Delayed Diagnosis of Giant Cell Arteritis in the Setting of Isolated Lingual Necrosis.

BACKGROUND: Lingual necrosis is a rare complication of giant cell arteritis (GCA). METHODS: A 77-year-old woman presented for treatment of a painful and discolored tongue, odynophagia, and dehydration refractory to antimicrobials over 2 weeks. An extensive, well-demarcated necrotic area was visualized on the anterior tongue upon admission. Leukocytosis, thrombocytosis, and elevated erythrocyte sedimentation rate were present. Computed tomography angiogram of the head and neck revealed an undulated-beaded appearance of the distal internal carotid arteries and vertebral arteries bilaterally. RESULTS: High-dose intravenous steroids were initiated for suspected vasculitis. Temporal artery biopsy confirmed the diagnosis of GCA. The patient's condition improved and the anterior tongue was well healed at 1 month follow-up. CONCLUSIONS: An atypical presentation of GCA (eg, isolated lingual necrosis) risks a delay in diagnosis and increased morbidity. Any patient above the age of 50 years presenting with tongue necrosis, in the absence of known cause, should undergo expedited workup for GCA.

Novel missense and 3'-UTR splice site variants in LHFPL5 cause autosomal recessive nonsyndromic hearing impairment.

LHFPL5, the gene for DFNB67, underlies autosomal recessive nonsyndromic hearing impairment. We identified seven Pakistani families that mapped to 6p21.31, which includes the LHFPL5 gene. Sanger sequencing of LHFPL5 using DNA samples from hearing impaired and unaffected members of these seven families identified four variants. Among the identified variants, two were novel: one missense c.452 G > T (p.Gly151Val) and one splice site variant (c.*16 + 1 G > A) were each identified in two families. Two known variants: c.250delC (p.Leu84*) and c.380 A > G (p.Tyr127Cys) were also observed in two families and a single family, respectively. Nucleotides c.452G and c.*16 + 1G and amino-acid residue p.Gly151 are under strong evolutionary conservation. In silico bioinformatics analyses predicted these variants to be damaging. The splice site variant (c.*16 + 1 G > A) is predicted to affect pre-mRNA splicing and a loss of the 5' donor splice site in the 3'-untranslated region (3'-UTR). Further analysis supports the activation of a cryptic splice site approximately 357-bp downstream, leading to an extended 3'-UTR with additional regulatory motifs. In conclusion, we identified two novel variants in LHFPL5, including a unique 3'-UTR splice site variant that is predicted to impact pre-mRNA splicing and regulation through an extended 3'-UTR.

Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish.

Cyclic AMP (cAMP) production, which is important for mechanotransduction within the inner ear, is catalyzed by adenylate cyclases (AC). However, knowledge of the role of ACs in hearing is limited. Previously, a novel autosomal recessive non-syndromic hearing impairment locus DFNB44 was mapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearing-impaired family members, a nonsense mutation c.3112C>T (p.Arg1038*) within adenylate cyclase 1 (ADCY1) was identified. This stop-gained mutation segregated with hearing impairment within the family and was not identified in ethnically matched controls or within variant databases. This mutation is predicted to cause the loss of 82 amino acids from the carboxyl tail, including highly conserved residues within the catalytic domain, plus a calmodulin-stimulation defect, both of which are expected to decrease enzymatic efficiency. Individuals who are homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafish adcy1b morphants had no FM1-43 dye uptake and lacked startle response, indicating hair cell dysfunction and gross hearing impairment. In the mouse, Adcy1 expression was observed throughout inner ear development and maturation. ADCY1 was localized to the cytoplasm of supporting cells and hair cells of the cochlea and vestibule and also to cochlear hair cell nuclei and stereocilia. Ex vivo studies in COS-7 cells suggest that the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli. These results demonstrate that ADCY1 has an evolutionarily conserved role in hearing and that cAMP signaling is important to hair cell function within the inner ear.

A point mutation in the gene for asparagine-linked glycosylation 10B (Alg10b) causes nonsyndromic hearing impairment in mice (Mus musculus).

The study of mouse hearing impairment mutants has led to the identification of a number of human hearing impairment genes and has greatly furthered our understanding of the physiology of hearing. The novel mouse mutant neurological/sensory 5 (nse5) demonstrates a significantly reduced or absent startle response to sound and is therefore a potential murine model of human hearing impairment. Genetic analysis of 500 intercross progeny localized the mutant locus to a 524 kilobase (kb) interval on mouse chromosome 15. A missense mutation in a highly-conserved amino acid was found in the asparagine-linked glycosylation 10B gene (Alg10b), which is within the critical interval for the nse5 mutation. A 20.4 kb transgene containing a wildtype copy of the Alg10b gene rescued the mutant phenotype in nse5/nse5 homozygous animals, confirming that the mutation in Alg10b is responsible for the nse5/nse5 mutant phenotype. Homozygous nse5/nse5 mutants had abnormal auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), and cochlear microphonics (CMs). Endocochlear potentials (EPs), on the other hand, were normal. ABRs and DPOAEs also confirmed the rescue of the mutant nse5/nse5 phenotype by the wildtype Alg10b transgene. These results suggested a defect in the outer hair cells of mutant animals, which was confirmed by histologic analysis. This is the first report of mutation in a gene involved in the asparagine (N)-linked glycosylation pathway causing nonsyndromic hearing impairment, and it suggests that the hearing apparatus, and the outer hair cells in particular, are exquisitely sensitive to perturbations of the N-linked glycosylation pathway.

Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89.

Previously, DFNB89, a locus associated with autosomal-recessive nonsyndromic hearing impairment (ARNSHI), was mapped to chromosomal region 16q21-q23.2 in three unrelated, consanguineous Pakistani families. Through whole-exome sequencing of a hearing-impaired individual from each family, missense mutations were identified at highly conserved residues of lysyl-tRNA synthetase (KARS): the c.1129G>A (p.Asp377Asn) variant was found in one family, and the c.517T>C (p.Tyr173His) variant was found in the other two families. Both variants were predicted to be damaging by multiple bioinformatics tools. The two variants both segregated with the nonsyndromic-hearing-impairment phenotype within the three families, and neither mutation was identified in ethnically matched controls or within variant databases. Individuals homozygous for KARS mutations had symmetric, severe hearing impairment across all frequencies but did not show evidence of auditory or limb neuropathy. It has been demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice. Moreover, KARS has strong localization to the spiral ligament region of the cochlea, as well as to Deiters' cells, the sulcus epithelium, the basilar membrane, and the surface of the spiral limbus. It is hypothesized that KARS variants affect aminoacylation in inner-ear cells by interfering with binding activity to tRNA or p38 and with tetramer formation. The identification of rare KARS variants in ARNSHI-affected families defines a gene that is associated with ARNSHI.