Endocrine Abstracts

Case History: We present a 3-week-old baby who presented to a District General Hospital with prolonged unconjugated hyperbilirubinaemia and evolving developmental delay.

Investigations: Initial thyroid function demonstrated a TSH at 2.41 mIU/l (0.8-5.4), free T3 at 7.39 pmol/l (3.40–7.60) and free T4 at 9.9 pmol/l (11.0–23.6). The TFT was repeated using an alternative assay with FT4 at 11.8 pmol/l (11.5–28.3), FT3 at 9.20 pmol/l (3.00–9.30) and TSH at 3.1 mIU/l (0.72–11.0). On referral to the regional paediatric endocrine centre, the low T4 was investigated via a TRH stimulation test. TSH peak reached 5.24 mIU/L with a baseline at 1.94 mIU/L. T4 at the time of testing was 10.9 pmol/l (11.0–23.6). Given the modest rise in TSH in conjunction with a low T4, the patient was treated for secondary hypothyroidism with 25 micrograms levothyroxine. However, remaining pituitary function was normal. Ultrasound scan of the thyroid was normal. T4 normalised to 14.1 pmol/l, with TSH =0.03 mIU/L and T3 at 7.35 pmol/l. Repeat thyroid function 4 months later showed a similar pattern of TSH and T4 on levothyroxine 37.5 micrograms but a supraoptimal T3 (8.12 pmol/l). Concerns over developmental delay lead to an MRI, which showed a normal pituitary gland but neuronal hypomyelination. Further investigations included plasma amino, organic acids and biotinidase, urine oligosaccharides, CSF cell count, amino acids, viruses, lactate, glucose and protein all of which were normal. Thyroid peroxidase antibodies were negative.

Results and Treatment: The FT3 was normalised following reduction in the levothyroxine dose but suboptimal T4 and TSH. In view of the combination of hypomyelination and supraoptimal FT3 with normal FT4 on levothyroxine, genetic analysis was performed revealing a pathogenic hemizygous base change in exon 4 of SLC16A2 consistent with Allen-Herndon-Dudley Syndrome (AHDS). This mutation results in a deleterious alternation in the transporter protein monocarboxylate transporter 8 (MCT8), leading to developmental delay as the brain is starved of T3. Following on from a recent multicentre interventional trial (NCT02060474 and NCT02396459) using the thyroid hormone analogue TRIAC (3, 5, 3’-triiodothyroacetic acid), our patient was commenced on an escalating dose of TRIAC in an attempt to prevent further neurological deterioration.

Conclusions and Discussion: Unusually this diagnosis of AHDS was reached through the combination of high-normal FT3 which rose on levothyroxine treatment, developmental delay and hypomyelination. Normally, AHDS is diagnosed on presentation with high FT3.