Deafness, Congenital, With Inner Ear Agenesis, Microtia, And Microdontia

A number sign (#) is used with this entry because of evidence that congenital deafness with inner ear agenesis (Michel aplasia), microtia, and microdontia is caused by homozygous or compound heterozygous mutation in the FGF3 gene (164950) on chromosome 11q13.

See also otodental dysplasia (166750), a syndrome of sensorineural deafness and globodontia, which has been associated with hemizygous microdeletion on chromosome 11q13 involving the FGF3 gene.

Nomenclature

Tekin et al. (2008) proposed that this syndrome be called deafness with labyrinthine aplasia, microtia, and microdontia (LAMM).

Clinical Features

Tekin et al. (2007) delineated a new autosomal recessive human malformation syndrome in 3 unrelated Turkish families including 9 affected individuals ranging in age from 7 to 42 years. All affected individuals had profound congenital sensorineural deafness, type I microtia with shortening of auricles above the crura of the antihelix, and microdontia with widely spaced teeth. In addition, anteverted ears were present in 7 of the 9 affected individuals. Computed tomography of the temporal bones in all patients showed the complete absence of inner ear structures bilaterally, including cochlea, vestibule, and semicircular canals (Michel aplasia) with normal-appearing middle ear structures. In one affected patient, cranial magnetic resonance imaging of the cerebellopontine angle showed the bilateral absence of cochleovestibular nerve with otherwise normal cerebral and cerebellar structures. Physical examination was normal in all patients. The standing heights of 2 patients were about the 97th percentile for normal Turkish children at the same age. A delay in gross motor skills during infancy, presumably caused by impaired balance, was noted in all patients. Seven affected subjects were students at local schools for the hearing impaired and had no difficulties in writing or reading. All children were reported to be average or above average students, with no problems communicating by use of an indigenous sign language. One individual, the father of 4 unaffected children, had a paying job and was responsible for the support of his family. Therefore, all affected individuals appeared to have normal cognitive abilities. The presence of auriculodental findings was considered suggestive of lacrimoauriculodentodigital (LADD) syndrome (149730), but the lacrimal and digital findings and dominant transmission of LADD were absent in these patients. Tekin et al. (2007) concluded that this might be the same disorder as that described by Hersh et al. (1991).

Tekin et al. (2008) reported 4 additional children from 2 consanguineous Turkish families with deafness with LAMM. All had the classic features of congenital deafness, microtia with shortened upper part of the auricles, and microdontia with widely spaced conical teeth. Additional features included skin tags at the superior medial aspect of the helical rim and small pits on the anterior portion of the helical crus. Radiographic findings indicated complete labyrinthine aplasia bilaterally, although 1 individual had a unilateral small cystic structure. Two individuals from 1 family showed pontocerebellar arachnoid cysts and stenosis of the jugular foramen. In a review of 13 patients from 5 families, including the patients reported by Tekin et al. (2007), Tekin et al. (2008) found that the most prominent findings of Michel aplasia were bilateral absence of inner ear structures, petrous bone hypoplasia, and a well-developed middle ear cavity with flat medial borders. Radiographic evaluation of the skull base detected jugular foraminal stenosis in 6 of 12 with LAMM and 2 of 2 available with nonsyndromic Michel aplasia. All these patients and 1 patient with a normal jugular cross-sectional area had enlarged emissary veins. FGF3 mutations were not identified in 8 additional probands with congenital deafness and various inner ear anomalies.

Alsmadi et al. (2009) reported a large consanguineous Saudi Arabian family in which 21 individuals had congenital sensorineural deafness associated with microtia and microdontia with widely spaced teeth. All affected family members were descendants of a common ancestor who had lived 6 generations ago in a geographically isolated small village. The proband was a 4-year-old girl with type 1 microtia and low-set anteverted dysplastic ears. Dysplastic ear changes were asymmetric and more pronounced in the upper half. Incisors and canine teeth were small and misaligned with increased space between the teeth. Otoacoustic emissions, indicating outer hair cell dysfunction, and brainstem auditory evoked potentials were absent, indicating profound deafness. On brain imaging, the right side vestibular and cochlear system were not visualized, whereas the left side had a cystic vestibulum. Inner ear structure revealed absent cochlea and no semicircular canals bilaterally. Neural structures also appeared to be absent. Other physical development was normal.

In Italian sibs with deafness, microtia, and microdontia, Sensi et al. (2011) observed involvement of the middle ear as well as inner ear structures, in contrast to previously reported patients. Examination of the petrous bones by CT and MRI showed bilateral hypoplasia/aplasia of the labyrinth and internal auditory canal in both sibs. In addition, CT scan in the 12-year-old brother showed hypoplasia of the petrous pyramid that was more evident on the right and bilateral hypo/dysplasia of the middle ear, with hypoplasia of the incus long process and absent stapes as well as absent oval and round windows. His affected 9-year-old sister also had bilateral hypoplasia of the middle ear on CT scan, with thick malleus handles and irregular malleus heads, hypoplasia of the incus long process, and absent oval and round windows. The stapes was present in the sister, however. Sensi et al. (2011) stated that the middle ear defects could be coincidental or they might represent a variable finding in LAMM syndrome.

Molecular Genetics

Tekin et al. (2007) found homozygosity for a different FGF3 mutation in each of 3 Turkish families with microtia, microdontia, and Michel aplasia. All 3 mutations were predicted to result in nonfunctional proteins.

Tekin et al. (2008) identified 2 homozygous FGF3 mutations (164950.0005 and 164950.0006, respectively) in affected members of 2 additional Turkish families with deafness with LAMM. Heterozygous mutation carriers did not have clinical abnormalities.

In affected members of a large consanguineous Saudi Arabian family with deafness, microtia, and microdontia, Alsmadi et al. (2009) identified a homozygous mutation in the FGF3 gene (164950.0004).

Sensi et al. (2011) reported 2 families with deafness, microtia, and microdontia, 1 from Albania and 1 from Italy, in which affected individuals were compound heterozygous for mutations in the FGF3 gene (164950.0002 and 164950.0007-164950.0009, respectively). The authors stated that these were the first compound heterozygotes for mutations in the FGF3 gene to be reported. In the Italian family, the heterozygous carrier mother had a history of ear surgery for a defect said to be similar to that of her affected daughter (no photographs were available).