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Compound Heterozygous Mutations in the Thyroglobulin Gene (1143delC and 6725GA [R2223H]) Resulting in Fetal Goitrous Hypothyroidism

Service d’Endocrinologie, Centre Hospitalier Universitaire Rangueil (P.C., D.M.), 31403 Toulouse, France; Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires (C.M.M., V.J.G., C.M.R., H.M.T.), 1120 Buenos Aires, Argentina; and Clinique Sarrus-Teinturiers (B.C.), 31076 Toulouse, France

Address all correspondence and requests for reprints to: Dr. Héctor M. Targovnik, Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Av. Córdoba 2351, 4^to piso-sala 5, 1120 Buenos Aires, Argentina. E-mail: htargovn{at}huemul.ffyb.uba.ar.

In a 22-yr-old healthy woman, a fetal goiter was diagnosed coincidentally by ultrasound during the sixth month of gestation, and hypothyroidism was affirmed by a high TSH (336 mU/liter) concentration after cordocentesis. A second ultrasound examination at 27 wk gestation showed further enlargement of the goiter (34/21 mm). Two intraamniotic injections of 200 µg levothyroxine were performed during the seventh month of pregnancy. Ultrasound studies revealed a fetal goiter size of 30/18 mm during the eighth month of gestation. The woman delivered at term a female infant with an Apgar score of 10 at 1 and 5 min. Cord blood analysis indicated elevated TSH (284 mU/liter) and low free T₄ (5.5 pmol/liter) levels. The serum thyroglobulin (Tg) concentration was low (0.8 ng/ml), whereas ultrasound of the neonate indicated an enlarged thyroid gland (32/15/14 mm). During the second pregnancy, ultrasound examination revealed a goiter, and fetal hypothyroidism was also confirmed after umbilical vein blood sampling (TSH, 472 mU/liter). After two intraamniotic injections of 500 µg levothyroxine, the woman delivered a male infant at 37 wk of pregnancy. In cord blood the serum TSH concentration was 39 mU/liter, and the serum Tg level was low (0.7 ng/ml). The parents were nonconsanguineous. After birth of the two affected siblings, genomic DNA sequencing identified the presence of compound heterozygous mutations of the Tg gene: the paternal mutation consists of a cytosine deletion at nucleotide 1143 in exon 9 (1143delC), resulting in a frameshift that generates a stop codon at position 382, and the maternal mutation is a guanine to adenine substitution at position 6725 in exon 38, creating the R2223H missense mutation in the acetylcholinesterase homology domain of Tg. In conclusion, we report two siblings with congenital goiter and hypothyroidism caused by compound heterozygous mutations of the Tg gene.

This work was supported by grants from Universidad de Buenos Aires (B 087/2001), Argentine National Research Council (0853/98), and Fondo para la investigación científica y tecnológica (05-08838/PICT 2000/2001).

P.C. and C.M.M. contributed equally to this study.

C.M.M. is a Research Fellow of the Universidad de Buenos Aires.

C.M.R. is a Research Fellow of the Argentine National Research Council.

H.M.T. is an Established Investigator with the Argentine National Research Council.

Abbreviations: ACHE, Acetylcholinesterase; d-, deoxy-; ER, endoplasmic reticulum; fT₄, free T₄; Tg, thyroglobulin; TPO, thyroperoxidase.

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