TARGOVNIK Hector Manuel
A new compound heterozygous for c.886C>T/c.2206C>T [p.R277X/p.Q717X] mutations in the thyroglobulin gene as a cause of foetal goitrous hypothyroidism
Lugar: Malden; Año: 2011 vol. 74 p. 533 - 533
The identification of thyroglobulin (TG) mutations has contributed significantly to the understanding of the molecular pathogenesis of congenital hypothyroidism because of dyshormonogenesis, an autosomal recessive inherited disorder characterized by congenital goitre. Fifty-one germline mutations have been identified in the human TG. Although the incidence of TG mutations is still unknown in France, previous studies have reported four TG mutations in two compound heterozygous patients. In the first, a foetal goitrous hypothyroidism, the paternal mutation consisted of a cytosine deletion at nucleotide 1143 in exon 9 (c.1143delC), resulting in a frameshift which generated a stop codon at position 382 (p.G362fsX382), and the maternal mutation was a c.6725G>A in exon 38, creating the p.R2223H missense mutation in the acetylcholinesterase (ACHE)-homology domain of the TG. The second patient was heterozygous for a nonsense mutation because of a c.4588C>T at exon 22 [p.R1511X] (father’s mutation) and for a c.5386C>T at exon 27 [p.Q1777X] (mother’s mutation).2 The aim of the present study was to characterize a novel compound heterozygous for TG mutations in a French family with foetal goitrous hypothyroidism. In a 27-year-old white women, a foetal goitre was diagnosed coincidentally by ultrasound at the 22th week of gestation during her first pregnancy. The ultrasound examination showed enlargement of the goitre (thyroid circumference 105 mm; >99th percentile for gestational age), but foetal vitality and amniotic fluid volume appeared normal. There was no historical evidence of iodine deficiency in the family, and the parents were nonconsanguineous. The thyroid parameters of the mother when foetal goiter was diagnosed were in the normal range, with no circulating autoantibodies (anti-TPO, anti-TG and anti-TSH receptor). Percutaneous umbilical vein blood sampling under ultrasound guidance was performed at the 25th week of gestation, showing important foetal hypothyroidism with high serum TSH (384 mU/l; reference values 10.2 ± 3.8 mU/l) and low free T4 (5.2 pmol/l; reference values 13.10 ± 1.60 pmol/l) levels. An intra-amniotic injection of 180 ìg l-thyroxine was performed at the end of the 27th week, at the beginning of the 30th week and at the end of the 32th week of gestation. At the 33th week, thyroid circumference decreased to 76 mm. The woman had a caesarean delivery at the 34th week of gestation for foetal suffering and delivered a female infant with a weight of 1980 g, a body height of 40.5 cm and a cranial circumference of 30 cm with an Apgar score of 10 at 1 min. The neonate had a moderate asymmetric thyroid goitre with right predominance. Scintigraphy showed a normally located thyroid gland with a goiter which was confirmed by ultrasound imaging. The right lobe measured 22 · 15 · 8 mm and the left lobe 20 · 10 · 8 mm. The lack of a complete reduction of the foetal goitre after intra-amniotic treatment in our case is in perfect agreement with the observed in a recently published cohort of 12 treated foetuses.5 Intra-amniotic treatment led to a reduction in the size of the goitre in 90% of the cases, but complete reduction was never observed with l-thyroxine dosage ranging from 200 to 800 ìg per injection and number of injections from 1 to 6, thus indicating that the optimal management of this disorder was still to be determined. Thyroid functions tests in our patient indicated elevated TSH (359 mUI/l; reference values: 0.5–5.0 mUI/l), low free T4 (5.8 pmol/l, reference values: 10–25 pmol/l) and low normal free T3 (4.2 pmol/l, reference values: 4–7 pmol/l) levels and anti-TPO negative. The serum TG concentration was low (0.3 lg/l, reference values: >30 lg/l) suggesting that dyshormonogenetic goitre could be related to defective TG synthesis. Treatment with l-thyroxine drops was started at 4 days (15 ìg/kg per day). She had a very good compliance, and her growth was normal. She had been evaluated at the age of 4 using the Battery for Rapid Evaluation of Cognitive Functions (BREV), and her results were in normal range. Written informed consent was obtained from the parents, and the research project was approved by the Institutional Review Board. Sequence analysis of the TG gene revealed that the index patient was heterozygous for a previously documented nonsense mutation owing to a cytosine to thymine transition at nucleotide 866 in exon 7 (c.886C>T, mother’s mutation) in one allele and for a novel also cytosine to thymine transition at nucleotide position 2206 in exon 10 (c.2206 C>T, father’s mutation) in the other allele. The c.886C>T and c.2206 C>T mutations resulted in premature stop codons at amino acids 277 [p.R277X] and 717 [p.Q717X], respectively. The p.R277X mutation is the most frequently reported mutation in the TG gene, and affected individuals are either homozygous or compound heterozygous. The clinical spectrum of the homozygous patients ranges from moderate to severe goitrous hypothyroidism. This putative truncated protein of 276 amino acids eliminates eight repetitive units Type 1, from Type 1–4 to 1–11, all elements of Type 2 and Type 3 repetitive, and ACHE-homology domain of TG. These domains are also eliminated in the putative truncated protein p.Q717X, with the difference that the deletion of Type 1 domain is localized between repeat motifs Type 1–7 and Type 1–11. ACHE-homology domain may function as an intramolecular chaperone for the efficient transport of the TG to extracellular space. It has been demonstrated that the presence of a stop codon in the position 175 in the mouse TG still allows the secretion of a truncated protein. This observation suggests that the intracellular transport and the secretion capacity continue to work despite the complete deletion of ACHE-like region, as observed in the p.R277X and p.Q717X peptides. In our reported case, some foetal L-T4 are present at the 25th week of gestation, indicating that both early truncated TG proteins could be externalized to the thyroid follicles where the enzymatic iodinating machinery could iodinate the truncated TG proteins, which still harbour both the hormonogenic acceptor tyrosine 5 and the donor tyrosine 130. In conclusion, we here describe a French family in whom a new compound heterozygous constellation (p.R277X/p.Q717X) was identified in the TG gene as the underlying molecular defect for a foetal goitrous hypothyroidism. The prevalence of a limited number of mutations in each population will facilitate greatly the molecular genetic testing.