Absence of TSH Receptor (TSHR) Gene Mutations in Severe Permanent Congenital Hypothyroidism Due to Apparent Athyreosis.

PAULA A, SCAGLIA; LAURA GRUÑEIRO DE PAPENDIECK; PATRICIA PAPENDIECK; LAURA PRIETO; HORACIO M. DOMENÉ; ANA CHIESA

Boston, Massachusetts

Congreso; 93th Annual Meeting of the Endocrine Society; 2011

The Endocrine Society

Resistance to TSH is a syndrome of reduced sensitivity to TSH, associated with molecular defects hampering the adequate transmission of the TSH stimulatory signal into the thyroid cells. The phenotype covers a wide spectrum of thyroid abnormalities going from mild hyperthyrotropinemia to severe congenital hypothyroidism (CH) with thyroid hypoplasia.Apparent athyreosis defined as negative 99Tc thyroid scan uptake with hypoplastic thyroid on ultrasound or detectable TG levels represents 7% of permanent CH detected in our neonatal screening program and 30% of those preliminarily classified as athyreotic.In order to search for mutations in TSHR gene, we retrospectively selected 19 CH patients (15 girls) with apparent athyreosis detected by the neonatal screening at a median age of 21 days (R:9-50) and confirmed as permanent CH with TSH >100 mU/l, median ( range ) T4: 1.0 ìg/dl (0.4-5.6 ) FT4: 0.2 ng/dl (0.11-0.64) T3: 57 ng/dl (19-109) TG: 34 ng/ml (1.8-81.5), negative anthythyroperoxidase (ATPO) and anti-thyroglobulin (ATG) antibodies, absence of thyroid image in a 99Tc scan, presence of a normally located hypoplastic thyroid gland on ultrasound and/or detectable serum TG. 99Tc thyroid scan and ultrasound were performed in the neonatal period and serum TSH, T4, FT4 and T3 were measured by EQLIA, ATPO and ATG antibodies by ICMA and TG by IFMA. The whole coding sequence of TSHR gene (exons 1 to 10) and intronic flanking regions were amplified by PCR from genomic DNA and automatically sequenced.Thirteen out of the 19 CH selected patients had negative 99Tc thyroid scan, positive ultrasound and median TG 32 ng/ml (1.8-65). The remaining 6 had negative 99Tc thyroid scan and ultrasound and TG levels of 45 ng/ml (6.8-81).Results: Analysis of TSHR gene sequence revealed 4 different SNPs in heterozygous state in 9 patients: 1 P52T (rs 2234919), 4 N187N (rs2075179), 2 D727E (rs1991517), 1 D727E / N187N and 1 D727E A459A (rs 113951800).No novel mutation or gene variants previously described to be associated with CH were found.Conclusion: TSHR gene mutations appear to be uncommon in severe permanent CH with apparent athyreosis in our population. Although a functional effect of TSHR polymorphisms could not be ruled out, previous studies of SNPs does not support this hypothesis. Other potential defect may include genes involved in TSH signaling and defects in NIS gene