SUN-275 A Rare Mutation in the TBX19 Gene Leading to Isolated ACTH Deficiency in Two Siblings

Hypoglycemia and hyperammonemia (>500µg/dl) in a newborn led to the suspicion of THAN (transient hyperammonemia of the newborn). Subsequently, hypoglycemic and salt losing episodes with low cortisol (<0,1 ug/dl) and ACTH (<0,16 pg/ml) levels pointed to ACTH deficiency. Genetic analysis showed a homozygous mutation c.302G>A for p.(Trp101*) in the TBX19 gene (a positive regulator of the transcription of POMC and the terminal differentiation of the corticotrophs), generating a premature stop codon. This mutation has been described only once and very recently by Abali et al (Hormones 18:229; 2019) in a 4 year old girl, but unlike our patients, this girl was obviously unaffected during her neonatal period. All other pituitary axes in our patient were normal, thus congenital isolated ACTH deficiency was the final diagnosis. Hyperammonemia resolved spontaneously and the suspected diagnosis of THAN could be dismissed. Hyperammonemia had probably been due to metabolic stress.After 16 months, a younger brother was born and showed hypoglycemia, hypotension and respiratory infection during his neonatal period. Cortisol and ACTH levels were also very low, thereafter, the same TBX19 mutation was detected.Both brothers were successfully treated with oral hydrocortisone substitution (6–10 mg/sqm/day q8 with increases during stress) and thrive well, except for several infections of the upper respiratory tract in the younger brother. In summary, we report the very rare condition of familial isolated congenital ACTH deficiency with a mutation of TBX19 that has never been described in newborns. Initial presentation may be accompanied by confounding pathological lab findings, while genetic analysis together with extremely low ACTH and cortisol levels confirm the correct diagnosis.