Correct neonatal free thyroxine reference intervals are crucial to detect central congenital hypothyroidism

European Journal of Endocrinology, vol. 194, pp. 778–785

Abstract

OBJECTIVE: In the Netherlands, after an abnormal newborn screening (NBS) result suggestive of central congenital hypothyroidism (CH), children are referred for confirmatory plasma-free thyroxine (fT4) measurement. Correct interpretation of these results relies on appropriate age- and assay-specific reference intervals (RI), which are often not available. The current study was performed to check whether the use of adult or other incorrect fT4 RIs during the post-screening work-up of neonates with an abnormal NBS had led to missed diagnoses of central CH. DESIGN: Retrospective cohort study with prospective re-evaluation. METHODS: Children born between 1 March 2018 and 1 April 2021 with an abnormal NBS result suggesting central CH were identified through the Dutch national screening registry (NEORAH). Children classified as having a "false positive" screening result based on post-screening confirmatory fT4 concentrations in the neonatal period were included if those fT4 concentrations were ≤ 3 pmol/L above the assay-specific lower limit of the adult RI. After obtaining informed consent, re-evaluation of thyroid function was performed. RESULTS: Six children were identified and informed consent was obtained from four participants. Two out of four participants received a new diagnosis of central CH, including one case of multiple pituitary hormone deficiencies (MPHD). CONCLUSIONS: This study highlights the critical need for age- and assay-specific RIs for plasma fT4 to accurately diagnose central CH in the neonatal period.

Authors 7

1. Mark R. Garrelfs corresponding Aachen Department of Pediatric Endocrinology

   Emma Kinderziekenhuis · Amsterdam University Medical Centers · Endo-ERN · Amsterdam Gastroenterology Endocrinology Metabolism · Vrije Universiteit Amsterdam · University of Amsterdam

   Affiliation as printed

   Amsterdam Gastroenterology Endocrinology Metabolism , Meibergdreef 9, Amsterdam 1105 AZ ,

   Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Centers, European Reference Network on Rare Endocrine Conditions (Endo-ERN), University of Amsterdam and Vrije Universiteit , Meibergdreef 9, Amsterdam 1105 AZ ,

2. Peter Lauffer Aachen Department of Pediatric Endocrinology

   Amsterdam UMC Location University of Amsterdam · Emma Kinderziekenhuis · Amsterdam University Medical Centers · Endo-ERN · Amsterdam Gastroenterology Endocrinology Metabolism · Vrije Universiteit Amsterdam · University of Amsterdam

   Affiliation as printed

   Amsterdam Gastroenterology Endocrinology Metabolism , Meibergdreef 9, Amsterdam 1105 AZ ,

   Department of Clinical Genetics, Amsterdam UMC, Location University of Amsterdam , Meibergdreef 9, Amsterdam 1105 AZ ,

   Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Centers, European Reference Network on Rare Endocrine Conditions (Endo-ERN), University of Amsterdam and Vrije Universiteit , Meibergdreef 9, Amsterdam 1105 AZ ,

3. Jacquelien J Hillebrand

   Amsterdam UMC Location University of Amsterdam · Amsterdam Gastroenterology Endocrinology Metabolism · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Amsterdam Gastroenterology Endocrinology Metabolism , Meibergdreef 9, Amsterdam 1105 AZ ,

   Endocrine Laboratory, Department of Laboratory Medicine, Amsterdam UMC, Location University of Amsterdam and Vrije Universiteit , Meibergdreef 9, Amsterdam 1105 AZ ,

4. Annemieke C. Heijboer

   Amsterdam UMC Location University of Amsterdam · Amsterdam Gastroenterology Endocrinology Metabolism · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Amsterdam Gastroenterology Endocrinology Metabolism , Meibergdreef 9, Amsterdam 1105 AZ ,

   Endocrine Laboratory, Department of Laboratory Medicine, Amsterdam UMC, Location University of Amsterdam and Vrije Universiteit , Meibergdreef 9, Amsterdam 1105 AZ ,

5. Anita Boelen

   Amsterdam UMC Location University of Amsterdam · Amsterdam Gastroenterology Endocrinology Metabolism · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Amsterdam Gastroenterology Endocrinology Metabolism , Meibergdreef 9, Amsterdam 1105 AZ ,

   Endocrine Laboratory, Department of Laboratory Medicine, Amsterdam UMC, Location University of Amsterdam and Vrije Universiteit , Meibergdreef 9, Amsterdam 1105 AZ ,

6. A S Paul van Trotsenburg Aachen Department of Pediatric Endocrinology

   Emma Kinderziekenhuis · Amsterdam University Medical Centers · Endo-ERN · Amsterdam Gastroenterology Endocrinology Metabolism · Vrije Universiteit Amsterdam · University of Amsterdam

   Affiliation as printed

   Amsterdam Gastroenterology Endocrinology Metabolism , Meibergdreef 9, Amsterdam 1105 AZ ,

   Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Centers, European Reference Network on Rare Endocrine Conditions (Endo-ERN), University of Amsterdam and Vrije Universiteit , Meibergdreef 9, Amsterdam 1105 AZ ,

7. Nitash Zwaveling‐Soonawala Aachen Department of Pediatric Endocrinology

   Emma Kinderziekenhuis · Amsterdam University Medical Centers · Endo-ERN · Amsterdam Gastroenterology Endocrinology Metabolism · Vrije Universiteit Amsterdam · University of Amsterdam

   Affiliation as printed

   Amsterdam Gastroenterology Endocrinology Metabolism , Meibergdreef 9, Amsterdam 1105 AZ ,

   Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Centers, European Reference Network on Rare Endocrine Conditions (Endo-ERN), University of Amsterdam and Vrije Universiteit , Meibergdreef 9, Amsterdam 1105 AZ ,