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Julia A Baran Division of Endocrinology and Diabetes, The Thyroid Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Mya Bojarsky Division of Endocrinology and Diabetes, The Thyroid Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Stephen Halada Division of Endocrinology and Diabetes, The Thyroid Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Julio C Ricarte-Filho Division of Endocrinology and Diabetes, The Thyroid Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Amber Isaza Division of Endocrinology and Diabetes, The Thyroid Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Aime T Franco Division of Endocrinology and Diabetes, The Thyroid Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Lea F Surrey Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Tricia Bhatti Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Zubair Baloch Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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N Scott Adzick Department of Surgery, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Sogol Mostoufi-Moab Division of Endocrinology and Diabetes, The Thyroid Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Ken Kazahaya Division of Pediatric Otolaryngology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Andrew J Bauer Division of Endocrinology and Diabetes, The Thyroid Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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A Surrey LF McGrath C Bhatti T Jalaly J Mostoufi-Moab S , et al. Indeterminate thyroid fine-needle aspirations in pediatrics: exploring the clinicopathologic features and utility of molecular profiling . Hormone Research in Paediatrics

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Paolo Cavarzere Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy

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Laura Palma Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy

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Lara Nicolussi Principe Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy

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Monica Vincenzi Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
Regional Center for Newborn Screening, Diagnosis and Treatment of Congenital Metabolic and Endocrinological Diseases, Verona, Italy

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Silvana Lauriola Neonatal Intensive Cure Unit, Department of Pediatrics, University Hospital of Verona, Verona, Italy

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Rossella Gaudino Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy
Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy

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Virginia Murri Pediatric Division, Hospital of San Bonifacio, Verona, Italy

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Luigi Lubrano Pediatric Division, Hospital of Legnago, Verona, Italy

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Giuliana Rossi Pediatric Division, Hospital of Mestre, Venezia, Italy

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Alessia Sallemi Pediatric Division, Hospital of Venezia, Venezia, Italy

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Ermanna Fattori Pediatric Division, Hospital of Negrar, Verona, Italy

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Marta Camilot Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
Regional Center for Newborn Screening, Diagnosis and Treatment of Congenital Metabolic and Endocrinological Diseases, Verona, Italy

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Franco Antoniazzi Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy
Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
Regional Center for the Diagnosis and Treatment of Children and Adolescents Rare Skeletal Disorders, Pediatric Clinic, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy

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0029-7844(9800369-x ) 10 Underland L Kenigsberg L Derrick KM Crespi R Kaushal T Lam L . Thyroid function testing in neonates with maternal history of disease . Clinical Pediatrics 2018 57 436 – 441 . ( https://doi.org/10

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Yun Jeong Lee Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Republic of Korea
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea

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Young Hun Choi Department of Radiology, Seoul National University Hospital, Seoul, Korea

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Youn-Hee Lim Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
Environmental Health Center, Seoul National University College of Medicine, Seoul, Republic of Korea

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Bung-Nyun Kim Division of Children and Adolescent Psychiatry, Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea

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Johanna Inhyang Kim Department of Psychiatry, Hanyang University Medical Center, Seoul, Republic of Korea

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Yun-Chul Hong Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
Environmental Health Center, Seoul National University College of Medicine, Seoul, Republic of Korea
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

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Young Joo Park Department of Internal medicine, Seoul National University Hospital, Seoul, Republic of Korea
Department of Internal medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

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Choong Ho Shin Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Republic of Korea
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea

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Sun Wook Cho Department of Internal medicine, Seoul National University Hospital, Seoul, Republic of Korea
Department of Internal medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

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Young Ah Lee Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Republic of Korea
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea

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Yo MH , Korean National Growth Chart: review of developmental process and an outlook . Korean Journal of Pediatrics 2007 51 1 – 25 . 14 Du Bois D & Du Bois EF . A formula to estimate the approximate surface area if height and weight be

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Georgios K. Markantes Division of Endocrinology – Department of Internal Medicine, University of Patras Medical School, Patras, Greece

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Marina A. Michalaki Division of Endocrinology – Department of Internal Medicine, University of Patras Medical School, Patras, Greece

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George A. Vagenakis Department of Pediatric Cardiology and Adult Congenital Heart Disease, Onassis Cardiac Surgery Center, Athens, Greece

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Fotini N. Lamari Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, University of Patras, Patras, Greece

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Efthymia Pitsi Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, University of Patras, Patras, Greece

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Maria Eliopoulou Endocrinology Unit, Karamandanio Hospital, Patras, Greece

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Nicholas G. Beratis Department of Pediatrics, University of Patras Medical School, Patras, Greece

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Kostas B. Markou Division of Endocrinology – Department of Internal Medicine, University of Patras Medical School, Patras, Greece

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0091-6749 11 Beratis NG , Georgiou G , Eliopoulou M . Increased activity of lysosomal enzymes in the peritoneal fluid of bacterial peritonitis . Pediatrics . 2002 Mar ; 109 ( 3 ): E44 . 10.1542/peds.109.3.e44 11875172 0031

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Joke Marlier Department of Endocrinology, Ghent University Hospital, Ghent, Belgium

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Guy T’Sjoen Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
Department of Internal Medicine & Pediatrics, Ghent University, Ghent, Belgium

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Jean Kaufman Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
Department of Internal Medicine & Pediatrics, Ghent University, Ghent, Belgium

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Bruno Lapauw Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
Department of Internal Medicine & Pediatrics, Ghent University, Ghent, Belgium

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Introduction

Thyroid hormone replacement in central hypothyroidism (CHT) is more difficult than in primary hypothyroidism (PHT), putting patients at risk for inappropriate substitution. In this study, we compared the dosage of thyroid hormone replacement in patients with CHT with that of patients with PHT. In addition, we explored and compared quality of life (QoL) between both groups, based on two questionnaires, the SF-36 health score and the thyroid-specific ThyPRO score.

Methods

This is a monocentric, cross-sectional study, performed at the Ghent University Hospital (Belgium). We included 82 patients in total, 41 patients with CHT and 41 patients with PHT. At the time of inclusion, all patients had to have a stable dose of levothyroxine over the past 6 months and patients with PHT needed to be euthyroid (defined as having a thyroid-stimulating hormone level within the reference range, 0.2–4.5 mU/L). All data were retrieved from medical files, and questionnaires on QoL were self-administered.

Results

The CHT and PHT groups were comparable regarding age and BMI. There was no significant difference between both groups regarding total daily dose of levothyroxine (100 (93.75–125.00) vs 107.14 (75.00–133.93) μg in CHT and PHT, respectively; P = 0.87) or daily dose of levothyroxine per kg body weight (1.34 (1.16–1.55) vs 1.55 (1.16–1.82) μg/kg, respectively; P = 0.13). Serum levels of fT4 (P = 0.20) and fT3 (P = 0.10) also did not differ between the two groups and both were in the normal (mid)range for the two groups. Regarding QoL, patients with CHT scored worse in terms of depressive and emotional symptoms, impaired daily and social life.

Conclusion

We could demonstrate a difference in QoL between patients with CHT and PHT. Although patients with CHT had a somewhat lower levothyroxine substitution dose than patients with PHT, this difference was also not significant and probably does not explain the difference in QoL.

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Andrew J Bauer Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Department of Pediatrics, The University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Jonathan D Wasserman Division of Endocrinology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada

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Steven G Waguespack Department of Endocrine Neoplasia and Hormonal Disorders and Department of Pediatrics-Patient Care, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Kevin Stroek Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Annemieke C. Heijboer Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands

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Marja van Veen-Sijne Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Annet M. Bosch Division of Metabolic Disorders, Department of Pediatrics, Emma Children’s Hospital, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Catharina P.B. van der Ploeg Department of Child Health, Netherlands Organization for Applied Scientific Research TNO, Leiden, The Netherlands

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Nitash Zwaveling-Soonawala Department of Paediatric Endocrinology, Emma Children’s Hospital, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Robert de Jonge Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit & University of Amsterdam, Amsterdam, The Netherlands

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A.S. Paul van Trotsenburg Department of Paediatric Endocrinology, Emma Children’s Hospital, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Anita Boelen Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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hypothyroidism of thyroidal and central origin in a neonatal screening program . Pediatrics . 2005 ; 116 ( 1 ): 168 – 73 . http://dx.doi.org/10.1542/peds.2004-2162 . 5 Stroek K , Heijboer AC , Bouva MJ , van der Ploeg CPB , Heijnen MA

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Theodora Pappa Departments of Medicine, Chicago, IL, USA

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Lars C. Moeller Department of Endocrinology and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Deborah V. Edidin Department of Pediatrics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA

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Silvana Pannain Departments of Medicine, Chicago, IL, USA

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Samuel Refetoff Departments of Medicine, Chicago, IL, USA
Departments of Pediatrics, Chicago, IL, USA
Departments of Committee on Genetics, The University of Chicago, Chicago, IL, USA

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Background: Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, TBG (SERPINA7) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD). Objective: We report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago. Methods: Family 1: The proband was 12.6 years old when she presented for delayed puberty and was placed on L-T<sub>4</sub>. Although her serum TSH normalized, her serum T<sub>4</sub> remained low. Affected family members had low total T<sub>4</sub> and T<sub>3</sub>, but a normal free T<sub>4</sub> index, even when serum TSH concentrations were normal. Family 2: A 71-year-old male presented with a history of a nonfunctioning pituitary adenoma and normal pituitary axes except for low total T<sub>4</sub> and T<sub>3</sub>. His brother had a similar thyroid phenotype. Results: Following direct DNA sequencing, both index patients were found to carry a missense mutation in the TBG gene (c.751T>G) producing p.V215G. The proposita of family 1 was heterozygous and the proband in family 2 was hemizygous for the mutation. Isoelectric focusing showed no alteration in the TBG isoforms and in vitro expression demonstrated a TBG with reduced affinity for T<sub>4</sub>. Conclusions: We report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T<sub>4</sub> resulting in low serum T<sub>4</sub>. However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.

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Manassawee Korwutthikulrangsri Department of Medicine, University of Chicago, Chicago, Illinois, USA
Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

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Chrysoula Dosiou Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Alexandra M. Dumitrescu Department of Medicine, University of Chicago, Chicago, Illinois, USA
Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois, USA

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Samuel Refetoff Department of Medicine, University of Chicago, Chicago, Illinois, USA
Department of Pediatrics, University of Chicago, Chicago, Illinois, USA
Committee on Genetics, University of Chicago, Chicago, Illinois, USA

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Background: Resistance to thyroid hormone beta (RTHβ) is characterized by elevated thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), caused by thyroid hormone receptor beta gene (THRB) defects. Most mutations producing RTHβ phenotype are located in CG-rich regions of THRB, encoding the T3-binding and hinge domains of the receptor. However, a region encompassing codons 384–425 is virtually devoid of RTHβ-causing mutations, termed “cold region.” Case: A 49-year-old woman was diagnosed with Hashimoto thyroiditis in her twenties, and levothyroxine (LT4) was initiated. During LT4 treatment she had slightly elevated free thyroxine and TSH levels, suggesting the possibility of RTHβ. Results: Sequencing of THRB identified a heterozygous missense variant c.1154G>A producing p.G385E in the proband. Since this variant of unknown significance (VUS) has not been reported in RTHβ individuals and considering its location in the “cold region” of THRB, we questioned its relevance. In silico functional prediction algorithms showed conflicting results: PolyPhen-2 predicted this VUS to be probably damaging with a score of 1.000, while SIFT predicted it to be tolerated with a score of 0.07, thus making additional investigations necessary. Genotyping of family members revealed that the proband’s mother and sister, without RTHβ phenotype, also harbored the same variant. This indicates that the THRB G385E variant is unlikely to manifest RTHβ phenotype and confirms its “cold” status. Conclusions: This study illustrates that assigning causality of a THRB VUS for RTHβ based only on in silico prediction algorithms is not always fully reliable. Additional phenotype-genotype segregation in family members can assist in predicting functional consequences of missense mutations.

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Heleen I Jansen Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC location Vrije Universiteit Amsterdam, Boelelaan, Amsterdam, The Netherlands
Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, The Netherlands
Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC location University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands

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Marije van Haeringen Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC location University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
Department of Computer Science, Vrije Universiteit, Boelelaan, Amsterdam, The Netherlands

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Marelle J Bouva Reference Laboratory Neonatal Screening, Center for Health protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands

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Wendy P J den Elzen Department of Laboratory Medicine, Laboratory Specialized Diagnostics & Research, Amsterdam UMC, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
Amsterdam Public Health, Amsterdam, The Netherlands

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Eveline Bruinstroop Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, The Netherlands
Department of Endocrinology and Metabolism, Amsterdam UMC location University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands

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Catharina P B van der Ploeg TNO - Child Health, Sylviusweg, Leiden, The Netherlands

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A S Paul van Trotsenburg Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, The Netherlands
Department of Paediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands

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Nitash Zwaveling-Soonawala Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, The Netherlands
Department of Paediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands

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Annemieke C Heijboer Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC location Vrije Universiteit Amsterdam, Boelelaan, Amsterdam, The Netherlands
Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, The Netherlands
Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC location University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

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Annet M Bosch Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, The Netherlands
Department of Pediatrics, Division of Metabolic Disorders, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands

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Robert de Jonge Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, The Netherlands
Department of Laboratory Medicine, Amsterdam UMC, Vrije Universiteit, Boelelaan, Amsterdam, The Netherlands
Department of Laboratory Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands

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Mark Hoogendoorn Department of Computer Science, Vrije Universiteit, Boelelaan, Amsterdam, The Netherlands

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Anita Boelen Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, The Netherlands
Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC location University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

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://doi.org/10.1186/1750-1172-5-17 ) 2 Robertson EF Wilkins AC Oldfield RK & Pollard AC . Blood spot thyroxine-binding globulin: a means to reduce recall rate in a screening strategy for neonatal hypothyroidism . Journal of Pediatrics 1980 97 604

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