NORD gratefully acknowledges Phillip L. Pearl, MD, Chief of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Harvard Medical School, for assistance in the preparation of this report.
DOOR syndrome is a rare genetic disorder that may be recognized shortly after birth. “DOOR,” an acronym for characteristic abnormalities associated with the syndrome, stands for (D)eafness due to a defect of the inner ear or auditory nerve (sensorineural hearing loss); (O)nychodystrophy or malformation of the nails; (O)steodystrophy, meaning malformation of certain bones; and mild to profound mental (R)etardation. In addition, in some cases, affected infants may have sudden episodes of uncontrolled electrical activity in the brain (seizures). Distinctive nail abnormalities may include underdeveloped, misshapen, or absent fingernails and/or toenails, while characteristic bone malformations may consist of an extra small bone in the thumbs and/or great toes (triphalangy) and/or underdevelopment (hypoplasia) of bones in other fingers and/or toes. DOOR syndrome is inherited as an autosomal recessive trait.
DOOR syndrome is a rare genetic disorder characterized by deafness at birth (congenital), malformation of the fingernails and toenails (onychodystrophy), defective formation of certain bones (osteodystrophy) of the fingers and toes, and intellectual disability. The syndrome may also be associated with seizure disorders.
In most cases, infants with DOOR syndrome have congenital deafness of both ears due to sensorineural hearing loss. In those with such hearing impairment, sound may be conducted normally through the external and middle ear. However, sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve, resulting in hearing loss. (With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain.) Although such sensorineural hearing loss is usually present at birth, it may not be detected until later during infancy. As affected children age, deafness may cause delays in or impaired development of speech.
Infants with DOOR syndrome also typically have characteristic abnormalities of the structure, texture, and color of the fingernails and toenails. Such abnormalities may include misshapen, discolored, underdeveloped (hypoplastic), and/or rudimentary nails. In addition, in some affected infants, some of the fingernails and/or toenails may be absent.
Various bone deformities of the fingers and/or toes (digits) may also be present. The thumbs and/or great toes are often long, with abnormal largeness of the bones at the ends of the digits (distal phalanges). In addition, an extra third bone (rather than the normal two) may be present in the thumbs and/or great toes, a condition known as “triphalangy.” In some cases, this accessory (supernumerary) bone may not be fully developed and/or may be malformed (rudimentary). There may also be underdevelopment (hypoplasia) or absence of the bones at the ends of the other fingers and/or toes (distal phalanges). In addition, affected infants may have distinctive, abnormal skin ridge patterns (dermatoglyphics) in which there are arch patterns on every finger.
Infants with DOOR syndrome may also have varying degrees of intellectual disability, ranging from mild to profound and, in some cases, variable delays in achieving developmental milestones (e.g., sitting, walking, etc.) in addition to speech. During the first year of life, some affected infants may also begin to experience sudden episodes of uncontrolled electrical activity in the brain, particularly grand mal seizures. Without sufficient management of seizures, such episodes may result in further deterioration of intellectual functioning in some cases. During a grand mal (generalized tonic-clonic) seizure, affected individuals may experience an abrupt loss of consciousness, generalized stiffening of muscles, rhythmic contraction and relaxation or uncontrollable jerking of muscle groups, and other findings. In addition, some may experience certain “warning symptoms” before a seizure. In severe cases, some affected individuals may have a prolonged series of such seizures, without fully regaining consciousness between attacks, or experience a prolonged, continuous seizure attack while unconscious (status epilepticus). In some individuals with DOOR syndrome, additional symptoms or findings may also be present.
DOOR syndrome is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In autosomal recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
Parents of several individuals with DOOR syndrome have been closely related by blood (consanguineous). With closely related parents, there may be an increased likelihood that both carry the same recessive disease gene, increasing the risk that their children may inherit the two genes necessary for the development of the disease.
The term “DOOR syndrome” has been used loosely to describe a number of different genetic syndromes, including an autosomal dominant disorder characterized by sensorineural deafness and nail malformations. (For more on this disorder, known as “deafness and onychodystrophy, dominant form,” please see the “Related Disorders” section below.) However, reports in the medical literature have noted that the “DOOR” acronym should only be used to refer to the recessive form of congenital sensorineural (D)eafness, (O)nycho-(O)steodystrophy, and mental (R)etardation (i.e., with triphalangeal thumbs and/or great toes, abnormal dermatoglyphics, and possible seizure disorder).
DOOR syndrome appears to affect males and females in equal numbers. Approximately 50 cases have been reported in the medical literature.
DOOR syndrome may be suspected shortly after birth by the identification of certain characteristic physical features (i.e., bone, dermatoglyphic, and nail abnormalities). A diagnosis of DOOR syndrome may be confirmed based upon a thorough clinical evaluation, a detailed patient history, and specialized testing, such as x-ray studies. X-ray studies may reveal the presence of an extra bone in the thumbs and/or great toes as well as underdevelopment of bones in other fingers and/or toes. Per the medical literature, infants with these characteristic abnormalities should be tested for sensorineural deafness.
Deafness may be suspected within the first few months of life and confirmed through a variety of specialized hearing (auditory) tests. Intellectual disability may also be present at birth but may not be detected until an affected infant is old enough to be thoroughly evaluated.
In those who also experience seizures, such seizure episodes usually begin during the first year of life. Diagnostic evaluation may include electroencephalography (EEG) and certain advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI). EEG records the electrical impulses produced by brain activity. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain’s tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain.
According to reports in the medical literature, some individuals with DOOR syndrome may also have elevated levels of the organic acid 2-oxoglutarate in the urine and fluid portion of the blood (plasma). The implications of this finding are not fully understood. However, some investigators have suggested that elevated 2-oxoglutarate levels may potentially be associated with more severe symptoms, findings, and disease course in some cases.
Recent whole exome sequencing research has identified the gene TBC1D24 as an important cause of the syndrome, although diverse phenotypes have been described. DOORS syndrome and can cause diverse phenotypes. In a cohort of 36 patients clinically diagnosed with DOORS syndrome, 13 individuals from 10 families had TBC1D24 mutations, while two patients had mutations in another gene known as SMARCB1, known to cause Coffin-Siris syndrome, which is associated with 2-oxoglutaric aciduria. There are several syndromes in the differential diagnosis of DOOR syndrome.
The treatment of DOOR syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians, surgeons, specialists who assess and treat hearing problems, physicians who diagnose and treat neurological disorders (neurologists), and/or other health care professionals.
Hearing impairment should be assessed and treated as early as possible to help minimize possible speech difficulties or improve communication ability as an affected child ages. In addition, clinical evaluation should be conducted early in development and on a continuing basis to help determine the extent of intellectual disability.
In individuals with seizure episodes, treatment may include various medications that may help to prevent, reduce, or control seizures (anticonvulsants). Prolonged seizures accompanied by unconsciousness (status epilepticus) require immediate medical intervention.
Early intervention is also important to ensure that children with DOOR syndrome reach their potential. Special services that may be beneficial include special remedial education, speech pathology, special social support, physical therapy, and other medical, social, and/or vocational services.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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