ESPE Abstracts

Introduction: Neonatal screening has undoubtedly proved its worth in detecting cases of congenital hypothyroidism at an early stage. If there are several affected individuals in a family, this should be a reason to consider a hereditary form and to initiate molecular genetic testing.

Case descriptions: the firstborn sister (15 yrs) presented with grossly elevated TSH of 223 mU/ml in neonatal screening and with congenital goiter. After confirmation, therapy with L-Thyroxin was initiated and goiter regressed. The second sister (13 yrs) presented with congenital goiter and elevated TSH (48 mU/l) in neonatal screening, but initially normal fT3 and fT4. At day 10 of life TSH increased further (55 mU/ml) while fT3 and fT4 decreased, so she was also started on thyroxin. Because of the family history, the youngest sister (8 yrs) was tested for hypothyroidism immediately after birth. However, all thyroid parameters (TSH 4,3 mU/l; fT3 3,7 pg/ml; fT4 1,7 ng/dl) were normal. Ultrasound revealed a thyroid gland of normal size and homogenous texture. Regular monitoring of thyroid parameters showed a rise in TSH from the age of 8 years onwards and thyroxin therapy was initiated as well. Autoantibodies against TG or TPO have always been negative in all three patients. The parents are consanguine and without problems of the thyroid gland.

Molecular genetics: The finding of three intrafamilial cases of congenital hypothyroidism led us to initiate a molecular genetic analysis. Sequencing showed for all three sisters the same pair of mutations, homozygous for the two older sisters (severer forms of hypothyroidism) and heterozygous for the youngest one (milder form).

The genetic defect affects the gene coding for thyroglobulin and thus concerns the thyroid hormone synthesis pathway. According to the current state of knowledge, these mutations have so far been regarded as of unclear clinical significance. However, our three similarly affected sisters prove that the mutations are clinically relevant, though we can not estimate whether it is the combination or just one of the two mutations which ultimately is decisive.

Conclusion: 1) Familial cases of congenital hypothyroidism should be followed by molecular genetic testing. 2) Our three intrafamilial cases provide evidence, that the mutations c.3001+6T>Gp.? and c.5402G>Tp.(Ser1801Ile) which have hitherto been of unclear significance, are of clinical relevance causing congenital hypothyroidism.