Search

A woman with ichthyosis, contractures, and progressive neuropathy represents the first case of phosphoserine aminotransferase deficiency diagnosed and treated in an adult. She has novel compound heterozygous mutations in the gene PSAT1. Treatment with high dose oral L-serine completely resolved the ichthyosis. Consideration of this diagnosis is important because early treatment with L-serine repletion can halt progression of neurodegeneration and potentially improve neurological disabilities. As exome sequencing becomes more widely implemented in the diagnostic evaluation of progressive neurodegenerative phenotypes, adult neurologists and geneticists will increasingly encounter later onset manifestations of inborn errors of metabolism classically considered in infancy and early childhood.

Background Chronic pelvic pain persists in some women with endometriosis even after lesion removal and optimized hormonal treatment. Objective Characterize the presence and distribution of pain, myofascial dysfunction and sensitisation beyond the pelvis in women with endometriosis-associated chronic pelvic pain. Methods Cross-sectional study of 30 women prior to participation in a clinical trial. Evaluation included pain-focused abdominopelvic gynaecologic examination with the identification of pelvic floor muscle spasm. Neuro-musculoskeletal examination assessed paraspinal allodynia and hyperalgesia bilaterally and myofascial trigger points in 13 paired muscles. Pressure-pain thresholds were measured over interspinous ligaments and trigger points. Women completed the body territories element of the Body Pain Index. Results All women had a pelvic floor muscle spasm that they self-identified as a major focus of pain. Twenty of 30 women described their pelvic pain as focal. However, all demonstrated widespread myofascial dysfunction with low pressure-pain thresholds and trigger points in over two-thirds of 26 assessed regions. Widespread spinal segmental sensitisation was present in 17/30, thoracic in 21/30 and lumbosacral/pelvic in 18/30. Cervical sensitisation manifested as low pressure-pain thresholds with 23/30 also reporting recurrent, severe headaches and 21/30 experiencing orofacial pain. Those reporting diffuse pelvic pain were more likely to have widespread (p = .024) and lumbosacral/pelvic (p = .036) sensitisation and report over 10 painful body areas (p = .009). Conclusions Women with endometriosis-associated chronic pelvic pain often have myofascial dysfunction and sensitisation beyond the pelvic region that may be initiated or maintained by on-going pelvic floor spasm. These myofascial and nervous system manifestations warrant consideration when managing pain in this population. Clinicaltrials.gov identifier: NCT01553201. Significance Women with endometriosis often have pelvic pain persisting after surgery despite hormonal therapies and these women have regional pelvic sensitisation and myofascial dysfunction. Pelvic floor muscle spasm is a major pain focus in this population. Sensitisation and myofascial dysfunction are widespread, beyond the pelvic region. On-going pelvic floor spasm may initiate or maintain sensitisation. Myofascial/sensitisation manifestations warrant consideration when managing pain in this population.

To assess the age at menarche and menopause of women with xeroderma pigmentosum, a DNA repair disease with premature aging, in a longitudinal natural history study.We conducted a natural history study that reviewed medical records for gynecologic and reproductive health of all female patients with xeroderma pigmentosum aged older than 9 years examined at the National Institutes of Health (NIH). We performed gynecologic and laboratory examinations on a subset of the patients. Women in a second subset, who could not be examined, were interviewed using a questionnaire. Women who were deceased or lost to follow-up formed a third subset.Sixty females with xeroderma pigmentosum aged older than 9 years (median 29 years, range 10-61 years) were evaluated at the NIH from 1971 to 2018. Of these 60, 31 had history, questionnaire, record review, and gynecologic evaluation; 14 had record review and questionnaire interview by telephone; and 15 had only NIH record review. Menarche in females with xeroderma pigmentosum occurred at a median age of 12.0 years (range 9-17 years), which was comparable with the U.S. general population. Among the 18 patients with menopause, the median age at menopause of 29.5 years (range 18-49.5 years) was more than 20 years younger than in the U.S. general population (52.9 years). Premature menopause (before age 40 years) occurred in 14 of the 45 (31%) women aged 18 years or older, and primary ovarian insufficiency was documented in nine of them. There were 32 live births among 21 of the women, five of whom subsequently developed premature menopause.Females with xeroderma pigmentosum in our study had a normal age at menarche and were fertile but had increased incidence of premature menopause. Premature menopause, a symptom of premature aging, should be considered for gynecologic and reproductive health as well as implicating DNA repair in maintaining normal ovarian function.ClinicalTrials.gov, NCT00001813.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles. Clinical manifestations include a bleeding diathesis due to a platelet delta storage pool deficiency, oculocutaneous albinism, inflammatory bowel disease, neutropenia, and pulmonary fibrosis. Ten genes associated with HPS are identified to date, and each gene encodes a protein subunit of either Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, BLOC-2, BLOC-3, or the Adaptor Protein-3 complex. Several genetic variants and phenotypic heterogeneities are reported in individuals with HPS, who generally exhibit easy bruisability and increased bleeding. Desmopressin, pro-coagulants, or platelet transfusion may be used as prophylaxis or treatment for excessive bleeding in patients with HPS. However, response to desmopressin can be variable. Platelets are effective in preventing or treating bleeding in individuals with HPS, but platelets should be transfused judiciously to limit alloimmunization in patients with HPS who are at risk of developing pulmonary fibrosis and may be potential candidates for lung transplantation. The discovery of new genes associated with HPS in people with excessive bleeding and hypopigmentation of unknown etiology may be facilitated by the use of next-generation sequencing or panel-based genetic testing.

Background Knowledge about inflammatory bowel disease (IBD) in patients with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, could provide insights into IBD in general. Objective To expand the understanding of IBD in patients with HPS. Methods Retrospective review of records from patients with HPS evaluated at the National Institutes of Health Clinical Center from 1995 to 2019 was conducted. Clinical features of IBD, genotyping results and histologic findings of colectomy specimens were analysed. Results IBD affected 37 (14.2%; 12 male, 25 female) of 261 patients with HPS. Median age of onset was 17 years; range was 1 to 52 years. The most common symptoms of HPS IBD were hematochezia, abdominal pain and loose stools. Fistulae or extra-intestinal manifestations developed in 30% or 22%, respectively. Genotyping showed that patients with biallelic variants in HPS1, HPS3, HPS4 or HPS6 were diagnosed with IBD. Six children had very early-onset IBD. Patients with HPS-3 had mild manifestations of IBD. Medical therapy and bowel resection were utilized to treat 73% and 35% of patients with HPS IBD, respectively; 7 of 13 patients receiving anti-tumor necrosis factor alpha therapy had prolonged clinical responses. Active cryptitis, chronic inflammatory changes, granulomas and ceroid lipofuscinosis were histopathologic findings in three colectomy specimens. Conclusions IBD resembling Crohn's disease affects some patients with HPS; genetic heterogeneity is a feature of HPS IBD. HPS3 is a new gene associated with human IBD. Very early-onset IBD can develop in HPS.

Purpose Limited information is available regarding chronic treatment with pirfenidone, an anti-fibrotic drug. Effects of long-term open-label pirfenidone were evaluated in a small cohort with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder with highly penetrant pulmonary fibrosis. Results Three patients with HPS pulmonary fibrosis treated with open-label pirfenidone and twenty-one historical controls randomized to placebo were studied at a single center. Mean duration of treatment with pirfenidone for 3 patients with HPS pulmonary fibrosis was 13.1 years. Annual changes in FVC and DLCO with pirfenidone treatment were 0.46 and − 0.93% predicted, respectively. In comparison, historical controls randomized to receive placebo experienced mean annual changes in FVC and DLCO of −4.4 and − 2.3% predicted, respectively. High-resolution computed tomography (HRCT) scans revealed improved ground glass opacities with development of minimal interstitial reticulations in 1 patient after 12.8 years of treatment with pirfenidone. Slowly progressive increase in bilateral interstitial fibrosis developed in a different patient, who received pirfenidone for 18.1 years and died at 73 years of age due to HPS pulmonary fibrosis. Another patient treated with pirfenidone for 8.4 years had attenuated ground glass opacification on HRCT scan and improved oxygenation; this patient died due to chronic complications from colitis, and not pulmonary fibrosis. Adverse effects were generally limited to mild gastrointestinal discomfort and transient elevations of alanine aminotransferase in one patient. Conclusions Chronic treatment with pirfenidone may provide clinical benefit with few adverse effects for some patients with HPS pulmonary fibrosis. These results suggest that compassionate use of pirfenidone could be considered on a case-by-case basis for patients with HPS pulmonary fibrosis.

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.

Hermansky–Pudlak syndrome (HPS) is a group of ten autosomal recessive multisystem disorders, each defined by deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor Protein (AP)-3 and Biogenesis of Lysosome-related Organelles Complex (BLOC)-1 through −3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management and treatment options. The prevalence of HPS is estimated at 1–9 per 1,000,000. Here we summarize 264 reported and novel variants in ten HPS genes and estimate that ~333 Puerto Rican HPS subjects and ~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies (MAF). Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostic and genetic counseling aspects of Hermansky-Pudlak syndrome.

GATA2 deficiency is a bone marrow failure syndrome effectively treated with hematopoietic cell transplantation (HCT), which also addresses the predisposition to many infections (prominently mycobacterial). However, many GATA2-deficient persons who come to HCT also have prevalent and refractory human papilloma virus disease (HPVD), which can be a precursor to cancer. We analyzed 75 HCT recipients for the presence of HPVD to identify patient characteristics and transplantation results that influence HPVD outcomes. We assessed the impact of cellular recovery and iatrogenic post-transplantation immunosuppression, as per protocol (PP) or intensified/prolonged (IP) graft-versus-host disease (GVHD) prophylaxis or treatment, on the persistence or resolution of HPVD. Our experience with 75 HCT recipients showed a prevalence of 49% with anogenital HPVD, which was either a contributing or primary factor in the decision to proceed to HCT. Of 24 recipients with sufficient follow-up, 13 had resolution of HPVD, including 8 with IP and 5 with PP. Eleven recipients had persistent HPVD, including 5 with IP and 6 with PP immunosuppression. No plausible cellular recovery group (natural killer cells or T cells) showed a significant difference in HPV outcomes. One recipient died of metastatic squamous cell carcinoma, presumably of anogenital origin, at 33 months post-transplantation after prolonged immunosuppression for chronic GVHD. Individual cases demonstrate the need for continued aggressive monitoring, especially in the context of disease prevalent at transplantation or prior malignancy. HCT proved curative in many cases in which HPVD was refractory and recurrent prior to transplantation, supporting a recommendation that HPVD should be considered an indication rather than contraindication to HCT, but post-transplantation monitoring should be prolonged with a high level of vigilance for new or recurrent HPVD.

Hermansky-Pudlak syndrome (HPS) encompasses disorders with abnormal function of lysosomes and lysosome-related organelles, and some patients who develop immunodeficiency. The basic mechanisms contributing to immune dysfunction in HPS are ill-defined. We analysed Natural Killer (NK) cells from patients diagnosed with HPS-1, HPS-2, HPS-4, and an unreported HPS subtype. NK cells from an HPS-2 and an unreported HPS subtype share a similar cellular phenotype with defective granule release and cytotoxicity, but differ in cytokine exocytosis. Defining NK cell activity in several types of HPS provides insights into cellular defects of the disorder and understanding of mechanisms contributing to HPS pathogenesis.

IMPORTANCE: Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms. OBJECTIVE: To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post–allogeneic transplant compared with female healthy volunteers. INTERVENTIONS: Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. DESIGN, SETTING, AND PARTICIPANTS: This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. MAIN OUTCOMES AND MEASURES: Anti-HPV-6, -11, -16, and -18–specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. RESULTS: Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P

Genital chronic graft-versus-host disease (GVHD) in women posthaematopoietic cell transplantation may cause vaginal mucosal sclerosis. Human papillomavirus (HPV) reactivation, also common post-transplantation, limits local immunosuppressive, but not oestrogen treatment. A 36-year-old nulliparous woman developed coincidental genital chronic GVHD and HPV 22 months after transplant for aplastic anaemia. Topical immunosuppression for GVHD led to an eruption of warts successfully treated with laser surgery and cone biopsy. She maintained normal ovarian function and used extended cycle combined hormonal contraception. A vaginal oestrogen ring used continuously limited most scarring for 8 years. Progressive apical vaginal scarring obstructed menstrual flow leading to haematocolpos and haematometra. Normal anatomy was restored with a cruciate incision in the cervicovaginal scar performed during menses. When HPV disease limits use of topical immunosuppression in women with vaginal GVHD, the local scar-reducing effect of a vaginal oestrogen ring is limited, and surgery may be needed and can be successful in treating haematocolpos. This study was registered in ClinicalTrials.gov with trial registration number of NCT00003838.

There is a growing population of women who have or will undergo hematopoietic stem cell transplant for a variety of malignant and benign conditions. Gynecologists play an important role in addressing the gynecologic and reproductive health concerns for these women throughout the transplant process. As women undergo cell transplantation, they should avoid becoming pregnant and are at risk of uterine bleeding. Thus, counseling about and implementing hormonal treatments such as gonadotropin-releasing hormone agonists, combined hormonal contraceptives, and progestin-only methods help to achieve therapeutic amenorrhea and can serve as contraception during the peritransplant period. In this commentary, we summarize the timing, risks, and benefits of the hormonal options just before, during, and for the year after hematopoietic stem cell transplantation.

Pulmonary fibrosis is a progressive, fatal manifestation of Hermansky-Pudlak syndrome (HPS). Some patients with advanced HPS pulmonary fibrosis undergo lung transplantation despite their disease-associated bleeding tendency; others die while awaiting donor organs. The objective of this study is to determine the clinical management and outcomes of a cohort with advanced HPS pulmonary fibrosis who were evaluated for lung transplantation. Six patients with HPS-1 pulmonary fibrosis were evaluated at the National Institutes of Health Clinical Center and one of two regional lung transplant centers. Their median age was 41.5 years pre-transplant. Three of six patients died without receiving a lung transplant. One of these was referred with end-stage pulmonary fibrosis and died before a donor organ became available, and donor organs were not identified for two other patients sensitized from prior blood product transfusions. Three of six patients received bilateral lung transplants; they did not have a history of excessive bleeding. One patient received peri-operative desmopressin, one was transfused with intra-operative platelets, and one received extracorporeal membrane oxygenation and intra-operative prothrombin complex concentrate, platelet transfusion, and desmopressin. One transplant recipient experienced acute rejection that responded to pulsed steroids. No evidence of chronic lung allograft dysfunction or recurrence of HPS pulmonary fibrosis was detected up to 6 years post-transplant in these three lung transplant recipients. In conclusion, lung transplantation and extracorporeal membrane oxygenation are viable options for patients with HPS pulmonary fibrosis. Alloimmunization in HPS patients is an important and potentially preventable barrier to lung transplantation; interventions to limit alloimmunization should be implemented in HPS patients at risk of pulmonary fibrosis to optimize their candidacy for future lung transplants.

Women with inherited metabolic disorders, including those with previously life-limiting conditions such as MMA, are reaching child-bearing age more often due to advances in early diagnosis and improved pediatric care. Information surrounding maternal and fetal complications associated with the underlying disorders remains largely unexplored.Pregnancies affected by maternal MMA were ascertained through study 04-HG-0127 "Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders" (clinicaltrials.gov identifier: NCT00078078) and via literature review. Prenatal and delivery records in study participants were reviewed.Seventeen pregnancies were identified in women with isolated MMA, including three abortions, one termination, and 13 completed pregnancies [three cases with cblA (four pregnancies), four cases of mut- (one cobalamin responsive, three non-responsive), five cases with unknown type of MMA]. Seventeen percent (3/17) of the pregnancies resulted in a first trimester abortion, while 38.5% (5/13) of the completed pregnancies resulted in preterm deliveries. A cesarean delivery rate of 53.8% (7/13) was noted among the cohort. Fetal distress or nonreassuring fetal status was the indication for 57% (4/7) cesarean deliveries. One patient was reported to have metabolic crisis as well as episodes of mild hyperammonemia. Malformations or adverse outcomes in the progeny were not observed.Although there have been a small number of pregnancies identified in women with MMA, the cumulative results suggest that the majority of pregnancies can be complicated by cesarean delivery and increased risk of prematurity. A pregnancy registry could clarify perinatal complications and define management approaches needed to ensure optimal maternal and fetal outcomes in this growing patient population.

This longitudinal single-center study describes the timing and risk factors for genital human papillomavirus (HPV) disease in women after allogeneic hematopoietic cell transplantation (HCT). Between 1994 and 2014, 109 females underwent HCT of whom 82 surviving transplant for >1 year had regular, comprehensive genital tract assessment and treatment of HPV disease. The cumulative proportions of any genital HPV infection at 1, 3, 5, 10 and 20 years were 4.8%, 14.9%, 28.1%, 36.7% and 40.9%, respectively. Demographic, disease-related factors, chronic GvHD (cGvHD) and its treatment were analyzed for their association with persistent, multifocal or severe genital HPV disease. Pre-transplant HPV disease was strongly associated with any posttransplant HPV (odds ratio (OR)=6.5, 95% confidence interval (CI)=1.65-25.85, P=0.008). Having either extensive or genital cGvHD was associated with increased risk of any HPV disease (OR=5.7, 95% CI=1.90-17.16, P=0.002) and a higher risk for severe genital dysplasia (CIN II-III/VIN II-III; OR=13.1, 95% CI=1.59-108.26, P=0.017), but no one developed HPV-related genital cancer. Persistent, multifocal or severe HPV disease occurred more frequently than in healthy populations. Women with extensive cGvHD, genital cGvHD or pre-transplant HPV are at greatest risk for post-transplant HPV disease. Early initiation of annual screening, comprehensive genital tract assessment and active management are cornerstones of their gynecology care.

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.

Objective Hepatic resection for recurrent ovarian carcinoma is controversial because of the paucity of relevant published data. The principles of cytoreduction before chemotherapy suggest that resection of measurable liver lesions in properly selected patients would be beneficial. To determine the effect of resection of metachronous liver metastases on morbidity and survival, we reviewed our experience with this treatment. Methods Medical records were reviewed retrospectively for all patients who had anatomic hepatic resection for metachronous parenchymal liver metastases from ovarian carcinoma (epithelial or malignant mixed Mullerian tumors) at Mayo Clinic from 1976 to 1999. Results We identified 26 patients (median age at hepatic resection, 62 years; range, 39–75 years) who had hepatic resection requiring complete segmentectomies or more extensive hepatic surgery for recurrent ovarian carcinoma. Cytoreduction was optimal (extrahepatic and hepatic residual disease ≤1 cm) in 21 patients and suboptimal in 5. No intraoperative or postoperative deaths occurred. Aside from blood loss requiring transfusion of more than 4 units of erythrocytes in 4 patients, only two complications were noted: one superficial wound infection and one small-bowel perforation that required reoperation. The overall median disease-related survival was 26.3 months after hepatic resection; 18 patients (69%) died of disease at a median of 14.6 months (range, 5.0–41.3 months). However, 8 patients (31%) were alive at median follow-up of 33.2 months (range, 3.6–49.6 months). Factors significantly associated with improved disease-related survival were consistent with known prognostic factors associated with cytoreductive surgery, including more than 12 months since original diagnosis (27.3 vs 5.7 months, P = 0.004) and less than or equal to 1 cm of residual disease after hepatic resection (27.3 vs 8.6 months, P = 0.031). Conclusion We present evidence that hepatic resection can be performed with minimal surgical morbidity and mortality by surgical teams trained in the procedures. Because of the disease-related survival advantage afforded women by optimal cytoreductive surgery, parenchymal liver metastases should not preclude secondary cytoreductive surgical efforts.

BACKGROUND In human immunodeficiency virus (HIV)-infected women, Bowen's disease may be difficult to treat successfully with surgery alone. Imiquimod cream, effective in treating Bowen's disease in healthy women, may be a useful postsurgical treatment in immunocompromised women. CASES Two HIV-infected women had both Bowen's disease and severe cervical dysplasia. In both cases, Bowen's disease, but not cervical dysplasia, recurred after surgical treatment. When treated with topical 5% imiquimod cream twice weekly for 4 months, 70-80% reduction in lesions were observed in both patients. Follow-up biopsies of remaining lesions were vulvar intraepithelial neoplasia 1. CONCLUSION Imiquimod cream, in combination with surgical treatment, may be an appropriate strategy for treatment of Bowen's disease in HIV-infected and other immunocompromised women.

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.

Vaginal chronic graft-versus-host disease (cGVHD) is a common complication of stem cell transplantation. Human papillomavirus (HPV) disease can reactivate after transplantation, presumably because of immune factors affecting systemic immunity, such as waning antibody titers, impaired T- and B-lymphocyte responses, and the use of immunosuppressive therapies. However, a relationship between the use of local immunosuppressive agents and HPV reactivation and spread has not been previously described, to our knowledge. A 30-year-old woman, 2 years post transplant receiving systemic cyclosporine for cGVHD, was treated with vaginal dilators, topical corticosteroids, and estrogen for vaginal cGVHD. Colposcopy and biopsy for abnormal cytology revealed condylomatous cervicitis. Over the next 4 months, while continuing dilator therapy, linear verrucous lesions developed in the vagina and vulva, and were successfully treated with laser therapy. Use of local immunosuppression and dilators for genital GVHD can enhance spread of HPV infection. Integration of HPV screening and treatment into the care of women with genital cGVHD and development of strategies to manage both conditions simultaneously are warranted.

Cowden syndrome is an autosomal-dominant condition associated with mutations in the tumor suppressor gene PTEN. Gynecologic malignancies are common with a 5-10% risk of endometrial cancer and 25-50% risk of breast cancer.A 37-year-old woman with a history of breast cancer, other neoplasms, and multiple skin lesions was diagnosed with Cowden syndrome after a germline PTEN mutation was identified. The endometrium had high glucose uptake on positron emission tomography scan and was irregularly thickened on ultrasonography; biopsy revealed endometrial polyps and simple hyperplasia. Fifteen months later, hysteroscopy again confirmed numerous benign endometrial polyps.Recurrent, multiple endometrial polyps portend a high risk of endometrial cancer in women with Cowden syndrome. Monitoring for malignancy and consideration of hysterectomy after childbearing is completed is warranted.

Hematopoietic stem cell transplant is an effective treatment strategy for a variety of hematologic disorders, but patients are at risk for dysfunctional coagulation and abnormal bleeding. Gynecologists are often consulted before transplant for management of abnormal uterine bleeding, which may be particularly challenging in this context.A premenopausal woman with MonoMAC (a rare adult-onset immunodeficiency syndrome characterized by monocytopenia and Mycobacterium avium complex infections resulting from mutations in GATA2, a crucial gene in early hematopoiesis) presented with pancytopenia, evolving leukemia, and recent strokes, necessitating anticoagulation. During preparation for hematopoietic stem cell transplant, she experienced prolonged menorrhagia requiring transfusions. Surgical therapy was contraindicated, and medical management was successful only when combined with balloon tamponade.Balloon tamponade may be a potentially life-saving adjunct to medical therapy for control of uterine hemorrhage before hematopoietic stem cell transplant.

The XPD(ERCC2) gene encodes a DNA helicase involved in DNA repair and transcription. Patients with mutations in XPD may have different autosomal recessive phenotypes including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). TTD patients have sulfur-deficient, brittle hair, short stature and developmental delay. In contrast, XP patients have freckle-like pigmentation and a greatly increased risk of sun-induced skin cancers. Mothers of TTD patients have been reported to have a high frequency of pregnancy and neonatal complications. We performed a molecular epidemiological study of 15 mothers of 17 TTD patients and 13 mothers of 17 XP patients, all with XPD mutations. We found that 94% (16/17) of the TTD pregnancies had pre-term delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, prematurity or low birth weight. None of the 17 XP pregnancies had these complications (P

Hermansky–Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding disorder, and, in some patients, granulomatous colitis and/or a fatal pulmonary fibrosis. There are eight different subtypes of HPS, each due to mutations in one of eight different genes, whose functions are thought to involve intracellular vesicle formation and trafficking. HPS has been identified in patients of nearly all ethnic groups, though it has primarily been associated with patients of Puerto Rican, Northern European, Japanese and Israeli descent. We report on the diagnosis of HPS type 1 in two African-American patients. Both brothers carried compound heterozygous mutations in HPS1: previously reported p.M325WfsX6 (c.972delC) and a novel silent mutation p.E169E (c.507G > A), which resulted in a splice defect. HPS may be under-diagnosed in African-American patients and other ethnic groups. A history of easy bruising or evidence of a bleeding disorder, combined with some degree of hypopigmentation, should prompt investigation into the diagnosis of HPS. Published 2009 Wiley-Liss, Inc.

Purpose: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype. Methods: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and BMI were calculated at different ages. Results: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between −4 and −8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes. Conclusion: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.

The effect of IL-1 blocking therapy on mucocutaneous manifestations of Behcet’s disease is incompletely understood. Six patients with Behcet’s disease and ongoing oral/genital ulcers for ≥1 month were enrolled into an adaptive, two-phase clinical trial and included in the analysis. Study duration was 6 months with extension up to 16 months. All were treated non-blinded with anakinra 100 mg subcutaneous daily with the option to escalate the dose to 200 mg in partial responders after 1 month and 300 mg after 6 months. Patients recorded the number and severity of ulcers in daily diaries. The primary outcome was remission defined as no ulcers on physical exam for two consecutive monthly visits between months 3 and 6. Secondary outcomes included the number and severity of patient-reported ulcers, patient/physician global scores, and standardized disease activity scores. Two of six patients achieved the primary outcome. Five of six patients had improvement in the number and severity of ulcers. Non-statistically significant improvements were seen in secondary outcomes. Over the entire study, patients reported ≥1 oral and ≥1 genital ulcer on 665 (66%) and 139 (14%) days, respectively. On anakinra 200 mg vs 100 mg, patients reported fewer days with oral ulcers (65% vs 74% of days, p = 0.01) and genital ulcers (10% vs 22% of days, p