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.

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).

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.

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.

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

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.

Mode of Inheritance

Congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one FGF3 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with LAMM syndrome are obligate heterozygotes (carriers) for a pathogenic variant in FGF3.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an FGF3 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the FGF3 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Introduction. Fibroblast growth factor (FGF) proteins function in embryonic development, cell growth, morphogenesis, tissue repair, and tumor growth and invasion [Pownall & Isaacs 2010]. They mainly function through three pathways:

• RAS/MAP kinase pathway (the main pathway)
• Phosphoinositides 3 kinase/AKT pathway
• Phospholipase C gamma pathway

Physiologically, FGF3 binds to the FGF receptor (FGFR) 1b and 2b to activate its signaling cascade, thus regulating cellular proliferation, survival, migration, and differentiation [Zelarayan et al 2007]. Along with FGF8 and FGF10, FGF3 plays a crucial role in the embryonic development of the otic placode (which forms the inner ear) and its eventual differentiation into the vestibular and cochlear structures [Vendrell et al 2000, Wright & Mansour 2003, Toriello et al 2004]. Studies in mice and zebrafish have also shown the role of FGF3 in dental morphogenesis [Kettunen et al 2000, Jackman et al 2004].

Mechanism of disease causation. Loss of function; reported FGF3 pathogenic variants include nonsense, frameshift, and missense variants in highly conserved amino acid residues.

Molecular modeling suggests that the p.Arg95Trp pathogenic variant does not impair the interaction of FGF3 with FGFR2b receptors or heparin sulfate binding sites, which may result in residual function of FGF3 [Riazuddin et al 2011].

Acknowledgments

This work was supported by NIH-NIDCD grant R01DC009645 to M.T.

Author Notes

John P Hussman Institute for Human Genomics: Genetic Studies of Deafness

Division of Clinical and Translation Genetics: Deafness Clinic

Revision History

• 4 April 2019 (sw) Comprehensive update posted live
• 20 September 2012 (me) Review posted live
• 9 June 2012 (mt) Original submission

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