Overview

De Barsy Syndrome (DBS) is a rare genetic disorder, usually characterised by loose skin and growth difficulties, affecting the eyes, brain and skeleton.¹ Although other rare genetic conditions are often studied to understand their relationship to the immune and endocrine (hormonal) systems, De Barsy Syndrome is unfortunately not yet receiving the same attention.

This article aims to present the main characteristics of DBS, with a focus on the immune and endocrine particularities.  

What is De Barsy Syndrome? 

The first record of De Barsy Syndrome was reported in 1968 by Dr Barsy, who described a progeria-like appearance, where infants appear much older. Since then, only approximately 27 cases have been reported worldwide, resulting in De Barsy Syndrome being considered a rare condition.¹

Signs and symptoms

De Barsy Syndrome is often characterised by distinct features in the following areas:¹

• Skin - loose and wrinkled as a result of premature degeneration of connective tissues, known as cutis laxa 
• Eyes - cloudy corneas, movement and vision difficulties
• Skeletal development - fragile, weak bones and joint dislocations sometimes resulting in scoliosis, sunken breast bone, inward-facing thumbs 
• Brain development - neurodevelopmental disorders, learning disabilities, seizures and involuntary movements

Although researchers have been able to establish the above ‘core’ symptoms, De Barsy Syndrome is not yet fully understood. Due to the nature of the condition, symptoms vary and individuals are affected differently.² Intrauterine Growth Restriction (IUGR) has been reported in 96% of cases, which can manifest in different ways but often leads to the baby’s underdevelopment and a premature birth.^2,3 

Causes  

De Barsy Syndrome is inherited in an autosomal recessive pattern, meaning children with the condition inherit two copies of a mutated gene – one from each biological parent. When a gene mutation occurs, the ‘protein product’, or the part of the body this genetic code is responsible for creating, can be damaged or missing entirely.¹ 

Some cases report mutations in PYCR1 or ALDH18A1 genes, which are responsible for limb and connective tissue development. Other research suggests De Barsy Syndrome belongs to a spectrum of mutations in the ATP6V0A2-CDG gene. However, the exact genetic mutation that causes the disorder remains unknown, highlighting the need for further research into De Barsy Syndrome.^1,2,4 

Diagnosis and prognosis

De Barsy Syndrome is diagnosed through identification of the core characteristic symptoms, a detailed patient history and various tests to rule out other conditions.¹ Molecular genetic testing is often used to confirm a diagnosis of De Barsy Syndrome, as this checks an individual’s DNA for mutations in specific genes, such as the PYCR1 gene.⁶    

The prognosis of De Barsy Syndrome is unknown, as the condition is rare, and some infants born with De Barsy Syndrome unfortunately die during childhood. The lifespan of the DBS patients faces difficulties in being estimated; they present complications associated with the disorder, such as recurring infections and brain functioning difficulties.⁷ In one case, palliative care was recommended for a two-day-old female, which involved preparation for the end of her life.⁵ 

Other cases have reported a much longer life expectancy for individuals living with De Barsy Syndrome. A 1985 study recorded the oldest case at the time, and the individual lived until he was at least 25 years old, although he did not speak and experienced severe delays with his brain development.⁸ More recently, in 2004, clinicians studied a boy from birth until he was 12 years old.⁹

Current research into De Barsy Syndrome

Research into De Barsy Syndrome has focused mainly on understanding its genetic causes, as well as the connective tissue, brain and eye-related aspects of the disorder. Throughout the research, there is a consistent understanding that De Barsy Syndrome is caused by mutated genes, inherited from both parents. Some cases of De Barsy Syndrome have been caused by mutations in the PYCR1 or ALDH18A1 genes, which are responsible for limb and connective tissue development. However, mutations in the PYCR1 or ALDH18A1 genes are not present in all cases of De Barsy Syndrome, as some individuals do not have these mutated genes.¹

Many genetic studies have researched autosomal recessive cutis laxa (ARCL) as a clinical spectrum, meaning they group together individuals with similar loose skin symptoms to study their mutated genes.^7,8,9,11,12 The findings often demonstrate mutations in elastin genes, which explain the looseness and wrinkle-like appearance of the skin in affected individuals. However, numerous different genetic disorders display differences in elastic fibre systems, so it is difficult to understand the exact genetic cause of ARCL, or De Barsy Syndrome.¹⁰

A 2008 study reported the full list of clinical symptoms for De Barsy Syndrome in an individual who had the gene mutation ATP6V0A2-CDG.¹³ Interestingly, other individuals who experienced similar symptoms consistent with De Barsy Syndrome did not carry the same mutated gene.¹² Therefore, the current research shows no significant relationship between the type of mutated gene and the symptoms of De Barsy Syndrome, highlighting the need for further research. 

Immune involvement in De Barsy Syndrome

Despite the fact that genetic mutations often cause immunodeficiency disorders, the immune aspect remains underresearched in relation to De Barsy Syndrome. Almost 40 years ago, the link was first established when a study reported weak white blood cells in an individual with De Barsy Syndrome.¹³ Since white blood cells are the body’s defence system for fighting against infection, this indicates a weakened immune system. 

More recent research has noted recurring infections as a common feature of De Barsy Syndrome, with multiple studies highlighting this as the reason for childhood deaths. The crucial role of the ATP6V0A2-CDG gene in immune development during pregnancy has also been investigated.¹⁴ As some cases of De Barsy Syndrome have a mutated version of this gene, it is striking that immune involvement has been so overlooked.   

The crucial role of the immune system in brain development and function is widely documented.¹⁵ Considering that neurodevelopmental delay is one of the characteristic features of De Barsy Syndrome, the lack of investigation into immune dysfunction represents a clear gap in the research. 

Endocrine involvement in De Barsy Syndrome

The potential role of hormone creation and release in De Barsy Syndrome is significantly underresearched. This is particularly surprising given that issues with endocrine functioning have been reported in research for similar disorders. A 2007 study reported a case of a newborn with a rare form of cutis laxa who also experienced congenital hypothyroidism.¹⁶ Thyroid hormones are part of the endocrine system and are responsible for regulating growth and development. Considering underdevelopment is a key feature of De Barsy Syndrome, it is surprising that not a single study researches the endocrine involvement in this disorder.  

Werner syndrome is similar to De Barsy Syndrome in that they are both rare autosomal recessive disorders caused by mutated genes. Their symptoms are also similar, with affected individuals experiencing progeria and loose connective tissue.¹⁷ Individuals with Werner’s Syndrome often experience delayed puberty, altered thyroid levels and insulin resistance, which are all linked to endocrine functioning.¹⁷ 

Endocrinologic investigation is common within Werner’s Syndrome, and is considered necessary to treat the disorder and improve quality of life. Further examination of endocrine involvement in De Barsy Syndrome is needed to better understand the disorder. 

Summary

De Barsy Syndrome is a rare genetic disorder characterised by loose skin, developmental delays and brain difficulties. First described in 1967, very few cases have been identified since. De Barsy Syndrome is inherited in an autosomal recessive pattern, where an individual inherits two copies of a mutated gene. Some cases have mutations in the PYCR1 gene, while others have mutations in ALDH18A1 or ATP6V0A2-CDG. The exact genetic cause is not yet fully understood.

Research has largely focused on identifying genetic mutations, although this remains inconclusive. Immune function in De Barsy Syndrome remains underresearched, despite an early study revealing weakened white blood cells in an individual with the disorder. 

Research also reports recurring infections as a common feature of De Barsy Syndrome, indicating its links to the immune system. Similarly, endocrine functioning has received little attention in De Barsy Syndrome research, despite related disorders, such as cutis laxa and Werner Syndrome, highlighting the effects of hormonal dysfunction on growth and development.

The immune and endocrine systems’ involvement in De Barsy Syndrome has been widely overlooked in the research. Further study into these areas could be significant for understanding De Barsy Syndrome and improving the quality of life for individuals with the disorder.