What Is De Barsy Syndrome?

Overview 

De Barsy Syndrome (DBS) is a very rare genetic disorder, with fewer than 100 documented cases identified from 1967 to the present day.¹ DBS is named after the Belgian paediatrician (a medical doctor who specialises in treating children) Anne-Marie De Barsy, who first discovered the condition in 1968. This discovery occurred when she observed a 22-month-old girl presenting with loose skin, impaired development of elastic fibres, underdeveloped motor skills, and muscle stiffness. This combination of symptoms had not been previously recorded. Consequently, De Barsy and her colleagues published their first paper describing these symptoms as a new syndrome. 

DBS primarily affects the connective tissues in your body, manifesting in a range of symptoms like oligophrenia (slowed mental development), degeneration of elastic tissue in the skin and eyes, and muscle stiffness.^2,3 While these symptoms offer an overview, variations in symptom presentation exist among specific cases of DBS. Keep reading to discover more about DBS, its causes, diagnosis, and current treatment options.

Genetic causes of De Barsy Syndrome 

DBS is an autosomal recessive disorder. It develops only when specific recessive genes are inherited from both parents. In such cases, both parents are carriers and may not show symptoms of DBS themselves. However, when a child inherits both copies of the recessive gene, DBS manifests. There is a 25% chance of this happening if both parents are carriers of the recessive gene.

The exact genes responsible for DBS have not yet been identified. However, mutations in the ALDH18A1 and PYCR1 genes have been associated with certain cases.¹ This association suggests that researchers observed mutations in these genes prevalent among a significant number of DBS cases. Yet, a clear conclusion linking these genes to the direct cause of DBS remains undetermined. Furthermore, the exact genetic nature of these mutations may vary from one individual to another. Thus, understanding the genetic foundations is necessary for accurate diagnosis, genetic counselling, and the potential development of targeted therapies for DBS in the future. 

Mutations in the ALDH18A1 and PYCR1 genes are associated with the preservation of connective tissue and synthesis of collagen—a protein responsible for the elasticity of skin and other vital biological structures, such as tendons and ligaments. PYCR1 mutation specifically contributes to one of two subtypes of DBS, which is primarily characterised by the prevalence of loose skin and joint laxity.³ This gene encodes the enzyme that catalyses the production of proline, an important amino acid for the generation of collagen. Therefore, mutation or disruption in this gene leads to poor muscle development and reduced skin elasticity due to errors in collagen synthesis.⁴

On the other hand, mutations or disruptions in the ALDH18A1 gene associated with DBS manifest in issues concerning skin elasticity, intellectual disability, and impaired motor functions.³ This gene is involved in the synthesis of pyrroline 5-carboxylate (P5C), an essential molecule for the production of collagen and Gamma-Aminobutyric Acid (GABA) neurotransmitter. GABA disruption can interfere with brain signalling related to motor and sensory reflexes and mental development. Moreover, ALDH18A1 is also known to be the main cause of dysmorphic facial features observed in DBS.⁵

Typical symptoms of De Barsy Syndrome 

DBS symptoms usually appear during infancy or early childhood. The severity of symptoms may vary among individuals, and there is a possibility of misdiagnosis with other diseases sharing similar symptoms. Understanding these symptoms allows early detection, ensuring timely access to essential care for individuals with DBS. These symptoms include:⁶

Dysmorphic facial features

One of the typical symptoms seen in DBS is dysmorphic facial features, which include an elongated face with a high and prominent forehead, a small chin (micrognathia), and prominent ears. In some cases, widely spaced or downward-slanting eyes are observed with the other features.

Joint and skin laxity

Patients with DBS often exhibit joint laxity and hypermobility, manifesting as an increased and sometimes injurious range of motion due to looseness in joints in multiple body areas. Confirming this in children, who are naturally more mobile and less stable on their feet compared to adults, can be particularly challenging.

Joint laxity arises from disruptions in collagen production, which is essential for the strength and elasticity of muscles and tendons. Collagen is equally essential for skin elasticity; thus, people with DBS will tend to have loose and prematurely ageing skin.³

Intellectual disabilities

Intellectual disabilities in DBS often result from a disruption of neurotransmitter function, leading to difficulties in growth and cognitive development. DBS commonly presents with developmental delays that affect patients' ability to learn the language, perform motor skills, and cognitive processing speed. Consequently, people with DBS often face learning difficulties due to these challenges.

Vision problems

Vision problems prevalent in DBS are attributed to the disruption in collagen production and delayed development. These issues often manifest as corneal clouding, which can disrupt vision, myopia (nearsightedness), cataracts (clouding of the eye's lens), and strabismus (eye misalignment). The vision complications observed in DBS can severely affect the patient's quality of life.⁴

Other symptoms like stunted growth, muscle stiffness, and hearing difficulties are also observed in patients with DBS. The manifestation of these symptoms varies among individuals, influenced by the type of genetic mutations underlying DBS, their genetic background, and environmental factors. Patients may show changes in the symptoms as they age; thus, it is important to understand the genetic basis of this disorder.

Diagnosis of De Barsy Syndrome

DBS diagnosis poses challenges due to the necessity of initial clinical evaluation by a geneticist or paediatrician. This evaluation includes assessing the physical symptoms, reviewing the patient's medical history to determine the possibility of DBS, and conducting molecular and genetic tests to confirm the suspected diagnosis. Because DBS is so rare, a comprehensive diagnosis typically requires a multidisciplinary approach to ensure accuracy in detection.

The primary diagnosis often includes assessing the elasticity of skin tissue to identify the specific subtype of muscle laxity present in DBS. However, identifying the subtype through this evaluation is not always easy without further molecular genetic testing. Patients need to be tested to detect specific protein synthesis defects related to one of the correlated genes like ALDH18A1 or PYCR1. This process is challenging as the presence of these abnormal proteins tends to fluctuate. Further, progress in diagnosis is impeded by the low number of available patients for study due to the rarity of the disease, the likelihood of misdiagnosis, and patients who remain undetected within the scientific and medical community.⁷

Moreover, DBS can easily be confused with other disorders that share similar symptoms, making it difficult to identify the condition based on physical manifestations alone. For example, Ehlers-Danlos syndrome exhibits skin and joint laxity similar to that observed in DBS. Additionally, Cutis-Laxa disorder presents skin laxity resembling the PYCR1 subtype of DBS. People with Marfan syndrome often display joint hypermobility and elongated facial features similar to DBS. The overlap of symptoms among these genetic conditions makes it necessary to rule out other disorders before confirming a DBS diagnosis. This complexity makes it challenging to diagnose DBS without specialist support and genetic testing. Access to such specialised facilities and personnel is often limited for patients, adding to the difficulty in obtaining a conclusive diagnosis.

Treatment of De Barsy Syndrome

Treatment primarily focuses on managing the symptoms and often includes palliative care. The oldest reported surviving case of DBS is a 24-year-old patient who participated in clinical studies investigating the disorder. Management and treatment of DBS require a comprehensive assessment of the patient’s needs and creating a care plan that involves collaboration among specialists, physical therapists, family support, and accurate medical interventions within a multidisciplinary approach. 

Achieving an accurate and early diagnosis is crucial to ensure that affected individuals receive the necessary support. This may include medical interventions to alleviate symptoms, such as:

• Physical and occupational therapy targeting coordination and muscle strength
• Orthopaedic interventions and skin treatments address joint and skin laxity
• Speech and language therapy aims to improve the condition of individuals with intellectual disabilities

For a genetic disorder like DBS, ongoing medical support and monitoring are essential. This can impose a significant financial strain on families affected by the condition. Financial considerations and advocacy are essential for these families, as they need not only physical and medical help with disease management but also psychological support to cope with the emotional challenges present.

Inclusion in social and community activities plays a significant role in promoting social integration and a sense of belonging, which can alleviate some of the difficulties associated with a debilitating illness. Online support groups dedicated to rare genetic diseases like Global Genes, RareConnect, Inspire, HealthUnlocked, and local Facebook support groups offer support and a sense of togetherness for people during tough times.

Informational websites such as National Organization for Rare Disorders (NORD), Rare Diseases Clinical Research Network (RDCRN), and Genetic and Rare Diseases Information Center (GARD) play a vital role in spreading knowledge and increasing awareness about rare diseases. These platforms serve as valuable resources, offering safe and accessible information for individuals seeking guidance and understanding in navigating the complexities of such conditions.

Summary

• De Barsy Syndrome (DBS) is a rare autosomal recessive disorder characterised by skin and joint laxity, dysmorphic facial features, intellectual disabilities, and stunted growth
• The research identified two subtypes of DBS associated with two different genes involved in collagen production
• Diagnosis requires a multi-disciplinary approach, while treatment focuses on symptom alleviation and enhancing the patient's quality of life
• Organizations supporting social integration for DBS patients and spreading disease awareness are vital in addressing rare illnesses