Clinical spreading of muscle weakness in amyotrophic lateral sclerosis (ALS): a study in 910 patients.

BACKGROUND: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally. METHODS: We conducted an observational study to define the initial sites of disease onset and the clinical progression ('spreading patterns') of motor deficits in a cohort of 910 ALS patients in Germany. RESULTS: Mean age of ALS onset was 59.0 ± 12.6 years for males and 61.2 ± 10.5 years for females, the mean ALSFRS-R was 35.1 ± 9.2, and 7.7% of the cohort reported a family history. Onset of motor symptoms was bulbar/upper limb in 26.8%/35.9%, the right arm initially being slightly more often affected than the left (18.5% vs.16.3%). Testing on concordance of handedness and onset in the dominant arm did not reach significance. Lower limb onset was observed in 37.3%. Unilateral limb onset patients reported horizontal spreading about three times more often than vertical spreading. 71/244 bulbar onset patients reported spreading pattern to the legs, and 17/339 lumbar onset patients reported spreading secondarily to the bulbar region. DISCUSSION: Our results indicate that, although the phenotype of so-called 'spinal' or 'intraspinal' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a 'spinal' or an 'intraspinal' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS.

Surgical Management of OHVIRA and Outcomes.

STUDY OBJECTIVE: Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) includes uterine didelphys, unilateral obstructed hemivagina, and ipsilateral renal anomaly. Surgical management of this condition relies on accurate diagnosis to excise the obstructed longitudinal vaginal septum (OLVS). Vital considerations involve identifying the side affected, ipsilateral renal anomaly (IRA), thickness of the septum (TS), septal axis (SA), and distance of the septum to perineum (DSP). The study aimed to evaluate the preoperative characteristics, imaging findings, and surgical outcomes of OHVIRA. METHODS: Institutional review board approval was obtained for this retrospective chart review. ICD-10 codes identified OHVIRA cases between 2012 and 2019 at a single children's hospital. Patient demographic characteristics, magnetic resonance imaging findings, surgical management, outcomes, and complications were reviewed. Descriptive statistics were utilized. RESULTS: Twenty-six patients met inclusion criteria. Most were diagnosed at puberty (92%). Abdominal pain (50%) was the most common presenting complaint. The mean age of diagnosis was 13.2 years overall and 11.2 years for those with regular cycles vs 13.4 years for those with irregular cycles. Preoperative imaging showed predominant right-sided OLVS (50%), IRA (77%), and oblique SA (65%). All patients underwent vaginoscopy, septum resection, and vaginoplasty, except 1 who was managed with an abdominal drain as a neonate. Four required postoperative vaginal stent or Foley, with DSP greater than 5 cm in all cases. One intraabdominal abscess complication occurred. No instances of hematocolpos re-accumulation or reoperation were observed during the 3-year follow-up period. CONCLUSION: This study demonstrates that detailed preoperative planning and a systematic surgical approach lead to favorable outcomes in OHVIRA irrespective of the OLVS laterality, TS, SA, or DSP.

Presentation and Management of Uterine Didelphys with Unilateral Cervicovaginal Agenesis/Dysgenesis (CVAD): A Multicenter Case Series.

INTRODUCTION: There are several well-described presentations of uterine didelphys (UD): UD without vaginal septum, UD with non-obstructed longitudinal vaginal septum, or UD with duplicated vaginas and an obstructed hemivagina on one side with ipsilateral renal anomaly. STUDY OBJECTIVE: To describe another variant of UD and compare the presentation and management across different institutions METHODS: This was a retrospective case series approved by the NASPAG Fellows Research Consortium. Participating institutions obtained IRB approval. Inclusion criteria included a diagnosis of UD and unilateral cervicovaginal agenesis/dysgenesis (CVAD). Descriptive statistics were used. RESULTS: Five patients met the inclusion criteria, with ages ranging from 13 to 27 years. Presenting symptoms included dysmenorrhea (80%), irregular bleeding (40%), acute onset left lower quadrant pain (20%), and abdominal mass (20%). Three patients had additional known abnormalities, including solitary kidney and solitary adrenal gland. All patients underwent pelvic magnetic resonance imaging. Two cases were only suspicious for unilateral CVAD on imaging and required pathology review postoperatively to confirm diagnosis. Two cases required a 2-staged approach with an initial diagnostic surgery followed by a second definitive procedure. Three patients were noted to have endometriosis intraoperatively. Postoperative follow-up ranged from 2 months to 2 years, with 1 patient reporting chronic pelvic pain. CONCLUSION: Diagnosis on the basis of pelvic imaging can be difficult, as this unique variant may mimic classic obstructed hemivagina with ipsilateral renal anomaly. In patients with UD with unilateral CVAD, standard management is removal of the obstructed uterine horn. This multicenter series stresses awareness about the clinical presentation, distinguishes cases of cervical agenesis from dysgenesis, and reviews approaches to management.

Critical elements in the operative management of pediatric malignant ovarian germ cell tumors.

Performance of the appropriate operation is highly important to ensure that any patient with a suspected ovarian germ cell tumor receives optimal therapy that prioritizes cure while simultaneoulsy minimizing risk of short and long-term toxicities of treatment. The following critical elements of any operative procedure performed for a suspected pediatric or adolescent ovarian germ cell tumor are reviewed: 1. Complete resection of the tumor via ipsilateral oophorectomy while avoiding tumor rupture and spillage, and 2. Performance of complete intraperitoneal staging at the time of initial tumor resection.

Laparoscopic salvage procedures for adnexal torsion in pediatric and adolescent patients during the COVID-19 pandemic: a retrospective cohort study.

BACKGROUND: Early management for adnexal torsion increases likelihood of ovarian/tubal salvage. The Coronavirus disease of 2019 (COVID-19) pandemic poses delays from symptom-onset to intervention. The primary objective was to evaluate rates of ovarian salvage and tubal salvage following ovarian torsion and adnexal torsion during the COVID-19 pandemic in a pediatric and adolescent gynecology population. METHODS: This was a retrospective quality improvement cohort study of pediatric and adolescent gynecology patients at a single children's hospital who underwent laparoscopy for suspected ovarian torsion/adnexal torsion between March 2020 to March 2021. Descriptive statistics and t-tests were utilized. RESULTS: There were 50 suspected adnexal cases in 47 patients. All underwent laparoscopy, revealing 39 adnexal torsion occurrences in 36 patients and 1 patient with recurrent adnexal torsion three times. All underwent pre-operative COVID-19 testing. Mean age was 13.9 ± 2.6 years for adnexal torsion cohort. Menarche was achieved in 88% (n = 44) and 12% (n = 6) were pre-menarchal. The primary outcome was ovarian salvage and tubal salvage rates, which were 97.4% (n = 38) and 89.7% (n = 35), respectively. Secondary outcomes assessed factors contributing to the primary outcome or operative delays. The mean age of menarche was 11.2 years (salvaged) and 12.5 years (non-salvaged) (p = 0.04). There were no differences in mean pain duration or mean COVID-19 testing time between groups. Left, right and bilateral adnexal torsion occurred in 42% (n = 21), 32% (n = 16), and 4% (n = 2) respectively. The most common pathologies were paratubal cyst (n = 17, 34%) and benign ovarian cyst (n = 16, 32%). CONCLUSIONS: Ovarian salvage and tubal salvage rates were 97.4% and 89.7%, respectively during the time frame studied. These salvage rates during the study period are comparable to previous rates in a pre-COVID cohort at our institution. Institutional and departmental quality and safety initiatives likely contributed to this outcome.

Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was used to further reproduce GREB1L findings in diverse genetic backgrounds. Proband and OMIM phenotypes annotated using the Human Phenotype Ontology were analyzed to quantitatively delineate the phenotypic spectrum associated with GREB1L variant alleles found in our MRKH cohort and those previously published. This study reports 18 novel GREB1L variant alleles, 16 within a multiethnic MRKH cohort and two within a congenital scoliosis cohort. Cohort-wide analyses for a burden of rare variants within a single gene identified likely damaging variants in GREB1L (MIM: 617782), a known disease gene for renal hypoplasia and uterine abnormalities (MIM: 617805), in 16 of 590 MRKH probands. GREB1L variant alleles, including a CNV null allele, were found in 8 MRKH type 1 probands and 8 MRKH type II probands. This study used quantitative phenotypic analyses in a worldwide multiethnic cohort to identify and strengthen the association of GREB1L to isolated uterine agenesis (MRKH type I) and syndromic MRKH type II.

The Effect of the Rate of Increase of Estrogen Replacement Therapy on Bone Mineral Density Accrual in Young Patients with Turner Syndrome.

BACKGROUND: Turner syndrome (TS) is caused by partial/complete X-chromosome monosomy with variable phenotypes, characterized by hypogonadism and short stature. To achieve pubertal changes, up to 50%-79% of patients with TS require estrogen replacement therapy (ERT), and 80% have low bone mineral density (BMD). Studies show that pubertal delays are associated with decreased BMD. Currently, guidelines suggest that ERT start at 12 years, increasing slowly, simulating pubertal progression. Many studies show that ERT increases BMD in adolescents with TS, but uncertainty remains as to how the rate of increase in ERT affects BMD. METHODS: Institutional review board approval was obtained from our institution for this retrospective chart review from 1991 to 2020. Charts were requested for the database using ICD 9-10 codes for TS and patients undergoing dual-energy X-ray absorptiometry. Biometric data and medical and treatment histories were extracted from charts. Multilevel random effects models were constructed to assess the time-dependent associations between ERT and bone density parameters. The primary independent variable of interest was the rate at which patients went from initiating ERT to reaching final doses. The primary dependent variables measured were total body BMD (tbBMD) and corresponding z-scores, calculated using dual-energy X-ray absorptiometry techniques. Analyses were done with SAS software (version 9.4, Cary, NC). RESULTS: Twenty-eight patients met the inclusion criteria. The mean age at TS diagnosis was 6.9 years; 8 patients had monosomy X, 16 had mosaic karyotypes, and 4 had unknown karyotypes. The average age for starting hormone replacement therapy was 14.1 years. Thirteen patients had spontaneous pubertal onset before starting hormone replacement therapy. tbBMD increased significantly with age (P = .03). However, change in BMD by age did not vary between patients who reached final adult doses of ERT within 0-2.5 years compared with patients who took 2.5-5.5 years (P = .7). Patients who took 2.5-5.5 years to reach final adult doses of ERT had a more negative trend in z-scores (-2.144) in comparison with patients who took 0-2.5 years (-1.776), although this difference did not reach statistical significance (P = .15). Future larger studies are needed to better understand the relationship between duration of ERT use and tbBMD. CONCLUSION: BMD in adolescents with TS increases with age. Neither absolute tbBMD values nor tbBMD z-scores increased faster when ERT doses were maximized within 2.5 years. This study identified a cohort of children under 12 years with TS who had not had any ERT or BMD measurements, a potential population for future larger prospective studies.

Structured Reporting in Multiple Sclerosis - Consensus-Based Reporting Templates for Magnetic Resonance Imaging of the Brain and Spinal Cord. / Strukturierte Befundung bei Multipler Sklerose ­ Konsensbasierte Befundvorlagen für die magnetresonanztomografische Untersuchung des Gehirns und des Rückenmarks.

As a result of technical developments and greater availability of imaging equipment, the number of neuroradiological examinations is steadily increasing [1]. Due to improved image quality and sensitivity, more details can be detected making reporting more complex and time-intensive. At the same time, reliable algorithms increasingly allow quantitative image analysis that should be integrated in reports in a standardized manner. Moreover, increasing digitalization is resulting in a decrease in the personal exchange between neuroradiologists and referring disciplines, thereby making communication more difficult. The introduction of structured reporting tailored to the specific disease and medical issue [2, 3] and corresponding to at least the second reporting level as defined by the German Radiological Society (https://www.befundung.drg.de/de-DE/2908/strukturierte-befundung/) is therefore desirable to ensure that the quality standards of neuroradiological reports continue to be met.The advantages of structured reporting include a reduced workload for neuroradiologists and an information gain for referring physicians. A complete and standardized list with relevant details for image reporting is provided to neuroradiologists in accordance with the current state of knowledge, thereby ensuring that important points are not forgotten [4]. A time savings and increase in efficiency during reporting were also seen [5]. Further advantages include report clarity and consistency and better comparability in follow-up examinations regardless of the neuroradiologist's particular reporting style. This results in better communication with the referring disciplines and makes clinical decision significantly easier [6, 7]. Although the advantages are significant, any potential disadvantages like the reduction of autonomy in reporting and inadequate coverage of all relevant details and any incidental findings not associated with the main pathology in complex cases or in rare diseases should be taken into consideration [4]. Therefore, studies examining the advantages of structured reporting, promoting the introduction of this system in the clinical routine, and increasing the acceptance among neuroradiologists are still needed.Numerous specific templates for structured reporting, e. g., regarding diseases in cardiology and oncology, are already available on the website www.befundung.drg.de . Multiple sclerosis (MS) is an idiopathic chronic inflammatory and neurodegenerative disease of the central nervous system and is the most common non-trauma-based inflammatory neurological disease in young adults. Therefore, it has significant individual and socioeconomic relevance [8]. Magnetic resonance imaging (MRI) plays an important role in the diagnosis, prognosis evaluation, and follow-up of this disease. MRI is established as the central diagnostic method in the diagnostic criteria. Therefore, specific changes are seen on MRI in almost all patients with a verified MS diagnosis [9]. Reporting of MRI datasets regarding the brain and spinal cord of patients with MS includes examination of the images with respect to the relevant medical issue in order to determine whether the McDonald criteria, which were revised in 2017 [10] and define dissemination in time and space clinically as well as with respect to MRI based on the recommendations of the MAGNIMS groups [11, 12], are fulfilled. A more precise definition of lesion types and locations according to the recommendations of an international expert group [13] is discussed in the supplementary material. Spinal cord signal abnormalities are seen in up to 92 % of MS patients [14-16] and are primarily located in the cervical spine [15]. The recommendations of the MAGNIMS-CMSC-NAIMS working group published in 2021 [11] explicitly recommend the use of structured reporting for MS patients.Therefore, a reporting template for evaluating MRI examinations of the brain and spinal cord of patients with MS was created as part of the BMBF-funded DIFUTURE consortium in consensus with neuroradiological and neurological experts in concordance with the recommendations mentioned above [11] and was made available for broad use (https://github.com/DRGagit/ak_befundung). The goal is to facilitate efficient and comprehensive evaluation of patients with MS in the primary diagnostic workup and follow-up imaging. These reporting templates are consensus-based recommendations and do not make any claim to general validity or completeness. The information technology working group (@GIT) of the German Radiological Society and the German Society for Neuroradiology strive to keep the reporting templates presented here up-to-date with respect to new research data and recommendations of the MAGNIMS-CMSC-NAIMS group [11]. KEY POINTS:: · consensus-based reporting templates. · template for the structured reporting of MRI examinations of patients with multiple sclerosis. · structured reporting might facilitate communication between neuroradiologists and referring disciplines. CITATION FORMAT: · Riederer I, Mühlau M, Wiestler B et al. Structured Reporting in Multiple Sclerosis - Consensus-Based Reporting Templates for Magnetic Resonance Imaging of the Brain and Spinal Cord. Fortschr Röntgenstr 2023; 195: 135 - 138.

NASPAG Pediatric and Adolescent Gynecology Surgery Compensation Survey.

INTRODUCTION: Over the last decade, the field of pediatric and adolescent gynecology (PAG) has rapidly expanded on the basis of a need for this specialized training to care for children and adolescents with gynecologic concerns. There are 18 PAG fellowship programs within the United States and Canada. Since 2017, which marked the beginning of the American Board of Obstetrics and Gynecology (ABOG) Focused Practice Examination in PAG and PAG Maintenance of Certification program, there has been a growing recognition of this specialty, given the unique population served. However, there is a paucity of information related to compensation in PAG. As the field has grown and more PAG fellow graduates are sought by children's hospitals throughout the United States and Canada, there is an urgent need to ensure that salary is equitable for these specialty PAG providers given the unique skills acquired during fellowship training, beyond that of obstetrics and gynecology (OBGYN) residency. This initial survey aimed to focus on compensation for PAG surgeons in the United States. OBJECTIVES: To survey NASPAG PAG surgeons in the United States about current benefits, practice metrics, and compensation METHODS: A 15-question anonymous survey was sent to PAG surgeons in the United States in February 2022, with 3 reminders sent by email to engage voluntary participation. The survey aimed to understand practice characteristics, current compensation, and relative value unit (RVU) benchmarks. Descriptive statistics were utilized. Compensation means and quartiles were calculated in U.S. dollars for the following categories: assistant professor, associate professor, and full professor. The compensation mean was also calculated for private/hybrid and instructor categories. RESULTS: Among 255 eligible members, 88 completed the survey, for a participation rate of 34.5%. Sixty-three point six percent reported having completed a PAG fellowship, whereas one-third reported specializing in this area with no fellowship available at the time. Three-fourths reported having achieved ABOG Focused Practice PAG certification. Most providers were academic (75%) and working full time (82.9%). Among academicians, most were assistant professors (48%) and on the non-tenure track (50.6%). RVU benchmarks varied, with 40.2% reporting OBGYN generalist targets and only 18.3% reporting PAG-specific targets, despite most physicians practicing only PAG (62.5%) and less than 30% practicing PAG plus some adult OBGYN. Salary support varied, with 57% employed by a hospital. Incentives were common, with most receiving a bonus at the end of the year (52.9%). As expected, full professors reported higher mean compensation ($345k) as compared with less senior colleagues ($248k and $302k for assistant and associate professors, respectively). Private practice/hybrid practitioners reported compensation ($251k) similar to that of assistant professors ($248k). Only 2 instructor-level physicians completed the survey. The mean number for this level is skewed and is not a reliable predictor for this academic level. Quartiles could not be calculated for this category. CONCLUSION: This is the first survey addressing compensation in the field of PAG in the United States. There is an ongoing need to collect this information to prepare PAG fellow graduates for the job market. Additional surveys, including an understanding of the compensation landscape in Canada, are needed in the future to address specific questions related to compensation for those who have less than 50% clinical time.

Imperforate Hymen: Clinical Pearls and Implications of Management.

Imperforate hymen is a common condition that with classic appearance and presentation in puberty. This may be diagnosed in a neonate when mucocolpos is noted. There are many great pretenders of this condition, but the hallmarks include a bulging hymen with blue hue at puberty. If this is not seen on external genital exam, the provider should proceed with magnetic resonance imaging to better assess the reproductive tract anatomy before engaging in surgery. For providers uncomfortable in managing conditions often confused with an imperforate hymen, referral to a Pediatric and Adolescent Gynecologist or specialist comfortable managing these conditions, is recommended.

Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome.

PURPOSE: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles. METHODS: Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining. RESULTS: We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423G>A (p.Leu141=) and c.839+5G>A variants impaired the normal splicing of TBX6 messenger RNA, c.422T>C (p.Leu141Pro) and c.745G>A (p.Val249Met) led to decreased protein expression, c.10C>T (p.Pro4Ser) and c.400G>A (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356G>A (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance. CONCLUSION: Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.

Diagnosis and Management of Mullerian Anomalies Across Differing Resource Settings: Worldwide Adaptations.

BACKGROUND: Mullerian anomalies affect 7% of reproductive age women. It is important to have a basic understanding of these conditions, given they can affect women at any stage of life and have potential impacts on fertility and pregnancy. This article seeks to review these anomalies as well as specific diagnostic pitfalls and strategies to approach these conditions in both high- and low-resource environments. METHODS: This review was undertaken with a PubMed focused search, using terms related to the diagnosis and management of Mullerian anomalies in many worldwide settings. Consideration was made to assess the medical resources available in low- and middle-income countries (LMICs), which could impact diagnostic and management decisions, compared with high-income countries (HICs). Concurrent medical conditions and both gynecologic and obstetric outcomes were also searched. Practice recommendations from international societies were also reviewed and compared. Finally, 4 conditions were evaluated more closely to assess management differences based on geographic locations and whether the countries were LMICs or HICs; specifically, those evaluated were lower vaginal atresia, uterovaginal agenesis, bicornuate uterus, and septate uterus. DISCUSSION: Mullerian anomalies encompass a wide variety of conditions, ranging from subtle anatomic changes without concurrent anomalies to complex conditions, associated with anomalies of the kidney or spine, which could impact the ability to manage certain conditions based on medical resources available geographically. A systematic approach and provider expertise is important for appropriate diagnosis and management, independent of geographic location. Counseling is critical for medical and surgical decision-making and might be limited or guided by the resources available in certain settings or even by existing laws. CONCLUSIONS: Limited outcomes are available among patients with Mullerian anomalies in LMICs; however, the management varies based on the basic tools available to address acute needs, as well as long-term fertility and obstetric concerns. More research is needed in this population, which could help drive the importance of early diagnosis and management not only in HICs but also in LMICs, where individualization strategies are key.

Review of Surgical Neovagina Techniques and Management of Vaginal Stricture.

STUDY OBJECTIVE: To review the currently available methods for surgical and nonsurgical neovaginal creation with an additional focus on situations requiring vaginal stretching, replacement, or augmentation and the management of vaginal stenosis or stricture. DESIGN: Review of the existing literature METHODS: PUBMED search with key words vaginal agenesis, neovaginal creation, vaginoplasty, vaginal stretching, vaginal augmentation, vaginal stenosis, outcomes of vaginoplasty, Mullerian anomalies, vaginal anomalies RESULTS: The need to perform vaginal stretching, replacement, or augmentation will vary depending on the underlying reproductive tract condition. CONCLUSIONS: A variety of techniques have been described to performed vaginal stretching, replacement, or augmentation. There are risks and benefits to each technique. Vaginal stricture and stenosis remain difficult problems given the high rates of these complications in patients undergoing these procedures. Although several techniques can alleviate this problem, they rely on the thickness of the stenosis and the location of the stenosis within the vagina.

Prevalence of Polycystic Ovary Syndrome in Patients With McCune Albright Syndrome.

STUDY OBJECTIVE: To identify polycystic ovarian syndrome (PCOS) in a population of female patients with McCune-Albright syndrome (MAS) by retrospective chart review. DESIGN: Retrospective study. SETTING: Academic setting. PARTICIPANTS: All female patients with a prior diagnosis of MAS who were more than 12 years of age at the time of chart review. Only complete medical records from January 2009 to January 2020 were included in the analysis. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Diagnosis of PCOS based on the Rotterdam 2003 criteria. RESULTS: Seventeen female patients with MAS were included in the analysis. PCOS appeared to be more prevalent in MAS patients than expected based on population estimates (exact binomial test = 0.353; CI = 0.142-0.617, P = .01). The average body mass index was not significantly different between MAS patients with and without PCOS (23.38 kg/m2 vs 23.44 kg/m2, 2-sample Wilcoxon rank-sum test with continuity correction, W = 29, P = 0.733). The majority of patients (71%) were treated with an aromatase inhibitor and/or a gonadotropin-releasing hormone (GnRH) agonist. CONCLUSIONS: The results of this study suggest that female individuals with MAS have a statistically higher prevalence of PCOS. These findings warrant further studies to determine whether the increased risk of PCOS may be associated with precocious puberty, treatment of precocious puberty, or other factors.

Whole-exome analysis of adolescents with low VWF and heavy menstrual bleeding identifies novel genetic associations.

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar "pathogenic" variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar "pathogenic" variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 × 10-6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

Imaging of Gαq Proteins in Mouse and Human Organs and Tissues.

G protein-coupled receptors (GPCRs) transfer extracellular signals across cell membranes by activating intracellular heterotrimeric G proteins. Several studies suggested G proteins as novel drug targets for the treatment of complex diseases, e.g., asthma and cancer. Recently, we developed specific radiotracers, [³H]PSB-15900-FR and [³H]PSB-16254-YM, for the Gαq family of G proteins by tritiation of the macrocyclic natural products FR900359 (FR) and YM-254890 (YM). In the present study, we utilized these potent radioligands to perform autoradiography studies in tissues of healthy mice, mouse models of disease, and human tissues. Specific binding was high, while non-specific binding was extraordinarily low, giving nearly identical results for both radioligands. High expression levels of Gαq proteins were detected in healthy mouse organs showing the following rank order of potency: kidney > liver > brain > pancreas > lung > spleen, while expression in the heart was low. Organ sub-structures, e.g., of mouse brain and lung, were clearly distinguishable. Whereas an acute asthma model in mice did not result in altered Gαq protein expressions as compared to control animals, a cutaneous melanoma model displayed significantly increased expression in comparison to healthy skin. These results suggest the future development of Gαq-protein-binding radio-tracers as novel diagnostics.

Surgical Approach to Pediatric Ovarian Growing Teratoma Syndrome: A Case Report.

BACKGROUND: Growing teratoma syndrome is defined as conversion of a metastatic immature tumor to a mature tumor after adjuvant chemotherapy and remains an area of investigation because of its unclear pathogenesis. Because of its risk of malignant transformation, the primary treatment strategy for pediatric patients is surgical resection. CASE: In this report we present a case of a pediatric patient with recurrent growing teratoma syndrome who was treated with chemotherapy, debulking procedures, and cryoablation for the growing nodules throughout her abdominal cavity. The patient has had a good clinical outcome without recurrent malignant tumor. SUMMARY AND CONCLUSION: These masses do not always regress with chemotherapy and complete surgical excision or ablation should be attempted when possible.

Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

The Utility of Blind Pap Tests in Young Adults with Developmental Delay: A Pilot Study.

STUDY OBJECTIVE: There are no guidelines specific to women with developmental delay who may not be able to tolerate a Papanicolaou (Pap) test in the office setting. The purpose of this study was to assess the utility of a less invasive method, a blind Pap for women with developmental delay, compared to the traditional Pap test performed in pediatric and adolescent gynecology (PAG) patients. DESIGN: Retrospective cohort pilot study. SETTING: Outpatient PAG clinics and the inpatient PAG service at a single institution. PARTICIPANTS: PAG patients who underwent a traditional Pap test and developmentally delayed PAG patients who underwent a blind Pap test. Patients were 26 years of age or less between July 2007 and March 2019. INTERVENTIONS AND MAIN OUTCOME MEASURES: Charts were reviewed to identify those who underwent a traditional Pap test (with a speculum and direct visualization) versus a blind Pap test (with a vaginal swab without a speculum). Descriptive statistics and Wilcoxon rank and Fisher exact tests compared specimen adequacy, presence of the endocervical/transformation zone (EC/TZ), and cytology results. RESULTS: Of 328 PAG patients identified, 314 patients had a traditional Pap test (control), and 14 patients had a blind Pap test (4.3%). The majority of Pap tests were satisfactory in both groups. The EC/TZ component was present in 279 (90%) specimens within the traditional Pap test group and 8 (57%) in the blind Pap test group (P = .002). The traditional Pap test group results varied, with most (81.9%) being negative for intraepithelial lesion or malignancy. All BP group pathology findings were negative for intraepithelial lesion or malignancy. CONCLUSION: Our study demonstrated an ability to perform a Pap test in a less invasive manner than a traditional Pap test. Although all blind Pap test specimens were adequate, only in 57% was the EC/TZ component reported to be present, compared to 90% of the traditional Pap test specimens.