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      Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

      research-article
      1 , 2 , 47 , 3 , 47 , 4 , 47 , 5 , 47 , 6 , 7 , 47 , 8 , 9 , 10 , 11 , 10 , 12 , 1 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 5 , 2 , 6 , 21 , 22 , 23 , 24 , 25 , 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 14 , 6 , 7 , 41 , 42 , 43 , 44 , 45 , 23 , 46 , 38 , 48 , * , 6 , 7 , 20 , 48 , *
      Nature reviews. Endocrinology

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          Abstract

          This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

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          Most cited references285

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          2014 European Thyroid Association Guidelines for the Management of Subclinical Hypothyroidism in Pregnancy and in Children

          This guideline has been produced as the official statement of the European Thyroid Association guideline committee. Subclinical hypothyroidism (SCH) in pregnancy is defined as a thyroid-stimulating hormone (TSH) level above the pregnancy-related reference range with a normal serum thyroxine concentration. Isolated hypothyroxinaemia (defined as a thyroxine level below the 2.5th centile of the pregnancy-related reference range with a normal TSH level) is also recognized in pregnancy. In the majority of SCH the cause is autoimmune thyroiditis but may also be due to iodine deficiency. The cause of isolated hypothyroxinaemia is usually not apparent, but iodine deficiency may be a factor. SCH and isolated hypothyroxinaemia are both associated with adverse obstetric outcomes. Levothyroxine therapy may ameliorate some of these with SCH but not in isolated hypothyroxinaemia. SCH and isolated hypothyroxinaemia are both associated with neuro-intellectual impairment of the child, but there is no evidence that maternal levothyroxine therapy improves this outcome. Targeted antenatal screening for thyroid function will miss a substantial percentage of women with thyroid dysfunction. In children SCH (serum TSH concentration >5.5-10 mU/l) normalizes in >70% and persists in the majority of the remaining patients over the subsequent 5 years, but rarely worsens. There is a lack of studies examining the impact of SCH on the neuropsychological development of children under the age of 3 years. In older children, the evidence for an association between SCH and impaired neuropsychological development is inconsistent. Good quality studies examining the effect of treatment of SCH in children are lacking.
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            Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.

            Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas. CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6, 7). Because of its similarities to the McCune-Albright syndrome and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.
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              European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults.

              Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.

                Author and article information

                Journal
                101500078
                35765
                Nat Rev Endocrinol
                Nat Rev Endocrinol
                Nature reviews. Endocrinology
                1759-5029
                1759-5037
                13 May 2019
                August 2018
                29 May 2019
                : 14
                : 8
                : 476-500
                Affiliations
                [1 ]Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
                [2 ]Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
                [3 ]Imprinting and Cancer Group, Cancer Epigenetic and Biology Program (PEBC), Institut d’Investigació Biomedica de Bellvitge (IDIBELL), Barcelona, Spain.
                [4 ]Pediatric Endocrinology Unit, Department of Public Health and Pediatric Sciences, University of Torino, Turin, Italy.
                [5 ]Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Lübeck, Lübeck, Germany.
                [6 ]APHP, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Platform of Expertise Paris-Sud for Rare Diseases and Filière OSCAR, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.
                [7 ]APHP, Endocrinology and diabetes for children, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.
                [8 ]Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK.
                [9 ]IPOHA, Italian Progressive Osseous Heteroplasia Association, Cerignola, Foggia, Italy.
                [10 ]K20, French PHP and related disorders patient association, Jouars Pontchartrain, France.
                [11 ]APHP, Department of medicine for adolescents, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.
                [12 ]Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
                [13 ]Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, Gasthuisberg, University of Leuven, Leuven, Belgium.
                [14 ]AEPHP, Spanish PHP and related disorders patient association, Huércal-Overa, Almería, Spain.
                [15 ]Albright Center & Center for Rare Bone Disorders, Division of Pediatric Endocrinology & Diabetes, Connecticut Children’s Medical Center, Farmington, CT, USA.
                [16 ]Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA.
                [17 ]APHP, Department of Endocrinology, Cochin Hospital (HUPC), Paris, France.
                [18 ]University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
                [19 ]Department of Medicine, Division of Endocrinology and Centre for Bone Quality, Leiden University Medical Center, Leiden, Netherlands.
                [20 ]INSERM U1169, Bicêtre Paris Sud, Paris Sud – Paris Saclay University, Le Kremlin-Bicêtre, France.
                [21 ]APHP, Department of Endocrinology and Reproductive Diseases, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.
                [22 ]INSERM U1185, Paris Sud – Paris Saclay University, Le Kremlin-Bicêtre, France.
                [23 ]UK acrodysostosis patients’ group, London, UK.
                [24 ]Department of Genetics, Reference Centre for Rare Disorders of Calcium and Phosphate Metabolism, Caen University Hospital, Caen, France.
                [25 ]BIOTARGEN, UNICAEN, Normandie University, Caen, France.
                [26 ]APHP, Department of Odontology, Bretonneau Hospital (PNVS), Paris, France.
                [27 ]Department of Endocrinology and Nutrition, La Paz University Hospital, Madrid, Spain.
                [28 ]Department of Medicine, Autonomous University of Madrid (UAM), Madrid, Spain.
                [29 ]Endocrine Diseases Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
                [30 ]Division of Endocrinology and Diabetes and Center for Bone Health, Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
                [31 ]Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
                [32 ]Osteometabolic Disorders Unit, Hormone and Molecular Genetics Laboratory (LIM/42), Endocrinology Division, Hospital das Clínicas HCFMUSP, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
                [33 ]Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, CIBERobn, ISCIII, Madrid, Spain.
                [34 ]Department of Pediatrics, Autonomous University of Madrid (UAM), Madrid, Spain.
                [35 ]Endocrine Diseases Research Group, Hospital La Princesa Institute for Health Research (IIS La Princesa), Madrid, Spain.
                [36 ]Division of Endocrinology, Chiba Children’s Hospital, Chiba, Japan.
                [37 ]Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
                [38 ]Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain.
                [39 ]Department of Medicine, Mayo Clinic, Rochester, MN, USA.
                [40 ]Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
                [41 ]Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK.
                [42 ]Pediatric Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN, USA.
                [43 ]Departments of Orthopaedic Surgery and Genetics, Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
                [44 ]APHP, Service de Biochimie et Génétique Moléculaires, Hôpital Cochin, Paris, France.
                [45 ]Department of Pediatrics, Division of Endocrinology and Diabetes, Marmara University, Istanbul, Turkey.
                [46 ]Department of Internal Medicine, Bone Center Erasmus MC – University Medical Center Rotterdam, Rotterdam, Netherlands.
                [47 ]These co-second authors contributed equally: Murat Bastepe, David Monk, Luisa de Sanctis, Susanne Thiele, Alessia Usardi
                [48 ]These are co-last authors: Guiomar Perez de Nanclares, Agnès Linglart; all the other authors are listed in alphabetical order
                Author notes

                Author contributions

                G.P.d.N., G.M. and A.L. researched data for the article, contributed to discussion of content, wrote the article and reviewed and/or edited the manuscript before submission. M.B., D.M., L.d.S., Su.T. and A.U. researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission. S.F.A., R.B., T.C., G.D.F., G.D., T.E., A.G.R., E.L.G.-L., L.G., N.H., P.H., O.H., H.J., P.K., N.K., M.-L.K., E.L.N., B.L., M.A.L., O.M., R.M., G.A.M.-M., M.M., P.M., A.P., R.P, L.R., R.R., A.R., V.S., A.H.S., E.M.S., C.S., P.W. and M.C.Z. contributed to discussion of content and reviewed and/or edited the manuscript before submission. F.M.E., K.F. and Se.T. researched data for the article and reviewed and/or edited the manuscript before submission.

                Author information
                http://orcid.org/0000-0003-0689-5549
                http://orcid.org/0000-0002-4643-3843
                http://orcid.org/0000-0002-1480-1576
                http://orcid.org/0000-0003-2152-4247
                http://orcid.org/0000-0002-2424-5294
                Article
                NIHMS1021559
                10.1038/s41574-018-0042-0
                6541219
                29959430
                84dfb30b-d3ce-4ec8-a741-e67a88238603

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