Page 82 - Clinical variability in Noonan syndrome with emphasison ear and eye

CHAPTER 5
Unfortunately, in two of these patients audiological tests were not performed. However, in the third patient a bilateral HI was found. The inner ear abnormalities found in the three cases had much in common. Reduced numbers of spiral ganglion cells were found, the endolymphatic sacs and vestibular aqueducts were dislocated and enlarged lateral semicircular canals were reported. The combination of these inner ear anomalies with conductive HI caused by otitis media may lead to mixed HI (16) and also the chronic or multiple otitis media infections may lead to SNHI. In one case a pure conductive HI was described with ossicular chain abnormalities during reconstruction, including the absence of the long process of the incus (5). We did not perform any histopathological examination in our NS patients.
Recommendations for future studies
In this study we used retrospective data from different clinics and hospitals. Further prospective studies about middle and inner ear abnormalities in NS can provide supplemental information of HI in NS and can show a more detailed audiological examination. In next studies it would be preferable to perform corresponding audiological examinations in all patients and to correlate them to genetic analysis.
Genotype-phenotype correlation
Genotype - phenotype correlation of NS and NS related disorders with HI was studied once before in literature (17). Among 24 PTPN11 positive patients, 5 had a SNHI. Among the other mutation-positive patients (SOS1, RAF1, BRAF, KRAS and SHOC2) no SNHI was measured. No information about the hearing test, severity of HI or ages was given. In this cohort we showed nine patients with SNHI, five PTPN11, two SOS1, one RAF1 mutation and in one patient no mutation was found. Five out of 48 PTPN11 positive patients were found to have SNHI. In our study the PTPN11 gene mutation was found in all four of the patients with severe bilateral congenital SNHI. They all received CI with good results. Interestingly, the two Noonan patients previously mentioned in the literature, who received CI, were also both diagnosed with mutations in the PTPN11 gene (18). These findings suggest a genotype-phenotype correlation between severe bilateral congenital SNHI in NS and the PTPN11 mutation. A larger cohort of SNHI in NS patients is needed to confirm this finding.
In our cohort in 73% of the NS patients a mutation was discovered. However, only 80 of the 97 patients were tested, suggesting a higher percentage of mutations is likely to be more representative. External ear anomalies are frequent NS characteristics. Low set ears, posteriorly rotated, thickened helices and protruding ears are not specific clinical criteria, but we would recommend to include these features to the recognized criteria of facial characteristics of NS.
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