ESPE Abstracts (2015) 84 P-3-1171

A Familial Case of Congenital Hypothyroidism due to a Mutation in the Thyroglobulin Gene Detected by Next Generation Sequencing

Maria Cristina Vigonea, Elena Peronia, Gaia Vincenzia, Giulia Gelminib, Tiziana de Filippisb, Fulvio Sileod, Luca Persanib,c & Giovanna Webera


aDepartment of Pediatrics, San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; bLaboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy; cDepartment of Clinical Sciences and Community Health, University of Milan, Milan, Italy; dDepartment of Endocrinology, Papa Giovanni XXIII Hospital, Bergamo, Italy


Background: Congenital hypothyroidism (CH) is a heterogeneous disorder. While the great majority of cases are considered sporadic, the use of next generation sequencing (NGS) may bring significant advances in elucidating the underlying molecular mechanisms.

Case presentation: We selected a family with three children affected by CH with gland in situ and diagnosed at neonatal screening: the index patient, his sister and his brother. Data at diagnosis and follow-up are listed in the Table 1. They present an important familiarity for thyroid diseases. The mother and her sister have a multinodular goiter in euthyroidism without anti-thyroid antibodies; the mother’s thyroglobulin (TG) level is 126 ng/ml (range 0–60 ng/ml). In addition, the maternal grandfather developed a multinodular goiter with a Plummer adenoma requiring thyroidectomy. All family members have an adequate dietary iodine intake. NGS analysis revealed a heterozygous missense mutation (p.P118L) in the TG gene of the three siblings and of their mother. The other analyzed genes (NKX2-1, PAX8, FOXE1, GLIS3, DUOX2, DUOXA2, SLC26A4, TPO, TSHR, and JAG1) resulted WT.

Table 1 (for abstract P3-1171)
PatientI spot TSH (mcIU/ml)Serum TSH (mcIU/ml)Serum FT4 (ng/dl)Thyroglobulin (ng/ml)USL-thyroxine therapy at diagnosisRe-evaluationRange of TSH values without therapy (mcIU/ml)
Index patient (2013)10.0116.9–11.071.2–1.07189 (0.2–55)NormalNoNo5.6–11.7
Sister (2005)12.542.81.15148 (0.2–55)NormalYesStopped L-T47.32–14.71
Brother (2002)10.719.511.134.8 (1–75)NormalYesStopped L-T46.39–10.25

Conclusions: According to the identification of the genetic variant in TG with a strong positive family history for multinodular goiter, an adequate ultrasound follow-up and a tailored therapeutic strategy are needed. Indeed, these patients could benefit from hormone replacement therapy with levothyroxine, even in case of a mild increase in TSH concentrations, in order to avoid thyroid surgery in the future.