Paula and Bobby
Parents of Lillie
Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and seizures syndrome (DOORS)
What is Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and seizures syndrome (DOORS)?
This rare disease is a congenital genetic condition that presents with a variety of different symptoms affecting multiple parts of the body.
There are just 50 cases diagnosed worldwide, to date.
The main features of the syndrome include intellectual disability, hearing impairment, and digit anomalies.
This syndrome is also known as:
Brachydactyly Due To Absence Of Distal Phalanges DDOD Digitorenocerebral Syndrome Door; Syndrome DOORS; syndrome Drc; Syndrome Eronen;
What gene changes cause Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and seizures syndrome (DOORS)?
Mutations in the TBC1D24 gene are responsible for the syndrome. The syndrome is inherited in an autosomal recessive pattern.
Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
What are the main symptoms of Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and seizures syndrome (DOORS)?
The symptoms are mainly congenital and most are present at birth.
The main symptoms of the syndrome include deafness (related to the inner ears), short or absent nails, short fingers and toes as well as intellectual disability and developmental delay.
Seizures are a common symptom of the syndrome and they may take the form of different types of seizures that vary in intensity and severity.
Physical and facial features of the syndrome include a very small head, a wide and fat nose, narrow and high arched palate, and possible dental abnormalities.
Many individuals with the syndrome also have an extra bone and joint in the thumb.
Individuals may also experience heart and urinary tract issues. Low levels of the thyroid hormone may also be a symptom.
Possible clinical traits/features:
Coarse facial features, Malformation of the heart and great vessels, Dandy-Walker malformation, Cystic renal dysplasia, Everted lower lip vermilion, Nail dystrophy, Downturned corners of mouth, Brachydactyly, Prominent nose, Profound sensorineural hearing impairment, High myopia, Microcephaly, Progressive, Muscular hypotonia, Intellectual disability, Anteverted nares, Low-set ears, Long philtrum, Autosomal recessive inheritance, Seizure, Renal agenesis, Optic atrophy, Sensorineural hearing impairment, Hyporeflexia, Abnormality of the skin, High palate, Short distal phalanx of finger, Triphalangeal thumb, Nail dysplasia, Wide nasal bridge, Bulbous nose, Cataract, Anonychia, Cerebral atrophy, Bilateral sensorineural hearing impairment, Blindness
How does someone get tested for Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and seizures syndrome (DOORS)?
The initial testing for Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and seizures syndrome (DOORS) can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and seizures syndrome (DOORS)
The main features of this severe autosomal recessive condition are contained in the expanded acronym. Some authors have added an S to DOOR, as seizures are a cardinal feature. The head circumference is usually normal at birth. The diagnosis is suggested by looking at the hands and feet. The big toes and thumbs are long, and often have three segments (triphalangy), while the other fingers and toes are short due to an absent or hypoplastic distal phalanx. The nails are absent or poorly formed. The facial features contribute to the diagnosis, especially the bilateral ptosis, short broad nose, the broad nasal tip, and large nostrils which are useful in forming a Gestalt.
Thornton et al., (1994) reported a case with hydronephrosis and hydroureter, and a VSD and secundum ASD. A sib had similar urinary tract anomalies. Reardon et al., (1994) reported a case with abnormal peripheral nerve conduction. The prognosis can be poor and status epilepticus can be a problem.
There are probably at least two distinct forms of this condition, one being dominant and the other recessive, but even these two groups are likely to be heterogeneous.
The entity here refers to sibs such as those described by Feinmesser and Zelig (1961), whose parents were consanguineous. The deafness was sensorineural, congenital but sub-total. Intelligence was thought to be normal. Hair and teeth were normal but the nails on the fingers and toes were rudimentary. See elsewhere for the DOOR syndrome in which retardation is usually profound.
Patton et al., (1987) noted elevated plasma and urinary 2-oxoglutarate in three severely affected unrelated patients. More mildly affected patients have been reported without increased excretion of 2-oxoglutarate (Bos et al., 1994). Note that infants with raised 2-oxoglutarate have been reported where the biochemical abnormality has been a deficiency of alpha-ketoglutarate. These infants have not had the dysmorphic features of DOOR syndrome (Bonnefont et al., 1992).
The condition is probably separate from that described by Goodman (1969) in a dominant family without retardation. Lin et al., (1993) reported a case without convulsions, but with EEG abnormalities, although the child was severely retarded. 2-oxoglutarate excretion was not raised in the urine.
The patient described by Eronen et al., (1985) has DOOR syndrome and excretes large amounts of 2-oxoglutarate (Somer, personal communication, 1991). Likewise, the sibs reported by Le Merrer et al., (1992) most likely have this syndrome (2-oxoglutarate was not measured) - additional features included cataracts, optic atrophy and Dandy-Walker malformation.
The patient reported by Lin et al., (1993) had mild developmental delay and no seizures. However, she did have severe sensorineural deafness and abnormal nails and terminal phalanges. Urinary 2-oxoglutarate excretion was normal.
A 3-generation family was reported by White and Fahey, (2011). Those affected had deafness, nail hypoplasia, hypoplasia of the terminal phalanges, finger-like thumbs and bulbous ends to their fingers.
Surendran et al., (2002) reported four patients from three families with the clinical features of DOOR and increased urinary levels of 2-oxoglutarate. The activity of 2-oxoglutarate in fibroblasts and white blood was decreased. The activity of E1component of the 2-Oxoglutarate dehydrogenase complex in fibroblasts and white blood cells was significantly lower compared to the controls. The condition is well reviewed by James et al., (2007).
Note the case (one of the twins) reported by Mihci et al., (2008) after conception by intracytoplasmic sperm injection. Twenty-six families were included in the study by Campeau et al., (2014). . Eleven persons from nine families had TBC1D24 mutations. Eight did not have seizures and three were not deaf.
Lugano et al., (2016) reported three siblings with compound heterozygous missense mutations in the TBC1D24 gene. Affected males died during infancy while the affected female died at four years of age. The proband also had an abnormal hearing screening.
A male patient with a novel homozygous mutation in the TBC1D24 gene was described by Atli et. al., (2017). An unusual feature was hypochromic microcytic anaemia.
* This information is courtesy of the L M D.
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