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BackgroundValid patient-reported outcome (PRO) measures are required to evaluate alopecia areata (AA) treatments.ObjectivesTo develop a content-valid and clinically meaningful PRO measure to assess AA scalp hair loss with scores comparable with the five-response-level Alopecia Areata Investigator Global Assessment (AA-IGA™).MethodsA draft PRO measure was developed based on input from 10 clinical experts in AA. The PRO measure was cognitively debriefed, modified and finalized through two rounds of qualitative semistructured interviews with patients with AA who had experienced ≥ 50% scalp hair loss. Data were thematically analysed.ResultsAdults (round 1: n = 25; round 2: n = 15) and adolescents aged 15-17 years (round 1: n = 5) in North America participated. All patients named scalp hair loss as a key AA sign or symptom. Patients demonstrated the ability to self-report their current amount of scalp hair using percentages. In round 1 not all patients interpreted the measurement concept consistently; therefore, the PRO was modified to clarify the measurement concept to improve usability. Following modifications, patients in round 2 responded without difficulty to the PRO measure. Patients confirmed that they could use the five-level response scale to rate their scalp hair loss: no missing hair, 0%; limited, 1-20%; moderate, 21-49%; large, 50-94%; nearly all or all, 95-100%. Almost all patients deemed hair regrowth resulting in ≤ 20% scalp hair loss a treatment success.ConclusionsThe Scalp Hair Assessment PRO™ is a content-valid, clinically meaningful assessment of distinct gradations of scalp hair loss for evaluating AA treatment for patients with ≥ 50% hair loss at baseline.

BackgroundContent-valid and clinically meaningful instruments are required to evaluate outcomes of therapeutic interventions in alopecia areata (AA).ObjectivesTo develop an Investigator's Global Assessment (IGA) to interpret treatment response in AA treatment studies.MethodsQualitative interviews were conducted in the USA with expert dermatologists and with patients with AA who had experienced ≥ 50% scalp-hair loss. Thematic data analysis identified critical outcomes and evaluated the content validity of the new IGA.ResultsExpert clinicians (n = 10) judged AA treatment success by the amount of scalp-hair growth (median 80% scalp hair). Adult (n = 25) and adolescent (n = 5) patients participated. Scalp-hair loss was the most bothersome AA sign/symptom for most patients. Perceived treatment success - short of 100% scalp hair - was the presence of ~ 70-90% scalp hair (median 80%). Using additional clinician and patient insights, the Alopecia Areata Investigator Global Assessment (AA-IGA™) was developed. This clinician-reported outcome assessment is an ordinal, static measure comprising five severity categories of scalp-hair loss. Nearly all clinicians and patients in this study agreed that, for patients with ≥ 50% scalp-hair loss, successful treatment would be hair regrowth resulting in ≤ 20% scalp-hair loss.ConclusionsWe recommend using the Severity of Alopecia Tool to assess the extent (0-100%) of scalp-hair loss. The AA-IGA is a robust ordinal measure providing distinct and clinically meaningful gradations of scalp-hair loss that reflects patients' and expert clinicians' perspectives and treatment expectations. What is already known about this topic? The Severity of Alopecia Tool is widely used to assess the extent of scalp-hair loss in patients with alopecia areata. Guidelines define treatment success as a 50% improvement in scalp hair, and clinical trials have used dynamic thresholds of 50% and 90%. However, there is no clinical consensus on these endpoints, and patient perspectives on treatment success are unknown. What does this study add? Through qualitative interviews with 10 expert dermatologists and 30 patients with alopecia areata who had experienced ≥ 50% scalp-hair loss, we developed the Alopecia Areata Investigator Global Assessment (AA-IGA™) to measure five clinically meaningful gradations of alopecia areata scalp-hair loss that reflects patients' and clinicians' perspectives and expectations of treatment success in alopecia areata treatment studies. What are the clinical implications of this work? The AA-IGA is a robust ordinal measure that can inform clinical evaluation of alopecia areata treatment outcomes. The AA-IGA can be used to determine clinically meaningful treatment success for alopecia areata, with success defined by patients and clinicians as reaching ≤ 20% scalp-hair loss. Linked Comment: Blome. Br J Dermatol 2020; 183:609.

The article discusses several observations on the occurrence of mitral and aortic valve diseases. In the 1950s and 1960s, most physicians attributed these diseases in adults to rheumatic heart disease. In 1970s, a congenitally malformed aortic valve was found to be frequent in adults with aortic stenosis (AS), and mitral valve prolapse (MVP) was recognized as a common cause of pure mitral regurgitation (MR). Their frequencies and causes in necropsy studies are highlighted.

The purpose of this study was to determine the effect of simultaneous coronary artery bypass grafting (CABG) and the influence of valve structure on both early and late survival in sexagenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (with or without aortic regurgitation). We analyzed survival and valve structure in 289 sexagenarians having AVR for AS from 1993 through 2005 at Baylor University Medical Center, including 147 (51%) with and 142 (49%) without simultaneous CABG. Of the 282 patients with information available, 13 (4.6%) died within 30 days of operation and 1 additional patient, from 31 to 60 days after operation (5.0% 60-day mortality). Sixty-day mortality was similar (6% and 4%) in the groups with and without simultaneous CABG. A total of 66 patients (23%) died from >60 days up to 13 years postoperatively. The unadjusted survival analysis showed that late survival was not affected by gender (male versus female), aortic valve structure (unicuspid, bicuspid, and quadricuspid versus tricuspid) or preoperative severity of the AS (transvalvular peak pressure gradient >50 mm Hg versus < or =50 mm Hg), or by performance of CABG. The aortic valve was congenitally unicuspid in 10 patients (3%), congenitally bicuspid in 170 (59%), 3-cuspid in 107 (37%), congenitally quadricuspid in 1 patient, and the valve structure was indeterminate in 1 patient. In conclusion, gender, valve structure, preoperative severity of the AS, or performance of simultaneous CABG did not effect unadjusted survival in sexagenarians undergoing AVR for AS. [ABSTRACT FROM AUTHOR]

Aortic valve replacement following an earlier coronary artery bypass grafting (CABG) procedure is fairly common. When this situation occurs, the type of valve dysfunction is usually stenosis (with or without regurgitation), and whether it was missed at the time of the earlier CABG or developed subsequently is usually unclear. We attempted to determine the survival in patients who had had aortic valve replacement after 2 previous CABG procedures. We describe 12 patients who had aortic valve replacement for aortic stenosis; rather than one previous CABG operation, all had had 2 previous CABG procedures. Only one patient died in the early postoperative period after aortic valve replacement, and the remaining 11 were improved substantially: all have lived at least 11 months, and one is still alive at over 101 months after aortic valve replacement. Aortic valve replacement remains beneficial for most patients even after 2 previous CABG procedures. [ABSTRACT FROM AUTHOR]

A 52-year-old woman is described in whom cardiac sarcoidosis was diagnosed clinically on the basis of high-grade heart block, recurring ventricular tachyarrhythmias, and acute cardiac decompensation. Confirmation of sarcoidosis was not determined until necropsy. When it causes cardiac dysfunction, sarcoidosis rarely causes dysfunction of another body organ, although small sarcoid granulomas may also be present in noncardiac organs or tissues. In the present patient, neurosarcoidosis accompanied the cardiac sarcoidosis, but it was the latter that produced the life-threatening symptoms and was fatal. [ABSTRACT FROM AUTHOR]

We sought to measure the accuracy of 2-dimensional transthoracic echocardiography in determining aortic valve structure in patients with aortic stenosis (AS) undergoing aortic valve replacement (AVR). Few studies have compared aortic valve structure determined by echocardiogram to that determined by examination of the operatively excised stenotic aortic valve. Two-dimensional echocardiograms were reviewed and interpreted by an expert echocardiographer in blinded fashion in 100 patients >50 years of age (mean 70) who had undergone AVR for isolated AS ± aortic regurgitation and the aortic valve structure (unicuspid, bicuspid, tricuspid) was compared to that from examination of the operatively excised stenotic valve. After excluding 14 cases in which echocardiograms were uninterpretable because of heavy calcium and/or poor image quality, congenitally malformed valves were present in 44 patients (51%) and tricuspid valves in 42 of the 86 patients (49%). Ten of the 14 patients (71%) with uninterpretable echocardiograms had congenitally malformed valves. Valve structure by echocardiogram was concordant with morphologic interpretation in 57 of 86 patients (66% accuracy, kappa = 0.33). Accuracy trended toward improvement as degree of AS decreased. In patients with valve areas similar to those enrolled in the recent transcatheter aortic valve implantation trial (PARTNER; 0.7 ± 0.2 cm(2)), aortic valve structure was accurately determined by echocardiography in 21 of 35 patients (60%). In conclusion, aortic valve structure was interpretable by transthoracic echocardiogram in 86 of 100 patients and accurate in 57 of these 86 patients (66%). [ABSTRACT FROM AUTHOR]

RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although BRAF gene mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAFKE/+) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca2+ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific AAV-BRAF KE delivery induced memory deficits, reactive astrogliosis, and increased astrocytic Ca2+ fluctuations. Notably, reducing ERK activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFKE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF KE-expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies.

Nasopharyngeal carcinoma (NPC) is an Asia-prevalent malignancy, yet its genetic underpinnings remain incompletely understood. Here, a transcriptome-wide association study (TWAS) is conducted on NPC, leveraging gene expression prediction models based on epithelial tissues and genome-wide association study (GWAS) summary statistics from 1577 NPC cases and 6359 controls of southern Chinese descent. The TWAS identifies VAMP8 on chromosome 2p11.2 as a novel susceptibility gene for NPC. Further fine-mapping analyses pinpoint rs1058588, located within VAMP8, as a causal variant through eQTL colocalization, and GWAS analyses across multiple cohorts, achieving GWAS significance (OR = 1.18, P = 3.09 × 10 -10 ). Functional assays demonstrate that VAMP8 exerts a tumorigenic role in NPC, enhancing cell proliferation, migration, and tumor growth. Mechanically, it is uncovered that rs1058588 modulates VAMP8 expression by altering its binding affinity to miR-185. Furthermore, the results show that VAMP8 interacts with DHX9 to facilitate the nuclear recruitment of p65, activating the NF-κB pathway. Collectively, the findings shed light on the genetic predisposition to NPC and underscore the critical role of the functional axis involving miR-185, VAMP8, DHX9, and the NF-κB pathway in NPC pathogenesis., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulk-transcriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC.

Objectives: To examine prevalence and risk correlates for post-traumatic stress disorder (PTSD) occurring during or after admission to a Veterans Administration (VA) skilled nursing facility., Design: Retrospective cohort analysis of electronic health record information extracted from the VA Corporate Data Warehouse., Setting: United States VA skilled nursing facility., Participants: 57,414 Veterans age 60+ with an admission during five fiscal years, 2018-2022, excluding those who died within six months of admission or were still admitted., Measurements: The dependent variable was PTSD diagnosis during or six-months following the admission. Risk correlates examined were: age, gender, race, rurality, clinical complexity, prior dementia diagnosis, length of stay, and facility size; odds ratios (OR) and confidence intervals (CI) are provided for each correlate., Results: 19.1% of Veterans had a diagnosis of PTSD, associated with younger age (age 60-69 compared to age 80+; OR: 2.92, 95% CI: 2.70-3.14; age 70-79 compared to age 80+ OR: 4.51, 95% CI: 4.20-4.84); female gender (OR: 1.65, 95% CI: 1.50-1.82); minoritized race (OR: 1.17, 95% CI: 1.12-1.23); higher clinical complexity (OR:1.22, 95% CI: 1.17-1.28). As compared to Veterans who had a prior PTSD diagnosis, Veterans with newly diagnosed PTSD were more likely to be older (age 60 group OR= 0.59, 95% CI:0.51-0.70; age 70 group OR= 0.54, 95% CI:0.46-0.62,), rural (OR=1.14, 95% CI:1.04-1.24) and admitted to a larger facility (OR=1.22, 95% CI:1.12-1.33)., Conclusions: PTSD is a significant concern for older Veterans admitted to VA skilled nursing facilities, supporting the need for trauma-informed care, particularly for those most at risk., Competing Interests: Disclosures The authors report no conflicts with any product mentioned or concept discussed in this article., (Copyright © 2024 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the clinical characteristics and genetic features of childhood-onset congenital combined pituitary hormone deficiency (cCPHD) in Korean patients., Methods: We retrospectively analyzed 444 patients diagnosed with childhood-onset CPHD at a tertiary center between 1994 and 2021. After excluding acquired case, 43 patients with cCPHD were enrolled. Anthropometric measurements, hormone evaluations, brain magnetic resonance imaging (MRI), extrapituitary phenotypes, and adult outcomes were analyzed. Genetic analyses were performed on 26 patients using a targeted gene panel or whole exome sequencing., Results: Mean age at diagnosis was 3.2 years, and 41.9% were diagnosed at less than 1 year old. Short stature was the most frequent (37.2%) initial presentation, and mean height z-score was -2.4. More than half (n=23, 53.5%) of patients had neonatal features suggestive of hypopituitarism; however, only 15 (65.2%) were diagnosed in infancy. Growth hormone deficiency (GHD) was prevalent in 42 (97.7%), and 33 (76.7%) had 3 or more hormone deficiencies. Extrapituitary phenotypes were identified in 31 (72.1%). Brain MRI abnormalities correlated with a higher number of hormone deficiencies (P for trend 0.049) and were present in 33 patients (80.5%). Adult GHD was diagnosed in all 17 investigated patients, and metabolic disturbances were noted in 10 (58.9%). Pathogenic variants in POU1F1, GLI2, HESX1, TBC1D32, and ROBO1 were found in 5 (19.2%)., Conclusion: Considering the high proportion of neonatal presentations, identification of the early neonatal features of hypopituitarism to manage pituitary and extrapituitary phenotypes is critical. The genetic etiology of cCPHD warrants further exploration.

Background and Objectives: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening inherited arrhythmogenic disorder. Recently, RYR2 , the major CPVT-causative gene, was associated with neuropsychiatric manifestations. We aimed to analyze the clinical presentations, neuropsychiatric manifestations, and treatment outcomes of children with CPVT., Methods: We retrospectively reviewed 23 patients diagnosed with CPVT before 19 years of age. Genetic analysis, history of neuropsychiatric manifestations, changes in ventricular arrhythmia burden before and after treatment, occurrence of cardiac events, and overall survival (OS) were investigated., Results: RYR2 variants were identified in 17 patients, and 14 were classified as pathogenic or likely pathogenic. Neuropsychiatric manifestations, including intellectual disability and attention deficit hyperactivity disorder, were identified in 10 patients (43.5%). The 5-year cardiac event-free survival rate was 31.2%, and the 10-year OS rate was 73.1%. Patients diagnosed since 2009 had a higher cardiac event-free survival rate than those diagnosed before 2009 (p=0.0028). Combined beta-blocker and flecainide therapy demonstrated a lower risk of cardiac events than beta-blocker monotherapy (hazard ratio [HR], 0.08; 95% confidence interval [CI], 0.02-0.38; p=0.002). Left cardiac sympathetic denervation (LCSD) reduced the ventricular arrhythmia burden in Holter monitoring. Occurrence of near-fatal cardiac events after diagnosis was an independent predictor of death (HR, 33.40; 95% CI, 6.23-179.95; p<0.001)., Conclusions: Neuropsychiatric manifestations are common in children with CPVT. Flecainide and/or LCSD, when added to beta-blocker therapy, reduce the ventricular arrhythmia burden and cardiac events, thereby improving treatment outcomes in recent years., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2024. The Korean Society of Cardiology.)

Heterozygous variants of MATN3 is one of the common causes of multiple epiphyseal dysplasia (MED). Here we report three individuals from two unrelated families who harbor compound heterozygous variants in MATN3 (p.Arg121Trp and p.Val220Ala). Contrary to the MED phenotype, these individuals exhibit spondyloepimetaphyseal dysplasia (SEMD) resembling the phenotypes caused by homozygous MATN3 variants. Clinical manifestations included short stature, aggravating genu varum, joint laxity, and spinal abnormalities. Radiographic findings were distinct from typical MED. These compound heterozygous variants in the von Willebrand factor A domain of MATN3 expand the phenotypic spectrum associated with MATN3, and suggest that extreme MATN3 dysfunction resulting from dual variants can lead to a specific pattern of SEMD., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Atopic dermatitis (AD) severity is traditionally evaluated during in-office consultations; however, this does not provide continuous monitoring and any intermittent flare/remission cycles are usually not recorded. The aim was to apply smartphone technology to evaluate AD severity, to explore if severity based on highly frequent sampling of photographs is associated with patient reported outcomes, and to investigate disease fluctuations and trigger associations based on passively collected environmental data., Methods: In this 12-week decentralized observational study, adult patients with AD were recruited online and used a tailored remote clinical trial platform app to perform all study tasks including capturing photographs and completing the Patient-Oriented Eczema Measure (POEM) weekly. AD severity was assessed based on photographs using the Eczema Area and Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD). Geographical location collected in the app was used to retrieve data on ambient temperature and carbon monoxide (CO), a common air pollutant., Results: A total of 42 patients (35 women) were recruited online. A total of 712 photographs were taken, with an average of 17 photographs per participant. Photographic SCORAD (r = 0.450) and EASI (r = 0.206) were significantly associated with subjective severity POEM. Patients experiencing AD fluctuation (n = 10) based on SCORAD had significantly higher risk of also having a psychiatric disorder (60 vs. 17%, p = 0.008). Anxiety was significantly associated with disease fluctuation based on EASI (40 vs. 7%, p = 0.01), and a tendency was observed for depression (40 vs. 13%, p = 0.06). Decreasing temperature was significantly associated with higher POEM (estimate -0.18, p = 0.012) and EASI score (estimate -0.14, p = 0.007), but not with SCORAD. High levels of CO were significantly associated with higher SCORAD (estimate 15.9, p < 0.001)., Conclusion: In this small study with a predominance of young adults, primarily women, we were able to recruit patients and monitor AD entirely remotely via smartphone-enabled photographic assessments; patients reported outcomes and passively collected environmental data without physical contact between patient and investigator., (© 2024 S. Karger AG, Basel.)

Competing Interests: Dr Daneshjou reported stock options from Revea and MDalgorithms, as well as personal fees from Pfizer, Frazier Healthcare Partners, and L'Oreal outside the submitted work; in addition, Dr Daneshjou had a patent for 17/937 714 pending and was a member of American Academy of Dermatology (AAD) Augmented Intelligence Committee. Dr Ko reports research collaboration with Google Health and serves as a medical advisor on the clinical advisory committee for Skin Analytics. Drs Pathmarajah, Chiou, and Author Cai have no conflicts of interest to declare.

Background: Sotos syndrome (SS) is a rare disorder characterized by overgrowth, distinctive facial features, and intellectual disability that is primarily caused by NSD1 pathogenic variants or 5q35 microdeletions., Methods: We retrospectively analyzed the clinical characteristics and 339 anthropometric measurements over an average of 4.3 years of follow-up in 57 Korean children with SS. Sex-specific percentile curves for height, weight, and head circumference were developed using a generalized additive model that included factors such as location, scale, and shape., Results: Males with SS demonstrated higher height before the age of 12.0, greater weight before 10.0, and larger head circumference before 15.5 compared to age- and sex-matched controls. Females with SS displayed higher height before 17.0, greater weight before 10.5, and larger head circumference before 12.0 compared to controls. Bone age was advanced compared to chronological age in 40% of males and 8% of females at their last visit. The predicted and target adult heights were not significantly different between groups. In subgroup analysis, the intragenic variant group (n = 48) showed a higher mean standard deviation score of height and weight in males, and head circumference in females compared to the microdeletion group (n = 9)., Conclusions: Korean children with genetically confirmed SS exhibited overgrowth in height, weight, and head circumference. Overgrowth phenotypes were more prominent in patients with NSD1 intragenic variants than in those with microdeletions. This is the first study to provide reference data on the growth of Korean children with SS., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Biopsy-based histology has been the foundation of disease diagnosis and management for over a century. A long-sought goal in dermatology is the development of an imaging modality with sufficient resolution and compositional detail to noninvasively interrogate skin histology in vivo. Here, we describe a system that achieves this goal using cross-sectionally scanned, multimodal microscopy (cross-modal). Cross-modal combines multiphoton and reflectance confocal microscopy into one compact system with coordinated three-axis scanning that preserves optical resolution in cross-section. A custom pinhole-free mechanism employing finite-infinite conjugates further simplifies and stabilizes confocal alignment. Evaluated in participants ages 9-81 and Fitzpatrick skin types (FST) 1-5, cross-modal images revealed histological details analogous to those obtained from traditional biopsied tissue. We observed dermal elastosis in sun-damaged skin, elevated melanin in pigmented skin, basaloid nests in basal cell carcinoma, and elongated rete ridges in seborrheic keratosis, supporting cross-modal's potential to deliver histological insights noninvasively., (© 2024. The Author(s).)

Background: Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer., Results: In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations., Conclusions: When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent., (© 2024. The Author(s).)

Objective: Hydrocephalus is one of the neurological risks occurring in patients with achondroplasia. Ventriculoperitoneal shunt (VPS) insertion is the most common treatment. However, reports of successful endoscopic third ventriculostomy (ETV) suggest that ETV may be a good alternative to VPS insertion in achondroplasia. However, it has been stated that ETV in achondroplasia patients is technically demanding to perform. The current study examined the anatomical variations of the third ventricle and the brainstem in achondroplasia patients and correlated the findings with the difficulty of performing ETV., Methods: A retrospective analysis of 51 patients with achondroplasia and 138 hydrocephalus patients without achondroplasia (48 patients had tumor-related hydrocephalus and 90 patients had hydrocephalus of nontumorous origin) who have visited the authors' institution since 2012 was performed. Preoperative T2-weighted sagittal MR images were used to measure α (steepness of the third ventricle floor), β (endoscopic angle of incidence), d1 (vertical distance between the dorsum sellae and basilar bifurcation), and d2 (horizontal distance between the dorsum sellae and basilar artery). Each value was compared using the Tukey multicomparison test., Results: Achondroplasia patients showed significantly smaller α (p < 0.001) and β (p < 0.001) angles, while there were no significant differences between the control groups (p = 0.947 for α, p = 0.836 for β). The d1 value was significantly larger in achondroplasia patients (p < 0.001), and d2 was smaller (p < 0.001). The control groups showed similar d1 and d2 values (p = 0.415 for d1, p = 0.154 for d2). Smaller α and β values meant that in achondroplasia patients the third ventricle floor stood more vertically than in other patients with hydrocephalus, and the endoscopic contact angles were small, increasing the risk of ventriculostomy devices slipping down into the infundibular recess. Additionally, a large d1 meant that the basilar artery was shifted upward and a small d2 indicated that the basilar artery was located closer to the dorsum sellae, potentially increasing the risk of basilar artery damage., Conclusions: Achondroplasia patients' skull and brain anatomies were significantly different from those of other hydrocephalus patients, with steeper third ventricle floors and basilar arteries closer to the dorsum sellae. Because these anatomical differences lead to difficulties in performing ETVs in achondroplasia patients, such differences should be considered when ETV is planned for the patients.