Abstract
SUMMARY: Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8-26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7-48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10-5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient. LEARNING POINTS: Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases. In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing. Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.