Homozygous novel truncating variant of CLPP associated with severe Perrault syndrome.

A female proband and her affected niece are homozygous for a novel frameshift variant of CLPP. The proband was diagnosed with severe Perrault syndrome encompassing hearing loss, primary ovarian insufficiency, abnormal brain white matter and developmental delay.

Developing a set of patient-centered outcomes for routine use in endometriosis: An international Delphi study.

INTRODUCTION: There is large variation in individual patient care for endometriosis. A uniform approach to measure outcomes could be incorporated into routine clinical practice to personalize and monitor treatments and potentially improve the quality of care. The aim of this study is to identify a group of patient-centered outcomes for use in routine endometriosis care which are relevant to all patient profiles. MATERIAL AND METHODS: By means of a modified two-round Delphi study with international representation including healthcare professionals, researchers and patient representatives (51 participants, 16 countries) we developed a set of patient-centered measurements. The participants evaluated 47 Patient Reported Outcome Measures (PROMs) and 30 Clinician Reported Outcome Measures (CROMs) regarding their feasibility and relevance for their use in routine endometriosis care. After the two rounds of quotation, meetings of the experts were convened to participate in a final discussion to finalize the consensus of the final set of included measures. RESULTS: The final set of patient-centered outcomes includes six PROMs (measuring symptomatic impact, pain, work productivity and quality of life) and 10 CROMs (measuring clinical, imaging and surgical indicators). A supplementary list of outcomes was added to include important dimensions that were considered essential by the expert panel but are not relevant to all patients. In addition the need for development of specific tools (PROMs) measuring the psychological impact and the impact in sexual activity of endometriosis was highlighted. CONCLUSIONS: We have developed a set of patient-centered outcomes measures in endometriosis care. The selected outcomes comprise the common features for all patients suffering from endometriosis. adapted for use in routine practice. The list of outcomes has been adapted for use in routine practice from which clinicians can chose, depending on their needs.

Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis.

Candida albicans causes debilitating, often azole-resistant, infections in patients with chronic mucocutaneous candidiasis (CMC). Amphotericin B (AMB) resistance is rare, but AMB use is limited by parenteral administration and nephrotoxicity. In this study, we evaluated cochleated AMB (CAMB), a new oral AMB formulation, in mouse models of oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC) and in patients with azole-resistant CMC. OPC and VVC were modeled in Act1-/- mice, and mucosal tissue fungal burden was assessed after once-daily treatment with CAMB, vehicle, or AMB-deoxycholate (AMB-d). Four patients with azole-resistant CMC enrolled in a phase 2 CAMB dose-escalation study. The primary endpoint was clinical improvement at 2 weeks followed by optional extension for long-term CMC suppression to assess safety and efficacy. CAMB-treated mice had significantly reduced tongue and vaginal fungal burdens compared to vehicle-treated mice and exhibited comparable fungal burden reduction relative to AMB-d-treated mice. All CAMB-treated patients reached clinical efficacy by 2 weeks, three at 400 mg twice daily and one at 200 mg twice-daily dosing. All patients continued to the extension phase, with three having sustained clinical improvement of OPC and esophageal candidiasis (EC) for up to 60 months. One patient had a relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical responses were not seen for onychomycosis or VVC. CAMB was safe and well-tolerated, without any evidence of nephrotoxicity. In summary, oral CAMB reduced tongue and vaginal fungal burdens during murine candidiasis. A proof-of-concept clinical trial in human CMC showed efficacy with good tolerability and safety. This study has been registered at ClinicalTrials.gov under identifier NCT02629419.

Gynaecological and reproductive health of women with telomere biology disorders.

Reproductive health may be adversely impacted in women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD). We evaluated gynaecological problems, fertility, and pregnancy outcomes in 39 females aged 10-81 years who were followed longitudinally in our DC/TBD cohort. Twenty-six had bone marrow failure and 12 underwent haematopoietic cell transplantation. All attained menarche at a normal age. Thirteen women reported menorrhagia; ten used hormonal contraception to reduce bleeding. Nine experienced natural normal-aged menopause. Gynaecological problems (endometriosis = 3, pelvic varicosities = 1, cervical intraepithelial neoplasia = 1, and uterine prolapse = 2) resulted in surgical menopause in seven. Twenty-five of 26 women attempting fertility carried 80 pregnancies with 49 (61%) resulting in livebirths. Ten (38%) women experienced 28 (35%) miscarriages, notably recurrent pregnancy loss in five (19%). Preeclampsia (n = 6, 24%) and progressive cytopenias (n = 10, 40%) resulted in maternal-fetal compromise, including preterm (n = 5) and caesarean deliveries (n = 18, 37%). Gynaecological/reproductive problems were noted mainly in women with autosomal-dominant inheritance; others were still young or died early. Although women with TBDs had normal menarche, fertility, and menopause, gynaecological problems and pregnancy complications leading to caesarean section, preterm delivery, or transfusion support were frequent. Women with TBDs will benefit from multidisciplinary, coordinated care by haematology, gynaecology and maternal-fetal medicine.

Gynecologic and reproductive health in patients with pathogenic germline variants in DICER1.

OBJECTIVE: Germline pathogenic variation in DICER1 underlies a tumor-predisposition disorder with increased risk for cervical embryonal rhabdomyosarcoma and ovarian sex-cord stromal tumors, particularly Sertoli-Leydig cell tumors. The gynecologic and reproductive health of these females has not yet been described. METHODS: All female subjects recruited from November 2011 to July 2018 participating in an epidemiologic study of families with pathogenic DICER1 germline variation were included in this cross-sectional analysis. Participant evaluation included obstetric-gynecologic history, physical examination, hormone testing, pelvic ultrasound and record review. RESULTS: Of 64 females aged 2-72 years, fifteen underwent treatment for pleuropulmonary blastoma as children and three were treated for cervical embryonal rhabdomyosarcoma. Of nine patients reporting a history of ovarian tumors, all presented with virilization or amenorrhea; eight occurred in adolescence. Post-pubertal females with no history of ovarian tumors experienced normal pubertal development, reported regular menstrual cycles, were fertile and underwent natural menopause at median age of 52 years. Thirty-two of 33 women who tried to conceive successfully delivered liveborn children. Of these 32, 10 experienced pregnancy-related thyroid enlargement resulting in thyroidectomy within one year of pregnancy; nine others had undergone pre-pregnancy thyroidectomy. CONCLUSION: In these DICER1-carrier females, DICER1-related gynecological tumors occurred during childhood or adolescence in some after which women generally experienced healthy reproductive lives. Individual education and screening for these tumors is warranted. The high rate of DICER1-related multinodular goiter resulting in pre- and post-pregnancy thyroidectomy underscores the importance of thyroid monitoring during pregnancy to ensure maternal and fetal wellbeing.

A Practical Guide to Gynecologic and Reproductive Health in Women Undergoing Hematopoietic Stem Cell Transplant.

Optimum care of female transplant recipients requires gynecologic care at several stages through the allogeneic hematopoietic stem cell transplantation (HCT) process. Sex-based considerations in women post-HCT span gynecologic sequelae of transplant along with assessment and maintenance of optimal sexual and gynecologic health. Pre-HCT, managing menstruation and abnormal uterine or genital bleeding, considering fertility preservation, and assessing for sexually transmitted infections, including human papillomavirus (HPV)-related disease and cervical cancer, enhance women's health. While inpatient during transplant when women are thrombocytopenic, menstrual bleeding requires suppression. Whenever graft-versus-host disease (GVHD) is assessed, screening for genital GVHD merits consideration. After the first 100 days, periodic assessments include obtaining a menstrual history, assessing ovarian function, and reviewing current hormonal use and contraindications to hormonal methods. Regular assessment for primary ovarian insufficiency, dyspareunia, and intimacy guides provision of contraception and hormone replacement options. As part of ongoing screening for genital GVHD and HPV-related disease, including sexually transmitted infections, periodic pelvic examinations are performed. Once successful long-term survival is achieved, planning for fertility may be considered. This article offers a comprehensive approach to these aspects of gynecologic care of patients throughout the trajectory of HCT and beyond into survivorship. We review the effects of HCT treatment on sexual health, ovarian function, and resulting menstrual changes and fertility challenges. Identification, treatment, and prevention of subsequent malignancies, including breast cancer, are discussed, with a focus on regular assessment of genital HPV disease and GVHD in long-term follow-up.

Methodological approaches to botulinum toxin for the treatment of chronic pelvic pain, vaginismus, and vulvar pain disorders.

INTRODUCTION AND HYPOTHESIS: Botulinum toxin (BoNT) is increasingly used for pain, especially with muscle spasm. We describe our methodology for BoNT treatment of chronic pelvic pain (CPP) in women and place it in the context of the literature on techniques for this use. METHODS: Databases were searched using terms "botulinum toxin," "pelvic pain," and "vaginismus." Reports on vaginismus/vulvodynia/vestibulodynia (included if pelvic floor muscles were injected) were grouped as "vaginismus/vulvar pain disorders" (V/VPD). We analyzed the type of report, condition, toxin serotype/brand, dose/dilution, muscle selection, guidance technique, and anesthesia. Publications from the same authors without unique information were combined for specific analyses. RESULTS: Thirty-eight reports had analyzable information; many lacked complete information. Most were open-label prospective reports; there were four technical reports, one randomized comparison of doses and one placebo-controlled study of efficacy. Pelvic floor muscles were approached transvaginally, transperineally or transgluteally. BoNT brand/dose/dilution varied widely. Muscle localization techniques included anatomical landmarks only, electromyography, electrical stimulation with/without ultrasound, and fluoroscopy/CT scanning. Papers discussing analgesia utilized general anesthesia, conscious sedation with/without topical/local anesthesia, topical/local agent alone or pudendal block before or after injection. Cumulatively, 58-100% of patients with CPP and 71-100% of those with V/VPD improved. Serious adverse events (transient fecal incontinence/constipation, urinary incontinence/retention) were more frequent with higher doses. CONCLUSIONS: BoNT can be safely and tolerably injected into pelvic floor muscles in women as an out-patient procedure. This study identifies methodological factors to be considered in future studies and the critical need for high-quality clinical trials for this emerging treatment.

Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes.

BACKGROUND: Children with inherited bone marrow failure syndromes (IBMFSs) may be symptomatic in utero, resulting in maternal and fetal problems during the pregnancy. Subsequent pregnancies by their mothers should be considered "high risk". METHODS: We retrospectively analyzed outcomes of 575 pregnancies in 165 unaffected mothers of offspring with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS) for events noted during pregnancy, labor, and delivery. We compared outcomes of pregnancies with affected and unaffected offspring within each group of mothers and with the general population. RESULTS: The rates of miscarriage (12-20%), elective abortion (5-10%), and live birth (68-78%) among mothers of all IBMFS groups were similar and comparable with general population rates but recurrent miscarriages (≥2) were significantly more common in mothers of offspring with DBA and SDS. Offspring with FA were more frequently born small for gestational age (SGA) than unaffected babies (39% vs. 4%) and had fetal malformations (46%) with 18% having three or more, often necessitating early delivery and surgery; offspring with DC had higher rates of SGA (39% vs. 8%) and fetal distress (26% vs. 3%); and offspring with DBA had fetal hypoxia (19% vs. 1%) leading to preterm and emergency cesarean deliveries (26% vs. 6%). Offspring with early-onset severe phenotypes had the most prenatal and peripartum adverse events. CONCLUSION: We identified the high-risk nature of pregnancies in mothers with IBMFS-affected fetuses, suggesting the need for prepregnancy counseling and monitoring of subsequent pregnancies by high-risk fetal-maternal specialists.

Early Diagnosis of Labial Fusion in Women After Allogeneic Hematopoietic Cell Transplant Enables Outpatient Treatment.

OBJECTIVE: The aim of the study was to describe the presentation and successful treatment of labial fusion in women after allogeneic hematopoietic cell transplantation (HCT). MATERIALS AND METHODS: During routine posttransplant gynecologic evaluation, labial fusion was identified in 5 female patients. Clinical data were collected regarding underlying disease, transplant regimen, genital symptoms, systemic sites of chronic graft-versus-host disease (cGvHD) and treatment, and follow-up. RESULTS: At presentation, women had a median age of 40 years (range = 35-50) and were 23-month to 8-year post-HCT. Four of the 5 patients with labial fusion had evidence of active cGvHD; 3 patients had severe sclerotic cGvHD, and 1 patient had bronchiolitis obliterans. One had rheumatoid arthritis and had recently stopped taking etanercept, but had no sites of cGvHD. One patient presented with only a pinpoint opening for passage of urine. Her complete labial fusion was lysed under general anesthesia. Three of the 4 others presented with dyspareunia. Their labia were fused between the clitoris and urethra narrowing the vaginal opening without obstructing the urethra. These labial adhesions were successfully lysed during an office procedure. Once the labial mucosa healed, the patients applied topical clobetasol and estrogen to prevent reagglutination. On follow-up, 1 month to 1 year later, all women were significantly improved. CONCLUSIONS: These patients highlight the importance of asking women who have undergone allogeneic HCT, especially those with severe cGvHD, about dyspareunia and dysuria. Those with genital symptoms warrant referral to a gynecologist. These cases illustrate that labial fusion, if diagnosed early enough, may be treated successfully with an office procedure and medical therapy.

A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G protein-coupled chemokine receptor CXCR4. The CXCR4 antagonist plerixafor, which is approved by the US Food and Drug Administration (FDA) for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1- to 2-week) phase 1 dose-escalation studies to correct neutropenia and other cytopenias in WHIM syndrome. However, long-term safety and long-term hematologic and clinical efficacy data are lacking. Here we report results from the first long-term clinical trial of plerixafor in any disease, in which 3 adults with WHIM syndrome self-injected 0.01 to 0.02 mg/kg (4% to 8% of the FDA-approved dose) subcutaneously twice daily for 6 months. Circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however, immunoglobulin levels and specific vaccine responses were not fully restored. No drug-associated side effects were observed. These results provide preliminary evidence for the safety and clinical efficacy of long-term, low-dose plerixafor in WHIM syndrome and support its continued study as mechanism-based therapy in this disease. The ClinicalTrials.gov identifier for this study is NCT00967785.

Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal Luteinizing Hormone Secretion in Lipodystrophy Patients.

BACKGROUND: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with lipodystrophy are unknown. AIM: We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naïve and leptin-treated subjects with lipodystrophy. METHODS: In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2). Leptin-naïve subjects (n = 8) were studied without leptin in period 1 and with leptin replacement in period 2. LH secretory dynamics were assessed (23:00-07:00 h, sampling every 10 min, analyzed by multiparameter deconvolution algorithm) at the end of each period. RESULTS: Mean (on vs. off: 5.0 ± 3.1 vs. 3.2 ± 1.3 IU/l, p = 0.04) and integrated LH concentrations (2,403 ± 1,495 vs. 1,534 ± 642 IU × l-1 × min-1, p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7± 15.4 vs. 7.0 ± 11.2 IU/l, p = 0.03) and tended to nonsignificantly increase LH burst frequency (0.77 ± 0.26 vs. 0.67 ± 0.24 h-1, p = 0.08). Consequently, leptin therapy increased the pulsatile production rate (64 ± 101 vs. 57 ± 73 IU × l-1 × 8 h-1, p = 0.01). On leptin, testosterone (507 ± 286 vs. 360 ± 174 ng/dl, p = 0.09) and estradiol levels (74 ± 36 vs. 29 ± 24 pg/ml, p = 0.01) were higher in males and females, respectively. CONCLUSIONS: Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy.

Vaginal Pessary for Uterine Repositioning during High-Intensity Focused Ultrasound Ablation of Uterine Leiomyomas.

In order to ensure safe magnetic resonance-guided, high-intensity focused, ultrasound ablation of uterine leiomyomas, the ultrasound beam path should be free of intervening scar and bowel. Pre-treatment MRI of a 9-cm long and 7.7-cm wide leiomyomatous uterus in a 39-year-old woman with menorrhagia and abdominopelvic pain initially demonstrated a focused ultrasound treatment path without a bowel between the uterus and the abdominal wall. On the day of ablation, however, multiple loops of bowel were observed in the ultrasound beam path by MRI. Uterine repositioning was accomplished with a 76-mm donut vaginal pessary, which anteverted the fundus and successfully displaced the bowel. A vaginal pessary may aid in repositioning an axial or retroverted uterus to enable ablation of uterine leiomyomas.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report.

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.

Sexual health in hematopoietic stem cell transplant recipients.

Hematopoietic stem cell transplantation (HSCT) plays a central role in patients with malignant and, increasingly, nonmalignant conditions. As the number of transplants increases and the survival rate improves, long-term complications are important to recognize and treat to maintain quality of life. Sexual dysfunction is a commonly described but relatively often underestimated complication after HSCT. Conditioning regimens, generalized or genital graft-versus-host disease, medications, and cardiovascular complications as well as psychosocial problems are known to contribute significantly to physical and psychological sexual dysfunction. Moreover, it is often a difficult topic for patients, their significant others, and health care providers to discuss. Early recognition and management of sexual dysfunction after HSCT can lead to improved quality of life and outcomes for patients and their partners. This review focuses on the risk factors for and treatment of sexual dysfunction after transplantation and provides guidance concerning how to approach and manage a patient with sexual dysfunction after HSCT.

Endometrial Cancer: Hidden Pathology in a Patient with Abnormal Uterine Bleeding and Known Leiomyoma.

Uterine leiomyomas and endometrial pathology are both associated with abnormal uterine bleeding. We report a case in which a nulliparous woman with heavy uterine bleeding and leiomyomas had undergone two prior hysteroscopic myomectomies for benign leiomyomas. She was evaluated, but was ineligible for a clinical trial of a novel Magnetic Resonance guided High Intensity Focused Ultrasound (MRgx200B;HIFU) device. The 8 cm, prolapsed submucosal leiomyoma hindered endometrial sampling and was inaccessible to HIFU treatment. Preoperatively, neither endometrial sampling nor saline sonohysterography was technically feasible. She underwent hysterectomy, and on histological examination of specimen, stage 1A grade 1 endometrial carcinoma was found on the endometrial side of the prolapsing fibroid. Endometrial pathology is an important consideration in the evaluation of abnormal uterine bleeding, even in women with large prolapsing leiomyoma.