Edition 66 - 2017, December / Subject Review

Subject Review – Ed. 66

Marco A. Rivarola y Alicia Belgorosky, Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina.

For the Subject Review Section of the present edition of “Endocrinología Pediátrica on Line” we are initially commenting on,  A) a few interesting free communications presented at the 10th INTERNATIONAL  MEETING OF PEDIATRIC ENDOCRINOLOGY, which took recently place in Washington, DC, USA (SEPTEMBER 10-12, 2017). Additionally, we have chosen to comment on two novel concepts, first the importance of microRNAs (miRs) as regulators of gene transcription in health and disease. [As an example, we have chosen a recent publication by Mohammed al. on the “adequate corpus luteum” (JCEM. 2017)], and second the report, by Katugampola et al (JCEM, 2017), of kisspeptin as a “novel regulator of human fetal adrenocortical development and function”.

A) 10th INTERNATIONAL MEETING OF PEDIATRIC ENDOCRINOLOGY.

Free Communication Session, Friday, September 15, 2017, Growth and GH/IGF Axis.

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PAPPA2 P.ALA1034VAL KNOCK-IN MOUSE MODEL RECAPITULATES HOMOZYGOUS HUMAN PAPPA2 MUTATION ASSOCIATED WITH SHORT STATURE. Andrew Dauber, MD; Melissa Andrew, BS/BA; Lihong Liao, MD; Vivian Hwa, PhD, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States.

Objectives: Pregnancy-associated plasma protein A2 (PAPP-A2), a metalloproteinase, is a key regulator of circulating IGF-1 bioavailability. IGF-I circulates in ternary complex with IGF binding protein IGFBP-3 or IGFBP-5, and acid labile subunit, and the cleavage of IGFBP-5 and IGFBP-3 by PAPP-A2 has been hypothesized to free the IGF-I for bioactivities. This critical role of PAPPA2 was supported by their report of the first homozygous loss-of-function PAPPA2 mutations identified in patients with post-natal growth failure and markedly low free IGF-I, despite significantly elevated total serum IGF-I levels. One of the two mutations was a missense mutation, p.Ala1033Val, located downstream of the peptidase domain. Authors demonstrated that this recombinant mutant protein, when compared to wild-type PAPPA2 in over-expressed HEK293 reconstituted systems, was functionally inactive, as it could not proteolyze either recombinant IGFBP-3 or IGFBP-5 proteins. To further validate the biological significance of this missense mutation, they sought to create a mouse model of this patient’s homozygous missense mutation. Methods: They successfully generated an in vivo knock-in (KI), Pappa2 p.Ala1034Val, mouse model (B6D2F1/J), employing CRISPR/CAS9 methodology. They then phenotyped the mice and measured total and free IGF-1 as well as intact IGFBP-3 in mouse serum via ELISA.

Results: Post-natal growth profiles of the homozygous KI (n=10) at 16 days of age, indicated weights were 17.7% ± 3.0% less than wild-type mice (n=8), P

Conclusions: The KI mouse model recapitulates the features of reduced IGF-I bioavailability and impaired post-natal growth profiles observed in the patients. Further investigations are in progress to determine if treatment of KI mice with recombinant PAPPA2 can rescue the impaired growth phenotype.

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GENETIC SCREENING OF PATIENTS WITH CONGENITAL GH DEFICIENCY IN THE GENESIS OBSERVATIONAL PROGRAM: MUTATION FREQUENCY, PHENOTYPE AND GROWTH OUTCOMES. Roland W Pfäffle, MD; Jürgen Klammt, PhD; Heike M Pfäffle, MTA, University of Leipzig, Leipzig, Germany; Serge Amselem, MD, Hôpital d’Enfants Armand-Trousseau , Paris, France; Marie Legendre, PhD, Hôpital Trousseau , Paris, France; Marie-Laure Sobrier, PhD, Inserm US013 , Paris, France; Christopher J Child, PhD; Christine Jones, PhD; Alan G Zimmermann, PhD, Eli Lilly and Company, Indianapolis, IN, United States; Werner F Blum, MD, University of Giessen, Giessen, Germany.

Objectives: Congenital GH deficiency (GHD) may be caused by mutations in genes involved in pituitary development, GH synthesis or secretion. Defects in GH1 & GHRHR commonly cause isolated GHD (IGHD). Defects in genes for transcription factors (GLI2, HESX1, LHX3, LHX4, SOX3, PROP1, POU1F1) that shape the developing pituitary & specify hormone-producing cells, cause multiple pituitary hormone deficiencies (MPHD). Using GeNeSIS DNA Analysis Sub-study data, they investigated mutation frequency, variability in phenotype, and final height (FH) gain in GH-treated with rhGH with and without mutations. Methods: single strand conformational polymorphism (SSCP), denaturing high-performance liquid chromatography (dHPLC), and direct sequencing analyses were performed based on a candidate gene approach in patients with IGHD or MPHD. DNA variants were classified as pathogenic according to the American College of Medical Genetics and Genomics standards. FH was defined by at least 1 of: closed epiphyses, height velocity

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MECHANISMS OF FIBROBLAST GROWTH FACTOR 21 (FGF21) MEDIATED GROWTH HORMONE RESISTANCE IN HUMAN GROWTH PLATE IN CHRONIC CHILDHOOD CONDITIONS. Jayna N Mistry, MRes; Gerard Ruiz-Babot, PhD, Queen Mary University of London, London, United Kingdom; Farasat Zaman, PhD, Karolinska Institutet, Stockholm, Sweden; Lars Sävendahl, MD, PhD, Karolinska University Hospital, Stockholm, Sweden; Leonardo Guasti, PhD; Leo Dunkel, MD, PhD, Queen Mary University of London, London, United Kingdom.

Objectives: FGF21 is an essential hormone regulating metabolic processes to the adaptation to fasting; inducing gluconeogenesis, fatty acid oxidation and ketogenesis. Undernutrition and chronic inflammation have been suggested to elevate FGF21 levels, developing Growth Hormone (GH) resistance and subsequent attenuation of longitudinal growth and growth plate chondrogenesis in both mice and humans through unknown mechanisms. Authors propose that chronic exposure to a high FGF21 environment promotes GH resistance by a direct action on human chondrocytes. The objective of this study is to identify the mechanistic interplay of FGF21 in GH-Receptor (GHR) signalling and GH resistance. Methods: Hek-293 stable lines expressing human GHR were generated and examined for FGF21 and receptor complex (FGFR1/ β-KLOTHO) expression. Immunohistochemistry on human growth plate was studied to identify the localisation of FGF21 and coreceptors within growth plate zonation. Stable lines and/or human growth plate explants were evaluated for GHR half-life and the activation of key GHR signalling mediators; STAT5, negative feedback regulator SOCS2 and IGF-1 in the presence or absence of rhGH and rhFGF21. For the validation of clinical significance, FGF21 and IGF-1 levels were measured serially in peripubertal Crohn’s patients.

Results: Expression of FGF21 receptor complex; FGFR1 iiic/β-KLOTHO and the molecular integrity of GHR signalling was confirmed in stable lines. In the human growth plate FGF21 and co-receptors were localised within the proliferative and pre-hypertrophic zones. Chronic exposure to FGF21 significantly reduced GHR half-life and GH induced STAT5 phosphorylation, whilst the expression of SOCS2 was increased. Ex vivo studies on human growth plate explants verified in vitro findings, whereby elevated FGF21 was seen to increase SOCS2 expression and supress IGF-1 expression. A negative association (p<0.005) of FGF21 with IGF-1 levels was found in peripubertal patients diagnosed with Crohn’s disease. Conclusions: Chronic FGF21 exposure inhibits key GHR signaling mediators, playing a central role in GH resistance secondary to chronic childhood conditions.

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REGULATION OF GROWTH PLATE CHONDROCYTE DIFFERENTIATION BY SPECIFIC microRNAS.

Youn Hee Jee, MD; Jinhee Wang, PhD; Melissa Jennings, Post-bac, NICHD/NIH, Bethesda, MD, United States; Ola Nilsson, Professor, Karolinska Institutet and University Hospital, Stockholm, Sweden; Julian C. Lui, PhD; Jeffrey Baron, MD, NICHD/NIH, Bethesda, MD, United States

Objectives: Growth plate (GP) chondrogenesis is the fundamental process that drives linear growth in children and consequently, defects in chondrogenesis cause short stature. In GP, chondrocytes undergo sequential differentiation to form the resting (RZ), proliferative (PZ), and hypertrophic zones (HZ). The important role of microRNAs in the GP was revealed by cartilage-specific ablation of dicer, an enzyme essential for biogenesis of microRNAs. Here, they sought to identify specific microRNAs that regulate differentiation of PZ chondrocytes to HZ chondrocytes. Methods: Individual GP zones were collected by microdissection from 4-day-old rat proximal tibias. Using Nanostring and RNAseq, they identified microRNAs that were downregulated in HZ vs PZ (>2 fold and FDRResults: Four microRNAs (mir-369-3p, mir-374-5p, mir-379-5p, mir-503-5p) that were downregulated in HZ vs PZ were selected based on the prioritization analysis. When inhibitors for these microRNAs were transfected into chondrocytes, proliferation decreased (38, 26, 46, 49%, respectively, P<0.001) vs control (scrambled microRNA). The inhibitors for three of microRNAs (mir-374-5p, mir-379-5p, mir-503-5p) also increased expression of genes physiologically upregulated in HZ: Ihh(7.6, 6.9, 8.0-fold increase respectively, P<0.01), Bmp2(7.6, 5.4, 5.6-fold, P=0.008, 0.06, 0.047), Bmp6(3.5, 2.9, 3.2-fold, P=0.008, 0.06, 0.047), and Col10a1(5.3, 4.5, 4.4-fold, P=0.015, 0.051, 0.04). Conclusions: These findings suggest that mir-374-5p, mir-379-5p, and mir-503-5p are downregulated in the PZ to HZ transition, thereby contributing to the inhibition of proliferation and stimulation of hypertrophic differentiation, which are important steps in endochondral bone formation at the GP.

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RESPONSE TO RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-1 AFTER TWO YEARS OF THERAPY IN TWO PATIENTS WITH PAPP-A2 DEFICIENCY. Maria T Muñoz-Calvo, MD, Hospital Infantil Universitario Niño Jesús/Universidad Autónoma de Madrid, Madrid, Spain; Vicente Barrios, PhD, Hospital Infantil Universitario Niño Jesús, CIBEROBN, Madrid, Spain; Jesus Pozo, MD, Hospital Infantil Universitario Niño Jesús/Universidad Autónoma de Madrid, Madrid, Spain; Gabriel Á. Martos-Moreno, MD; PhD., Hospital Infantil Universitario Niño Jesús. UAM. , Madrid, Spain; Federico Hawkins, MD; PhD, Hospital 12 de Octubre/Universidad Complutense, Madrid, Spain; Julie A Chowen, PhD, Hospital Infantil Universitario Niño Jesús, CIBEROBN, Madrid, Spain; Luis A Perez-Jurado, MD, Universidad Pompeu Fabra, Barcelona, Spain; Claus Oxvig, PhD, Aarhus University, Aarhus, Denmark; Jan Frystyk, MD, Aarhus University Hospital, Aarhus, Denmark; Jesús Argente, MD, PhD, Hospital Infantil Universitario Niño Jesús. UAM, Madrid, Spain

Objectives: PAPP-A2 is a metalloproteinase that specifically cleaves IGFBP3 and IGFBP5. We have recently described the first mutations in the PAPP-A2 gene that cause postnatal growth failure in humans and specific skeletal features, due to the resulting decrease in IGF-1 bioavailability. The objectives are: 1. To determine auxological, hormonal and metabolic parameters after administration of rhIGF-1 to two patients with complete lack of PAPP-A2 activity. 2. To assess the safety of this treatment after two years. Methods: The study included two prepubertal siblings, a 10.5-year-old female (patient 1) and a 6-year-old boy (patient 2), born to non-consanguineous Spanish parents. Both patients exhibited very high serum levels of IGF-I, IGF-II, ALS, IGFBP3 and IGFBP5, as well as a similar phenotype and short stature due to a homozygous loss-of-function frameshift mutation in the exon 3 of the PAPPA2 gene (p.D643fs25*) and undetectable PAPP-A2 activity. Both siblings were treated with rhIGF-1 (Mecasermin, Increlex®; Ipsen), with progressive doses (40, 80, 100 y 120 μg/kg), twice daily for 2 years. After 6 months of treatment with rhIGF-I, patient 1 entered puberty (Tanner II). In an attempt to improve her final height, she receives Triptorelin (3.75 mg/28 days). Results: Treatment with rhIGF-1 accelerated growth velocity, clearly improving height SDS according to age and sex in both patients at 6 mo, 12 mo and 24 mo of therapy (Table). Acutely, rhIGF-I administration increased bioactive IGF-I 60-120 minutes later. Twelve hours after treatment, serum bioactive IGF-I, total IGF-I and IGFBP-3 levels were similar to their pretreatment levels (Table). At 1 yr of treatment, fasting hyperinsulinemia was normalized (patient 1: 11 μU/mL; patient 2: 8 μU/mL) with normal glycemia and glycosylated hemoglobin before and during treatment. Treatment with rhIGF-1 produced an increase in total body mineral conent (DXA) (patient 1: 23% and patient 2: 30%) after 2 years) and increased the percentage of lean body mass in both patients. Neither patient experienced episodes of hypoglycemia or hyperglycemia or any other previously described secondary effect of rhIGF-I. Conclusions: Treatment with rhIGF-I in children with PAPP-A2 deficiency improves growth after two years, with no apparent adverse effects.

Free Communication Session, Friday, September 15, 2017, 7:30-8:30am

Syndromes FC6 – FC 10

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IDENTIFICATION OF SMCHD1 MUTATIONS IN A SEVERE FORM OF KALLMANN SYNDROME (KS) WITH ABSENCE OF THE NOSE (ARHINIA) ATTESTS TO THE POWER OF EXTREME PHENOTYPES IN HUMAN REPRODUCTIVE GENE DISCOVERY. Natalie D Shaw, MD, National Institute of Environmental Health Sciences, Durham, NC, United States; Harrison Brand, PhD, Massachusetts General Hospital, Boston, MA, United States; Zachary A Kupchinsky, PhD, DUKE UNIVERSITY MEDICAL CENTER, DURHAM, NC, United States; Hemant Bengani, PhD, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom; Lacey Plummer, BS/BA, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital , Boston, MA, United States; Takako I Jones, PhD, University of Massachusetts, Worcester, MA, United States; Serkan Erdin, PhD, Massachusetts General Hospital, Boston, MA, United States; Kathleen A Williamson, MD, Institution of Genetics and Molecular Medicine, University of Endinburgh Western General Hospital, Edinburgh, United Kingdom; Joe Rainger, PhD, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom; Alexei Stortchevoi, PhD, Massachusetts General Hospital, Boston, MA, United States; Kaitlin Samocha, PhD, Broad Institute of MIT and Harvard, Cambridge, MA, United States; Benjamin B Currall, PhD, Massachusetts General Hospital, Boston, MA, United States; Donncha S Dunican, MD, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom; Ryan L Collins, PhD, Massachusetts General Hospital, Boston, MA, United States; Jason R Willer, PhD, Duke University Medical Center, Durham, NC, United States; Angela Lek, PhD, Harvard Medical School, Boston, MA, United States; Monkol Lek, PhD, Broad Institute of MIT and Harvard, Cambridge, MA, United States; Malik Nassan, MD, Mayo Clinic, Rochester, MN, United States; Shahrin Pereira, BS/BA; Tammy Kammin, MS/MA, Brigham and Women’s Hospital, Boston, MA, United States; Diane Lucente, MS/MA; Alexandra Silva, BS/BA; Catarina M Seabra, BS/BA; Colby Chiang, PhD; Yu An, PhD, Massachusetts General Hospital, Boston, MA, United States; Morad Ansari, PhD, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom; Jacqueline K Rainger, PhD, Institue of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom; Shelagh Joss, PhD, South Glasgow University Hospitals, Glasgow, United Kingdom; Jill Clayton Smith, MD, Institute of Human Development, Manchester Centre for Genomic Medicine, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, United Kingdom; Margaret F Lippincott, MD; Syliva S Singh, MD; Nirav Patel, BS/BA; Jenny W Jing, BS/BA, Massachusetts General Hospital, Boston, MA, United States; Jennifer R Law, MD, University of North Carolina, Chapel Hill, NC, United States; Nalton Ferraro, MD, Boston Children’s Hospital, Boston, MA, United States; Alain Verloes, MD, Robert Debre Hospital, Paris, France; Anita Rauch, MD, Univeristy of Zurich, Schlieren-Zurich , Switzerland; Katharina Steindl, MD; Markus Zweier, MD, University of Zurich, Schlieren-Zurich, Switzerland; Ianina Scheer, MD, Children’s Hospital, Zurich, Switzerland; Daisuke Sato, MD, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Nobuhiko Okamoto, MD, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan; Christiana Jacobsen, MD, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States; Jeanine Tryggestad, MD, Universtiy of Oklahoma Health Sciences Center, Oklahoma City, OK, United States; Steven D. Chernausek, MD, University of Oklahoma Health Science Center, Oklahoma City, OK, United States; Lisa A Schimmenti, MD, Mayo Clinic, Rochester, MN, United States; Benjamin Brasseur, MD, University of Miami Leonard M. Miller Schoolof Medicine, Miami, FL, United States; Claudia Cesaretti, MD, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Milan, Italy; Jose E Garcia-Ortiz, MD, Instituto Mexicano del Seguro Social, Guadalajara, Mexico; Tatiana Pineda Buitrago, MS/MA, Universitario de San Jose, Bogota, Colombia; Orlando Perez Silva, MD, de Medicina de Colombia, Bogota, Colombia; Jodi D Hoffman, MD, Tufts Medical Center, Boston, MA, United States; Wolfgang Muhlbauer, MD, ATOS Klinik , Munich , Germany; Klaus W Ruprecht, MD, University Hospital of the Saarland, Homburg, Germany; Bart L Loeys, MD, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; Masato Shino, MD, Gunma University Graduate School of Medicine, Gunma , Japan; Angela M Kaindl, MD, Charite- University Medicine Berlin and Berlin Institute of Health, Berlin, Germany; Ravikumar Balasubramanian, MD; et E Hall, MD; Stephanie B Seminara, MD, Massachusetts General Hospital, Boston, MA, United States; Daniel Macarthur, PhD, Broad Institute of MIT and Harvard, Cambridge, MA, United States; Steven A Moore, MD, University of Iowa Carver College of Medicine, Iowa City, IA, United States; Koh-Ichiro Yoshiura, MD, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; James F Gusella, MD, Massachusetts General Hospital, Boston, MA, United States; Joseph A Marsh, PhD, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom; John M Graham, Jr, MD, Cedars Sinai Medical Center, Los Angeles, CA, United States; Angela E Lin, MD, Massachusetts General Hospital, Boston, MA, United States; Nicholas Katsanis, PhD, DUKE UNIVERSITY MEDICAL CENTER, Durham, NC, United States; Peter L Jones, PhD, University of Nevada, Reno, NV, United States; William F Crowley, Jr, MD, Massachusetts General Hospital, Boston, MA, United States; Erica E Davis, PhD, DUKE UNIVERSITY MEDICAL CENTER, Durham, NC, United States; David R Fitzpatrick, MD, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom; Michael E Talkowski, PhD, Massachusetts General Hospital, Boston, MA, United States; Chie-Hee Cho, MD, University Hospital of Bern, Bern, Switzerland; Cynthia C Morton, MD, Broad Institute of MIT and Harvard, Cambridge, MA, United States; Richard R Meehan, PhD; Veronica Van Heyningen, MD, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, United Kingdom; Eric C Liao, MD, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States

Objectives: The study of patients with extreme clinical phenotypes is an efficient strategy for gene discovery. Harnessing the phenotypic depth and size of our cohort of subjects with hypogonadotropic hypogonadism (HH), we applied this approach to a group of KS subjects with a completely absent external nose (arhinia). Methods: Through an international consortium, we expanded our arhinia cohort to 41 cases, performed whole-exome sequencing (WES) and defined the full reproductive phenotypic spectrum. Results: Rare mutation burden testing in WES data from cases vs ExAC controls identified 1 gene, SMCHD1, exceeding genome-wide significance. 86% of cases had a rare, heterozygous missense variant in SMCHD1, which encodes an epigenetic repressor that causes a rare form of muscular dystrophy. SMCHD1 is expressed in the human olfactory epithelium, a tissue highly relevant to arhinia and GnRH ontogeny. Cases did not harbor rare sequence variants (RSVs) in any genes associated with KS. Reproductive function was assessed in 22M and 10F; 97% had HH, cryptorchidism, microphallus, or 1o amenorrhea. Three patients had apulsatile LH profiles, consistent with GnRH deficiency, and physiologic GnRH administration induced ovulation in a female while a male (with eutopic testes) had an exaggerated FSH response and modest T rise, suggesting coexistent testicular resistance. Neuroimaging revealed absent olfactory structures. In 3 multiplex families, an SMCHD1 RSV segregated with arhinia or subphenotypes (anosmia) but not with KS, indicating that HH is incompletely penetrant or variably expressed, compatible with oligogenicity. Smchd1 suppression in zebrafish produced aberrant facial cartilage and a much shorter GnRH-immunopositive terminal nerve. RNAseq of blood cells from arhinia patients vs unaffected family revealed altered expression of craniofacial but not KS genes. Conclusions: 1) SMCHD1 alterations cause a broad spectrum of phenotypes that are incompletely penetrant and variably expressed, suggesting pleiotropy, oligogenicity, or environmental modifiers 2) Epigenetic modification by SMCHD1 appears to play a role in reproductive developmental biology, and 3) KS patients with phenotypic extremes provide critical genetic insights into human reproductive function.

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METABOLOMIC PROFILE OF SEVERE VERSUS ATTENUATED MUCOPOLYSACCHARIDOSIS TYPE I

Lynda E Polgreen, MD; Patricia I Dickson, MD; Jennifer K Yee, MD; Kent D Taylor, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, United States; David Elashoff, PhD, UCLA, Los Angeles, CA, United States; Ellen Fung, PhD, Children’s Hospital Oakland Research Institute, Oakland, CA, United States; Bradley S. Miller, MD, PhD; Weston P Miller, MD; Paul J Orchard, MD; Troy C Lund, PhD, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, United States

Objectives: Mucopolysaccharidosis type I (MPSI) is a lysosomal storage disease caused by a mutation in the IDUA gene that results in progressive multi-system disease. MPSI can be separated into two phenotypes: MPSIH (for MPSI Hurler), which is the most severe phenotype and treated with hematopoietic cell transplantation, and MPSIA (for MPSI attenuated), a “milder” clinical phenotype that is treated with enzyme replacement therapy alone. Both treatments are most effective if initiated prior to the onset of clinical signs of disease. As the era of newborn screening for MPSI begins, so does the promise of early diagnosis and treatment. However, current diagnostics cannot predict which of the two profoundly different MPSI phenotypes will manifest, and thus cannot adequately guide treatments. Thus we aimed to identify a biochemical signature that distinguishes MPSIH from MPSIA. Methods: Metabolomics analysis was performed on 25 samples from treated patients with MPS I (17 MPSIH; 8 MPSIA). Welch’s twosample t-test was used to identify metabolites that differed significantly between groups and an estimate of the false discovery rate (q-value) was calculated. Random forest analysis ranked metabolites for their ability to separate groups. Finally a sparse partial least squares discriminant analysis was performed to determine the combination of metabolites that would best predict MPSIH. Results: 125 metabolites were different and generally increased in treated MPSIH versus MPSIA (p<0.05); 14 of those metabolites also had a q-valueConclusions: We have identified 14 plasma metabolites that effectively distinguish MPSIH from MPSIA after adjustment for multiple comparisons. Of these, the combination of two biomarkers distinguished MPHIH from MPSIA in our cohort of treated MPSI patients. These findings establish a starting point for evaluating a biomarker-based diagnostic tool to predict phenotype in newborns diagnosed with MPSI.

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MIRAGE SYNDROME: ADDITIONAL CASES WITH SAMD9 MUTATIONS, CLINICAL AND BIOLOGICAL CHARACTERIZATION. Florence Roucher-Boulez, MD; Delphine Mallet-Motak, PhD, Hospices Civils de Lyon Université Lyon 1, Lyon, France; Dulanjalee Kariyawasam, MD, Hopital Necker – Enfants Malades. Université Paris Descartes, Paris, France; Graziella Pinto, MD, Hopital Necker -Enfants Malades. Université Paris Descartes, Paris, France; Marion Gerard, MD, CHU de Caen, Caen, France; Virginie Ribault, MD, Centre Hospitalier Universitaire, Caen, France; Christel Chalouhi , MD, Hopital Necker – Enfants Malades. Université Paris Descartes, Paris, France; Julien Thevenon, MD, CHU Dijon, Université de Bourgogne, Dijon, France; Raja Brauner, MD, Fondation Rothchild, Paris, France; Patricia Bretones, MD, Hospices Civils de Lyon Université Lyon 1, Lyon, France; Pierre Simon Jouk , MD, CHU de Grenoble site Nord , Grenoble, France; Veronique Tardy-Guidollet , MD, Hospices Civils de Lyon Université Lyon 1, Lyon, France; Candace Ben Signor, MD, CHU Dijon, Université de Bourgogne, Dijon, France; Yves Morel, MD, Hospices civils de Lyon, Université Lyon 1, Lyon, France

Objectives: The new MIRAGE (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, and Enteropathy) syndrome, described in 2015, is due to de novoheterozygotes mutations in SAMD9 gene. Our objective was to screen the patients of our cohort with intrauterine growth restriction, adrenal insufficiency and / or disorder of sex differentiation (DSD) and to characterize the adrenal and DSD phenotype. Methods: SAMD9 Sanger sequencing for 20 patients (20 families). Results: Mutations were found for 8 patients. 3 had the previous described mutations by Narumi et al: p.Arg459Gln, p.Glu974Lys. The other mutations were: p.Arg685Gln, p.Thr778Ile, p.Arg982His (2 patients), p.Ser1074Ile. Those mutations have never been reported in databases. They all had MIRAGE syndrome with additional or missing symptoms. All patients had intrauterine growth restriction (IUGR) and born pre-termed. They had recurrent invasive infections. All the patients had a 46,XY DSD but with a variable degree of masculinisation. Nevertheless only one was reared as a boy. No mullerien residue has been detected but AMH was always low when available. Gonads were ectopic and testosterone low in most cases. Adrenal insufficiency was revealed rapidly at birth associated with high ACTH and low steroids, except D4 androstenedione and 11-desoxycortisol which could be normal or high, suggesting an impairment of CYP450 type II involved in the steroidogenesis. Additionally, 2 had hypoplastic kidney, 6 had respiratory distress. 1 died in utero, 4 died before 3 months of life, 2 at 1 year old but interestingly one patient is still alive and actually 14 years old. This patient has a particular phenotype without adrenal insufficiency but with thrombocytopenia and necrotizing enterocolitis at birth. Conclusions: As MIRAGE syndrome may be incomplete, sequencing of SAMD9 gene should be done with the association of IUGR, adrenal insufficiency and/or 46, XY DSD and polymalformative syndrome. Those additional and future cases, with hormonal assays (steroids, AMH, gonadotrophins), are very interesting for a better understanding of the role of this gene on adrenal and gonadal development.

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SHOULD 45,X/46,XY BOYS WITHOUT DSD BE EVALUATED? RETROSPECTIVE LONGITUDINAL STUDY OF GROWTH, PUBERTY AND PHENOTYPIC FEATURES OF 34 PATIENTS. Laurence Dumeige, MBBS, University of Paris, Robert Debré Hospital, Paris, France; Livie Chatelais, MD, University Hospital of Angers, Angers, France; Claire Bouvattier, MD, University of Paris, Bicêtre Hospital, Le Kremlin Bicêtre, France; Marc De Kerdanet, MD, University Hospital of Rennes, Rennes, France; Blandine Esteva, MD, University of Paris, Armand Trousseau Hospital, Paris, France; Dinane Samara-Boustani, MD, University of Paris, Necker-Enfants Malades Hospital, Paris, France; Delphine Zenaty, MD, University of Paris, Robert Debré Hospital, Paris, France; Marc Nicolino, MD, University Hospital of Lyon, Paris, France; Sabine Baron, MD, University Hospital of Nantes, Nantes, France; Chantal Metz, MD, Brest Regional Medical Center, Brest, France; Catherine NaudSandreau, MD, Bretagne Sud Medical Center, Lorient, France; Clémentine Dupuis, MD, University Hospital of Grenoble, Grenoble, France; Jean-Claude Carel, MD, University of Paris, Robert Debré Hospital, Paris, France; Régis Coutant, MD, University Hospital of Angers, Angers, France; Laetitia Martinerie, MD, University of Paris, Robert Debré Hospital, Paris, France

Objectives: Few studies of patients with a 45,X/46,XY mosaicism, have considered those with normal male phenotype, while they represent ~90% of the patients born with this karyotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia (unilateral cryptorchidism or glandular hypospadias), in terms of growth, puberty and other phenotypic characteristics. Methods: We present a retrospective longitudinal study of 34 patients followed between 1982 and 2016 in 13 French reference centers for pediatric endocrinology. Results: Twenty patients had a prenatal diagnosis whereas 14 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, decreasing during puberty with a mean adult height of 156 +/- 6 cm, i.e. -2.3DS with correction for target height. Seventy percent of patients presented with Turner syndrome features including 5 patients with cardiac anomalies (comprising 2 bicuspid aortic valves and 1 aortic dilation) and 3 patients with renal malformations. Nineteen patients had minor abnormalities of external genitalia, and one patient developed a testicular embryonic carcinoma, underlining evidence of some level of gonadal dysgenesis in these patients. Puberty occurred spontaneously in most cases but 56% of patients evaluated at the end of puberty presented signs of declined Sertoli testicular function (increased level of FSH and low level of inhibin B). Conclusions: Despite a clear selection bias, this study emphasizes the need to follow, up to adulthood, 45,X/46,XY patients born with a normal male phenotype, which present similar prognosis to those born with a difference in sex development. Screening for cardiac and renal malformations, and regular testicular examination appear to be indicated in all these patients, as well as monitoring of growth and testicular function during puberty. Currently, most of these patients are diagnosed in adulthood with infertility and azoospermia, which is consistent with our observations of decreased testicular function at the end of the puberty. Early management may lead to fertility preservation strategies in these patients.

B) Next, we will comment on two recent publications on two new subjects relevant for pediatric endocrinology.

1) Role of microRNAs in ovulation. microRNAs are important post-transcriptional regulators of mRNAs in multiple gene functions. An example is human ovarian ovulation. In support of this, we have selected to comment a recent publication of Mohammed et al. (JCEM 2017) on the role of microRNAs on this essential function for human reproduction:

J Clin Endocrinol Metab. 2017 Mar 20. doi: 10.1210/jc.2017-00259. The adequate corpus luteum: miR-96 promotes luteal cell survival and progesterone production. Mohammed BT1, Sontakke SD1, Ioannidis J1, Duncan WC2, Donadeu FX1.1 The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK. 2 The Queen’s Medical Research Institute, MRC Centre for Reproductive Health, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

Abstract. CONTEXT: Inadequate progesterone production from the corpus luteum is associated with pregnancy loss. Data available in model species suggest important roles of miRNAs in luteal development and maintenance. OBJECTIVE: To comprehensively investigate the involvement of miRNAs during the ovarian follicle-luteal transition. DESIGN: The effects of specific miRNAs on survival and steroid production by human luteinized granulosa cells (hLGCs) were tested using specific miRNA inhibitors. Candidate miRNAs were first identified through microarray analyses of follicular and luteal tissues in a bovine model. SETTING: UK academic institution associated with teaching hospital. PATIENTS OR OTHER PARTICIPANTS: hLGCs were obtained by standard transvaginal follicular fluid aspiration from 35 women undergoing assisted conception. INTERVENTIONS(s): Inhibition of candidate miRNAs in vitro. MAIN OUTCOME MEASURE(S): Levels of miRNAs, mRNAs, FOXO1 protein, apoptosis and steroids were measured in tissues and/or cultured cells. Results: Two specific miRNA clusters, miR-183-96-182 and miR-212-132, were dramatically increased in luteal relative to follicular tissues. miR-96 and miR-132 were the most upregulated miRNAs within each cluster. Database analyses identified FOXO1 as a putative target of both these miRNAs. In cultured hLGCs, inhibition of miR-96 increased apoptosis and FOXO1 protein levels, and decreased progesterone production. These effects were prevented by siRNA-mediated downregulation of FOXO1. In bovine luteal cells, miR-96 inhibition also led to increases in apoptosis and FOXO1 protein levels. CONCLUSIONS: miR-96 targets FOXO1 to regulate luteal development through effects on cell survival and steroid production. The miR-183-96-182 cluster could provide a novel target for the manipulation of luteal function.

Excerpts from this publication.

Ovulation involves rupture of the wall of a mature follicle and release of the contained oocyte for fertilization. After ovulation, the follicular remnants undergo profound remodeling, resulting in formation of a highly vascular, highly steroidogenic corpus luteum (CL), with a critical role in establishment and maintenance of pregnancy. Luteal development involves fine-tuned changes in proliferation, survival, migration, and differentiation, simultaneously affecting many cell types. Particularly critical is the differentiation of estrogen-producing follicular cells into luteal cells with the ability to produce high levels of progesterone. miRNAs are ubiquitously involved in posttranscriptional gene regulation during tissue development and differentiation. Cattle provide a convenient model to study human ovarian physiology, allowing study of clinically relevant follicular and luteal tissues difficult to access in women.

Microarray analyses. Bovine samples from six large (12- to 17-mm diameter), steroidogenically active follicles [classified based on CYP19A1 and estradiol levels], and six early CLs were analyzed with the miRCURY LNA microRNA array sixth generation (containing 1488 capture probes targeting all miRNAs for human, mouse, or rat in miRBase 16.0; Exiqon Services, Denmark). Differences in miRNA expression were determined using Student t test with Benjamini and Hochberg false discovery rate adjustment. Raw microarray data were deposited in NCBI’s National Center for Biotechnology Information Gene Expression Omnibus repository (gene accession no. GSE54692).

miR-183-96-182 and miR-212-132 clusters are highly upregulated during the follicular-luteal transition. To identify miRNAs potentially involved in the follicular-luteal transition in the monovular ovary, they collected bovine large antral follicles and early-cycle CLs. Expression profiles of selected genes were consistent with those naturally encompassing the follicle-luteal transition. Upon microarray analyses, a total of 545 probes yielded hybridization intensities above background across all samples, corresponding to 523 unique miRNAs, including 191 sequences registered as bovine in miRBase 18.

A total of 11 and 22 unique miRNAs were up- and downregulated, respectively (>2.5-fold; false discovery rate, 0.01) in CLs relative to large antral follicles The top four differentially expressed sequences corresponded to the homologs of human miR-183-5p, miR-96-5p, miR-182-5p, and miR-132-3p, and were all upregulated in the CL. These sequences derive from two different miRNA clusters: miR-183-96-182 and miR-212-132. Only one of the -3p homologs in the miR-183-96-182 cluster, miR-183, was also detected by microarray, and was slightly upregulated in the CL. In addition, the homologs of human miR-132-5p and miR-212-3p (none registered as a bovine sequence in miRBase 18), but not miR-212-5p, were also detected and were upregulated in the CL. Because bta-miR-96 and bta-miR-132 were the top up regulated miRNAs within each cluster and, based on cycle-threshold values, were also the most abundant in ovarian tissues, our subsequent analyses focused on these two miRNAs (referred to as miR-96 and miR-132, for simplicity).

Quantitative polymerase chain reaction (qPCR) screening across bovine tissues revealed neither miR-96 nor miR-132 was restricted to the ovary. Nevertheless, miR-132 was expressed at highest levels in CL, although in situ hybridization showed that within the CL, this miRNA was broadly distributed and not restricted to any particular cell type. Next, to ascertain whether the increase in miR-96 and miR-132 during luteinization involves granulosa derived cells, the major source of luteal progesterone, they induced bovine granulosa cells to luteinize in culture, and showed that, indeed, this was associated with a distinct increase in the expression of miR-96, miR-132, and other miRNAs from the same genomic clusters.

They selected a subset of genes that (1) were predicted targets of both miRNAs, (2) contained conserved target sites, and (3) were known to be involved in luteal development, and they then determined their relative expression in ovarian tissues. In this way, the transcription factor, FOXO1, a critical regulator of cell survival and metabolism was identified as high-confidence target, based on its clearly decreased expression in CL relative to follicles. They then determined their relative expression in ovarian tissues. After detecting that FOXO1 is a putative target of miR-96 and miR-132 during the follicle-luteal transition they found that miR-96 has an antiapoptotic effect in hLGCs mediated by FOXO1.

To investigate the involvement of these miRNAs in the human ovary, they first determined changes in miRNA expression in hLGCs (corresponding to an early stage of luteinization) that had been treated with hCG to induce further differentiation in culture. Results showed that, as in bovine cells, the two miRNAs were upregulated in response to a luteinization stimulus in human cells. Next, they investigated whether, as suggested by the results of miRNA target analyses, these two miRNAs may regulate luteal cell survival. They transfected hLGCs with anti-miRNAs and determined the effects on apoptotic responses to serum removal. They found that anti-miR-96, but not anti-miR-132, led to a significant mean increase (1.6-fold) in the Caspase 3/7 activation response to serum starvation. Interestingly, similar Caspase 3/7 responses were obtained even in non-stressed cells maintained in serum; in addition, under those conditions, simultaneous inhibition of both miRNAs produced a Caspase 3/7 response similar to that induced by inhibition of miR-96 only. The pro-apoptotic effect of miR-96 inhibition was confirmed by annexin V staining.

They then determined whether the effects of miR-96 could be mediated by its putative target, FOXO1 protein. Indeed, inhibition of miR-96 induced a robust mean increase (1.8-fold) in FOXO1 protein 1 day after transfection, with a slightly smaller (1.7-fold) although significant increase induced also by miR-132 inhibition. Again, simultaneous inhibition of the two miRNAs did not have a synergistic effect on FOXO1 levels. To confirm a causal involvement of FOXO1 in the observed apoptotic response to anti-miR-96, we transfected cells simultaneously with anti-miR-96 and FOXO1 siRNA. We showed that this effectively prevented both an increase in FOXO1 protein and the activation of Caspase 3/7 in response to anti-miR-96, thus indicating that miR-96 promotes hLGC survival by targeting FOXO1, cP, 0.01 (Benjamini and Hochberg adjusted) in all cases. miR-96 has an antiapoptotic effect in hLGCs mediated by FOXO1.

To investigate the involvement of these miRNAs in the human ovary, they first determined changes in miRNA expression in hLGCs (corresponding to an early stage of luteinization) that had been treated with hCG to induce further differentiation in culture. Results showed that, as in bovine cells, the two miRNAs were upregulated in response to a luteinization stimulus in human cells. Next, they investigated whether, as suggested by the results of the miRNA target analyses, these two miRNAs may regulate luteal cell survival. They transfected hLGCs with anti-miRNAs and determined the effects on apoptotic responses to serum removal. They found that anti-miR-96, but not anti-miR-132, led to a significant mean increase (1.6-fold) in the Caspase 3/7 activation response to serum starvation. Interestingly, similar Caspase 3/7 responses were obtained even in nonstressed cells maintained in serum; in addition, under those conditions, simultaneous inhibition of both miRNAs produced a Caspase 3/7 response similar to that induced by inhibition of miR-96 only. The proapoptotic effect of miR-96 inhibition was confirmed by annexin V staining. They then determined whether the effects of miR-96 could be mediated by its putative target, FOXO1. Indeed, inhibition of miR-96 induced a robust mean increase (1.8-fold) in FOXO1 protein, 1 day after transfection, with a slightly smaller (1.7-fold) although significant increase induced also by miR-132 inhibition. Again, simultaneous inhibition of the two miRNAs did not have a synergistic effect on FOXO1 levels. To confirm a causal involvement of FOXO1 in the observed apoptotic response to anti-miR-96, they transfected cells simultaneously with anti-miR-96 and FOXO1 siRNA. They showed that this effectively prevented both an increase in FOXO1 protein and the activation of Caspase 3/7 in response to anti-miR-96, thus indicating that miR-96 promotes hLGC survival by targeting FOXO1.

Given the reported involvement of miRNAs in steroidogenesis, they investigated the short-term effects of miR-96 and miR-132 on progesterone and estradiol production, by analyzing spent culture media of hLGCs transfected with anti-miR-96 and/or anti-miR-132. All treatments resulted in a decrease in mean progesterone levels at 24 hours; however, this was significant only in response to anti-miR-96, alone or in combination with anti-miR-132 (1.6-fold; P, 0.01). Moreover, the effects of anti-miRs on progesterone were transient; differences were no longer detected 48 hours after transfection (P, 0.01; not shown). In contrast, significant changes in estradiol levels were not detected (P. 0.1) in response to transfection with anti-miRNAs. They then determined whether the observed stimulatory effects of miR-96 on progesterone may involve repression of FOXO1. This was, indeed, the case, because transfection with FOXO1 siRNA prevented the temporary reduction in progesterone levels by anti-miR-96, indicating that, in hLGCs, an inhibitory effect of FOXO1 on progesterone synthesis is relieved by an increase in miR-96 upon luteinization.

To investigate the mechanisms behind the observed effects of miR-96 and FOXO1 on steroid levels, they quantified the expression of several genes involved along the cholesterol and steroid synthesis pathways, the transcript levels of which were previously shown to be regulated by FOXO1, in rodent granulosa cells. They did not detect significant differences in the levels of any of the transcripts analyzed in response to inhibition of miR-96 in the absence or presence of FOXO siRNA. This indicated that distinct molecular mechanisms, which could possibly include changes in protein levels and/or activity of steroidogenic gene products, may account for the effects of FOXO1 in steroid production in hLGCs.

Finally, to investigate the functional conservation of miR-96 during the follicle-luteal transition in other species, they established whether the observed effects of this miRNA in human ovarian cells also occurred in bovine. They collected cells from bovine CLs and cultured them in the presence or absence of anti-miR-96. Consistent with data in humans, inhibition of miR-96 led to an increase in Caspase 3/9 activity in response to serum deprivation, together with an increase in FOXO1 protein levels. In contrast, progesterone production by bovine cells was not affected by miR-96 inhibition.

In summary, using a cross-species approach, miR-96 was identified as a novel regulator of the follicle-luteal transition, through FOXO1-mediated promotion of luteal cell survival and progesterone production. Reported wider roles for FOXO1 in the ovary suggest that miR-96 and, indeed, the miR-183-96-182 cluster, likely has broader effects during the follicle-luteal transition. Such effects may be important not only in ensuring a normal luteal phase but also in regulating luteal rescue and the establishment of pregnancy, a potential key link for investigation in future studies.

2)  Kisspectin regulates development and function of human fetal adrenal.

The fetal zone of fetal adrenal plays important roles in the endocrine control of gestation and delivery. In this zone a great production of kisspectin is synthesized, which could regulate placentation, initiation of gestation, and have a key role in uterine homeostasis and in maintenance of pregnancy.

The following publication refers to this novel subject.

Kisspeptin Is a Novel Regulator of Human Fetal Adrenocortical Development and Function: A Finding With Important Implications for the Human Fetoplacental Unit.  Harshini Katugampola,1 * Peter J. King,1 * Sumana Chatterjee,1 Muriel Meso,1 Andrew J. Duncan,2 John C. Achermann,2 Leo Guasti,1 Lea Ghataore,3 Norman F. Taylor,3 Rebecca Allen,4 Shemoon Marlene,4 Joseph Aquilina,4 Ali Abbara,5 Channa N. Jaysena,5 Waljit S. Dhillo,5 Leo Dunkel,1 Ulla Sankilampi,6 and Helen L. Storr1 1 Centre for Endocrinology, William Harvey Research Institute, London, EC1M 6BQ, United Kingdom; 2 Genetics & Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, United Kingdom; 3 Steroid Laboratory, Department of Clinical Biochemistry (Viapath Analytics), King’s College Hospital, London SE5 9RS, United Kingdom; 4 Fetal Medicine Centre, Royal London Hospital, Barts Health Trust, London E1 1BB, United Kingdom; 5 Section of Endocrinology and Investigative Medicine, Imperial College London, London W12 0NN, United Kingdom; and 6 Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland

Abstract.

CONTEXT: The human fetal adrenal (HFA) is an integral component of the fetoplacental unit and important for the maintenance of pregnancy. Low kisspeptin levels during pregnancy are associated with miscarriage, and kisspeptin and its receptor are expressed in the HFA. However, the role of kisspeptin in fetal adrenal function remains unknown. Objective: To determine the role of kisspeptin in the developing HFA. DESIGN: Experiments using H295R and primary HFA cells as in vitro models of the fetal adrenal. Association of plasma kisspeptin levels with HFA size in a longitudinal clinical study. SETTING: Academic research center and tertiary fetal medicine unit. PARTICIPANTS: Thirty-three healthy pregnant women were recruited at their 12-week routine antenatal ultrasound scan. MAIN OUTCOME MEASURES: The spatiotemporal expression of Kiss1R in the HFA. The production of dehydroepiandrosterone sulfate (DHEAS) from HFA cells after kisspeptin treatment, alone or in combination with adrenocorticotropic hormone or corticotropin-releasing hormone. Fetal adrenal volume (FAV) and kisspeptin levels at four antenatal visits (;20, 28, 34, and 38 weeks’ gestation). RESULTS: Expression of Kiss1R was present in the HFA from 8 weeks after conception to term and was shown in the inner fetal zone. Kisspeptin significantly increased DHEAS production in H295R cells and second-trimester HFA cells. Serial measurements of kisspeptin confirmed a correlation with FAV growth in the second trimester, independent of sex or estimated fetal weight.

Excerpts from this publication

There is compelling evidence that decreased kisspeptin may be a biomarker of placental dysfunction in pregnancy and may also identify asymptomatic pregnant women at greater risk of miscarriage. The mechanisms underlying these associations are unknown. The functional role of the HFA is to produce steroid precursors, which are converted to estrogens by the placenta. Placental estrogens are critical for intrauterine homeostasis, fetal maturation, and the activation of parturition. Soon after birth, the HFA undergoes rapid involution, with rapid disappearance of the FZ. There is 50-fold higher expression of Kiss1R in the HFA compared with the adult adrenal, and Kiss1R expression has been confirmed, not only in the definitive, but also in the transient zones of the HFA. The HFA may be an important target for the high levels of circulating kisspeptin in pregnancy. Circulating kisspeptin concentrations increase dramatically during pregnancy, and its levels reflect the amount of viable placental tissue. Consequently, a decline in the levels may be associated with increased miscarriage and preeclampsia risk. This association was also demonstrated in twin pregnancies, where the death of one twin was associated with lower kisspeptin levels. Serial measurements of plasma kisspeptin in pregnant women have not previously been undertaken, but cross-sectional data suggest that the levels increase as pregnancy progresses. We report a significant increase in circulating kisspeptin in pregnant women between 20 and 28 weeks’ gestation, which correlates with the second-trimester rise in FAV.

Conclusions. Kisspeptin–Kiss1R signaling may be a key regulator of HFA development and steroidogenesis and therefore an integral component of the fetoplacental unit. As well as being critical in regulating placentation in early pregnancy, it may have a key physiological role in intrauterine homeostasis and the maintenance of pregnancy, particularly in the second trimester. Therefore, data suggest a functional role for kisspeptin in utero.


Posted in Edition 66 - 2017, December, Subject Review
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