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G453(P) Uncommon aetiology of congenital hypothyroidism
  1. E Al-Zuhairi,
  2. A Jeyaraman,
  3. K Tharian
  1. Paediatrics, Northern Lincolnshire and Goole Hospitals NHS Foundation Trust, Scunthorpe, UK


Background Early detection and treatment of congenital hypothyroidism (CH) through newborn screening prevents neurocognitive disability and optimises developmental outcome. 85% of permanent cases of CH are due to thyroid dysgenesis and remaining is a result of dyshormonogenesis. The incidence of resistance to thyroid stimulating hormone (RTSH) is unknown. Mutations in Thyroid stimulating hormone (TSH) receptors are increasingly recognised as a cause of CH.

Case report We are reporting a case of CH secondary to RTSH. Congenital hypothyroidism was diagnosed through newborn screening test with raised thyroid stimulating hormone (TSH 10mU/l) confirmed by blood test (TSH 32mU/l, T4 12.5pmol/l). Thyroxine replacement therapy was commenced with regular adjustments based on clinical and laboratory follow up. His development remained normal and there were no signs or symptoms of hypothyroidism.

However, at age of 3 years with further increase to thyroxine dose in response to persistent raised TSH, he was noted to have symptoms of thyroxine overtreatment (abnormal behaviour, hyperactivity, aggression and sleep disturbances). Of note the grandmother was diagnosed with hypothyroidism on replacement thyroxine treatment.

Further evaluation for the aetiology of CH showed normal thyroid ultrasound scan excluding thyroid dysgenesis. A normal Isotope perchlorate discharge ruled out dyshormonogenesis. Genetic tests sequencing TSH receptor gene showed two heterozygous sequence changes in exon 10 of the gene.

  • A nonsense mutation, c. 1465C >T, p.(Gln489Ter) which has not been previously reported but is highly likely to be pathogenic mutation (missense changes of this amino acid have been previously reported as causing hypothyroidism)

  • A missense change, c.1748T >C, p.(Ile583Thr). This change has previously been described in association with mild hyperthyrotropinaemia.

In summary, the impression was that he has partial compensated RTSH congenital hypothyroidism as it was noted that free T4 drops to lower end of normal range when not on treatment. Therefore, he was advised smaller dose of thyroxine to maintain T4 at normal ranges and accept higher TSH levels. But parents reported recurrence of symptoms of overtreatment. At present, he is not on thyroxine but under careful monitoring of thyroid function, growth and development.

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