Athanasia Stoupa1,2,3, Rim Chaabane4, Manelle Guériouz2, Catherine Raynaud-Ravni5, Patrick Nitschke6, Christine Bole-Feysot7, Mouna Mnif8, Leila Ammar Keskes4, Mongia Hachicha9, Neila Belguith4,10, Michel Polak1,2,3,11,12, Aurore Carré2,3. 1. 1 Pediatric Endocrinology, Diabetology, and Gynecology Department, Necker Children's University Hospital , Assistance Publique Hôpitaux de Paris, Paris, France . 2. 2 INSERM U1163, IMAGINE Institute , Paris, France . 3. 3 INSERM U1016, Cochin Institute , Paris, France . 4. 4 Laboratory of Human Molecular Genetics, Medicine School, University of Sfax , Sfax, Tunisia . 5. 5 Pediatric Endocrinology Department, Saint Etienne University Hospital , Saint Etienne, France . 6. 6 Bioinformatics Platform, INSERM U1163, IMAGINE Institute , Paris, France . 7. 7 Genomics Platform, INSERM U1163, IMAGINE Institute , Paris, France . 8. 8 Department of Endocrinology, CHU Hedi Chaker , Sfax, Tunisia . 9. 9 Department of Pediatrics, CHU Hedi Chaker , Sfax, Tunisia . 10. 10 Department of Medical Genetics, CHU Hedi Chaker , Sfax, Tunisia . 11. 11 Rare Growth and Development Diseases Center, Centre de référence des maladies endocriniennes rares de la croissance et du développement , Paris, France . 12. 12 Paris Descartes University , Sorbonne Paris Cité, Paris, France .
Abstract
BACKGROUND: Primary congenital hypothyroidism (CH) affects about 1:3000 newborns worldwide and is mainly caused by defects in thyroid gland development (thyroid dysgenesis [TD]) or hormone synthesis. A genetic cause is identified in <10% of TD patients. The aim was to identify novel candidate genes in patients with TD using next-generation sequencing tools. PATIENT FINDINGS: Whole exome sequencing was used to study two families: a consanguineous Tunisian family (one child with severe thyroid hypoplasia) and a French family (two newborn siblings, with a thyroid in situ that was not enlarged on ultrasound at diagnosis). Variants in candidate genes were filtered according to type of variation, frequency in public and in-house databases, in silico prediction tools, and inheritance mode. Unexpectedly, three different variants of the thyroid peroxidase (TPO) gene were identified. A homozygous missense mutation (c.875C>T, p.S292F) was found in the Tunisian patient with severe thyroid hypoplasia. The two French siblings were compound heterozygotes (c.387delC/c.2578G>A, p.N129Kfs*80/p.G860R) for TPO mutations. All three mutations have been previously described in patients with goitrous CH. In these patients, treatment was initiated immediately after diagnosis, and the effect, if any, of thyrotropin stimulation of these thyroids remains unclear. CONCLUSIONS: The first cases are reported of thyroid hypoplasia at diagnosis during the neonatal period in patients with CH and TPO mutations. These cases highlight the importance of screening for TPO mutations not only in goitrous CH, but also in normal or small-size thyroids, and they broaden the clinical spectrum of described phenotypes.
BACKGROUND:Primary congenital hypothyroidism (CH) affects about 1:3000 newborns worldwide and is mainly caused by defects in thyroid gland development (thyroid dysgenesis [TD]) or hormone synthesis. A genetic cause is identified in <10% of TD patients. The aim was to identify novel candidate genes in patients with TD using next-generation sequencing tools. PATIENT FINDINGS: Whole exome sequencing was used to study two families: a consanguineous Tunisian family (one child with severe thyroid hypoplasia) and a French family (two newborn siblings, with a thyroid in situ that was not enlarged on ultrasound at diagnosis). Variants in candidate genes were filtered according to type of variation, frequency in public and in-house databases, in silico prediction tools, and inheritance mode. Unexpectedly, three different variants of the thyroid peroxidase (TPO) gene were identified. A homozygous missense mutation (c.875C>T, p.S292F) was found in the Tunisian patient with severe thyroid hypoplasia. The two French siblings were compound heterozygotes (c.387delC/c.2578G>A, p.N129Kfs*80/p.G860R) for TPO mutations. All three mutations have been previously described in patients with goitrous CH. In these patients, treatment was initiated immediately after diagnosis, and the effect, if any, of thyrotropin stimulation of these thyroids remains unclear. CONCLUSIONS: The first cases are reported of thyroid hypoplasia at diagnosis during the neonatal period in patients with CH and TPO mutations. These cases highlight the importance of screening for TPO mutations not only in goitrous CH, but also in normal or small-size thyroids, and they broaden the clinical spectrum of described phenotypes.
Authors: Maricel F Molina; Patricia Papendieck; Gabriela Sobrero; Viviana A Balbi; Fiorella S Belforte; Elena Bueno Martínez; Ezequiela Adrover; María C Olcese; Ana Chiesa; Mirta B Miras; Verónica G González; Mauricio Gomes Pio; Rogelio González-Sarmiento; Héctor M Targovnik; Carina M Rivolta Journal: Endocrine Date: 2022-05-04 Impact factor: 3.925
Authors: Richard J Q McNally; Jeremy H Jones; Mohamad Guftar Shaikh; Malcolm D C Donaldson; Karen Blakey; Tim D Cheetham Journal: Thyroid Date: 2020-12-29 Impact factor: 6.568