SFEBES2018 Featured Clinical Cases Featured Clinical Cases (10 abstracts)
Missplicing due to a silent exonic substitution in the T-box transcription factor TBX19 resulting in Isolated ACTH deficiency
Ashwini Maudhoo 1 , Avinaash Maharaj 1 , Federica Buonocore 2 , Gabriel Angel Martos-Moreno 3 , Jesús Argente 3, , John Achermann 2 , Li Chan 1 & Lou Metherell 1
1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK; 3Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación Sanitaria La Princesa, Universidad Autónoma de Madrid. CIBER obn. Instituto de Salud Carlos III, Madrid, Spain; 4IMDEA Food Institute, Madrid, Spain.
Background: 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 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. To date 25 mutations in TBX19 have been described, five of which are splicing mutations. The previously described splice mutations are all within canonical splice site motifs.
Patient and methods: We report a neonate of Romanian origin, who presented at 15 hours of life with respiratory arrest and hypoglycaemia. Over the following 2 weeks, recurrent hypoglycaemia was documented. On examination, he had normal male genitalia and no hyperpigmentation. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol <1 μg/dl; NR 7.8–26.2) and inappropriate plasma ACTH levels (22.1 pg/ml; NR 4.7–48.8). He responded to hydrocortisone treatment and continues on replacement. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. The effect of the novel mutation was assessed by an in vitro splicing assay, pET01 ExonTrap cloning vector (MobiTec), comparing wild type and mutant heterologous minigenes.
Results: A novel homozygous synonymous mutation p.Thr96= (g.1:168260482; c.288G>A; rs376493164; allele frequency 1x10−5, no homozygous) was found in exon 2 of the TBX19 gene. In an in vitro splicing assay, the mutation resulted in aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the wild-type vector spliced exon 2 normally.
Conclusion: We have identified a silent TBX19 mutation causing aberrant splicing as the likely cause of isolated ACTH deficiency 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.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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