Genetic Hearing Impairment: Clinical, Genetic and Audiological Aspects of Turner syndrome and MYH9-Related Disease

Thorough descriptions of genotype-phenotype correlations in genetic hearing impairment facilitates accurate genetic counseling and allows early diagnosis and intervention. The aim of this thesis was to further delineate the knowledge about the clinical, genetic and audiological aspects of patients with Turner syndrome (TS) and MYH9-related disease (MYH9-RD). TS is a chromosomal disorder which is caused by complete or partial absence of one X-chromosome. Prominent features are short stature, estrogen deficiency, and dysmorphic abnormalities. This thesis shows that otologic disease, including middle ear pathology and hearing loss, is an important characteristic in TS. TS patients frequently suffer from recurrent otitis media and are prone to develop cholesteatoma. Sensorineural hearing loss (SNHL) is more pronounced in young adult TS women, whilst conductive hearing loss is most commonly seen in TS children. Oxandrolone, a weak androgen steroid, which has a growth enhancing effect in TS, has no effects on hearing. Hearing thresholds in general appeared to be about 10 dB worse in patients with a monosomy 45,X or isochromosome 46,X,i(Xq) karyotype (complete monosomy of the short arm of the X-chromosome (Xp)) compared with those with a mosaicism or other structural X-chromosomal anomaly (partial monosomy Xp). These results support the hypothesis that genes located on the Xp are of importance in hearing. Careful follow-up during childhood as well as adulthood is necessary to detect ear and hearing problems, especially for those with complete monosomy Xp. MYH9-RD is an autosomal dominant disorder deriving from mutations in MYH9, the gene for the non-muscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and non-congenital manifestations, namely SNHL, nephropathy, cataract, and/or alterations of liver enzymes. This thesis shows that the p.R705H mutation of the MYH9 gene is associated with MYH9-RD and not only with the non-syndromic deafness DNFA17 as was previously reported. Furthermore, the audiological features of patients with MYH9-RD are described. We show that severity and progression of SNHL are largely dependent on the causative NMMHC-IIA mutation. Age-related typical audiograms (ARTA) showed that the most progressive type of SNHL was associated with the p.R702C, p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. The p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas mutations at the non-helical tailpiece did not show any substantial progression. These data provide useful tools to predict the propensity for progression and the expected degree of severity of SNHL in individual MYH9-RD patients, especially in young subjects. Consequences in clinical practice are relevant not only for appropriate patient counseling, but also to set up personalized clinical management. Finally, this thesis shows that cochlear implantation is safe and effective in restoring hearing ability in most patients with MYH9-RD and severe to profound SNHL. Stricter follow-up should be considered for patients with unfavorable genotypes and cochlear implantation should be offered to these patients when they develop the criteria for candidacy.