DOORS Syndrome - Clinical Features, Causes, Diagnosis, and Management

Introduction:

DOORS syndrome is a genetic disorder, and the acronym DOORS stands for D for deafness, O for onychodystrophy (changes in the growth, color, shape, and texture of nails of hands and feet), O for osteodystrophy (malformation of bones causing short fingers and toes), R for mental retardation, and S for seizures. Deafness is present by birth, and infants may be affected by both ears, which occurs mainly due to damage in the inner ears, and due to this, there is a delay or impairment in speech. Individuals with DOORS syndrome have a normal lifespan but can be affected by intellectual disability for a lifetime.

What Is DOORS Syndrome?

DOORS syndrome is an inherited genetic disorder that occurs due to a mutation in the TBC1D24 (TBC1 domain family member 24) gene. Individuals with DOORS syndrome have multiple abnormalities, and the main features are abnormal nails, deafness, short fingers and toes, and intellectual disability.

What Are the Clinical Features of DOORS Syndrome?

The clinical features of DOORS syndrome can be recognized after birth and may vary among individuals. Some individuals may not be affected by all the features.

The clinical features of limbs include:

• Onychodystrophy can affect both feet and hands.

• Osteodystrophy occurs due to impaired growth of finger and toe bones.

• Triphalangeal thumb is a condition in which the thumb has three parts instead of two that look like an extra finger.

• Hypoplasia or absence of bones at the end of fingers and toes.

• Abnormal dermatoglyphics (skin pattern).

• Delay in development.

Features of the nervous system include:

• Hyporeflexia (absent reflex of muscles).

• Cerebral atrophy (damage of nerve cells).

• Intellectual disability.

• Seizures (abnormal electrical brain activity that causes abnormal movements and behavior) occur during infancy. The types of seizures that can occur are:

  • Generalized tonic-clonic seizures or grand mal seizures are the most common type of seizure in which there is loss of consciousness, convulsions (quick muscle contraction and relaxation that causes uncontrollable movements), and rigidity.

  • Partial seizure affects one part of the brain and has no loss of consciousness.

  • Absent seizures occur for a short period and can look like staring into space.

  • Myoclonic seizures are non-repetitive contractions involving the upper extremity commonly, and if generalized, it causes bilateral jerking.

  • Status epilepticus is a seizure for more than 30 seconds. This requires immediate emergency care. It is life-threatening.

In some individuals, the seizures can be very severe and can cause life-threatening conditions.

Features of the genitourinary system include:

• Renal agenesis (absence of kidneys).

• Increased level of 2-oxoglutaric acid in the urine.

• Cystic renal dysplasia (reduced function of kidneys).

Features of the head and neck include:

• Deafness, in some cases, can be severe and mostly occurs due to damage in the inner ears, called sensorineural deafness.

• Microcephaly (small head).

• Bulbous nose.

• High-arched palate.

• Wide alveolar ridges that hold the tooth.

• Short lingual frenum (a mucous membrane that extends from the midline of the tongue to the floor of the mouth).

• Cleft palate (slit in the roof of the mouth).

• Open mouth.

• Low-set ears.

Features of the eye include:

• Cataract (hazy lens).

• Myopia (nearsightedness where the near object can be seen properly).

• Hypertelorism (increased distance between the eyes).

• Ptosis (stooping of upper eyelid).

• Optic nerve atrophy.

• Blindness.

Other features include:

• Thickened nuchal skin fold (a thick fold of skin that is present at the back of the neck of the fetus).

• Atrial and ventricular septal defect (an abnormal passage in the walls of the heart).

• Hypothyroidism.

What Are the Causes of DOORS Syndrome?

50 percent of the DOORS syndrome cases occur due to a mutation in the TBC1D24 gene, and in the other half of the cases, the cause is unknown. This condition is inherited in an autosomal recessive pattern in which the mutated gene is present in both the parents and is passed down to the child, that has two copies of the mutated gene. The parents are not affected by the condition and are called carriers. The features of this gene include:

• The TBC1D24 gene is located on chromosome 16.

• This gene provides information in the production of a protein called TBC1D24 protein.

• TBC1D24 protein, along with other proteins, is involved in the movement of vesicles which are fluid-filled small sacs that help in transferring proteins and other substances within the cell.

• TBC1D24 protein also helps in responding to oxidative stress, which occurs due to an imbalance in the free radicals and antioxidants in which the free radicals are increased and damage the cells.

• TBC1D24 protein is active in the brain, which helps in its development, and in stereocilia which are present in the inner ear, which helps in hearing.

Mutation in the TBC1D24 gene causes decreased function of the TBC1D24 protein leading to features of DOORS syndrome.

What Is the Diagnosis Of DOORS Syndrome?

The diagnosis of DOORS syndrome includes:

• DOORS syndrome can be identified soon after birth by identifying physical features such as nail abnormalities, bone abnormalities, and abnormal skin patterns.

• Further diagnosis can be confirmed by detailed patient history and family history.

• X- rays show abnormal abnormal fingers and toes and an extra bone in the thumb.

• Auditory tests can be done to suspect deafness.

• Increased levels of 2-oxoglutarate in the plasma (the liquid part of the blood) and urine.

• Molecular genetic testing reveals a mutation in the TBC1D24 gene.

What Is the Differential Diagnosis Of DOORS Syndrome?

The differential diagnosis of DOORS syndrome involves:

• Deafness and Onychodystrophy, dominant Form: A genetic disorder that causes deafness, nail abnormalities, and delayed development. This is also known as autosomal dominant (one mutated gene from one parent is enough to cause the disorder) type of DOORS syndrome.

• Eronen Syndrome (Digitorenocerebral Syndrome): A genetic disorder that affects the finger and toes, brain, and kidney.

• Coffin-Siris Syndrome: A genetic disorder that affects many body systems. Its main features include an abnormal pinky finger, developmental disability, and classical facial features such as a wide mouth, large lips, large eyebrows, excess body hair, and a small head.

What Is the Management Of DOORS Syndrome?

There is no cure for DOORS syndrome, but the treatment of symptoms involves multiple specialty teams such as pediatricians, neurologists, audiologists, surgeons, and other specialists. Management includes:

• Early intervention for hearing impairment can help in improving speech and communication.

• In case of seizures, anticonvulsants are given, and in case of status epilepticus, emergency treatment should be given.

• Early intervention should include special remedial education, social support, medical and vocational services, and physical therapy.

• Genetic counseling should be given to the affected individuals and families as they have a risk of passing down the syndrome to the next generation.

Conclusion:

Individuals with DOORS syndrome and family members should receive genetic counseling since it is inherited in an autosomal recessive pattern. The couple who are carriers have a 25 percent risk of transmitting the syndrome to the child, a 50 percent risk of being carriers by their children, and the other 25 percent of children may have normal genes and are not affected by this condition.