Congenital Deafness With Labyrinthine Aplasia, Microtia, And Microdontia
Summary
Clinical characteristics.
Congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) is characterized by: profound bilateral congenital sensorineural deafness associated with inner ear anomalies (most often bilateral complete labyrinthine aplasia); microtia (type I) that is typically bilateral (although unilateral microtia and normal external ears are observed on occasion); and microdontia (small teeth). Individuals with LAMM syndrome commonly have motor delays during infancy presumably due to impaired balance from inner ear (vestibular) abnormalities. Growth, physical development, and cognition are normal.
Diagnosis/testing.
The diagnosis of LAMM syndrome is established in a proband by identification of biallelic pathogenic variants in FGF3 on molecular genetic testing.
Management.
Treatment of manifestations: Enrollment in appropriate early-intervention programs and educational programs for the hearing impaired; consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia; consideration of cochlear implantation for those with a cochleovestibular nerve and a cochlear remnant; routine ophthalmologic management of strabismus.
Prevention of secondary complications: Attention to the increased risk for accidents secondary to delayed gross motor development and deafness.
Surveillance: Yearly evaluations with a physician familiar with LAMM syndrome or other forms of hereditary deafness; regular ENT and dental evaluations.
Agents/circumstances to avoid: Individuals with residual cochlear function should avoid noise exposure. Because of the high risk for disorientation when submerged in water, swimming needs to be undertaken with caution.
Evaluation of relatives at risk: It is recommended that sibs have hearing screening to allow early diagnosis and treatment of hearing impairment.
Genetic counseling.
LAMM syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FGF3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
The diagnosis of congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) should be suspected in individuals with the following:
- Profound congenital sensorineural deafness
- Severe inner ear anomalies diagnosed by CT scan or MRI of the inner ear. The most common inner ear anomaly is complete labyrinthine aplasia with no recognizable structure in the inner ear (also referred to as Michel aplasia) (Figure 1C).
- Microtia with shortening of the upper part of the auricles (also referred to as type I microtia) (Figure 1A)
- Microdontia (small teeth) with widely spaced teeth (Figure 1B)
Figure 1.
Congenital deafness with labyrinthine aplasia, microtia, and microdontia A. Microtia with anteverted ears
Some individuals may also show gross motor developmental delay during infancy (presumably due to the absence of vestibular system) accompanied by additional features that include:
- Hypoplasia/dysplasia of middle ear anatomic structures identified by imaging studies;
- Stenosis of the jugular foramen with enlarged emissary vein identified by imaging studies.
Establishing the Diagnosis
The diagnosis of LAMM syndrome is established in a proband by identification of biallelic pathogenic variants in FGF3 on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of LAMM syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of LAMM syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of LAMM syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of FGF3 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes FGF3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of LAMM syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| FGF3 | Sequence analysis 3 | 15 reported 4 |
| Gene-targeted deletion/duplication analysis 5 | 3 reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Tekin et al [2007], Tekin et al [2008], Alsmadi et al [2009], Ramsebner et al [2010], Dill et al [2011], Riazuddin et al [2011], Sensi et al [2011], Singh et al [2014], Basdemirci et al [2019]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Gregory-Evans et al [2007]
Clinical Characteristics
Clinical Description
Labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) was originally described by Tekin et al [2007]. Since then more than 60 individuals with homozygous and compound heterozygous FGF3 pathogenic variants from more than 20 families (consanguineous and nonconsanguineous) have been reported [Sensi et al 2011]. Age at diagnosis is typically age 50 years or younger (range: 1 month to 50 years).
Profound congenital sensorineural deafness is bilateral in all individuals reported to date. Most have bilateral complete labyrinthine aplasia, some have unilateral complete labyrinthine aplasia and visible but severely malformed inner ear structures in the other ear, and a few have some inner ear structure present bilaterally [Tekin et al 2007, Ramsebner et al 2010, Riazuddin et al 2011].
Type I microtia with shortening of auricles above the crura of the antihelix tends to be bilateral in most. Unilateral microtia and bilateral normal external ears have been reported in individuals with the p.Arg95Trp pathogenic variant. Anteverted ears and large skin tags or lobulation of the upper side of the auricle can be seen in some [Tekin et al 2008].
Small teeth have been observed in all reported individuals. Dental anomalies include conical shape and decreased tooth diameter resulting in widely spaced teeth. Loss of tooth height and peg-shaped lateral incisors have been seen. Supernumerary upper lateral incisors and absence of the first premolars have been observed.
Mild micrognathia and excessive caries were noted in one adult.
Hypodontia or dental root anomalies have not been observed [Tekin et al 2007].
Other
- Motor delays during infancy, presumably the result of impaired balance; commonly seen
- Stenosis of the jugular foramen with enlarged emissary vein diagnosed by cranial imaging with no clinical manifestations
- Normal growth and physical development
- Average or above-average cognition; affected individuals often attend and thrive at schools for the hearing impaired.
- Absence of limb anomalies and lacrimal findings (seen in some FGFR-related syndromes)
Findings that may be incidental to LAMM syndrome include: mild anatomic defects including unilateral stenosis of the uretero-pelvic junction, ocular abnormalities such as strabismus-hypermetropia; brain anomalies such as pontocerebellar arachnoid cysts; cardiovascular findings such as prominent azygos vein; and mildly distinctive facial features such as long facies, downslanting palpebral fissures, deep-set eyes, high nasal bridge, hypoplastic alae nasi, and mild micrognathia.
Life span is not typically altered in individuals with LAMM syndrome. Healthy adults in their 40s and 50s have been reported [Tekin et al 2007, Alsmadi et al 2009].
Genotype-Phenotype Correlations
The variant p.Arg95Trp is associated with a less severe phenotype than the other FGF3 pathogenic variants [Ramsebner et al 2010, Riazuddin et al 2011].
- Microtia was not observed in eight of 11 individuals homozygous for p.Arg95Trp; in contrast, none of the persons reported with other pathogenic variants had normal-appearing external ears.
- Inner ear structures were identified in seven of 20 individuals homozygous for p.Arg95Trp; in contrast, persons reported with other pathogenic variants had either no inner ear components or primitive vesicle-like structures.
Prevalence
LAMM syndrome is very rare; no prevalence estimates have been established. It has been reported in more than 60 individuals from more than 20 unrelated families.
Differential Diagnosis
Table 2.
Other Genes of Interest in the Differential Diagnosis of LAMM Syndrome
| Gene(s) | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/LAMM syndrome | Distinguishing from LAMM syndrome | |||
| FGF10 FGFR2 FGFR3 | Lacrimo-auriculo-dento-digital (LADD) syndrome (OMIM 149730) | AD |
|
|
| EYA1 SIX1 SIX5 | Branchiootorenal spectrum disorder | AD | Hearing loss |
|
| KMT2D KDM6A | Kabuki syndrome | AD XL |
|
|
| SALL1 | Townes-Brocks syndrome | AD |
|
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked; LAMM = labyrinthine aplasia, microtia, and microdontia
Other single-gene disorders or microdeletion/microduplication syndromes should be considered in individuals who have intellectual disability in addition to typical anomalies seen in LAMM syndrome [Dill et al 2011].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia
| System/ Concern | Evaluation | Comment |
|---|---|---|
| ENT | CT &/or MRI of the temporal bones | Evaluate inner ear anomalies |
| Hearing | Audiologic evaluation | Evaluate for sensorineural hearing loss |
| Dental | Dental evaluation | Evaluate for dental anomalies |
| Renal | Consider renal ultrasound. | Evaluate for kidney anomalies incl unilateral stenosis of the uretero-pelvic junction |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Ideally, the team evaluating and treating a deaf individual should include an otolaryngologist with expertise in the management of early-childhood otologic disorders, an audiologist experienced in the assessment of hearing loss in children, a clinical geneticist, and a pediatrician. The expertise of an educator of the Deaf, a neurologist, and a pediatric ophthalmologist may also be required.
- Enrollment in appropriate early-intervention programs and educational programs for the hearing impaired is appropriate.
- An important part of the evaluation is determining the appropriate habilitation option. Possibilities include hearing aids, vibrotactile devices, brain stem implants, and cochlear implantation:
- Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [Riazuddin et al 2011]
- Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children over age 12 months with severe-to-profound hearing loss.
- Routine ophthalmologic management of strabismus, if present, is indicated.
Prevention of Secondary Complications
Regardless of its etiology, uncorrected hearing loss has consistent sequelae: Auditory deprivation through age two years is associated with poor reading performance, poor communication skills, and poor speech production. Educational intervention is insufficient to completely remediate these deficiencies.
In contrast, early auditory intervention (whether through amplification or cochlear implantation) is effective (see Hereditary Hearing Loss and Deafness Overview). However, the presence of severe inner ear anomalies and Michel aplasia in individuals with LAMM syndrome limits auditory habilitation options.
Delayed gross motor development (presumably the result of impaired balance and profound deafness) increases the risk for accidents and trauma.
- The risk for accidents can be addressed in part by use of visual or vibrotactile alarm systems in homes and schools.
- The risk for pedestrian injury can be reduced by choosing routes with visual displays of crosswalks.
- Anticipatory education of parents, health providers, and educational programs about hazards can help address the risk for falls [Gaebler-Spira & Thornton 2002, Chakravarthy et al 2007].
Surveillance
Table 4.
Recommended Surveillance for Individuals with Deafness with Congenital Labyrinthine Aplasia, Microtia, and Microdontia
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Deafness | ENT evaluation | Annually |
| Strabismus | Ophthalmologic evaluation | Annually |
| Dental | Dental evaluation | As necessary |
Yearly evaluations by the multidisciplinary team mentioned in Treatment of Manifestations is appropriate.
Agents/Circumstances to Avoid
Noise exposure is a well-recognized environmental cause of hearing loss. Since this risk can be minimized by avoidance, individuals with LAMM syndrome and a residual cochlea should be counseled appropriately.
Because of the high risk for disorientation when submerged in water, swimming needs to be undertaken with caution.
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic sibs of an affected individual by molecular genetic testing for the FGF3 pathogenic variant in the family in order to allow early diagnosis and treatment of hearing impairment. (Note: Affected sibs may have normal-appearing ears.)
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.