Otodental syndrome, also known as otodental dysplasia, is an exceptionally rare disease that is distinguished by a specific phenotype known as globodontia, that in rare cases can be associated with eye

coloboma A coloboma (from the Greek , meaning "defect") is a hole in one of the structures of the eye, such as the iris, retina, choroid, or optic disc. The hole is present from birth and can be caused when a gap called the choroid fissure, which is ...

and high frequency hearing loss. Globodontia is an abnormal condition that can occur in both the primary and secondary

dentition Dentition pertains to the development of teeth and their arrangement in the mouth. In particular, it is the characteristic arrangement, kind, and number of teeth in a given species at a given age. That is, the number, type, and morpho-physiology ...

, except for the incisors which are normal in shape and size. This is demonstrated by significant enlargement of the canine and molar teeth. The premolars are either reduced in size or are absent.Chen, Ren-Jye, Horng-Sen Chen, Li-Min Lin, Cheng-Chung Lin, and Ronald J. Jorgenson. "“Otodental” Dysplasia." Oral Surgery, Oral Medicine, Oral Pathology 66.3 (1988): 353-58 In some cases, the defects affecting the teeth, eye and ear can be either individual or combined.Gregory-Evans, C. Y., M. Moosajee, M. D. Hodges, D. S. Mackay, L. Game, N. Vargesson, A. Bloch-Zupan, F. Ruschendorf, L. Santos-Pinto, G. Wackens, and K. Gregory-Evans. "SNP Genome Scanning Localizes Oto-dental Syndrome to Chromosome 11q13 and Microdeletions at This Locus Implicate FGF3 in Dental and Inner-ear Disease and FADD in Ocular Coloboma." Human Molecular Genetics 16.20 (2007): 2482-493 When these conditions are combined with eye coloboma, the condition is also known as oculo-otodental syndrome. The first known case of otodental syndrome was found in Hungary in a mother and her son by Denes and Csiba in 1969. Prevalence is less than 1 out of every 1 million individuals.Bloch-Zupan, Agnès. "The Portal for Rare Diseases and Orphan Drugs."Orphanet: Otodental Syndrome. N.p., Last Updated Nov. 2010. Web. 03 Mar. 2014. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2791 The cause of otodental syndrome is considered to be genetic. It is an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

inheritance and is variable in its expressivity.Santos-Pinto L, Oviedo M, Santos-Pinto A, Iost HI, Seale NS, Reddy AK. Otodental syndrome: three familial case reports. Pediatr Dent. 1998;20:208–211

Haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...

in the fibroblast growth factor 3 (

FGF3 INT-2 proto-oncogene protein also known as FGF-3 is a protein that in humans is encoded by the ''FGF3'' gene. Function FGF-3 is a member of the fibroblast growth factor family. FGF3 binds to Fibroblast Growth Factor Receptor 3 (FGFR3) to serve ...

) gene (11q13) has been reported in patients with otodental syndrome and is thought to cause the

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

. Both males and females are equally affected. Individuals diagnosed with otodental syndrome can be of any age; age is not a relevant factor. Currently there are no specific genetic treatments for otodental syndrome. Dental and orthodontic management are the recommended course of action.

Symptoms and signs

Symptoms of otodental syndrome can and usually appear in early development and progress with age. Although the specific frequency of the symptoms is not known, the duration is recognized to be for life; assuming no treatment has been undergone. The symptoms are variable to each individual, can range greatly in severity and are dependent on

gene expression Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

. More severe symptoms include: * Globodontia – an abnormal condition that can occur in both primary and secondary tooth development, in which the molars and canines are greatly enlarged. It refers to the enlarged bulbous fused malformed posterior teeth with almost no discernible cusps or grooves. The molars are known to have a rounded globe-like shape. Can attribute to pain. *

Sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ (cochlea and associated structures), or the vestibulocochlear nerve (Cranial nerves, cranial nerve VIII). SNHL accounts for a ...

(SNHL) – also known as nerve related hearing loss, is a form of hearing loss associated with complications within the inner ear."Types, Causes and Treatment , Hearing Loss Association of America." HLAA Updates. N.p., n.d. Web. 04 Mar. 2014. * Taurodontism – known as a condition in which the body of a tooth is enlarged at the expense of the roots. This results in an enlarged pulp chamber, lack of proper bonding at the

cementoenamel junction In dental anatomy, the cementoenamel junction (CEJ) is the location where the enamel, which covers the anatomical crown of a tooth, and the cementum, which covers the anatomical root of a tooth, meet. Informally it is known as the neck of the t ...

, and can cause the pulpal floor to be displaced towards the root.Rajendran R. Shafer's Text Book of Oral Pathology. 7th ed. New Delhi (India): Elsevier (Reed Elsevier India); 2009. Developmental disturbances of oral and paraoral structures; p. 45. Discomfort and pain are usually associated with these characteristics. * Endodontic- Periodontic

lesions A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...

– oral lesions that can potentially form into abscesses. May cause further soreness and pain. Other possible, less severe, symptoms involve: * Absent premolars – individuals suffering from otodental syndrome will typically lack the ability to develop premolars due to its genetic related affects. * Ocular

– an existent hole within the eye of the individual. The hole can be present in either the iris, choroid, optic disc, or retina and is acquired during early/prenatal development. Individuals with these symptoms may exhibit sensitivity to light, blurred vision, and/or blind spots; depending on the size of the missing tissue and its location in the eye.

Mechanism

Otodental syndrome is a rare condition that is genetically inherited in an

manner. Although there is no specific biological mechanism for otodental syndrome, what is recognized is that there is a genetic mutation, known as

haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...

, that occurs in the fibroblast growth factor 3 (

) gene (11q13). This is the alleged cause of the physical abnormalities and symptoms associated with otodental syndrome. Although in individuals with signs of ocular

, a

microdeletion In genetics, a deletion (also called gene deletion, deficiency, or Deletion anomaly, deletion mutation) (sign: delta (letter), Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA rep ...

in the Fas-associated death domain (

FADD FAS-associated death domain protein, also called MORT1, is encoded by the ''FADD'' gene on the 11q13.3 region of chromosome 11 in humans. FADD is an Signal transducing adaptor protein, adaptor protein that bridges members of the Tumor necrosi ...

) gene (11q13.3) was also found to be responsible. There is variable penetrance and variable

within these genetic mutations. Individuals with

sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ (cochlea and associated structures), or the vestibulocochlear nerve (Cranial nerves, cranial nerve VIII). SNHL accounts for a ...

are believed to have a local

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...

in the auditory segment of the inner ear, known as the

cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus (cochlea), modiolus. A core component of the cochlea is the organ of Cort ...

. The biological mechanism for this is currently unknown as well.

Diagnosis

Diagnosis of otodental syndrome was established using clinical, histopathological and audiometric methodologies. In normal individuals, by the age of 2-3,

radiograph Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical ("diagnostic" radiography and "therapeu ...

images should depict any signs of premolar development. A formal diagnosis of no premolar growth can be done by age 6 in order to check for signs of otodental syndrome.

can be another measure for proper diagnosis as well as checking for ocular

. The latter is usually noticed at an around birth. Molecular

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

can aid in the diagnosis of the affected individual, which would determine if there are any abnormalities in the

gene (11q13) or the

gene (11q13.3). Additional tests that can help diagnose otodental syndrome are ear infection tests, hearing tests, oral examination, and eye examinations to check for the specific phenotypic associations. Due to the rarity of otodental syndrome, most symptoms are looked at on an individual basis unless multiple symptoms are all apparent at once. There is potential for differential diagnosis due to similarities in symptoms. Other diseases that share common symptoms are chondroectodermal dysplasia, achondrodysplasia, and

osteopetrosis Osteopetrosis, literally , also known as marble bone disease or Albers-Schönberg disease, is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which ...

Treatment

There is currently no specified treatment for individuals suffering from otodental syndrome. Considering that there are many possible genetic and phenotypic associations with the condition, treatment is provided based on each individual circumstance. It is recommended that those affected seek ear, nose & throat specialists, dental health specialists, and facial oral health specialists immediately; in order to determine potential treatment options. Common treatment methods given are: * Dental treatment/management – which can be complex, interdisciplinary and requires a regular follow up. Tooth extraction(s)and if needed, medications may be administered for pain, anxiety, and anti-inflammation. The affected individual is usually placed on a strict and preventative dental regiment in order to maintain appropriate

oral hygiene Oral hygiene is the practice of keeping one's oral cavity clean and free of disease and other problems (e.g. bad breath) by regular brushing of the teeth (dental hygiene) and adopting good hygiene habits. It is important that oral hygiene be carr ...

and health. * Endodontic treatment – individuals consult with an endodontist to analyze the individuals

dental pulp The pulp is the connective tissue, nerves, blood vessels, and odontoblasts that comprise the innermost layer of a tooth. The pulp's activity and signalling processes regulate its behaviour. Anatomy The pulp is the neurovascular bundle cen ...

. Typically endodontic treatment proves to be difficult due to duplicated pulp canals within the affected teeth. There may be a need for multiple extractions as well.

Dental prosthesis A dental prosthesis is an intraoral (inside the Human mouth, mouth) prosthesis used to dental restoration, restore (reconstruct) intraoral defects such as missing Human tooth, teeth, missing parts of teeth, and missing soft or hard structures of ...

and/or

dental implants A dental implant (also known as an endosseous implant or fixture) is a prosthesis that interfaces with the bone of the jaw or skull to support a dental prosthesis such as a crown, bridge, denture, or facial prosthesis or to act as an orthod ...

may be necessary for individuals that lack proper oral function, appearance, and comfort. *

Orthodontic Orthodontics (also referred to as orthodontia) is a dentistry specialty that addresses the diagnosis, prevention, management, and correction of mal-positioned teeth and jaws, as well as misaligned bite patterns. It may also address the modificati ...

treatment – given the predicament of the size and location of the affected oral area, molars and canines, orthodontic treatment is generally required in order treat any problems associated with the individuals bite pattern and tooth appearance. *

Hearing aids A hearing aid is a device designed to improve hearing by making sound audible to a person with hearing loss. Hearing aids are classified as medical devices in most countries, and regulated by the respective regulations. Small audio amplifiers ...

– in some cases affected individuals will suffer from hearing imparities and it may be necessary for hearing aid use.

Prognosis

The functional prognosis is mostly good with those that suffer from otodental syndrome. Appropriate dental treatment, hearing aids, and visitation to necessary specialists are recommended. Quality of life may be affected by psychological and functional aspects. It is also recommended that genetic counseling be given to families that have or may have this condition.

Recent research

Currently there are no open research studies for otodental syndrome.ClinicalTrials.gov. A Service of the U.S. National Institutes of Health, n.d. Web. 04 Mar. 2014. Due to the rarity of this disease, current research is very limited. The most recent research has involved

case studies A case study is an in-depth, detailed examination of a particular case (or cases) within a real-world context. For example, case studies in medicine may focus on an individual patient or ailment; case studies in business might cover a particular fi ...

of the affected individuals and/or families,K Colter JD, Sedano HO. Otodental syndrome: A Case Report. Pediatr Dent. 2005 Nov-Dec;27(6):482-5 all of which show the specific phenotypic symptoms of otodental syndrome. Investigations on the effects of

and

have also been performed. These studies have shown successes in supporting previous studies that mutations to

and neighboring genes may cause the associated phenotypic abnormalities.Sensi, Alberto, Stefano Ceruti, Patrizia Trevisi, Francesca Gualandi, Micol Busi, Ilaria Donati, Marcella Neri, Alessandra Ferlini, and Alessandro Martini. "LAMM Syndrome with Middle Ear Dysplasia Associated with Compound Heterozygosity for FGF3 Mutations." American Journal of Medical Genetics Part A 155.5 (2011): 1096-101 According to recent studies involving

zebrafish The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...

embryos An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

, there is also support in that the

gene contributed to ocular coloboma symptoms as well. Future research studies are required in order to better grasp the specific relationship between the gene involved and its effect on various tissues and organs such as teeth, eyes, and ear. Little is known and there is still much to be determined.

References

External links

{{Medical resources , ICD10 = K00.2 , OMIM = 166750 , Orphanet = 2791 Genetic syndromes Congenital oral disorders Syndromes