DOOR syndrome

DOOR (deafness, onychodystrophy, osteodystrophy, and mental retardation) syndrome is a genetic disease which is inherited in an autosomal recessive fashion. DOOR syndrome is characterized by mental retardation, sensorineural deafness, abnormal nails and phalanges of the hands and feet, and variable seizures. A similar deafness-onychodystrophy syndrome is transmitted as an autosomal dominant trait and has no mental retardation. Some authors have proposed that it may be the same as Eronen Syndrome, but since both disorders are extremely rare it is hard to make a determination.

Signs and symptoms

Not all of the DOOR symptoms are consistently present. They can vary in severity, and additional features can be noted in individuals affected by DOOR syndrome.

Some of these additional features are:

• Polyhydramnios (increased amniotic fluid during pregnancy) and increased nuchal fold during pregnancy
• Specific facial features such as a large nose
• Severe and sometimes refractory seizures, abnormalities on the magnetic resonance imaging of the brain
• Increased 2-oxoglutaric acid in the blood and urine - this compound is made or used by several enzymes
• Finger-like thumbs
• Visual impairment
• Peripheral neuropathy (nerves conducting sensation from extremities to the brain) and insensivity to pain

Intellectual impairment is present in all reported cases, but the severity can vary widely. The prognosis in terms of survival also varies greatly from early childhood till adulthood.

Cause

DOORS syndrome can be caused by mutations in the TBC1D24 gene. This gene provides instructions for making a protein whose specific function in the cell is unclear. Studies suggest the protein may have several roles in cells. The TBC1D24 protein belongs to a group of proteins that are involved in the movement (transport) of vesicles, which are small sac-like structures that transport proteins and other materials within cells. Research suggests that the TBC1D24 protein may also help cells respond to oxidative stress. Oxidative stress occurs when unstable molecules called free radicals accumulate to levels that can damage or kill cells. Studies indicate that the TBC1D24 protein is active in a variety of organs and tissues; it is particularly active in the brain and likely plays an important role in normal brain development. The TBC1D24 protein is also active in specialized structures called stereocilia. In the inner ear, stereocilia project from certain cells called hair cells. The stereocilia bend in response to sound waves, which is critical for converting sound waves to nerve impulses.

TBC1D24 gene mutations that cause DOORS syndrome are thought to reduce or eliminate the function of the TBC1D24 protein, but the specific mechanism by which loss of TBC1D24 function leads to the signs and symptoms of DOORS syndrome is not well understood.

In about half of affected individuals, no TBC1D24 gene mutation has been identified. The cause of DOORS syndrome in these individuals is unknown.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Diagnosis

Patients are checked for each of the 5 major characteristics by X-rays of the hands and feet, a brain stem auditory evoked response test for hearing loss, and an electroencephalogram (EEG). Elevated levels of 2-oxoglutaric acid in the urine and plasma have repeatedly been reported mostly in patients with TBC1D24 mutations. If present, DOORS syndrome is suspected, although elevated levels can also occur in other disorders. Molecular genetic testing identifying a TBC1D24 mutation may confirm the diagnosis but absence of the mutation does not mean a diagnosis of DOORS syndrome is incorrect.

Treatment

Treatment is based on symptoms. Long-term management involves regular ophthalmologic and hearing tests as well as neurological exams such as EEGs. A feeding tube is necessary in infants with feeding difficulties. Antiepileptic medication are used to prevent or decrease the frequency of seizures but is not always effective.

External links

Classification	ICD-10: Q87.8 OMIM: 220500

NIH genetic and rare disease info

• NIH info on DOOR syndrome

DOOR syndrome is a rare disease.

DOOR syndrome Resources
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