Novel TBX19 Mutation as Cause of Hypoglicemia in Two Siblings

Andrea Castagna; Arianna Bottero; Jessica Ruggiero; Anna Viola; Chiara Perrotti; Daniela Oprandi; Stefano Rossi; Raffaele Badolato; Maria Rosa Cutrì; Chiara Mingotti; Livia Grazzani; Fabio Buzi; Alba Pilotta

We describe a female neonate born from consanguineous parents who presented at birth with respiratory distress and severe hypoglycemia. At six months of age, the child was admitted to the Intensive care Unit because of two critical episodes characterized by fever and loss of consciousness. Child condition were critical and suggestive of sepsis, but blood tests showed severe hypoglycemia (19 mg/dl), hyponatremia (Na 132 mmol/l), compensated metabolic acidosis and increased inflammatory markers (CRP 209 mg/l, normal value <5, PCT 32.6 ng/ml, n.v. <2). During the hypoglycemia episode, endocrine analyses revealed low levels of ACTH (<5 pg/ml), cortisol (<1 mcg/dl) and basal GH (2.22 ng/ml), but normal thyroid hormones. The magnetic resonance imaging of brain and of the pituitary gland showed normal morphology. After diagnosis of central hypocortisolism we immediately started her on substitution therapy with hydrocortisone. During the follow-up the infant showed decreased growth velocity which was diagnosed as GH deficiency on the basis of low GH levels in response to arginine (GH = 4.21 ng/ml) and low IGF-1 levels (<25 ng/ml). At 14 months of life she was started on GH therapy. After two years, a second child was born in the same family: he presented at three hours of life with profuse sweating, severe hypoglicemia and persistent vomiting. Because of the family history, we performed blood tests which revealed isolated central hypocortisolism (ACTH <5 pg/ml, serum cortisol <1 mcg/dl), while basal GH, thyroid hormone levels and magnetic resonance imaging of brain and pituitary gland were normal. We started him on substitutive therapy with hydrocortisone with quick improvement of his clinical condition. Genetic analysis of the two siblings by using a specially constructed NGS panel revealed a novel homozygous mutation of TBX19 gene (c.269 T> C (Leu> Pro) of exon 2) in both of them and as heterozygous in their parent. Biallelic mutations of this gene are associated with congenital ACTH deficiency. This mutation, not previously described, affects a highly conserved region of the protein, and was reported as probably damaging suggesting that is most likely causative of the central hypocortisolism described in the two brothers.

ESPE Abstracts

P2-8