Topical platelet-rich plasma as a possible treatment for olfactory dysfunction-A randomized controlled trial.

BACKGROUND: Olfactory dysfunction (OD) affects many survivors of COVID-19. Prior studies have investigated the use of platelet-rich plasma (PRP) injections for OD. We describe the first randomized controlled trial investigating topical PRP for OD treatment and contribute to existing literature illustrating PRP as an emerging therapeutic. METHODS: This is a single-blinded, randomized controlled trial conducted from July 2022 to December 2023. Adult patients with OD ≥6 months secondary to COVID-19 with Brief Smell Identification Test (BSIT) scores of ≤8/12 or SCENTinel odor intensity of ≤40/100 were included. Patients were randomized to three, monthly PRP or placebo-impregnated Surgifoam treatments into bilateral olfactory clefts. The BSIT, SCENTinel, and Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) were completed monthly through month 12. RESULTS: Of 104 patients screened, 83 participated. No significant differences in age, OD duration, BSIT, SCENTinel, or QOD-NS scores were found between PRP (n = 42) and placebo (n = 41) patients at baseline. PRP patients experienced a statistically significant increase in BSIT scores from baseline at months 5‒9, 11, and 12, while placebo patients did not (p < 0.05). However, total BSIT scores were similar between the two groups throughout the study. Neither the SCENTinel odor intensity scores nor the change from baseline were significantly different between the treatment groups. At month 12, PRP patients experienced minor improvement in OD-related quality-of-life compared with placebo. CONCLUSIONS: This study is the first to describe topical PRP as a safe, experimental treatment for OD in humans. PRP may impact odor identification in post-COVID-19 OD patients, although the lack of difference in total BSIT scores highlights the need for further study.

Integrating the Patient's Voice into the Research Agenda for Treatment of Chemosensory Disorders.

World-wide some 658 million people were infected with COVID-19 and millions suffer from chemosensory impairment associated with long COVID. Current treatments for taste and smell disorders are limited. Involving patients has the potential to catalyze the dynamic exchange and development of new ideas and approaches to facilitate biomedical research and therapeutics. We assessed patients' perceptions of the efficacy of treatments for chemosensory impairment using an online questionnaire completed by 5,815 people in the U.S. Logistic regression determined variables predictive of reported treatment efficacy for patients aged 18-24, 25-39, 40-60 and 60+ yrs. who were treated with nasal steroids, oral steroids, zinc, nasal rinse, smell training, theophylline, platelet rich plasma, and Omega 3. The most consistent predictor was age, with the majority of those 40-60 and 60+ reporting that nasal steroids, oral steroids, zinc, nasal rinse and smell training were only slightly effective or not effective at all. Many of these treatment strategies target regeneration and immune response, processes compromised by age. Only those under 40 reported more than slight efficacy of steroids or smell training. Findings emphasize the need to include patients of all ages in clinical trials. Older adults with olfactory impairment are at increased risk for Alzheimer's disease (AD). We speculate that olfactory impairment associated with long COVID introduces the potential for a significant rise in AD. Long COVID-associated chemosensory impairment increases the urgency for translational and clinical research on novel treatment strategies. Suggestions for high priority areas for epidemiological, basic, and clinical research on chemosensory impairment follow.

Predictors of Subjective Olfactory Dysfunction and Sinonasal Quality-of-Life After Endoscopic Transsphenoidal Pituitary Surgery.

BACKGROUND: This is the largest study in North America investigating olfactory outcomes after pituitary surgery to date. OBJECTIVE: Characterize factors associated with subjective olfactory dysfunction (OD) and worsened sinonasal quality-of-life (QOL) after endoscopic TSA. METHODS: Patients undergoing primary TSA for secreting and non-secreting pituitary adenomas between 2017 and 2021 with pre- and post-operative SNOT-22 scores were included. Subjective OD was determined by the smell/taste dysfunction question on the SNOT-22 (smell-SNOT). RESULTS: 159 patients with pre- and post-operative SNOT-22 scores were included. Average total SNOT-22 scores worsened from pre-operative (16.91 ± 16.91) to POM1 (25.15 ± 20.83, P < .001), with no difference from pre-operative (16.40 ± 15.88) to POM6 (16.27 ± 17.92, P = .936) or pre-operative (13.63 ± 13.54) to POM12 (12.60 ± 16.45, P = .651). Average smell-SNOT scores worsened from pre-operative (0.40 ± 1.27) to POM1 (2.09 ± 2.01, P < .001), and pre-operative (0.46 ± 1.29) to POM6 (1.13 ± 2.45, P = .002), with no difference from pre-operative (0.40 ± 1.07) to POM12 (0.71 ± 1.32, P = .100). Female gender had a 0.9-point (95% CI 0.1 to 1.6) P = .021, increase in smell-SNOT at POM1, resolving by POM6 (0.1 [-0.9 to 1.1], P = .800) and POM12 (0.0 [-1.0 to 0.9], P = .942). Septoplasty with tunnel approach had a 1.1 [0.2 to 2.0] out of 5-point (P = .023) increase in smell-SNOT at POM1, resolving by POM6 (0.2 [-1.1 to 1.6], P = .764) and POM12 (0.4 [-0.9 to 1.6], P = .567). Female gender had a 9.5 (4.0 to 15.1)-point (P = .001) increase in SNOT-22 scores at POM1, resolving by POM6 (3.4 [-3.0 to 9.8], P = .292) and POM12 (6.4 [-5.4 to 18.2], P = .276). Intra-operative CSF leak had an 8.6 [2.1 to 15.1]-point (P = .009) increase in SNOT-22 scores at POM1, resolving by POM6 (5.4 [-1.7 to 12.5], P = .135), and POM12 (1.1 [-12.9 to 15.1], P = .873). CONCLUSION: Changes in subjective olfaction and sinonasal QOL after TSA may be associated with gender, operative approach, and intra-operative CSF leak, resolving 6-12 months post-operatively.

Safety of Ambulatory Surgery For Obstructive Sleep Apnea: A Retrospective Review.

OBJECTIVE: Assess the safety of ambulatory surgery performed for obstructive sleep apnea. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care hospital. METHODS: Demographic data including age, gender, race, body mass index, insurance status, socioeconomic status, and distance traveled for surgery was collected, as well as comorbidities, and apnea-hypopnea index (AHI). Outcome variables included continuous positive airway pressure reinitiation, planned/unplanned postoperative admission, emergency department (ED) presentation, or readmission within 7 and 14 days of surgery. RESULTS: A total of 601 patients were included, who underwent sleep surgery between 2017 and 2022. The median age was 55 years [interquartile range: 19]. A total of 437 patients (73%) were male, 502 (84%) were Caucasian, and the median distance traveled was 20 miles [27]. The median AHI was 27.1 [26]. A total of 286 hypoglossal nerve stimulators, 12 tonsillectomies, 160 expansion sphincteroplasties (ESP), and 201 nasal procedures were performed. There were 9 (1%) planned and 23 (4%) total admissions postoperatively. Sixteen patients (2%) presented to ED within 7 days, and 22 (3%) within 14 days. Nine (1%) were readmitted within 7 days, and 12 (2%) within 14 days. There were significantly more planned admissions, unplanned admissions, ED presentations, and readmissions for ESP. There were no significant differences in demographic or clinical data between patients who underwent single versus multiple surgeries. CONCLUSION: Outpatient sleep surgery is generally safe. Close postoperative monitoring is necessary and overnight observation should be considered in those with very severe sleep apnea and/or significant comorbidities. The distance a patient travels should also be considered for overnight admission.

Medication utilization for patients with chronic rhinosinusitis with nasal polyposis and asthma in 12 months pre- and post-dupilumab initiation.

KEY POINTS: This study examines the impact of dupilumab on medication use for chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma patients. Patients on dupilumab had a reduction in oral/inhaled/topical steroids, antibiotics, and leukotriene receptor antagonists (LTRAs). The reduction in medication use had no impact on total polyp or SNOT-22 scores.

Stellate ganglion block for treating post-COVID-19 parosmia.

BACKGROUND: Post-COVID parosmia may be due to dysautonomia and sympathetic hyperresponsiveness, which can be attenuated by stellate ganglion block (SGB). This study evaluates SGB as a treatment for post-COVID olfactory dysfunction (OD). METHODS: Retrospective case series with prospective data of patients with post-COVID OD undergoing unilateral (UL) or bilateral (BL) SGB. Patients completed Brief Smell Identification Tests (BSIT) (12 points maximum) and post-procedure surveys including parosmia severity scores on a scale of 1 (absent) to 10 (severe). Scores were compared from before treatment (pre-SGB) to after first (SGB1) or second (SGB2) treatments in overall, UL, and BL cohorts. RESULTS: Forty-seven patients with post-COVID OD underwent SGB, including 23 UL and 24 BL. Twenty patients completed pre- and post-SGB BSITs (eight UL and 12 BL). Twenty-eight patients completed postprocedure surveys (11 UL and 17 BL). There were no differences in BSIT scores from pre-SGB to post-SGB1 or post-SGB2 for the overall (p = 0.098), UL (p = 0.168), or BL (p = 0.230) cohorts. Parosmia severity for the overall cohort improved from pre-SGB (8.82 ± 1.28) to post-SGB1 (6.79 ± 2.38) and post-SGB2 (5.41 ± 2.35), with significant differences from pre-SGB to post-SGB1 (p < 0.001) and pre-SGB to post-SGB2 (p < 0.001), but not post-SGB1 to post-SGB2 (p = 0.130). Number of parosmia triggers decreased for overall (p = 0.002), UL (p = 0.030) and BL (p = 0.024) cohorts. Quality of life (QOL) improved for all cohorts regarding food enjoyment, meal preparation, and socialization (p < 0.05). CONCLUSION: SGB may improve subjective parosmia and QOL for patients with post-COVID OD, however it may not affect odor identification. Further placebo-controlled studies are warranted.

Demographic disparities in children with retropharyngeal and parapharyngeal abscesses.

PURPOSE: To explore the impact that demographic and socioeconomic factors such as age, gender, race, and insurance status have on the diagnosis of retropharyngeal (RPA) and parapharyngeal abscesses (PPA) in the pediatric population. METHODS: The 2016 HCUP KID was searched for all RPA/PPA discharges using the joint ICD-10 code J39.0. Descriptive statistics, univariate, and multivariate analyses were performed to assess the relationship between demographic factors and their impact on RPA/PPA diagnosis. Results were reported with their corresponding odds ratio with a 95 % confidence interval and p-value. RESULTS: 56.4 per 100,000 weighted discharges were discharged with a diagnosis of a RPA/PPA, the average age was 5.7 years old, with a male predominance. Pediatric discharges diagnosed with a RPA/PPA were less likely to identify as Hispanic or Asian/Island Pacific. They were also less likely to be insured by Medicaid and reside in zip codes with a lower median income. CONCLUSION: The analysis of this national pediatric database demonstrated significant demographic differences in children diagnosed with RPA/PPAs. Following the multivariate analysis, children from a higher socioeconomic background and those with private insurance were more likely to be diagnosed with a RPA/PPAs. However, disparities in children's overall hospital course and complications is a potential area for future research.

Oncologic Safety of Close Margins in Patients With Low- to Intermediate-Grade Major Salivary Gland Carcinoma.

Importance: Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence. Objective: To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins. Design, Setting, and Participants: The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023. Main Outcomes and Measures: Main outcomes were risk factors for local recurrence. Results: A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group. Conclusions and Relevance: In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Optimizing the timing of biologic and surgical therapy for patients with refractory chronic rhinosinusitis with nasal polyposis (CRSwNP).

INTRODUCTION: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is often treated with endoscopic sinus surgery (ESS); however, patients may require revision surgery due to recurrence. To date, no studies have compared outcomes for combined surgery and biologic therapy for CRSwNP compared with biologic therapy alone. METHODS: Retrospective case-control study of CRSwNP patients who underwent ESS while on dupilumab or mepolizumab (ESS-biologic cohort) compared with CRSwNP patients on biologic therapy (biologic-only controls). Cohorts were matched according to indication, aspirin-exacerbated respiratory disease (AERD), sinonasal outcome test-22 (SNOT-22), and total polyp scores. RESULTS: Sixteen patients underwent ESS while on biologic therapy (13 dupilumab and 3 mepolizumab). Sixteen patients were biologic-only controls. There were no significant differences between indication, baseline SNOT-22 scores, polyp scores, and AERD status between cohorts. Patients underwent surgery a median of 33 days after starting biologic therapy. After 12 months of follow-up, the total polyp score for the ESS-biologic cohort decreased from 4.73 to 0.09 compared with a decrease from 5.22 to 3.38 for the biologic-only controls (95% confidence interval [CI] of difference: -5.37 to -1.38, Cohen's d: 2.40, p = 0.005). In the ESS-dupilumab subanalysis, the ESS-dupilumab cohort had a significant reduction in polyp burden from 4.85 to 0.00 compared with 4.88 to 3.50 for the controls (95% CI of difference: -5.68 to -1.32, Cohen's d: -1.69, p = 0.009). CONCLUSION: In CRSwNP patients, combined ESS and biologic therapy results in a significant and sustained decrease in polyp burden compared with biologic therapy alone. Larger studies are warranted to further examine the impact of combined therapy.

Benefits of Immunoglobulin (Ig) Replacement Therapy for Primary and Secondary Immunodeficiency in Chronic Rhinosinusitis.

This is the first study to examine chronic rhinosinusitis (CRS) outcomes after starting immunoglobulin (Ig) replacement therapy for patients with primary (PID) and secondary immunodeficiency (SID). This is a retrospective review of patients diagnosed with CRS from 2018 to 2022 prior to initiating Ig therapy for the treatment of PID or SID. Outcomes included medication use and Sinonasal Outcome Test (SNOT-22) scores. Ten patients met the inclusion criteria. PID and SID patients had a decrease in antibiotics (PID: 9.40 to 3.20, P = .05, SID: 8.20 to 2.00, P = .04) and steroids (PID: (5.40 to 0.60; P = .06; SID: 2.20 to 0.20, P = .047) prescribed in the year after Ig compared to the year prior. Patients with SID had a decrease in mean SNOT-22 scores by 12 months after Ig (47.50 to 20.50, P = 0.03). Patients receiving Ig for PID and SID showed decreased medication use and SID patients experienced subjective improvement in CRS symptoms in year-over-year comparison.

Patient Insights into the Diagnosis of Smell and Taste Disorders in the United States.

OBJECTIVES: Diagnosis of smell/taste dysfunction is necessary for appropriate medical care. This study examines factors affecting testing and diagnosis of smell/taste disorders . METHODS: The online USA Smell and Taste Patient Survey was made available to US patients with smell/taste disorders between April 6-20, 2022. 4,728 respondents were included. RESULTS: 1,791 (38%) patients reported a documented diagnosis. Patients most often saw family practitioners (34%), otolaryngologists (20%), and Taste/Smell clinics (6%) for smell/taste dysfunction. 64% of patients who went to Taste/Smell clinics received smell testing, followed by 39% of patients who saw otolaryngologists, and 31% of patients who saw family practitioners. Factors associated with increased odds of diagnosis included age (25-39 years (OR 2.97, 95% CI [2.25, 3.95]), 40-60 (OR 3.3, 95% CI [2.56, 4.52]), and >60 (OR 4.25, 95% CI [3.21, 5.67]) vs. 18-24 years), male gender (OR 1.26, 95% CI [1.07, 1.48]), insurance status (private (OR 1.61, 95% CI [1.15, 2.30]) or public (OR 2.03, 95% CI [1.42, 2.95]) vs. uninsured), perception of their family practitioner to be knowledgeable (OR 2.12, 95% CI [1.16, 3.90]), otolaryngologic evaluation (OR 6.17, 95% CI [5.16, 7.38]), and psychophysical smell testing (OR 1.77, 95% CI [1.42, 2.22]). CONCLUSION: Psychophysical testing, otolaryngologic evaluation, patient assessment of family practitioner knowledge level, insurance, age, and gender are significant factors in obtaining smell/taste dysfunction diagnosis. This study identifies barriers to diagnosis including lack of insurance or access to specialist evaluation and highlights the importance of educating family practitioners in diagnosis and management of patients with smell/taste disorders.

Trends in Endoscopic and Microscopic Approaches to Transsphenoidal Pituitary Surgery in the US.

OBJECTIVES: Among the transsphenoidal (TSS) approaches to pituitary tumors, the microscopic approach (MA) has historically been the predominant technique with the increasing adoption of the endoscopic approach (EA). This study investigates national trends in TSS approaches and postoperative outcomes for MA and EA through 2021. METHODS: The TriNetX database was queried for patients undergoing TSS (MA and EA) between 2010 and 2021. Data were collected on demographics, geographic distribution of surgical centers, postoperative complications, stereotactic radiosurgery (SRT), repeat surgery, and postoperative emergency department (ED) visits. RESULTS: 8644 TSS cases were queried between 2010 and 2021. MA rates were highest until 2013 when rates of EA (52%) surpassed MA (48%) and continued to increase through 2021 (81%). From 2010 to 2015 EA had higher odds of a postoperative CSF leak (OR 3.40) and diabetes insipidus (DI (OR 2.30)) versus MA (p < 0.05); from 2016 to 2021 differences were not significant. Although there was no significant difference among approaches from 2010 to 2015 for syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia, or bacterial meningitis, from 2016 to 2021 EA had lower odds of SIADH (OR 0.54) and hyponatremia (OR 0.71), and higher odds of meningitis (OR 1.79) versus MA (p < 0.05). EA had higher odds of additional surgery (either EA or MA) after initial surgery from 2010 to 2021. From 2010 to 2015 EA had lower odds of postoperative SRT compared to MA, whereas in 2016-2021 there was no statistical difference among approaches. CONCLUSION: This study demonstrates increasing EA adoption for TSS in the United States since 2013. Complication rates have overall improved for EA compared to MA, potentially as a result of improving surgeon familiarity and experience. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2135-2140, 2023.

Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder.

OBJECTIVE: Copy number variants (CNVs) are strongly associated with neurodevelopmental and psychotic disorders. Early-onset psychosis (EOP), where symptoms appear before 18 years of age, is thought to be more strongly influenced by genetic factors than adult-onset psychotic disorders. However, the prevalence and effect of CNVs in EOP is unclear. METHODS: The authors documented the prevalence of recurrent CNVs and the functional impact of deletions and duplications genome-wide in 137 children and adolescents with EOP compared with 5,540 individuals with autism spectrum disorder (ASD) and 16,504 population control subjects. Specifically, the frequency of 47 recurrent CNVs previously associated with neurodevelopmental and neuropsychiatric illnesses in each cohort were compared. Next, CNV risk scores (CRSs), indices reflecting the dosage sensitivity for any gene across the genome that is encapsulated in a deletion or duplication separately, were compared between groups. RESULTS: The prevalence of recurrent CNVs was significantly higher in the EOP group than in the ASD (odds ratio=2.30) and control (odds ratio=5.06) groups. However, the difference between the EOP and ASD groups was attenuated when EOP participants with co-occurring ASD were excluded. CRS was significantly higher in the EOP group compared with the control group for both deletions (odds ratio=1.30) and duplications (odds ratio=1.09). In contrast, the EOP and ASD groups did not differ significantly in terms of CRS. CONCLUSIONS: Given the high frequency of recurrent CNVs in the EOP group and comparable CRSs in the EOP and ASD groups, the findings suggest that all children and adolescents with a psychotic diagnosis should undergo genetic screening, as is recommended in ASD.

Underrepresentation of Phenotypic Variability of 16p13.11 Microduplication Syndrome Assessed With an Online Self-Phenotyping Tool (Phenotypr): Cohort Study.

BACKGROUND: 16p13.11 microduplication syndrome has a variable presentation and is characterized primarily by neurodevelopmental and physical phenotypes resulting from copy number variation at chromosome 16p13.11. Given its variability, there may be features that have not yet been reported. The goal of this study was to use a patient "self-phenotyping" survey to collect data directly from patients to further characterize the phenotypes of 16p13.11 microduplication syndrome. OBJECTIVE: This study aimed to (1) discover self-identified phenotypes in 16p13.11 microduplication syndrome that have been underrepresented in the scientific literature and (2) demonstrate that self-phenotyping tools are valuable sources of data for the medical and scientific communities. METHODS: As part of a large study to compare and evaluate patient self-phenotyping surveys, an online survey tool, Phenotypr, was developed for patients with rare disorders to self-report phenotypes. Participants with 16p13.11 microduplication syndrome were recruited through the Boston Children's Hospital 16p13.11 Registry. Either the caregiver, parent, or legal guardian of an affected child or the affected person (if aged 18 years or above) completed the survey. Results were securely transferred to a Research Electronic Data Capture database and aggregated for analysis. RESULTS: A total of 19 participants enrolled in the study. Notably, among the 19 participants, aggression and anxiety were mentioned by 3 (16%) and 4 (21%) participants, respectively, which is an increase over the numbers in previously published literature. Additionally, among the 19 participants, 3 (16%) had asthma and 2 (11%) had other immunological disorders, both of which have not been previously described in the syndrome. CONCLUSIONS: Several phenotypes might be underrepresented in the previous 16p13.11 microduplication literature, and new possible phenotypes have been identified. Whenever possible, patients should continue to be referenced as a source of complete phenotyping data on their condition. Self-phenotyping may lead to a better understanding of the prevalence of phenotypes in genetic disorders and may identify previously unreported phenotypes.

RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes.

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.