Endocrine Abstracts (2008) 16 P698

Absence of sonic hedgehog mutations in a large cohort of children with thyroid dysgenesis

Marina Muzza1, Tiziana de Filippis2, Roberto Gastaldi4, Giovanna Weber3, Renata Lorini4, Paolo Beck-Peccoz1, Luca Persani2 & Laura Fugazzola1


1Endocrine Unit, Department of Medical Sciences, University of Milan, Ospedale Maggiore IRCCS, Milan, Italy; 2Department of Medical Sciences, University of Milan and Istituto Auxologico IRCCS, Milan, Italy; 3Department of Pediatrics, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; 4Department of Pediatric Endocrinology, Ospedale Gaslini, Genova, Italy.


Thyroid dysgenesis accounts for 75% of all cases of congenital hypothyroidism (CH), and includes thyroid agenesis or hemiagenesis, thyroid hypoplasia, and thyroid ectopy. Thyroid transcription factors TTF-1, TTF-2 and Pax-8, which are involved in the development of the thyroid gland and its normal migration, have been indicated as the best candidate genes but have been found to be mutated in a minority of cases. Sonic Hedgehog (Shh) protein is involved in several key events during vertebrate embryogenesis, as well as left-right axis determination and organ development. In mice, Shh is expressed in cardiac bud and indirectly governs the symmetric bilobation of the thyroid. Shh knockout mice develop a single unilateral thyroid mass and ectopic thyroid tissue remnants from the presumptive trachea. The aim of this study was to investigate if mutations of SHH gene could be implicated in human thyroid dysgenesis.

The SHH gene has been analyzed in 23 cases of CH associated with thyroid ectopy. Three cases were of particular interest due to a particular dysgenetic phenotype: sublingual ectopy was associated with a thyroglossal duct cyst in one and with hemiagenesis in the second, the third patient was euthyroid with an in situ thyroid gland and an incidentally discovered intracardiac thyroid ectopy. The three coding exons of SHH have been amplified and directly sequenced, but no mutations have been detected. A novel silent polymorphism at codon 299 (CTG→CTC) has been found in one patient with isolated thyroid ectopy.

In conclusion, no germline mutations of SHH gene have been found in a large group of children with CH and thyroid ectopy. Though a key role in mouse thyroid development has been proposed, SHH defects may be rarely involved in the pathogenesis of isolated thyroid dysgenesis in humans.

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