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Last updated: 05/11/2023
Years published: 1997, 2001, 2003, 2012, 2015, 2023
NORD gratefully acknowledges Regan Hines and Annika Knuth, NORD Editorial Interns from the University of Notre Dame and Philippe M. Campeau, MD, Medical Genetics Service, Sainte-Justine Hospital, Montreal, Canada, for assistance in the preparation of this report.
DOORS syndrome is a rare multisystem genetic disorder that is typically recognized shortly after birth. DOORS is an acronym for the abnormalities that characterize the disorder: (D)eafness (sensorineural hearing loss); (O)nychodystrophy (malformation of the nails); (O)steodystrophy (malformation of certain bones); intellectual disability (previously referred to as mental (R)etardation), and in many cases, affected infants may experience (S)eizures (sudden episodes of uncontrolled electrical activity in the brain). DOORS syndrome is inherited in an autosomal recessive pattern. Treatments are directed toward specific symptoms of affected individuals.
DOORS syndrome is typically identified at birth by these symptoms: deafness, malformation of the fingernails and toenails (onychodystrophy) and defective formation of certain bones (osteodystrophy) of the fingers and toes. The syndrome may also be associated with seizure disorders.
Most infants with DOORS syndrome have congenital deafness in both ears due to sensorineural hearing loss. This means that 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. Hearing loss may not be detected until later during infancy. Deafness may cause delays in speech or impaired development of speech.
Infants with DOORS syndrome also typically have abnormalities of the structure, texture and color of the fingernails and toenails (onychodystrophy). These abnormalities may include misshapen, discolored, underdeveloped and/or rudimentary nails. 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 (osteodystrophy). The thumbs and/or great toes are often long, with abnormally large bones at the ends of the digits. In addition, an extra third bone (rather than the normal two) may be present in the thumbs and/or great toes (triphalangeal thumb/great toe). In some patients, this extra bone may not be fully developed and/or may be malformed. Patients may have a permanent curving of the fifth finger (clinodactyly). There may also be underdevelopment or absence of the bones at the ends of the other fingers and/or toes. In addition, affected infants may have distinctive, abnormal skin ridge patterns (dermatoglyphics) in which there are arch patterns on every finger.
Infants with DOORS syndrome may also have varying degrees of intellectual disability, ranging from mild to profound. Some children may have variable delays in achieving developmental milestones (e.g., sitting, walking, etc.) as well as speech delay. Intellectual disabilities can vary significantly between patients but are often severe and require intervention.
During the first year of life, some affected infants may also begin to experience sudden episodes of uncontrolled electrical activity in the brain (seizures). Without sufficient management of seizures, this may result in further deterioration of intellectual functioning. During the most common type of seizure, 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 โwarning symptomsโ before a seizure. Severely affected children 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). Some patients experience seizures that are difficult to control even with multiple antiepileptic medications, which have led to status epilepticus and can be life threatening.
Other possible symptoms include a wide nasal base, wide nasal bridge, gum enlargement (gingival overgrowth), low set ears, wide set eyes (hypertelorism), coarse facial features, downturned corners of mouth and a bulbous nose.
In most patients, DOORS syndrome is caused by harmful changes (variants) in the TBC1D24 gene. Some patients with DOORS syndrome have variants in the ATP6V1B2 gene.
DOORS syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Approximately 50 cases of DOORS syndrome have been reported in the medical literature, most often diagnosed at birth. DOORS syndrome appears to affect males and females in equal numbers.
DOORS syndrome may be suspected shortly after birth by the identification of certain physical features (i.e., bone, dermatoglyphic, and nail abnormalities). X-ray studies may show an extra bone in the thumbs and/or great toes as well as underdevelopment of bones in other fingers and/or toes. Genetic testing for variants in the TBC1D24 or ATP6V1B2 genes can confirm the diagnosis.
Clinical Testing and Work-Up
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.
Seizure episodes usually begin during the first year of life. Diagnostic evaluation includes certain advanced imaging techniques. Electroencephalography (EEG) records the electrical impulses produced by brain activity. Computerized tomography (CT) scanning is where a computer and x-rays are used to create a film showing cross-sectional images of the brainโs tissue structure. Magnetic resonance imaging (MRI) uses 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 DOORS 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 still being researched.
Treatment
The treatment for DOORS syndrome is directed toward the specific symptoms apparent in each individual. Treatment requires the coordinated efforts of a team of medical professionals such as pediatricians, surgeons, specialists who assess and treat hearing problems, dentists, physicians who diagnose and treat neurological disorders (neurologists), therapists and/or other health care professionals.
Treatment for seizures 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.
Hearing impairment should be assessed and treated through audiologic evaluation and/or cochlear implants, as early as possible to help minimize possible speech difficulties or improve communication ability. In addition, clinical evaluation should be conducted early in development and on a continuing basis to help determine the extent of intellectual disability. Early educational intervention and physical, occupational and speech therapy can benefit the patient in this regard. Additional special services that may be beneficial include special remedial education, special social support and other medical, social, and/or vocational services. Other treatment is symptomatic and supportive.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., deafness, seizures, etc.)
JOURNAL ARTICLES
Qiu S, Zhao W, Gao X, et al. Syndromic deafness gene ATP6V1B2 controls degeneration of spiral ganglion neurons through modulating proton flux. Front Cell Dev Biol. 2021;9:742714. doi:10.3389/fcell.2021.742714 [doi].
Gao X, Dai P, Yuan YY. Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes. Hum Genet. 2021. doi:10.1007/s00439-021-02310-2 [doi].
Salian S, Benkerroum H, Nguyen TTM, et al. PIGF deficiency causes a phenotype overlapping with DOORS syndrome. Hum Genet. 2021;140(6):879-884. doi:10.1007/s00439-020-02251-2 [doi].
Beauregard-Lacroix E, Pacheco-Cuellar G, Ajeawung NF, et al. DOORS syndrome and a recurrent truncating ATP6V1B2 variant. Genet Med. 2021;23(1):149-154. doi:10.1038/s41436-020-00950-9 [doi].
Parzefall T, Frohne A, Koenighofer M, et al. A novel variant in the TBC1D24 lipid-binding pocket causes autosomal dominant hearing loss: evidence for a genotype-phenotype correlation. Front Cell Neurosci. 2020;14:585669. doi:10.3389/fncel.2020.585669 [doi].
Tona R, Lopez IA, Fenollar-Ferrer C, et al. Mouse models of human pathogenic variants of TBC1D24 associated with non-syndromic deafness DFNB86 and DFNA65 and syndromes involving deafness. Genes (Basel). 2020;11(10):1122. doi: 10.3390/genes11101122. doi:10.3390/genes11101122 [doi].
Zรกdori D, Szalรกrdy L, Reisz Z, et al. Clinicopathological relationships in an aged case of DOORS syndrome with a p.Arg506X mutation in the ATP6V1B2 gene. Front Neurol. 2020;11:767. doi:10.3389/fneur.2020.00767 [doi].
Danarti R, Rahmayani S, Wirohadidjojo YW, Chen W. Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature. Eur J Dermatol. 2020;30(4):404-407. doi:10.1684/ejd.2020.3850 [doi].
Aprile D, Fruscione F, Baldassari S, et al. TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons. Cell Death Differ. 2019;26(11):2464-2478. doi:10.1038/s41418-019-0313-x [doi].
Mucha BE, Banka S, Ajeawung NF, et al. A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay. Genet Med. 2019;21(5):1058-1064. doi:10.1038/s41436-018-0290-3 [doi].
Campeau PM, Hennekam RC, DOORS syndrome collaborative group. DOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome. Am J Med Genet C Semin Med Genet. 2014;166C(3):327-332. doi:10.1002/ajmg.c.31412 [doi].
Campeau PM, Kasperaviciute D, Lu JT, et al. The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol. 2014;13(1):44-58. doi:S1474-4422(13)70265-5 [pii].
James AW, Miranda SG, Culver K, Hall BD, Golabi M. DOOR syndrome: Clinical report, literature review and discussion of natural history. Am J Med Genet. 2007;143A(23):2821-2831. doi:https://doi.org/10.1002/ajmg.a.32054.
Rajab A, Riaz A, Paul G, Al-Khusaibi S, Chalmers R, Patton MA. Further delineation of the DOOR syndrome. Clin Dysmorphol. 2000;9(4):247-251. doi:10.1097/00019605-200009040-00003 [doi].
Patton MA, Krywawych S, Winter RM, Brenton DP, Baraitser M. DOOR syndrome (deafness, onycho-osteodystrophy, and mental retardation): elevated plasma and urinary 2-oxoglutarate in three unrelated patients. Am J Med Genet. 1987;26(1):207-215. doi:10.1002/ajmg.1320260131 [doi].
Nevin NC, Thomas PS, Calvert J, Reid MM. Deafness, onycho-osteodystrophy, mental retardation (DOOR) syndrome. Am J Med Genet. 1982;13(3):325-332. doi:10.1002/ajmg.1320130316 [doi].
INTERNET
Genetic and Rare Diseases Information Center. Last Updated: Nov. 8, 2021. https://rarediseases.info.nih.gov/diseases/1685/door-syndrome. Accessed Nov 15, 2022.
Mucha BE, Hennekam RCM, Sisodiya S, et al. TBC1D24-Related Disorders. 2015 Feb 26 [Updated 2017 Dec 7]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK274566/ Accessed Nov 15, 2022.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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