Endocrine Abstracts

Although congenital hypothyroidism is sporadic in the majority, recessive and X-linked inheritance can also occur in monogenic disorders. In familial cases, the finding of genetic variation could identify specific phenotypes and unravel thyroid pathobiology.

We describe three siblings born to non-consanguineous parents. The index case, a boy, presented at 1 year of age with severe developmental delay, expressive aphasia and hypotonia. Thyroid function showed elevated TSH and fT3 levels, with fT4 being in the normal range. Thyroid ultrasound scan was normal and anti-TPO antibodies and anti-TSH-receptor antibodies were negative. He was treated with levothyroxine with reduction in TSH levels. A similar clinical phenotype was present in his younger brother, who was also treated with levothyroxine. Their elder sister had borderline hypothyroidism with elevated fT3 levels and mild learning disability. Genetic investigations excluded mutations in MCT8, MCT10, TRa1 T3 and Dio3 mutations. High resolution hybridisation arrays and next generation sequencing identified a hemizygous mutation in an X-linked gene in all children and their mother.

This X-linked gene mutation is associated with intellectual disability, short stature and behavioural issues, as observed in the family. However, a thyroid phenotype has not been reported. It would be important to recognise abnormal thyroid function in children with X-linked intellectual disability. The mechanism by which this mutation may cause thyroid dysfunction remains to be established, although we hypothesise a role in thyroid hormone transporters, as the phenotype is similar to children with MCT8 mutations.