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DOORS syndrome
DOORS syndrome is a rare inherited disorder involving a specific set of symptoms: deafness, abnormal nails, bone malformations, learning difficulties, and seizures. It impacts development and neurological function from an early age.
Overview
DOORS syndrome is a very rare genetic condition, named using an acronym for its main features: Deafness, Onychodystrophy (nail abnormalities), Osteodystrophy (bone abnormalities), mental Retardation (now referred to as intellectual disability or learning difficulties), and Seizures [PMID:33678566]. Individuals with DOORS syndrome often experience profound hearing loss and a range of challenges affecting their development and nervous system. It is present from birth, although specific symptoms may become more apparent as a child grows. The condition affects various body systems, making it a complex disorder to manage.
Symptoms & clinical features
The symptoms of DOORS syndrome typically become noticeable in infancy or early childhood. Hearing impairment is a consistent feature, often profound, affecting both ears [PMID:33678566]. Nail abnormalities can include small or absent fingernails and toenails, and sometimes issues with nail growth or shape. Bone anomalies are varied; individuals might have unusually short bones in the fingers and toes (brachydactyly), or differences in the structure of the spine or other bones. Developmental delays leading to learning difficulties are common, impacting cognitive function and motor skills. Seizures vary in type and severity, and may begin in early life, sometimes being resistant to standard treatments.
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Affected organs
DOORS syndrome primarily affects the neurological system, leading to seizures and developmental delays with associated learning difficulties. The auditory system is also significantly impacted, causing profound deafness. Additionally, the condition affects skeletal development, resulting in bone and nail abnormalities, particularly in the hands and feet. Other systems, including the kidneys, heart, and brain structure, can sometimes be involved, leading to a broader range of potential health concerns in some individuals.
Risks & severity
DOORS syndrome presents with a wide spectrum of severity, though many individuals experience significant health challenges. The condition is often associated with profound sensorineural hearing loss and substantial developmental delays. Seizures can be difficult to control, and their frequency and severity can impact daily life. While the exact prevalence is not well established due to its rarity, the condition typically leads to lifelong care requirements. Complications from various affected systems can impact overall health and well-being, necessitating comprehensive medical support throughout life [PMID:37517676].
Genetic causes
DOORS syndrome is caused by pathogenic variants in the TBC1D24 gene [PMID:33678566]. The TBC1D24 gene provides instructions for making a protein that is thought to be involved in several cellular processes, including neuron development and migration, maintenance of communication between nerve cells, and the transport of vesicles within cells [PMID:30129759]. This protein also plays a role in regulating the fusion of cell membranes. When the TBC1D24 gene has a pathogenic variant, the protein it produces may not function correctly or may be absent. This disruption to normal cellular processes, particularly in the nervous system, leads to the wide range of symptoms seen in DOORS syndrome, including impaired brain development, hearing loss, and seizures.
- TBC1D24 TBC1 domain family member 24
Inheritance pattern
DOORS syndrome is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered TBC1D24 gene, one from each parent, to develop the condition. If a person inherits only one copy of the altered gene, they are considered a 'carrier'. Carriers typically do not show symptoms of DOORS syndrome themselves. When two carriers have children together, there is a 25% chance with each pregnancy that their child will inherit two altered copies of the gene and develop DOORS syndrome. There is also a 50% chance the child will be a carrier, and a 25% chance the child will inherit two typical 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 DOORS syndrome typically involves a combination of clinical evaluation and genetic testing. A paediatrician or clinical geneticist may suspect the condition based on the presence of the characteristic features such as profound deafness, nail and bone abnormalities, developmental delay, and seizures. Magnetic resonance imaging (MRI) of the brain might reveal structural differences. Confirmation of DOORS syndrome usually relies on genetic testing to identify pathogenic variants in the TBC1D24 gene. In the UK, genetic testing for suspected DOORS syndrome may be accessed via the NHS Genomic Medicine Service, often following referral to a clinical genetics service. This testing would generally fall under relevant R-codes for neurodevelopmental disorders or syndromic deafness.
Management & lifestyle
Due to the multiple systems affected, the management of DOORS syndrome requires a multidisciplinary approach, focusing on supporting the individual's specific needs. This typically involves input from specialists such as audiologists for hearing aids or cochlear implants, neurologists for seizure management, developmental paediatricians, and physiotherapists and occupational therapists for motor skill development. Educational support tailored to learning difficulties and hearing impairment is also crucial. Regular monitoring for potential complications involving various organ systems is often part of a comprehensive care plan. Genetic counsellors can provide essential information and support to families regarding the inheritance pattern and implications for future family planning.
UK care pathway
In the UK, individuals suspected of having DOORS syndrome would typically be referred to a clinical genetics service through their GP or another specialist. This service can offer a formal diagnosis, genetic counselling, and coordination of care. Genetic testing is usually performed through the NHS Genomic Medicine Service (GMS) pathways, often listed under specific R-codes related to neurodevelopmental disorders or syndromic conditions. A genetic counsellor can help families understand the condition, its inheritance, and implications for relatives, and guide them through the available support and services.
Frequently asked questions
What is the life expectancy for someone with DOORS syndrome?
The impact of DOORS syndrome on life expectancy can vary significantly depending on the severity of symptoms and the presence of complications. While many individuals require lifelong care, advances in medical management continue to improve outcomes for those affected.
How common is DOORS syndrome?
DOORS syndrome is considered a very rare condition. The exact number of affected individuals is not precisely known, but it is diagnosed in a very small number of families globally.
Can DOORS syndrome be prevented?
DOORS syndrome is a genetic condition caused by specific changes in the TBC1D24 gene, typically inherited in an autosomal recessive pattern. It cannot be prevented. For families with a known history of DOORS syndrome, genetic counselling can provide information about recurrence risks and family planning options.
What kind of support is available for families affected by DOORS syndrome in the UK?
In the UK, families can access support through clinical genetics services, rare disease support groups, and charities. A genetic counsellor can help connect families with appropriate medical and educational resources, as well as peer support networks.
Are there any specific treatments for DOORS syndrome?
There is currently no cure for DOORS syndrome, and treatments focus on managing individual symptoms. This includes medications for seizures, hearing aids or cochlear implants for deafness, and various therapies to support development and learning. Management is tailored to each person's unique needs.
References
- Adam MP, Bick S, Mirzaa GM. TBC1D24-Related Disorders. 1993. PMID: 25719194
- Beauregard-Lacroix E, Pacheco-Cuellar G, Ajeawung NF. DOORS syndrome and a recurrent truncating ATP6V1B2 variant. Genetics in medicine : official journal of the American College of Medical Genetics. 2021. PMID: 32873933
- Rehman AU, Friedman TB, Griffith AJ. Unresolved questions regarding human hereditary deafness. Oral diseases. 2017. PMID: 27259978
- Cebeci D, Rıfkı D. Doors Syndrome: Case Report. Indian journal of dermatology. 2022. PMID: 36092206
- Gao X, Dai P, Yuan YY. Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes. Human genetics. 2022. PMID: 34232384
- Campeau PM, Hennekam RC, DOORS syndrome collaborative group. DOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome. American journal of medical genetics. Part C, Seminars in medical genetics. 2014. PMID: 25169651
- Carpentieri G, Cecchetti S, Bocchinfuso G. Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. HGG advances. 2024. PMID: 39210597
- Beauregard-Lacroix E, Pacheco-Cuellar G, Ajeawung NF. Correction: DOORS syndrome and a recurrent truncating ATP6V1B2 variant. Genetics in medicine : official journal of the American College of Medical Genetics. 2021. PMID: 32934366