ESPE Abstracts

Background: Central congenital hypothyroidism (CCH) is a rare disorder. It may be a component of multiple pituitary hormone deficiency or (more rarely) represent an isolated entity, for which several monogenic causes are described.

Aims: We report here a case of severe hypothyroidism caused by a novel homozygous variant in the TSHB gene.

Results: The proband, a male from a consanguineous family of Turkish ancestry, was born at the 41st week of gestation with the weight 4560 g and the length 56 cm. At 3 months a delay of motor development became evident. Investigations for suspected congenital myopathy and inborn errors of metabolism revealed no positive findings. At 7 months, the patient presented with macroglossia, muscle weakness, severe developmental delay and oedema. His height was 59 cm (SDS=-4.5), the weight 7.4 kg (BMI SDS=2.3). Serum fT4 was below the limit of detection of 5.0 pmol/L, TSH was 0.001 mU/L. Levothyroxine 50 ug/day resulted in rapid disappearance of macroglossia and oedema and improvement of psychomotor development. At 10 months the height was 73 cm (SDS=-0.7), the weight 10 kg (BMI SDS=0.9), serum fT4, 13.1 pmol/L. DNA sequencing showed a novel homozygous NM_000549.5: c.152G>A variant predicted to cause p.Cys51Tyr substitution in the TSHβ. Cys51 is the last residue of the highly conserved CAGYC region of TSHβ, which in turn is a core part of the so-called cysteine knot sequence, essential for the structural integrity of glycoprotein hormones.

Conclusions: In conclusion, we described a case of CCH caused by a novel homozygous variant affecting the third cysteine knot residue of TSHβ. The case confirms the association of pathogenic TSHB variants with severe clinical presentation of congenital hypothyroidism.