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Helsmoortel-Van der Aa syndrome
This syndrome is caused by changes in the ADNP gene and affects neurological development, leading to variable intellectual disability and often involves behavioural and physical characteristics. It is typically diagnosed in childhood.
Overview
Helsmoortel-Van der Aa syndrome (HVDAS) is a rare neurodevelopmental disorder. Individuals with HVDAS typically experience global developmental delay, meaning they reach developmental milestones later than expected, and intellectual disability [PMID:27088983]. The severity of intellectual disability can vary significantly among affected individuals.
Alongside developmental challenges, people with HVDAS often present with a range of other features. These can include distinctive facial characteristics, behavioural differences, and sometimes problems affecting other body systems. It is considered a relatively newly recognised condition.
Symptoms & clinical features
The clinical presentation of Helsmoortel-Van der Aa syndrome varies widely between individuals. Common features often include developmental delay, affecting areas such as speech, motor skills, and cognitive function. Most people with this condition will experience intellectual disability, which can range from mild to severe [PMID:27088983].
Behavioural characteristics are frequently observed and may include features associated with autism spectrum disorder, such as difficulties with social interaction, repetitive actions, and anxiety. Attention deficit hyperactivity disorder (ADHD) traits have also been noted. Physical features can include specific facial characteristics, such as a prominent forehead, widely spaced eyes (hypertelorism), and a broad nasal bridge. Other potential indicators involve differences in growth patterns, sleep disturbances, and sometimes issues with vision or hearing.
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Affected organs
Helsmoortel-Van der Aa syndrome primarily affects the brain and nervous system, leading to its characteristic neurological and developmental features. This impact on brain development underpins the intellectual disability, developmental delay, and behavioural differences seen. While the brain is the main organ affected, the syndrome can also sometimes have an impact on other body systems, though this occurs less consistently.
Some individuals may experience eye-related issues, such as strabismus (crossed eyes) or refractive errors, and hearing problems have also been reported. Gastrointestinal issues and heart abnormalities are less common but can occur in some cases, indicating the potential for broader systemic involvement.
Risks & severity
Helsmoortel-Van der Aa syndrome is considered a rare condition, although its precise prevalence is not yet well established. The severity of the syndrome can vary considerably among affected individuals. Developmental delays are generally noticeable in infancy or early childhood, with intellectual disability typically becoming apparent as a child develops [PMID:33675079].
The lifelong impact of HVDAS can range from moderate learning difficulties to requiring more significant support for daily living activities. While some individuals may achieve a degree of independence, others will need ongoing care. There is no specific age of onset for the full range of symptoms, as developmental challenges are often identified early in life.
Genetic causes
Helsmoortel-Van der Aa syndrome is caused by pathogenic variants (sometimes called mutations) in the ADNP gene. The ADNP gene provides instructions for creating a protein known as activity-dependent neuroprotector homeobox protein [PMID:27088983]. This protein plays a vital role in brain development and function, including the formation of nerve cells (neurons) and the regulation of other genes.
Pathogenic variants in ADNP can disrupt the normal function of the ADNP protein. This disruption can affect how the brain develops and operates, leading to the characteristic features of HVDAS. Most reported pathogenic variants in ADNP result in a truncated (shortened) protein that cannot function correctly, or a complete loss of protein function. This often occurs through a mechanism known as haploinsufficiency, where having only one functional copy of the gene is insufficient for normal development.
- ADNP activity dependent neuroprotector homeobox
Inheritance pattern
Helsmoortel-Van der Aa syndrome is inherited in an autosomal dominant pattern. This means that an individual only needs one copy of the ADNP gene with a pathogenic variant to develop the condition. In most cases of HVDAS, the pathogenic variant arises spontaneously, meaning it is a new change that was not inherited from either parent. This is known as a *de novo* pathogenic variant.
If a person has HVDAS due to a *de novo* pathogenic variant, the chance of their future children inheriting the condition is very low, as neither parent carries the pathogenic variant. However, if an individual with HVDAS has children, there is a 50% chance for each child to inherit the pathogenic variant and therefore develop the syndrome. Families may wish to discuss specific risk information with a genetic counsellor.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of Helsmoortel-Van der Aa syndrome is typically suspected based on a combination of clinical features, including developmental delay, intellectual disability, and characteristic physical and behavioural traits. Confirmation of the diagnosis requires genetic testing to identify a pathogenic variant in the ADNP gene.
Genetic testing is usually performed using a blood sample. The NHS Genomic Medicine Service (GMS) provides access to advanced genomic testing, such as whole exome sequencing or specific gene panel testing. A referral to Clinical Genetics services by a paediatrician or other specialist is the usual pathway for accessing these diagnostic tests in the UK. A genetic counsellor can help interpret test results and discuss implications for the individual and their family.
Management & lifestyle
The management of Helsmoortel-Van der Aa syndrome focuses on supporting individuals to achieve their full potential and addressing specific symptoms as they arise. Since the syndrome affects many different areas of development, a multidisciplinary team approach is often recommended. This team may include paediatricians, neurologists, geneticists, speech and language therapists, occupational therapists, physiotherapists, and educational psychologists.
Early intervention programmes are often beneficial for developmental delays. Therapies such as speech and language therapy, physiotherapy, and occupational therapy can help with communication, motor skills, and daily living activities. Behavioural interventions may be helpful for managing autism spectrum disorder traits or ADHD symptoms. Regular medical check-ups are important to monitor for any associated health issues, such as vision or hearing problems. Management plans are individualised and evolve as the person grows and develops, guided by their specific needs within the NHS framework.
UK care pathway
In the UK, individuals suspected of having a rare genetic condition like Helsmoortel-Van der Aa syndrome typically access care through the NHS Genomic Medicine Service (GMS). Initial assessment is usually by a general paediatrician or specialist, who may then refer to a Clinical Genetics service. Clinical geneticists can coordinate genomic testing, often covered by relevant NHS R-codes for developmental disorders.
Genetic counsellors are an integral part of this pathway, offering information and support to families regarding inheritance, testing options, and implications of a diagnosis. Once a diagnosis is confirmed, ongoing care is managed by a network of specialists tailored to the individual's needs, ensuring access to appropriate therapies and support services within the NHS.
Frequently asked questions
What is the life expectancy for someone with Helsmoortel-Van der Aa syndrome?
Information on life expectancy for Helsmoortel-Van der Aa syndrome is still emerging, as it is a relatively newly described condition. Information is limited, and long-term outcomes are still being understood.
Can Helsmoortel-Van der Aa syndrome be prevented?
Helsmoortel-Van der Aa syndrome is caused by genetic changes in the ADNP gene, which are usually spontaneous (*de novo*) and not inherited. Therefore, it cannot typically be prevented. For families who have had a child with HVDAS, genetic counselling can provide detailed information about recurrence risks for future pregnancies.
Are there any specific treatments for Helsmoortel-Van der Aa syndrome?
There is currently no specific cure for Helsmoortel-Van der Aa syndrome. Management focuses on symptomatic and supportive care. This includes various therapies like speech, occupational, and physical therapy, along with educational support and behavioural interventions tailored to the individual's needs.
How common is Helsmoortel-Van der Aa syndrome?
Helsmoortel-Van der Aa syndrome is considered a rare condition. The exact prevalence is not precisely known, partly because it was only recently identified. As awareness and genetic testing become more widespread, it is possible that more individuals will be diagnosed with the condition.
Where can I find support for Helsmoortel-Van der Aa syndrome in the UK?
In the UK, support for rare conditions can often be found through national charities and patient organisations. Your local Clinical Genetics service or genetic counsellor should also be able to provide information on relevant support groups or networks for individuals and families affected by Helsmoortel-Van der Aa syndrome or similar neurodevelopmental conditions.
References
- Adam MP, Bick S, Mirzaa GM. ADNP-Related Helsmoortel-Van der Aa Syndrome. 1993. PMID: 27054228
- Van Dijck A, Vulto-van Silfhout AT, Cappuyns E. Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP. Biological psychiatry. 2019. PMID: 29724491
- Szabó TM, Balogh I, Ujfalusi A. Helsmoortel-Van der Aa Syndrome-Cardiothoracic and Ectodermal Manifestations in Two Patients as Further Support of a Previous Observation on Phenotypic Overlap with RASopathies. Genes. 2022. PMID: 36553633
- Harutyunyan L, D'Incal CP, Jansen AC. A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome. Brain sciences. 2025. PMID: 41594725
- Sarli C, van der Laan L, Reilly J. Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype. American journal of medical genetics. Part C, Seminars in medical genetics. 2024. PMID: 38884529
- Breen MS, Garg P, Tang L. Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype. American journal of human genetics. 2020. PMID: 32758449
- Al-Enezi E, Alghamdi M, Al-Enezi K. Helsmoortel-Van der Aa syndrome in a 13-year-old girl with autistic spectrum disorder, dysmorphism, a right solitary kidney, and polycystic ovaries: a case report. Journal of medical case reports. 2024. PMID: 39232847
- Chen LJ, You ZM, Chen WH. Helsmoortel-van der Aa syndrome in a Chinese pediatric patient due to ADNP nonsense mutation: A case report. Frontiers in pediatrics. 2023. PMID: 37063667