To present a case series of patients with Chudley - McCullough syndrome (CMS) and provide audiometric outcomes pre - and post - cochlear implantation. A retrospective case series was written based on six patients with CMS and hearing loss. Patients were treated in a tertiary-care medical center for their hearing loss with hearing aid fitting and cochlear implantation. Audiometric outcomes pre- and post-cochlear implantation were analyzed. Three out of six patients were diagnosed with auditory neuropathy spectrum disorder (ANSD), one patient was suspected of ANSD, and in two patients, the presence of ANSD could neither be confirmed nor excluded. All patients were fitted with hearing aids, and all had limited benefit. In most cases, hearing deteriorated rapidly and eventually, all patients received a cochlear implant (CI), unilateral or bilateral. In general, aided thresholds with CIs were satisfactory. However, speech recognition varied widely between patients and was, on average, worse compared to patients with sensorineural hearing loss without CMS. CMS was often diagnosed relatively late during childhood, and sometimes hearing loss was the first apparent symptom. Hearing loss was found to be progressive, often not detected shortly after birth and often complicated by ANSD. Cochlear implantation emerged as the optimal treatment, demonstrating superiority over hearing aid rehabilitation to improve hearing performance. Auditory and speech-language development outcomes remained poorer than in children with CI and without CMS. Based on these results, we advocate considering cochlear implantation early for children who have CMS and hearing loss.

Chudley-McCullough syndrome (CMS) is a rare autosomal recessive disorder. It is characterized by the association of early-onset sensorineural hearing loss and typical brain malformations, in contrast with preserved or only mildly affected psychomotor development. The first cases were reported in 1997 by Chudley et al. in a brother and sister born to consanguineous parents. It was not until 2012 that Doherty et al. identified mutations in the GPSM2 gene (G-protein signaling modulator 2) as the cause of CMS. We present the case of CMS in a 3-year-old girl with bilateral sensorineural deafness and characteristic brain malformations on MRI (callosal splenium agenesis, colpocephaly, interhemispheric cyst, cerebellar dysplasia, midline polymicrogyria and gray matter heterotopia).

Chudley-McCullough syndrome (CMS) is a rare autosomal recessive disorder characterized by sensorineural hearing loss and cerebral abnormalities, including ventriculomegaly and partial dysgenesis of the corpus callosum. CMS is caused by two inactivating mutations of the G protein signaling modulator 2 (GPSM2), which maintains inner hair cell polarity and spindle orientation. Since its initial description, CMS has been reported approximately 30 times in the medical literature with several individuals undergoing cochlear implantation to restore their hearing. Interestingly, within the past two years, we encountered two cases of CMS in our hospital, which primarily serves patients within a 30-mile radius. To our knowledge, the literature has yet to evaluate two unrelated cases of CMS occurring in such close succession. This case report describes two successful cases of bilateral cochlear implantation in two children with CMS. Notably, these individuals have no family history of consanguinity or prior hearing loss.

The most recent modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta®), has been shown to improve clinical outcomes in most patients with cystic fibrosis (PwCF). Unfortunately, the clinical benefits are sometimes variable; thus, improving our knowledge of the possible causes of this variability can help reduce it. Circulating mononuclear cells (CMCs) and plasma were collected from 16 PwCF (including those on Trikafta® therapy) and 4 non-CF subjects. Cystic fibrosis transmembrane conductance regulator (CFTR) activity and matrix metalloprotease 9 (MMP9) expression were monitored before and after therapy, together with some clinical parameters. The relationship between MMP9 expression and the modulation of the extracellular-regulated 1/2 (ERK1/2) and nuclear factor-kB (NF-kB) pathways was also analyzed. MMP9, markedly expressed in the CMCs and plasma of all the patients included in the study, was downregulated in the clinically responsive PwCF. In the non-responder, the MMP9 levels remained high. The modulation of MMP9 following treatment with Trikafta® may be controlled by the NF-kB pathway. These data strongly suggest that MMP9 downregulation is a potential biomarker of therapy efficacy and that it could be useful in understanding the molecular events underlying the variable clinical responses of patients to Trikafta®. This knowledge could be helpful for future studies of personalized medicine and thereby ensure improvements in individual responses to therapies.