Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation, And Seizures Syndrome

A number sign (#) is used with this entry because deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome (DOORS) is caused by homozygous or compound heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.

Description

The DOOR syndrome is an acronym for deafness, onychodystrophy, osteodystrophy, and mental retardation. Cantwell (1975) suggested this designation for the disorder, which can also include triphalangeal thumbs, seizures, and abnormal dermatoglyphics. Inheritance is autosomal recessive.

See also DDOD syndrome (124480), which shows autosomal dominant inheritance of congenital deafness and onychodystrophy without mental retardation.

Clinical Features

Walbaum et al. (1970) described a brother and sister with mental retardation, perceptive deafness, dysplasia of the fingernails, triphalangeal thumbs, hypoplasia of the terminal phalanges, and 'decapsalidic' fingerprints, i.e., an arch pattern on each finger. The patient reported by Qazi and Smithwick (1970) may have had the same disorder.

Eronen et al. (1985) reported a constellation of features in a male infant who had 2 double first cousins, females, who had died with the same disorder. The patients had absence of the distal phalanges and nails of all 10 digits, cystic dysplasia of the kidneys, and dilated right cerebral ventricle. The 2 cousins died at age 2 years and 2 hours, respectively. The proband and the older surviving cousin had convulsions. Le Merrer et al. (1992) described this syndrome in 2 unrelated children. Absence or hypoplasia of the distal phalanges of the toes and fingers was a particularly striking feature. Expression of the renal and cerebral manifestations was variable. One patient had seizures with abnormal EEG and a double kidney with 2 ureters and 2 renal arteries; he died at the age of 6 months. Both patients showed a large nose with wide nasal tip.

Lin et al. (1993) reported what they considered to be the seventeenth case of the recessive form of the DOOR syndrome. The parents were not known to be consanguineous. The patient had developmental delay, severe sensorineural deafness, and abnormal nails and phalanges in the hands and feet. Urinary 2-oxoglutarate excretion was normal. There were no seizures in infancy.

Rajab et al. (2000) reported an additional 4 cases of DOOR syndrome in 2 related sibships from an extended Omani family. The children had deafness, onychodystrophy, osteodystrophy, microcephaly, and global developmental retardation with progressive blindness. Seizures, which were associated with hypsarrhythmia, were frequent and difficult to control and ultimately were the cause of death in 2 patients. An MRI of the brain in 1 patient showed a number of abnormalities including markedly reduced myelination. The urine organic acid analysis showed a 10-fold increase of 2-oxoglutarate. In 1 patient the placenta was noted to have multiple fluid-filled cysts. Rajab et al. (2000) suggested that there may be genetic heterogeneity in the autosomal recessive form of this syndrome, and that the presence of increased 2-oxoglutarate is associated with a more severe phenotype, which is frequently lethal.

Surendran et al. (2002) studied the activity of 2-oxoglutarate decarboxylase in the fibroblasts and white blood cells of 4 patients with autosomal recessive DOOR syndrome and found significantly lower levels as compared to controls.

Felix et al. (2002) reported 3 cases of DOOR syndrome in unrelated Brazilian children. One of the cases also had a congenital cardiac defect. None had organic acid abnormalities.

James et al. (2007) reported an infant girl with features of DOOR syndrome, including sensorineural deafness, distal phalangeal hypoplasia of the hands and feet, hypoplastic nails, and increased urinary 2-oxoglutaric acid and 2-hydroxyglutaric acid. She had coarse facial features with high forehead, mild hypertelorism, epicanthal folds, broad nasal bridge with prominent nasal tip and nares, long philtrum, and large mouth. She had poor feeding, recurrent respiratory infections, and died at age 10 months.

In a literature review, James et al. (2007) identified 32 patients with DOOR syndrome compiled from 18 publications. Universal features included profound deafness, usually from infancy, malformations of the nails and digits, and mental retardation. Most patients had coarse facial features with broad nasal bridge, anteverted nares, everted lower lip, and high-arched palate. Ophthalmologic anomalies were reported in 43% of patients, including optic atrophy and blindness, high myopia, and iris hypoplasia. Other neurologic abnormalities included neonatal hypotonia, seizures, and peripheral neuropathy. Less common findings included dental, renal, and cardiac anomalies. The disorder follows a progressive course and 32% die in early childhood from seizures or respiratory distress. James et al. (2007) postulated a neurometabolic etiology.

Mihci et al. (2008) reported DOOR syndrome in a patient born after conception with intracytoplasmic sperm injection. Her dizygotic twin was unaffected and healthy. The affected girl demonstrated speech delay, classic facial features of DOOR syndrome, and malformations of the nails and digits. She did not have organic acid abnormalities and showed only mild neurologic involvement.

Campeau et al. (2014) reported 11 patients from 9 unrelated families with DOORS syndrome. All patients had the 5 classic features of the disorder, including developmental delay and intellectual disability, deafness, abnormal fingers with short terminal phalanges, abnormal fingernails, and seizures. All but one had abnormal toes and toenails, and 3 had triphalangeal thumbs. Seizure types were variable and included generalized tonic-clonic, complex partial, focal clonic, and infantile spasms. Six patients had increased urinary 2-oxoglutaric acid.

Biochemical Features

Patton et al. (1987) described 3 further cases, 2 of which were from consanguineous Pakistani families. The patients showed an increase of 2-oxoglutarate in the plasma and an increase of 2-oxoglutarate and its metabolite alpha-hydroxy-glutarate in the urine. Patton et al. (1987) stated that similar levels of 2-oxoglutarate had been found in 1 of the patients reported by Nevin et al. (1982).

Inheritance

Sanchez et al. (1981) reported 2 affected sisters who were the offspring of second-cousin parents. Nevin et al. (1982) reported parental consanguinity. Qazi and Nangia (1984) reported affected brother and sister. Patton et al. (1987) described 3 further cases, 2 of which were from consanguineous Pakistani families.

Molecular Genetics

In 11 affected individuals from 9 unrelated families with deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome, Campeau et al. (2014) identified homozygous or compound heterozygous mutations in the TBC1D24 gene (see, e.g., 613577.0007-613577.0011). The mutations in the first families were found by whole-exome sequencing and confirmed by Sanger sequencing. Most of the mutations were missense substitutions; functional studies were not performed. The 9 families were ascertained from a larger cohort of 26 families with clinical features suggestive of the disorder. The remaining families did not carry TBC1D24 mutations, indicating genetic heterogeneity.

History

Although the patients reported by Eronen et al. (1985) and Le Merrer et al. (1992) were initially thought to have a novel distinct syndrome, Winter (1993) concluded that the disorder in those patients was identical to DOOR syndrome.