metabolic problems.^1,3 This may affect how energy is produced in cells, how tissues grow and repair, and how the body handles stress.^1,3

People with mutations in the ALDH18A1 gene may develop autosomal recessive cutis laxa type 3A, which is a type of DBS.^1,3,4

In some cases, doctors may find abnormal levels of certain amino acids in the blood.^1,2,3 Some individuals may also have mildly elevated ammonia levels in the blood, which can lead to tiredness, poor feeding, or other symptoms in infants and young children. These findings can help guide diagnosis and treatment.^1,2,3,4

Understanding the PYCR1 gene and its role in DBS

The PYCR1 gene gives the body instructions to make an important enzyme called PYCR1.^4,5 This enzyme helps the body produce an amino acid called proline, which is essential for the growth, repair, and structure of tissues, such as the skin, muscles, and bones. Proline also plays a key role in helping cells manage stress inside the mitochondria, the parts of cells that produce energy and regulate many vital processes.^4,5,6

When there are mutations (changes) in the PYCR1 gene, the body may not produce enough functional enzyme.^1,5,6 As a result, the level of proline in cells may decrease, leading to problems in tissue maintenance and causing oxidative stress (a condition where harmful molecules build up in the cells).^5,6 This stress can affect how mitochondria work and contribute to the symptoms seen in DBS and related conditions.^5,6

Children with PYCR1-related DBS typically have a milder form of the condition compared to those with ALDH18A1-related cases.^1,4,5,6

Like ALDH18A1-related cases, PYCR1-related DBS is inherited in an autosomal recessive pattern, meaning a child must inherit one faulty gene from each parent to be affected.^1,5,6

Conclusion

De Barsy syndrome (DBS) is a rare genetic condition that affects many parts of the body, including the skin, eyes, brain, and bones. It is part of a group of connective tissue disorders called cutis laxa and is mainly caused by mutations in the ALDH18A1 or PYCR1 genes. These mutations interfere with the body’s ability to produce important enzymes needed for making amino acids, managing energy, and repairing tissues. As a result, individuals may experience loose, aged-looking skin, delayed growth, distinctive facial features, joint problems, intellectual disabilities, and vision issues. 

While the ALDH18A1 gene mutation often leads to a more severe form of the condition, the PYCR1 mutation typically results in milder symptoms. Understanding the genetic and metabolic basis of DBS can help families and healthcare providers better manage symptoms and plan care. Although there is currently no cure, supportive treatments and coordinated medical care can improve quality of life. Continued research is needed to fully understand DBS and develop better diagnostic tools and therapies. Genetic counselling is also important for families, especially for those planning to have children.