Cochlear Implantation in Noonan Syndrome With and Without Multiple Lentigines: A Case Report and Systematic Review

Objectives: To describe outcomes after bilateral cochlear implantation (CI) in a patient with a pathologic PTPN11 variant associated with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML). Additionally, to assess the utility of CI in this specific population based on our outcome and previous reports. Study Design: Retrospective case report with literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Patients: A young boy with various multiorgan abnormalities, speech and language delay, and persistent hearing loss who was found to have a heterozygous PTPN11 gene mutation at age 2. Interventions: Bilateral tympanostomy tube placement, diagnostic imaging, and eventual staged bilateral CI. Main Outcome Measures: Objective audiometric testing and developmental milestone attainment. Results: Bilateral CI was successfully completed over a 2-month period. The patient illustrated significant improvement in objective audiologic measurement. However, he continues to sign as his main form of communication without significant speech progression. Conclusions: Early diagnostic and therapeutic intervention in patients with NS/NSML can help improve long-term audiologic and speech development. Given the heterogeneity of NS/NSML, a multidisciplinary approach is needed for optimal outcomes.

Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome, is an autosomal dominant disorder most commonly caused by a mutation in the tyrosine phosphatase non-receptor type 11 gene (PTPN11) (1).This gene is also involved in Noonan syndrome (NS), which occurs in 1 in 1000 to 2500 live births (1).
NSML and NS share a broad range of clinical findings including lentigines, electrocardiographic conduction defects, hypertelorism, pulmonary stenosis, genital abnormalities, deafness, and growth and mental retardation (2).Due to phenotypic variation, clinical diagnosis is challenging and often supplemented with genetic testing.
There are a number of studies reporting hearing loss (HL) in both NS and NSML patients.Sharland et al (3) described HL in 58 out of 146 NS patients, 3% of which suffered from isolated sensorineural hearing loss (SNHL).van Trier noted HL in 34 of 97 NS patients.SNHL was present in 20% of these patients, while mixed HL and conductive HL were each found in 4% (4).Other studies demonstrate various temporal bone abnormalities in patients with NS/NSML (5,6).
Despite the prevalence of HL in both NS and NSML patients, outcomes after cochlear implantation (CI) in this population remain poorly characterized.This case and systematic review assess the literature regarding CI outcomes in NS and NSML patients, illustrate our experience with bilateral CI in a patient with a PTPN11 mutation, and further explore the genetics behind these unique syndromes.

MATERIALS AND METHODS
A case report of a patient with a PTPN11 mutation undergoing bilateral CI is described.A systematic review was performed, which included case reports/series of patients with NS and/or NSML who underwent CI, without restriction for gender or age.Articles of any publication date and status were accepted.Exclusion criteria included reviews, editorials, commentaries and papers published in a non-English language.Studies were identified in ovid Medline and PubMed using the keywords: leopard syndrome, cochlear implantation, noonan syndrome, and hearing loss.Reference lists of retrieved review papers were manually searched to identify additional relevant studies.The last search was performed on March 30, 2021.No review protocol was used in this review.
Eligibility was assessed by 3 independent investigators (D.B., B.L., J.L.) and disagreements were resolved by consensus.After the initial literature search, each study was screened for eligibility based on title and abstract.Full text was retrieved for all articles that met inclusion criteria and independently reviewed by the authors (D.B., B.L., J.L.).Data extracted included: demographics (eg, age, gender, ethnicity), diagnosis and genetic variant if available, pre-and post-CI audiology results, diagnostic imaging, and follow-up assessments.Bias risk assessment tools were not employed given the nature of included articles (ie, case reports/ series).The authors (D.B., B.L.) graded the quality of evidence for each study using the modified version of the Oxford Centre for Evidence-Based Medicine levels of evidence.Each study included was a case report or case series; therefore, level 4 evidence.
Objectives: To describe outcomes after bilateral cochlear implantation (CI) in a patient with a pathologic PTPN11 variant associated with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML).Additionally, to assess the utility of CI in this specific population based on our outcome and previous reports.Study Design: Retrospective case report with literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Patients: A young boy with various multiorgan abnormalities, speech and language delay, and persistent hearing loss who was found to have a heterozygous PTPN11 gene mutation at age 2. Interventions: Bilateral tympanostomy tube placement, diagnostic imaging, and eventual staged bilateral CI.Main Outcome Measures: Objective audiometric testing and developmental milestone attainment.Results: Bilateral CI was successfully completed over a 2-month period.The patient illustrated significant improvement in objective audiologic measurement.However, he continues to sign as his main form of communication without significant speech progression.Conclusions: Early diagnostic and therapeutic intervention in patients with NS/NSML can help improve long-term audiologic and speech development.Given the heterogeneity of NS/NSML, a multidisciplinary approach is needed for optimal outcomes.

RESULTS
Literature and manual search of reference lists yielded a total 60 articles after duplicate removal.After title and/or abstract screening, 9 review articles were excluded, as well as 6 articles for not pertaining to patients with NS/NSML.Of the remaining 45 articles, 6 met inclusion criteria and were included in this review (Fig. 1).These 6 articles are organized in Table 1.

Case
A full term male presented with notable speech and language delay at age 15 months.Gestation and delivery were uncomplicated and family history was unremarkable for syndromic pathology.No abnormalities were identified at birth and the patient passed his newborn hearing screening.During his first year of life, he was diagnosed with pulmonary valve stenosis, otitis media with effusion, and bilateral nephrosis.At presentation, audiologic evaluation revealed absent transient evoked otoacoustic emissions (TEOAEs) and flat tympanometry on the right, and unattainable TEOAEs with normal tympanometry on the left.Repeat testing at age 2 illustrated type B tympanograms bilaterally and mild-to-moderate bilateral HL at 500-1000 and 4000 Hz.Minimal improvement was noted after bilateral myringotomy and tympanotomy tube placement.Subsequently, sedated audiometry brainstem response revealed bilateral severe-to-profound SNHL from 500 to 4000 Hz.
The patient failed to make progress after a 6-week trial with bilateral hearing aids.Subsequent audiometry illustrated response to tonal and narrowband noise stimuli in the moderate-to-severe hearing range from 500 to 2000 Hz, but absent response at 4000 Hz (Fig. 2).Both speech awareness threshold (SAT) and Aided Ling Sounds were found in the severe-to-profound HL range.As a result, bilateral CI was recommended.Meanwhile, the patient underwent genetic testing given the presence of SNHL and pulmonary valve stenosis, revealing a heterozygous PTPN11 gene with a c.1529A>G variant.
Preoperative MRI of the internal auditory canal demonstrated normal-appearing inner ear structures with no evidence of retrocochlear lesions (Fig. 3).At 2.5 years of age, CI was performed    successfully in the left ear but postponed in the right due to poor insertion trajectory secondary to anterior displacement of the facial nerve.There was also notable round window ossification on the right side.Right ear CI was reattempted 2 months later, which required incus buttress removal and intraoperative CT-based guidance.Full electrode insertions were achieved with each surgery.Audiogram at 7 months after activation of his left CI and 5 months after activation of right CI is shown (Fig. 4).Audiologic testing revealed an SAT of 40 dB HL on the right, left, and bilaterally.The patient is now able to consistent discern speech and sounds.However, the patient continues to predominantly communicate through sign.

DISCUSSION
Individuals with NS and NSML possess variable and overlapping phenotypic characteristics; including diverse otologic manifestations and hearing abnormalities.Our experience adds to the growing list of audiologic abnormalities found in patients with pathologic PTPN11 variants.The patient's 7-month postoperative outcomes advocate for early intervention with CI for improved audiometric function.However, practitioners and parents must be aware of the mixed speech outcomes seen in patients with underlying cognitive deficits.CI was surgically successful in our patient and in all documented cases despite anatomical challenges.All accounts in the literature that included preoperative and postoperative audiometric measures displayed marked improvement in auditory performance over time with differing speech and language outcomes.van Nierop et al (10) describe 5 patients with improved audiometric measures and phoneme discrimination testing; however, 4 patients continued to have delayed speech and language development.Similarly, Scheiber et al (7) describe 2 patients with improved objective audiologic findings and subsequent scholastic improvement through educational milestones.Vermeire et al ( 9) reported a 1-year-old with bilateral SNHL who acclimated to a regular school program with home speech therapy 1.5 years later after CI.In another study, a 5-year-old with bilateral profound SNHL showed improvement in hearing perception 1 year after CI, but was unable to achieve meaningful communication (8).
Our patient's auditory thresholds demonstrate objective improvement in his ability to detect sounds after CI.However, his speech development remains limited despite intensive auditory verbal therapy and immersion in a learning environment with an emphasis on auditory and verbal communication.His course illustrates the uncertain outcomes in NS/NSML patients secondary to their underlying intellectual deficits.Long-term follow-up with Otolaryngology and speech language pathology practitioners is vital to help children with similar impairments progress past sign communication.Additionally, parents must be made aware that outcomes are difficult to predict and that successful CI placement and audiometric improvement may not translate quickly, if at all, to oral speech.
Mental deficiencies in various domains have been reported in NS/NSML patients.These include poor attention and executive functioning, diminished verbal skills and reasoning, and special educational requirements (11)(12)(13).Roelofs et al (12) found that children with NS have low performance and verbal intelligence quotient (IQ) while adults advance to a normal performance IQ over time.However, verbal IQ does not develop proportionately.This longitudinal study does not include patients with CI; however, it does provide important information that helps inform parents and patients on long-term expectations.
Although HL and timely interventions play a role, it is possible that PTPN11 gene variants impact cognitive development.Notably, Gauthier et al (14) demonstrated the critical role of PTPN11 gene products in neurogenesis and regulation using in vitro murine cultured cortical precursors.The in vivo cortical abnormalities observed may help to explain the cognitive impairment resistant to improved audiologic measures and the varied outcomes after CI.More research is required to better identify specific mutations that are associated with treatment-resistant behavioral delay.
The large variability in clinical manifestations and outcomes in NS/NSML is related to the genetic heterogeneity of these overlapping syndromes.PTPN11 gene mutations are most commonly seen in inherited forms of NS (50%) and NSML (>85%), but other variants have been implicated (15).A number of PTPN11 variants also exist, and evidence illustrates inconsistent phenotypic presentation among patients with the same mutation (16).This is evident in 2 patients reviewed with the c.992A alteration who underwent CI.One patient passed newborn hearing screening while the other failed.This not only denotes inconsistent phenotypic expression but suggests that newborn hearing screens may not rule out HL in NS and NSML patients (7,10).
Interestingly, gene expression studies localize PTPN11 to hair cells, supporting cells and spiral ganglion neurons (SGNs).However, they are predominantly found in SGN over the other 2 locations (17).Shearer et al (17) illustrate that mutations specific to the SGNs are the most predictive factors for CI failure to date and may explain the poor outcomes in NS and NSML patients.There are numerous documented SGN-specific mutations including but not limited to TMPRSS3, AIFM1, DIAPH3, DFNB59, MT-RNR1, and OPA1.These discoveries bring with them a growing concern that patients with these defects may not gain the same benefit from CI as those with defects in other areas of the peripheral auditory system (17,18).However, there is limited data in SGN-specific mutations' CI outcomes due in large part to the low overall incidence and novel area of research.Moving forward, genetic testing should be encouraged prior to CI to allow practitioners and parents to engage in a more informative discussion regarding prognosis following CI based on the location of their child's mutation.
The genetic complexity behind clinical outcomes, however, must be weighed conjointly with the benefits of early intervention.Holder et al (19) recently reported on improved CI outcomes in pediatric patients with TMPRSS3 mutations when compared to their adult counterparts undergoing the same procedure later in life.The specific mutation is found in SGNs and is thought to cause SNHL.These authors advocate for early intervention in their pediatric population.Whether a similar or earlier window of opportunity exists in patients with PTPN11 mutations is unknown.While the mutations differ, this study reinforces that early CI implantation may benefit patients with PTPN11 mutations despite their underlying deficits.More widespread and early genetic testing may identify individuals with these mutations prior to the onset of HL and enable a better clinical monitoring for disease progression.

CONCLUSIONS
Given the heterogeneity of NS/NSML, a multidisciplinary approach is needed for optimal outcomes.Early genetic testing in patients with SNHL and multivisceral abnormalities is critical for diagnosis, patient education, prognosis, and joint decision-making.Although there is limited data on CI outcomes in NS/NSML patients, this intervention should be discussed with parents as a viable treatment modality to improve audiologic and speech development.Identifying the specific mutation remains an underutilized modality and should be incorporated into practice better counsel patients on their audiologic and speech improvements after CI placement.Future studies that stratify cognitive deficits based on specific mutations will enhance our understanding of the pathophysiology behind NS/ NSML and improve clinical decision-making when predicting CI outcomes.

FUNDING SOURCES
None declared.

CONFLICT OF INTEREST
M.H. holds the position of Associate Editor for Otology and Neurotology Open and has been recused from reviewing or making decisions for the article.The remaining author discloses no conflicts of interest.

TABLE 1 .
Systematic review of NS and/or NSML patients undergoing cochlear implantation