DOOR syndrome

Overview

DOOR syndrome is a rare genetic disorder named for its key features: Deafness, Onychodystrophy (abnormal nails), Osteodystrophy (abnormal bone development), and Retardation (intellectual disability). It is also known as DOOR(S) syndrome when seizures are present. The syndrome typically presents in infancy or early childhood and affects multiple organ systems, especially the nervous system and skeletal structures. DOOR syndrome is extremely rare, with fewer than 100 cases documented worldwide.

Causes

DOOR syndrome is usually inherited in an autosomal recessive pattern, meaning a child must inherit one defective copy of the gene from each parent to develop the condition. Most cases have been linked to mutations in the TBC1D24 gene, which plays a role in cellular processes like membrane trafficking and neurotransmitter release. Mutations in this gene disrupt normal nerve and bone development, contributing to the characteristic symptoms of the disorder.

Symptoms

The clinical features of DOOR syndrome vary in severity but typically include the following:

• Sensorineural hearing loss: Usually present from birth and often profound.

• Nail abnormalities (onychodystrophy): Thick, misshapen, or absent nails, especially on fingers and toes.

• Bone abnormalities (osteodystrophy): Abnormal growth or development of the bones in the hands and feet, particularly the terminal phalanges.

• Intellectual disability: Ranging from mild to severe, often with delayed developmental milestones.

• Seizures: Present in many cases (when included, the condition is referred to as DOORS syndrome), sometimes difficult to control with medication.

• Vision issues: Some patients may experience retinal abnormalities or optic nerve atrophy.

• Facial features: Some individuals may have coarse facial features or a prominent forehead.

Diagnosis

Diagnosis of DOOR syndrome involves recognizing the characteristic combination of symptoms and confirming with genetic testing. Diagnostic steps include:

• Clinical evaluation: Thorough physical and neurological examination to identify the key features of the syndrome.

• Hearing tests: To confirm the presence and severity of hearing loss.

• Imaging studies: X-rays of the hands and feet can show bone abnormalities.

• Genetic testing: Sequencing of the TBC1D24 gene to identify pathogenic variants.

• EEG (electroencephalogram): Used to evaluate and monitor seizure activity.

Treatment

There is no cure for DOOR syndrome, so treatment focuses on managing symptoms and improving quality of life. Treatment typically involves a multidisciplinary team and may include:

• Hearing aids or cochlear implants: To address hearing impairment and support language development.

• Seizure management: Antiepileptic drugs (AEDs) are used to control seizures, though some cases may be drug-resistant.

• Special education services: Tailored to the child’s intellectual and developmental needs.

• Speech, occupational, and physical therapy: To assist with communication, mobility, and daily living skills.

• Orthopedic care: May be needed for bone deformities or functional impairments.

• Genetic counseling: Recommended for families to understand inheritance patterns and recurrence risks.

Prognosis

The prognosis for individuals with DOOR syndrome varies based on the severity of symptoms. Many individuals experience lifelong challenges due to intellectual disability, hearing loss, and seizure disorders. Some patients can achieve a degree of independence with early intervention and consistent support, while others may require lifelong care. Seizures, when severe or uncontrolled, can significantly affect quality of life and development. With multidisciplinary care, many of the complications can be managed to improve function and comfort.