What are the clinical features, genetic cause, and recommended management for DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, Intellectual disability, Seizures)?

DOORS Syndrome: Clinical Features, Genetic Basis, and Management

Overview and Diagnosis

DOORS syndrome is a rare autosomal recessive neurodevelopmental disorder characterized by five cardinal features: sensorineural Deafness, Onychodystrophy (nail hypoplasia/aplasia), Osteodystrophy (shortened terminal phalanges), intellectual disability (mental Retardation), and Seizures, with mutations in TBC1D24 and ATP6V1B2 genes accounting for the majority of genetically confirmed cases. 1, 2

Clinical Features

Cardinal Manifestations

• Sensorineural hearing loss is present in all affected individuals and represents a defining feature of the syndrome 1, 3
• Onychodystrophy manifests as hypoplastic or completely absent nails on hands and feet 1, 3
• Osteodystrophy includes small or absent distal phalanges of hands and feet, with characteristic finger-like thumbs 4, 3
• Intellectual disability ranges from moderate to severe and is universally present 1, 3
• Seizures typically begin in infancy and persist throughout life 1, 3

Characteristic Facial Features

• Coarse facial features include a large nose with wide nasal bridge, bulbous tip, and anteverted nares 3
• Long prominent philtrum with downturned corners of the mouth are consistently observed 3
• These facial features are under-appreciated but aid in clinical recognition 3

Additional Clinical Manifestations

• Ophthalmologic abnormalities including retinal anomalies and progressive optic atrophy occur in a subset of patients 1, 3
• Neurological deterioration follows a progressive course with peripheral polyneuropathy developing over time 3
• Structural brain malformations such as Dandy-Walker malformation have been reported 1
• Cardiac defects including ventricular septal defects and atrial septal defects can occur 4
• Urinary tract abnormalities including hydronephrosis and hydroureter have been documented 4
• Skeletal abnormalities including scoliosis and rocker bottom feet may be present 1
• Respiratory difficulties can complicate the clinical course 1

Metabolic Findings

• Elevated 2-oxoglutaric acid in urine and plasma is found in the majority of patients and serves as a useful diagnostic marker 1, 3

Genetic Basis

Primary Causative Genes

• TBC1D24 mutations account for approximately half of patients with complete DOORS syndrome phenotype 1, 2
• ATP6V1B2 mutations represent the second major genetic cause, with both genes involved in endolysosomal function and membrane trafficking 5, 2
• Inheritance pattern is autosomal recessive for both TBC1D24 and ATP6V1B2-related DOORS syndrome 1, 2

Differential Diagnosis and Genetic Overlap

• SMARCB1 mutations causing Coffin-Siris syndrome can present with overlapping features including deafness, nail hypoplasia, and intellectual disability 1
• Distinguishing features for Coffin-Siris syndrome include absence of seizures, presence of retinal anomalies, Dandy-Walker malformation, and 2-oxoglutaric aciduria 1
• KCNH1 and KCNN3 mutations cause Zimmermann-Laband syndrome with overlapping nail and intellectual disability features but distinct gingival hypertrophy 2

Natural History and Prognosis

Progressive Deterioration

• Neurological decline is characteristic, with progressive sensorineural deafness, worsening seizure control, and development of peripheral polyneuropathy 3
• Early mortality is common, with many patients dying in early infancy, particularly when cardiac or renal anomalies are present 4
• Tauopathy development has been documented in aged cases, suggesting premature neurodegenerative changes related to lysosomal dysfunction 5

Recommended Management

Initial Diagnostic Workup

• Genetic testing should include targeted sequencing of TBC1D24 and ATP6V1B2 genes, or whole exome sequencing to identify causative mutations 1, 2
• Metabolic screening must include urine and plasma 2-oxoglutaric acid levels as a diagnostic marker 1, 3
• Audiological evaluation with brainstem auditory evoked responses to confirm and characterize sensorineural hearing loss 3
• Cardiac evaluation with echocardiography to screen for congenital heart defects 4
• Renal ultrasound to identify urinary tract abnormalities 4
• Ophthalmologic examination to detect retinal anomalies and monitor for progressive optic atrophy 1, 3
• Brain MRI to identify structural malformations such as Dandy-Walker malformation 1
• Skeletal survey to document extent of osteodystrophy 3

Seizure Management

• Antiepileptic therapy should be initiated promptly given the universal presence of seizures and their onset in infancy 1, 3
• Neurological monitoring with serial EEGs to guide seizure management 3

Hearing and Communication Support

• Cochlear implantation should be considered, though efficacy may be limited by progressive neurological decline 3
• Alternative communication strategies including sign language and augmentative communication devices are essential given the severity of hearing loss 3

Developmental and Educational Support

• Early intervention services including physical, occupational, and speech therapy should begin immediately upon diagnosis 3
• Special education services tailored to the degree of intellectual disability are required 3

Multidisciplinary Surveillance

• Cardiology follow-up for patients with identified cardiac defects 4
• Nephrology monitoring for those with urinary tract abnormalities 4
• Ophthalmology surveillance with regular examinations to monitor for progressive optic atrophy 3
• Neurology follow-up to monitor progressive neurological deterioration and adjust seizure management 3
• Orthopedic evaluation for scoliosis and other skeletal complications 1

Genetic Counseling

• Recurrence risk counseling should emphasize the 25% recurrence risk for future pregnancies given autosomal recessive inheritance 1, 2
• Prenatal testing options including targeted mutation analysis should be offered to families with known mutations 2

Pitfalls to Avoid

• Do not overlook cardiac and renal screening as these abnormalities significantly impact mortality but may not be immediately apparent 4
• Do not assume static disease course as progressive neurological deterioration is characteristic and requires ongoing monitoring 3
• Do not confuse with Coffin-Siris syndrome when SMARCB1 mutations are present, as management implications differ 1