Congenital sensorineural hearing loss as the initial presentation of <i>PTPN11</i>-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms.

Abstract

Germline variants in <i>PTPN11</i> are the primary cause of Noonan syndrome with multiple lentigines (NSML) and Noonan syndrome (NS), which share common skin and facial symptoms, cardiac anomalies and retardation of growth. Hearing loss is considered an infrequent feature in patients with NSML/NS. However, in our cohort, we identified a group of patients with <i>PTPN11</i> pathogenic variants that were primarily manifested in congenital sensorineural hearing loss (SNHL). This study evaluated the incidence of <i>PTPN11-</i>related NSML or NS in patients with congenital SNHL and explored the expression of <i>PTPN11</i> and the underlying mechanisms in the auditory system. A total of 1502 patients with congenital SNHL were enrolled. Detailed phenotype-genotype correlations were analysed in patients with <i>PTPN11</i> variants. Immunolabelling of Ptpn11 was performed in P35 mice. Zebrafish with <i>Ptpn11</i> knockdown/mutant overexpression were constructed to further explore mechanism underlying the phenotypes. Ten NSML/NS probands were diagnosed via the identification of pathogenic variants of <i>PTPN11</i>, which accounted for ~0.67% of the congenital SNHL cases. In mice cochlea, Shp2, which is encoded by <i>Ptpn11</i>, is distributed in the spiral ganglion neurons, hair cells and supporting cells of the inner ear. In zebrafish, knockdown of <i>ptpn11a</i> and overexpression of mutant <i>PTPN11</i> were associated with a significant decrease in hair cells and supporting cells. We concluded that congenital SNHL could be a major symptom in <i>PTPN11</i>-associated NSML or NS. Other features may be mild, especially in children. Screening for <i>PTPN11</i> in patients with congenital hearing loss and variant-based diagnoses are recommended.