DiagnosisClinical Diagnosis The diagnosis of congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) is suspected in individuals with the following: Profound congenital sensorineural deafness Severe inner ear anomalies diagnosed by a 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 sized teeth) with widely spaced teeth (Figure 1B) FigureFigure 1. Congenital deafness with labyrinthine aplasia, microtia, and microdontia
A. Microtia with anteverted ears
B. Microdontia with widely spaced teeth
C. CT image demonstrating bilateral petrous bone aplasia and (more...)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 Molecular Genetic Testing Gene. FGF3 is the only gene in which mutations are known to cause congenital deafness with labyrinthine aplasia, microtia, and microdontia. Table 1. Summary of Molecular Genetic Testing Used in Congenital Deafness with Labyrinthine Aplasia, Microtia, and MicrodontiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityFGF3Sequence analysisSequence variants 213/13 unrelated families 3 ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletionsUnknown, none reported 5Research only1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Sensi et al [2011]4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Although no large deletions/duplications have been reported in FGF3, such testing would be expected to detect exonic, multiexonic, and whole-gene deletions/duplications.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy Confirmation of the diagnosis in a proband. In an individual with characteristic clinical findings, identification of a deleterious FGF3 mutation by molecular genetic testing confirms the diagnosis of LAMM syndrome. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in FGF3. Note: Microdeletion at chromosome 11q13 in a region containing FGF3 led to the suggestion that FGF3 haploinsufficiency may be the cause of otodental syndrome [Gregory-Evans et al 2007]. However, this observation is inconsistent with the detection of heterozygous null FGF3 mutations (resulting in haploinsufficiency) in phenotypically normal parents of individuals with LAMM syndrome; a role for mutation of FGF3 in otodental syndrome is expected to be more complex than this proposed mechanism.}

Natural History Labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) was originally described by Tekin et al [2007]. Since then 56 individuals with homozygous and compound heterozygous FGF3 mutations from 13 consanguineous and non-consanguineous families have been reported [Sensi et al 2011]. Age at diagnosis ranges from one 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 labyrinth 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 mutation. 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].OtherMotor delays during infancy, presumably the result of impaired balance; commonly seenStenosis of the jugular foramen with enlarged emissary vein diagnosed by cranial imaging with no clinical manifestations Normal growth and physical development are normalAverage 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 or part of the LAMM syndrome spectrum include: hypoplastic alae nasi, mild anatomic defects including unilateral stenosis of the uretero-pelvic junction, ocular abnormalities such as strabismus-hypermetropia, and mildly distinctive facial features such as long facies, downslanting palpebral fissures, deep-set eyes, high nasal bridge, and mild micrognathia. Life span is not typically altered in individuals with classic LAMM syndrome. Healthy adults reaching their 40s and 50s have been reported [Tekin et al 2007, Alsmadi et al 2009].

Genotype-Phenotype Correlations Intra- and interfamilial variability of the clinical phenotype is currently minimal in LAMM syndrome, except for those individuals with the c.283C>T (p.Arg95Trp) mutation (see Molecular Genetics); p.Arg95Trp is associated with a less severe phenotype than the other FGF3 mutations [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 mutations 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 mutations had either no inner ear components or primitive vesicle-like structures.

Differential DiagnosisLADD (lacrimo-auriculo-dento-digital) syndrome is a multiple congenital anomaly syndrome characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary systems; cup-shaped ears; hearing loss; and dental and digital (particularly thumb) anomalies. Mutations in FGFR2, FGF10, and FGFR3 have been associated with this syndrome. Inheritance is autosomal dominant.Other single gene disorders or microdeletion/microduplication syndromes should be considered in individuals with intellectual disability in addition to typical anomalies seen in LAMM syndrome [Dill et al 2011].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome), the following evaluations are recommended:ENT evaluation with CT/MRI of the temporal bones to evaluate inner ear anomalies that may influence habilitation options (see Treatment of Manifestations)Audiology evaluation Dental evaluationRenal ultrasound examination to evaluate for kidney anomalies, including unilateral stenosis of the uretero-pelvic junctionOphthalmology evaluation for strabismus and hypermetropiaMedical genetics consultationTreatment of ManifestationsIdeally, 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-impairedAn 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 labyrinth 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 Prevention of Secondary ComplicationsRegardless 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 [Smith et al 2012]. However, the presence of severe inner ear anomalies and Michel aplasia in individuals with LAMM syndrome limits auditory habilitation options.Delayed gross 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]. SurveillanceYearly evaluations by the multi-disciplinary team mentioned in Treatment of Manifestations is appropriate.Agents/Circumstances to AvoidNoise 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 RiskSince some individuals with LAMM syndrome can have normal-appearing ears, an audiology evaluation is recommended for sibs at 25% risk to allow early diagnosis and treatment of hearing impairment. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFGF311q13​.3Fibroblast growth factor 3FGF3 homepage - Mendelian genesFGF3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia (View All in OMIM) View in own window 164950FIBROBLAST GROWTH FACTOR 3; FGF3 610706DEAFNESS, CONGENITAL, WITH INNER EAR AGENESIS, MICROTIA, AND MICRODONTIANormal allelic variants. The normal full-length cDNA is encoded in three exons spanning 9.4 kb (9457 bp) of the genomic DNA. The cDNA comprises 1548 bp with an open reading frame of 720 nucleotides encoding 239 amino acids. Pathologic allelic variants. Twelve FGF3 mutations have been described in LAMM syndrome. Six mutations are missense and six are nonsense mutations or small deletions. Most are private mutations except for p.Arg104*, which has been observed in Turkish, Pakistani, and Italian families [Ramsebner et al 2010, Riazuddin et al 2011, Sensi et al 2011]. Table 2. Selected FGF3 Allelic Pathologic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.17T>Cp.Leu6ProNM_005247​.2
NP_005238​.1c.146A>Gp.Tyr49Cysc.150C>Ap.Cys50*c.196G>Tp.Gly66Cysc.255delTp.Ile85Metfs*15c.283C>Tp.Arg95Trpc.310C>Tp. Arg104*c.394delCp. Arg132GLyfs*26c.466T>Cp.Ser156Proc.616delGp.Val206Serfs*117c.317A>Gp.Tyr106Cysc.457_458delTGp.Trp153Valfs*51See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. Fibroblast growth factor proteins function in embryonic development, cell growth, morphogenesis, tissue repair, and tumor growth and invasion [Pownall & Isaacs 2010]. They mainly function through three pathways including the RAS/MAP kinase pathway (the main pathway), phosphoinositides 3 kinase/AKT pathway, and the phospholipase C gamma pathway. Physiologically, FGF3 binds to the FGFR (fibroblast growth factor receptor) 1b and 2b to activate its signaling cascade, thus regulating cellular proliferation, survival, migration, and differentiation [Zelarayan et al 2007]. A unique feature of FGFs is that they act in concert with heparin or heparin sulfate proteoglycans to activate the signaling cascade and induce a variety of cellular processes. 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].Abnormal gene product. Mutations reported are mainly nonsense and frameshift (leading to truncated proteins), null mutations (absence of protein from nonsense-mediated mRNA decay), or missense mutations in highly conserved amino acid residues (probably resulting in greatly reduced or absent protein). Molecular modeling suggests that the p.Arg95Trp mutation 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].