ESPE Abstracts

Of the several genetic defects responsible for thyroid dyshormonogenesis, mutations in TPO gene are the most prevalent causes of inherited defects in CH. Prevalent mutations are in exons 8-11 (catalytic site).

Case presentation: Girl, born at 16d after term, before the introduction of the neonatal screening, with asphyxia, BL 55 cm, BW 4 kg. Because of insufficient weight gain, feeding difficulties, prolonged jaundice she was referred to a pediatric endocrine clinic highly suspicious for congenital hypothyroidism (CH). At d 42 classical clinical signs of CH were fully present, the clinical diagnosis was confirmed by the hormonal constellation, a gland in situ was present as well (table). L-T4 treatment was introduced, the dosages increased gradually up to 75 μg/d. At 11 yrs the treatment was discontinued by the mother and permanent primary CH with an eutopic thyroid were reconfirmed. The therapeutic strategy changed (gradual increment of L-T4, not until ‘toxic’ dosages), a stable euthyroid situation was achieved, the adherence of the patient and the family improved. Normal growth and development, very good school and academic results were evident during the complex follow up including the entire transition period. The patient presents a suitable candidate for the hTPO study (permanent severe CH, eutopic thyroid, measurable Tg). A homozygous mutation c.1268G>A (p.Gly393Arg) and a heterozygous missense c.208C>G (p.Ala70Pro) were found by Sanger sequencing. The homozygous mutation is new, undescribed in the databases. A stop-gain mutation, with the functional consequence of a protein lacking the catalytic site and therefore inability of effective thyroid hormone synthesis (p.Gly393*Ter), on the same position has been described. The missense heterozygote c.208C>G (p.Ala70Pro) in exon 4 is a rare variant (Exac MAF=0.007) with unknown clinical significance and may also contribute to the phenotype as it is predicted as possibly damaging and deleterious by Polyphen and SIFT prediction programs.

Conclusions: Early molecular genetic studies are important for patients with primary CH and eutopic thyroid glands for refining the treatment strategy; increased risk for thyroid cancer should be kept in mind. Genetic consultation and possibilities for having healthy offsprings in patients diagnosed before screening introduction is nowadays part of the complex personalized care. The patient contributes to the genotype-phenotype data in CH due to hTPO mutations.