Neil Silverman

Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene

Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and in some other tissues such as cartilage, and is implicated in cell growth and differentiation. Mice lacking the perlecan gene (Hspg2) have a severe chondrodysplasia with dyssegmental ossification of the spine and show radiographic, clinical and chondro-osseous morphology similar to a lethal autosomal recessive disorder in humans termed dyssegmental dysplasia, Silverman-Handmaker type (DDSH; MIM 224410). Here we report a homozygous, 89-bp duplication in exon 34 of HSPG2 in a pair of siblings with DDSH born to consanguineous parents, and heterozygous point mutations in the 5′ donor site of intron 52 and in the middle of exon 73 in a third, unrelated patient, causing skipping of the entire exons 52 and 73 of the HSPG2 transcript, respectively. These mutations are predicted to cause a frameshift, resulting in a truncated protein core. The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies. Biochemically, truncated perlecan was not secreted by the patient fibroblasts, but was degraded to smaller fragments within the cells. Thus, DDSH is caused by a functional null mutation of HSPG2. Our findings demonstrate the critical role of perlecan in cartilage development.

Maternal uniparental disomy of chromosome 16 and body stalk anomaly

We report on a fetus with placental trisomy 16, maternal uniparental disomy (UPD), and body stalk anomaly. Body stalk anomaly is a rare, fatal developmental abnormality consisting of a defective abdominal wall with abdominal organs in a sac outside the abdominal cavity covered by amnion adherent to the placenta with absence or severe shortness of the umbilical cord. Trisomy 16 was identified in the placenta in all cells. Amniocentesis was karyotypically normal. Parental origin studies showed maternal UPD for chromosome 16 in post-termination fetal tissue. The cause of the body stalk anomaly is not clearly defined. There are no other reports of placental karyotype or UPD investigations with body stalk anomaly. To our knowledge, this is the first report of placental trisomy 16, UPD in fetus, and body stalk anomaly, suggesting placental insufficiency or imprinting effects as cause of this anomaly. Am. J. Med. Genet. 94:284-286, 2000.

Leukorrhea and bacterial vaginosis as in-office predictors of cervical infection in high-risk women

OBJECTIVE To evaluate 1) whether microscopic detection of leukorrhea or bacterial vaginosis identifies patients at high risk for cervical infection with Chlamydia trachomatis or Neisseria gonorrhoeae, and 2) if pregnancy alters the predictive value of these findings. METHODS Wet‐mount screening examination of vaginal discharge was performed on all new patients seen at two resident‐staffed clinics serving primarily indigent women. Leukorrhea was defined as >10 white blood cells per high‐power field on microscopic examination; Amsel criteria were used to determine the presence of bacterial vaginosis, with a positive clue cell test result defined as >20% of epithelial cells. The diagnoses of C trachomatis and N gonorrhoeae infection were established by deoxyribonucleic acid amplification tests. RESULTS The study population consisted of 194 women, 118 (61%) of whom were pregnant. Overall, 11% of women had positive cultures for chlamydia or gonorrhea. Although both leukorrhea and clue cells were independently associated with positive cervical cultures, multivariate analysis found that clue cells did not contribute to the predictive value of leukorrhea alone among both pregnant (relative risk [R = 15.7) and nonpregnant (RR = 58.7) women. Negative predictive values for the screening test were comparably high (98–100%), independent of pregnancy status. CONCLUSION Leukorrhea, in the presence or absence of bacterial vaginosis, was strongly associated with cervical infections with C trachomatis or N gonorrhoeae among both pregnant and nonpregnant patients. In settings where patient follow‐up is uncertain, on‐site screening tests identify women for whom empiric antibiotic therapy for sexually transmitted diseases may be appropriate.

Initial Multicenter Experience With DoubleNucleoside Therapy for Human ImmunodeficiencyVirus Infection During Pregnancy

Objective: To study maternal and neonatal effects of combination nucleoside analog therapy administered to human immunodeficiency virus (HIV)-infected pregnant women for maternal indications.

Candida lusitaniae as an unusual cause of recurrent vaginitis and its successful treatment with intravaginal boric acid

Increasing use of short-course antifungal therapies in patients with recurrent vulvovaginitis may enable the emergence of less-common, more resistant yeast strains as vaginal pathogens. We report the case of a patient with chronically symptomatic and repeatedly treated vaginal candidiasis whose infection was attributable to Candida lusitaniae, a previously unreported cause of candidal vaginitis .

Zika Risk and Pregnancy in Clinical Practice: Ongoing Experience as the Outbreak Evolves

OBJECTIVE To describe a single U.S. perinatal centers ongoing experience with evaluating pregnant patients with potential exposure to Zika virus infection. METHODS This is an institutional review board-approved longitudinal observational study from January to August 2016 from a single perinatal referral center. Patients who had traveled to or had sexual contact with a person who traveled to a region with documented local Zika virus transmission were included in the study. The aim of the study was to identify the rate of confirmed infection among pregnant women referred to our center with established risk factors for Zika virus acquisition. We also sought to characterize travel patterns that constituted risk, to identify rates of symptoms suggesting infection, and to potentially describe findings suggestive of congenital Zika virus infection in prenatal ultrasound evaluations. RESULTS We evaluated 185 pregnant women with potential Zika virus exposure. Testing was offered in accordance with the version of the Centers for Disease Control and Prevention guidelines in place at the time of the consultation visit. Geographic exposure data showed Mexico (44%), the Caribbean (17%), North America (16%), South America (13%), and Central America (9%) to be the most common areas in which potential exposure occurred. One hundred twenty-three (67%) patients reported insect bites and 19 (10%) patients reported symptoms. Overall, five (3% of all) patients had prenatal ultrasound findings suggestive of possible fetal Zika virus infection; all their Zika virus test results returned negative. These findings included microcephaly, echogenic intracardiac foci, and ventricular calcifications. Of the 153 Zika virus screening tests ordered, eight (5%) immunoglobulin M results returned positive or equivocal with only one positive through confirmatory testing. Overall, 1 of 185 (0.5%) of all those consulted and 1 of 153 (0.7%) of those tested had a confirmed Zika virus infection with no confirmed fetal or neonatal infections. CONCLUSION We identified low rates of confirmed maternal Zika virus infection in our cohort, but the number of patients described here demonstrates the magnitude of concern existing among both patients and physicians regarding possible perinatal Zika virus infection. It also underscores the need for health care providers to be prepared to answer questions, explain laboratory and ultrasound results, and describe testing options for concerned patients and their families.

Use of eculizumab in pregnancy-associated atypical hemolytic uremic syndrome

Abstract Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare disorder, with an estimated incidence of 1 in 25,000 pregnancies [Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S, Couzi L, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859–67.]. Unlike classic hemolytic uremic syndrome (HUS), aHUS is not related to Escherichia coli 0157:H7 infections. Rather, it arises from uncontrolled alternative complement pathway activation leading to diffuse endothelial damage. The formation of the resulting fibrin and platelet microthrombi in the vasculature leads to hemolysis, thrombocytopenia and ischemic end-organ damage in the form of acute kidney injury [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Triggers for hyperactivation of the complement pathway include infection, inflammation, malignancy, endothelium-affecting drugs, maternal-fetal hemorrhage and pre-eclampsia [Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Thirty percent of individuals with aHUS are found to have mutations in the genes encoding complement regulatory proteins, such as protein factor H, complement factor I and complement 3 [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.]. Outcomes of an untreated aHUS are poor: up to 50% of patients with aHUS progress to end-stage renal disease within a year and 25% die during the acute phase [Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Laurence J, Haller H, Mannucci PM, Nangaku M, Praga M, Rodriguez de Cordoba S. Atypical hemolytic uremic syndrome (aHUS): essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol. 2016;14(Suppl 11):2–15.]. We present an unusual case of a 37-year-old primigravida who developed p-aHUS in the setting of hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. She was successfully treated with a relatively novel medication; eculizumab, a terminal complement inhibitor. In contrast to previous reports of long-term treatment, she received a total of six doses of eculizumab and remained in remission at 12 months postpartum.

Antibiotic resistance patterns of group B streptococcus in antenatal genital cultures

OBJECTIVE To identify the antibiotic susceptibility patterns of group B streptococcus (GBS) isolated from antenatal genital screening cultures. STUDY DESIGN One hundred thirty-five sequential GBS isolates underwent susceptibility testing by Kirby-Bauer disk diffusion to a variety of commonly used antibiotics. RESULTS All isolates were susceptible to cefazolin, chloramphenicol and vancomycin. Resistance to clindamycin and erythromycin, the currently recommended alternative antibiotics for intrapartum GBS prophylaxis in penicillin-allergic women, was found in 8.2% and 9.6% of GBS isolates tested, respectively. CONCLUSION These findings raise concerns regarding the need for both confirmation of a history of penicillin allergy in pregnant women and performance of antibiotic susceptibility testing on GBS isolated in genital screening cultures from penicillin-allergic patients.