ESPE Abstracts (2014) 82 P-D-1-1-239

Genotype and Phenotype Characterization of a Series of Italian Patients Affected with Idiopatic Central Hypothyroidism

Marco Bonomia, Paolo Duminucoa, Alessandro Salvatonib, Mario Maggic, Fabio Buzid, Alba Pilottae, Giorgio Radettif, Paolo Beck-Peccozg, Irene Campig, Nadia Schoenmakersh, Sjoerd Joustrai,j, Jan Maarten Witi, Daniel Bernardk, Luigi Nespolib, Mauro Bozzolal & Luca Persanig


aLaboratorio di Ricerche Endocrino-Metaboliche e Divisione di Medicina ad indirizzo Endocrino-Metabolico, Milano, Italy; bDipartimento di Pediatria, Università dell’Insubria, Varese, Italy; cDipartimento di Fisiopatologia Clinica, Università di Firenze, Firenze, Italy, dDipartimento di Pediatria, Ospedale A.Poma, Mantova, Italy; eDipartimento di Auxo-Endocrinologia, Spedali Civili di Brescia, Brescia, Italy, fDipartimento di Pediatria, Ospedale Regionale di Bolzano, Bolzano, Italy; gDipartimento di Scienze Cliniche e di Comunità, Università di Milano, Milano, Italy; hMetabolic Research Lab, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK; iDepartment of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; jDepartment of Endocrinology and Metabolism and Center for Endocrine Tumors Leiden, Leiden University Medical Center, Leiden, The Netherlands; kDepartment of Pharmacology and Therapeutics, McGill University Montreal, Montreal, Quebec, Canada; lDipartimento Materno-infantile, Policlinico San Matteo, Pavia, Italy


Background: Central hypothyroidism (CeH) is a rare thyroid hormone deficiency due to an insufficient stimulation of a normal thyroid gland. Candidate genes for isolated CeH include TSHβ, TRH receptor (TRHR) or IGSF1 genes while the combined pituitary hormone deficits (CPHDs) are the consequence of defects in embryonic pituitary transcription factors or in the prokineticin receptor 2 (PROKR2).

Patients series: Here we report nine males (M) and 15 females (F), with CPHD in three cases and Isolated CeH in the remaining 21 and affected with low/normal TSH levels and low free T4 levels. Familiarity was previously known in only two cases.

Results: In 1M and 2F that were negative at neonatal TSH screening, severe congenital hypothyroidism was diagnosed at 44 or 81 days or 4 months, while other patients with milder forms were diagnosed during childhood or adulthood (2–58 years). All had a normal pituitary MRI, but two with a partial empty sella and other two with pituitary hyperplasia or a microlesion. Their history was invariably negative for traumatic or ischemic brain injuries. Thyroid ultrasound did not uncover any sign of thyroid autoimmunity and thyroid autoantibodies were negative in all cases. Among the eight cases presenting with blunted TSH responses to TRH stimulation but normal PRL increases we had detected two homozygous mutations in the TSHβ gene (Q49X e IVS2+5) in two neonates (1F and 1M) associated with severe hypothyroidism. Two mutations of the TRHR gene (R17X) and two mutations in the IGSF1 gene (E1200fsX3; S770N) were found in 3M and 1F having an absent TSH/PRL responses after TRH stimulation. In all the three cases with CPHDs we identified a genetic cause: 2 cases were associated with PROP1 defects (1M was heterozygous for a novel variant, R104Q, whereas 1F was homozygous for the known R73H variant), whereas we identified a heterozygous PROKR2 variant (H20MfsX23) in a 58-year-old male patient.

Conclusion: In the present series, we identified a genetic cause in eight out 24 CeH subjects. Since genetic variations were identified in all three CPHD cases, the pathogenesis remains unexplained in the majority of patients with isolated CeH.