Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases

Abstract

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.

Keywords: FGF3; LAMM syndrome; and microdontia; congenital deafness; external ear abnormalities; labyrinthine aplasia; microtia.

Figure 1

Axial T2 high resolution 3D sequence on the internal auditory canal (IAC) in patient 1 (A,B) show absence of membranous labyrinth in both petrous bones (*) with presence of VII nerves (arrows in A) and V nerves (arrows in B). Axial CT petrous bone in patient 7 shows incomplete partition type 1 malformation on the right (C′,C″), characterised by dysplastic lateral semicircular canal (white arrow in C′), dilated vestibular aqueduct (black arrow in C′), dilated cochlea and vestibule without visualisation of the modiolus (arrows in C″). In the same patient on the left (D) there is a rudimentary otocyst (arrow) with very narrowed IAC (dotted arrow). Axial T2 high resolution 3D sequence on the IAC in patient 7 (E,F) demonstrates presence of VII (dotted arrow) and VIII (black arrow) cranial nerves in the ponto-cerebellar angle on both sides. The rudimentary otocyst on the left is also noted (F, white arrow).

Figure 2

Axial CT petrous bone in patient 8 of the right (A,A′) and left (B,B′) ears shows complete labyrinthine aplasia (Michel deformity) characterised by absence of the inner ear structures: cochlea, vestibule, semicircular canals and vestibular and cochlear aqueducts. The otic capsule is hypoplastic and only a vestigial IAC is observed in the left ear (B′). Middle ear ossicles are bilaterally present and normal.

Figure 3

Mutational spectrum in the human FGF3 gene responsible for LAMM syndrome and its correlation at protein level. The mutation notation at DNA level is referred to the coding sequence (CDS, position 1 to 720), thus the position +1 corresponds to the adenine of the initiation codon (ATG) and the position 720 corresponds to the guanine in the last position of the stop codon (TAG). 5′UTR = 5′ Untranslated region in exon 1; 3′UTR = 3′ Untranslated region in exon 3; SP = signal peptide (1 to 17aa); FGF domain (44 to 181aa). Number coordinates and protein domains were obtained from the NCBI reference sequences NM_005247.4 (nucleotide) and NP_005238 (protein), respectively.