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.

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.

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.

HMB in the Adolescent: A Review of the Modern Approach to Diagnosis and Management.

Heavy menstrual bleeding in the adolescent is a cause for concern whether occurring acutely or chronically. There are a number of important considerations during the initial presentation that will help guide the practitioner during workup, which ultimately guides management strategies. The cornerstone of management in the adolescent is that of medical therapy (hormonal and nonhormonal), with avoidance of invasive and irreversible measures, as maintenance of fertility is paramount. Ultimately, the majority of adolescents can be successfully managed in the acute setting and transitioned to maintenance therapy for long-term control of heavy menses. Here, we will review the modern approach to this condition as well as tips and tricks for the practitioner.

Physiologic Ovarian Cysts versus Other Ovarian and Adnexal Pathologic Changes in the Preadolescent and Adolescent Population: US and Surgical Follow-up.

Background Ovarian and adnexal cysts are frequently encountered at US examinations performed in preadolescent and adolescent patients, yet there are few published studies regarding the outcomes of cysts in this population. Purpose To identify characteristics at US that help to distinguish physiologic ovarian cysts from nonphysiologic entities. Materials and Methods Female patients who underwent pelvic US with or without Doppler from January 2009 through December 2013 were identified by using a centralized imaging database. Patients older than 7 years and younger than 18 years with ovarian or adnexal cysts at least 2.5 cm were included. Demographic characteristics, date of surgery, surgical notes, and pathologic reports were extracted from the electronic medical record. Initial and follow-up dates of US, cyst size and complexity, imaging diagnosis, and change on subsequent US images were recorded. Statistical analysis was performed with the Wilcoxon rank sum and Kruskal-Wallis tests for continuous variables and the Fisher exact test for categorical variables. Results Of 754 patients who met inclusion criteria (age, 8-18 years; mean age, 14.6 years ± 1.9 [standard deviation]; mean cyst size, 5 cm ± 3.3), 409 patients underwent complete follow-up that included resolution at imaging (n = 250) or surgery (n = 159). In the patients with complete imaging follow-up, mean time to US documentation of resolution was 194 days ± 321; 59.6% (149 of 250) patients had nonsimple cyst characteristics. One-hundred fifty-nine patients underwent surgical intervention (mean cyst size, 8.5 cm ± 5.3), and 69.8% (111 of 159) of the cysts had simple characteristics. Of the 159 cysts, 100 (62.8%) were defined in the pathologic report as paratubal cysts. Of 409 patients, no malignancies were encountered in this study population with surgical or imaging resolution. Conclusion No malignancies were encountered in the study population and the majority of cysts resolved at follow-up imaging. Large size, persistence, and separability from the ovary were most helpful for identification of nonphysiologic paratubal cysts. © RSNA, 2019.

Can We Improve Vaginal Tissue Healing Using Customized Devices: 3D Printing and Biomechanical Changes in Vaginal Tissue.

BACKGROUND: Determining biomechanical changes in vaginal tissue with tissue stretch is critical for understanding the role of mechanotransduction on vaginal tissue healing. Noncontact dynamic optical coherence elastography (OCE) can quantify biomechanical changes in vaginal tissues noninvasively. Improved vaginal tissue healing will reduce postoperative complications from vaginal surgery. AIMS: (1) To complete dimensional assessments (DAs) of the vaginal tract. (2) To elucidate biomechanical properties (BMP) of porcine vaginal tissues (PVT). (3) Compare BMPs of piglet and adult PVTs after placement of customized vaginal dilators (VD) by OCE and uniaxial mechanical testing (MT). METHODS: Pilot study using adult nulliparous pig and piglet PVTs (n = 20 each). DA of PVTs was performed using silicone molding. 3D-printed VDs were used to achieve different Relative Diameter Change (RDC) of the PVTs (no dilatation, and -50%, 0%, 50% RDC). Elastographic testing using OCE and MT. RESULTS: Using OCE, no significant differences (SD) were noted between adult and piglet PVT (p = 0.74) or by stretch direction (p = 0.300). SD was noted with increasing RDC (p = 0.023). Using MT, there were SD in tissue stiffness between adult and piglet PVT (p = 0.048), but no SD as a function of RDC (p = 0.750) or stretch direction (p = 0.592). CONCLUSIONS: This study quantified biomechanical changes in PVT with customized stretching by 3D printed VD using both OCE and MT. This work has implications for the mechanotransduction of vaginal wound healing and noninvasive assessment of vaginal diseases.

Evaluation and management of heavy menstrual bleeding in adolescents.

PURPOSE OF REVIEW: Heavy menstrual bleeding (HMB) is a common condition in women of reproductive age; however, adolescents with this issue present unique challenges in both diagnosis and management. Much of the research into this topic focuses on the adult population, with variable applicability to adolescents. There are currently no standard guidelines for the work up and treatment of adolescents with HMB. RECENT FINDINGS: Current research into this topic has explored the utilization of standardized protocols in the evaluation of HMB in adolescents, the efficacy of various hormonal, nonhormonal, and surgical treatment modalities, and the benefits of a multidisciplinary approach. Recent literature has focused on adolescents found to have an underlying bleeding disorder, recommending more comprehensive bleeding disorder work up to identify these patients in a timely manner and initiate effective treatment plans. SUMMARY: Providers in the primary care setting should be aware of the definitions for normal menses, and be able to recognize abnormal bleeding and HMB. Early recognition of HMB in adolescents can then lead to appropriate diagnosis of underlying disorders, and current research has proposed standard protocols to assist with the evaluation, ultimately leading to effective long-term management into adulthood.VIDEO ABSTRACT.

Gynecologic findings in Goltz syndrome: A case series.

There is limited information available related to the gynecologic findings in Goltz syndrome. We report exclusively on external genitalia findings in 17 girls with a known diagnosis of focal dermal hypoplasia. This is the largest series to date. Some of our findings have been reported previously; however, some novel features including short perineum body not previously mentioned are noted as well. We recommend referral to a pediatric gynecologist for early evaluation of the reproductive tract as this can have an impact on the future fertility of these girls.

A Multidisciplinary Approach to Puberty and Fertility in Girls with Turner Syndrome.

Women with Turner Syndrome (TS) have a variety of medical needs throughout their lives; however, the peripubertal years are particularly challenging. From a medical perspective, the burden of care increases during this time due to growth optimization strategies, frequent health screenings, and puberty induction. Psychologically, girls begin to comprehend the long-term implications of the condition, including their diminished fertility potential. Unfortunately, clear guidelines for how to best approach this stage have not been established. It remains to be determined what is the best age to begin treatment; the best compound, dose, or protocol to induce puberty; how, when or what to discuss regarding fertility and potential fertility preservation options; and how to support them to accept their differences and empower them to take an active role in their care. Given the complexity of this life stage, a multidisciplinary treatment team that includes experts in endocrinology, gynecology, and psychology is optimal.

Androgen Insensitivity Syndrome: Management Considerations from Infancy to Adulthood.

Androgen insensitivity syndrome (AIS) is an undervirilization syndrome in individuals with 46, XY karyotype. The undervirilization can be complete feminization or incomplete virilization with grades of ambiguity. AIS is caused by mutations in the androgen receptor, resulting in resistance to the physiologic activities of androgens. Differing degrees of resistance lead to three phenotypes: a complete form with female-appearing external genitalia, a partial form with a wide range of virilization, and a mild form with only minor undervirilization. AIS presents different challenges depending on whether resistance is complete or partial. Challenges include sex assignment, which impacts other medical decisions such as gonadectomy, hormonal replacement, and other surgical interventions. This review describes medical, psychosocial, and ethical concerns for each stage of development in complete and partial AIS, from the neonatal period to adulthood. These aspects of care should be addressed within an ethical framework by a multidisciplinary team, with the patients and families being the stakeholders in the decision-making process. We use the GRADE system when appropriate to appraise the existing evidence and provide recommendations and guidelines for management of AIS and appropriate transition of patients from pediatric to adult care.

The management of an ectopic ovary in the inguinal canal: literature review and discussion.

We report the case of a female adolescent who had an ectopic ovary in the inguinal canal without an associated hernia, a unicornuate uterus, and ipsilateral renal agenesis. The incidental discovery of the ectopic ovary and other Mullerian anomalies, as well as the surgical correction that followed, highlights important fertility considerations in children and available treatment algorithms for these rare cases.

Nonclassical congenital adrenal hyperplasia: targets of treatment and transition.

Nonclassical congenital adrenal hyperplasia (NCCAH) caused by 21-hydroxylase deficiency is a common autosomal recessive condition that can present with a wide range of hyperandrogenemic signs in childhood or adulthood. The management of children with NCCAH can be challenging, as no universally accepted guidelines have been established. Our goal was to evaluate the literature and develop an evidence-based guideline for the medical management of children and adolescents with NCCAH. We reviewed the published literature and used the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system when appropriate to grade the evidence and provide recommendations for the medical management of children and adolescents with NCCAH, appropriate transition practices from pediatric to adult endocrine care, and psychological issues that should be addressed in parents and patients with NCCAH. We offer recommendations, based on the available evidence, for the management of NCCAH at the different developmental stages from diagnosis through transition to adulthood.

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.

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.

Utility of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia.

BACKGROUND: Von Willebrand disease (VWD), and in particular, VWD type 1 and low VW factor (defined as Von Willebrand Ristocetin cofactor activity (RCoF) <30 and <50 IU/dl, respectively with normal multimers) are frequently detected in adolescents with menorrhagia and both groups benefit from similar management. Platelet function analyzer (PFA-100®) is often used as a screening test to detect VWD. We analyzed the utility of PFA-100® as a screening tool in the detection of VWD type 1 and low VW factor (VWF) in an exclusive adolescent population with menorrhagia. METHODS: The study population consisted of adolescents with menorrhagia who had simultaneously drawn blood samples for VWD and PFA-100®. Abnormal PFA-100® was defined as values >183 seconds for collagen/epinephrine and/or >126 seconds for collagen/ADP. RESULTS: Of a total of 235 patients tested, 23 patients had RCoF <50 IU/dl and normal multimer patterns. Statistical analysis of the utility of PFA-100® in detecting RCoF <50 IU/dl with normal multimers yielded sensitivity, specificity, positive predictive, and negative predictive values of 52%, 89%, 34%, and 95%, respectively. CONCLUSIONS: Based on our results, PFA-100® was not sufficiently sensitive to detect RCoF values <50 IU/dl with normal multimer patterns in teen-aged women with menorrhagia. We conclude that in the setting of adolescent menorrhagia, PFA-100® does not have utility as an initial screening test for the diagnosis of VWD and in particular, low VWF and that clinicians need to be aware of this limitation of PFA-100® while evaluating adolescents with menorrhagia.

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.

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.

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.

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.

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.