Schimmenti, Lisa A.

ABSTRACT Bardet‐Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by clinical and genetic heterogeneity. Data on the prevalence of clinical manifestations and comorbidities in BBS, particularly in pediatric patients, are limited. This study aimed to assess the prevalence and various manifestations of endocrine and other clinical comorbidities among pediatric and adult patients with BBS. This retrospective chart review included pediatric and adult patients with BBS evaluated at an academic tertiary care center in the United States between 2000 and 2024. The study included 31 patients (7 children and 24 adults) with seven identified pathogenic variants associated with BBS. The most common genetic etiology was biallelic variants in BBS1 (36%). Obesity was diagnosed in 86% of children and 100% of adults. No children had diabetes or prediabetes, whereas 46% of adults were affected. Dyslipidemia was identified in 29% of children and 46% of adults. No thyroid abnormalities were identified in children, whereas 25% of adults were affected. Retinal dystrophy was present in 71% of children and 96% of adults. Polydactyly was observed in 100% of children and 75% of adults. Chronic kidney disease was present in 29% of children and 63% of adults. This study highlights the clinical heterogeneity and substantial multisystem burden of BBS across pediatric and adult patients. The greater prevalence of diabetes/prediabetes, dyslipidemia, thyroid abnormalities, chronic kidney disease, and visual impairment among adults suggests that these complications may emerge or progress over time. Early recognition, proactive longitudinal surveillance, and comprehensive multidisciplinary care are essential to optimize management across the lifespan.

ABSTRACT Stickler syndrome is most commonly caused by variants in COL2A1 and COL11A1 genes. The purpose of this study was to describe genetic variants and phenotypes in COL2A1 and COL11A1 Stickler syndrome. We performed a retrospective genotype–phenotype evaluation of COL2A1 and COL11A1 Stickler syndrome subjects. Thirty‐two subjects with COL2A1 and 13 subjects with COL11A1 Stickler syndrome were last seen in clinic at a mean age of 17.2 ± 13.1 and 12.6 ± 3.8 years, respectively ( p = 0.08). We found that 50% of COL2A1 subjects had lattice degeneration, whereas 8% of the COL11A1 subjects had lattice degeneration ( p = 0.015). The most common type of variant for COL2A1 Stickler syndrome was a premature termination codon (12 out of 18 families, 67%); and the most common types of variants for COL11A1 Stickler syndrome were glycine missense variants (4 out of 10 families, 40%) and splice site variants (4 out of 10 families, 40%). There was a higher rate of lattice degeneration in COL2A1 patients compared with COL11A1 patients, a finding that could be influenced by a trend towards older age at last follow‐up in the COL2A1 group.

Objective: Characterize pathogenic variants, rates of mosaicism, genetic testing yield, and disease severity among patients with NF2-related schwannomatosis dichotomized by diagnosis before or after the age of 30. Study design: Retrospective analysis. Setting: Tertiary referral center multidisciplinary NF2 clinic from 2021 to 2024. Patients: Patients with NF2-related schwannomatosis. Intervention: Next-generation sequencing. Main outcome measure: Rates of mosaicism, genetic testing rates and yield, and overall disease severity by tumor burden. Results: From 2021 to 2024, there were 32 patients ≥30 years of age and 39 patients diagnosed at younger ages. Patients diagnosed ≥30 years exhibited decreased likelihood of receiving genetic testing (53% vs. 85%; P =0.009) and decreased genetic yield (defined as identification of a pathogenic genetic variant in those undergoing testing; 65% vs. 85%; P =0.20). Both age groups demonstrated similar rates of pathogenic variant type with loss-of-function being the predominant variant detected in 73% vs. 67%, for ≥30 vs. <30 years of age; P =0.90. Those ≥30 years harbored fewer number of average anatomic regions involved by tumor (2.3 vs. 3.4; P <0.001) and decreased total number of tumors (7 vs. 12; P <0.001). Conclusions: Patients diagnosed with NF2-related schwannomatosis at age ≥30 years exhibited reduced disease severity compared with those diagnosed at a younger age despite harboring similar distributions of genetic pathogenic variants inclusive of loss-of-function pathogenic variants. These observations emphasize the importance of considering patient age in addition to genetic testing for diagnostic framing tailored to patients’ biology and clinical context to optimize care in the setting of NF2-related schwannomatosis.

Abstract M.D.-Ph.D. programs in the United States have traditionally followed a “2- n -2” curricular model, with the graduate phase occurring between the pre-clerkship and clerkship portions of medical training. While well established, this format can limit trainee autonomy in shaping their physician-scientist training trajectories. In response, some programs have introduced a “3- n -1” model, allowing students to complete clerkships before beginning Ph.D. training. Our institution implemented multiple flexible curricula in 2017. Understanding why trainees choose one pathway is important as programs consider implementing more adaptable training structures. To investigate these factors, we surveyed M.D.-Ph.D. students at our institution, which offers multiple flexible curricular alternatives, about contributions to their curricular decisions. Responses supported that trainees weigh considerations across medical education, scientific development, and integrated physician-scientist training domains. Although the traditional pathway was a popular option, most students pursued one of the flexible pathways. Our findings suggest that introducing flexibility in the timing of undergraduate medical education and graduate training can support diverse educational, logistical, and personal priorities while maintaining the rigor of physician-scientist training. Offering multiple pathways empowers trainees to design trajectories that best fit their needs. Continued longitudinal studies are needed to assess the long-term impacts of flexible curricula on physician-scientist career outcomes.

Abstract Background DDX3X- syndrome is a rare neurodevelopmental disorder characterized by varying degrees of intellectual disability, predominantly affecting females. We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of DDX3X- syndrome. Methods We conducted a retrospective chart review of patients diagnosed with DDX3X -syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with DDX3X -syndrome. Results A total of 200 patients with DDX3X -syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with DDX3X -syndrome, at a median age of 4.5 years (IQR 1.2–9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects. Conclusion DDX3X -syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis.

ABSTRACT Myhre syndrome is a rare multisystem disorder characterized by distinctive facial features, hearing loss, and progressive fibrosis affecting the skin, joints, lungs, and cardiovascular system. It is caused by heterozygous pathogenic variants in the SMAD4 gene. In this review, we detail the cutaneous manifestations observed in two previously reported patients with genetically confirmed Myhre syndrome. While skin biopsies demonstrated pan‐dermal thickening of collagen bundles, the immunohistochemical staining patterns were distinct from those seen in other inflammatory sclerosing disorders. Additionally, we conducted a comprehensive literature review of the cutaneous features associated with Myhre syndrome, identifying 175 patients with confirmed SMAD4 pathogenic variants. The most reported cutaneous finding was thickened or stiff skin (76%), followed by keratosis pilaris (22%) and impaired wound healing or abnormal scarring (18%). Genotype–phenotype analysis suggested a diagnostic delay in patients with the codon 496 variant, who were more frequently diagnosed in adulthood. This variant may also be associated with a milder cutaneous phenotype, highlighting the clinical heterogeneity of Myhre syndrome. These findings underscore the importance of recognizing cutaneous features as potential early diagnostic clues in patients with suspected Myhre syndrome.

Abstract Cockayne Syndrome is an ultra-rare premature aging condition associated with UV sensitivity, neurocognitive decline, retinopathy, metronidazole-induced lethality, and sensorineural hearing loss. In 70% of affected patients, bi-allelic pathogenic variants in ERCC6 are identified. Although the role of ERCC6 in DNA damage repair has been studied, little is known about the mechanism for defective ERCC6 function in clinical findings, particularly hearing loss. To identify the mechanism of disease caused by pathogenic variants in ERCC6, we developed a zebrafish (Danio rerio) ercc6 loss of function model. We assessed survival after UV and metronidazole exposure, measured basal respiration rates, and evaluated mechanoelectrical transduction function and counts of lateral line hair cells. We found that UV exposure significantly reduces ercc6−/− larval viability. Metronidazole treatment results in complete lethality; wildtype controls show nearly complete survival. ercc6−/− embryos have significantly increased oxygen consumption, suggesting abnormal mitochondrial function. Phalloidin staining of lateral line hair cells with and without UV treatment shows no difference in hair cell counts per neuromast between treatment groups. Mechanoelectrical transduction function after UV exposure, measured by FM1–43 uptake, is reduced. Metronidazole lethality is reduced, oxygen consumption rates are restored, and mechanoelectrical transduction function is preserved by treatment with Mn(III)tetrakis(4-benzoic acid)porphyrin Chloride (MnTBAP), a superoxide dismutase mimetic. We propose that defective mitochondrial function and increased reactive oxygen species levels provide a mechanism for hair cell dysfunction in this model of Cockayne Syndrome. These results provide a foundation for further experiments to explore disease mechanisms and treatment modalities for this premature aging condition.

ABSTRACT Post‐translational modifications, such as glycosylation and phosphorylation, play a critical role in protein trafficking, interactions, and stability. Disruptions in these pathways can lead to glycosylphosphatidylinositol (GPI) deficiencies, which present with a spectrum of clinical features, including congenital anomalies, dysmorphic features, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGV , a key mannosyltransferase in GPI biosynthesis, cause Hyperphosphatasia with Impaired Intellectual Development Syndrome 1 (HPMRS1), a rare disorder characterized by hyperphosphatasia, seizures, developmental delay, hypotonia, abnormal MRI findings, and distinct facial dysmorphisms. Fewer than 30 cases have been reported to date. We conducted a case study and literature review; with clinical data obtained from medical records. A 2‐year‐old female presented with developmental delay, myoclonic epilepsy, hypotonia, and mild facial dysmorphism. Laboratory results showed elevated alkaline phosphatase (899 U/L) and low pyridoxal 5′‐phosphate levels in cerebrospinal fluid (CSF). Brain MRI revealed diffuse cerebral volume loss and ventriculomegaly. Trio genome sequencing identified two PIGV variants: c.1415T>C‐p.(Leu472Pro) and c.524T>C‐p.(Leu175Pro). Functional studies using PIGV ‐knockout HEK293 cells transfected with wild‐type or mutant PIGV constructs demonstrated reduced GPI‐anchored protein (GPI‐AP) expression under weaker promoters, indicating impaired enzymatic activity. We report two novel PIGV variants associated with HPMRS1, emphasizing the value of functional assays in variant interpretation. Our findings also highlight the diagnostic relevance of alkaline phosphatase measurement in patients with refractory seizures.