A Novel TBX19 Gene Mutation in a Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Presenting with Recurrent Respiratory Tract Infections

Abstract

IntroductionCongenital isolated adrenocorticotropic hormone deficiency (CIAD) is a rare disease characterized by low adrenocorticotropic hormone (ACTH) and cortisol levels. To date, recurrent pulmonary infections in infancy have not been reported as an accompanying symptom of CIAD.Case presentationA 7-year-old boy was hospitalized nine times for recurrent lower respiratory tract infections. The results of all tests for the possible causes of wheezing were within the normal limits. His ACTH and cortisol levels were persistently low. All other pituitary hormone levels, and adrenal ultrasound and pituitary magnetic resonance imaging results, were normal. Molecular analyses confirmed the diagnosis of CIAD by identifying compound heterozygosity for two mutations in the TBX19 gene. The first was a novel frameshift c.665delG variant in exon 4 of the TBX19 gene, leading to premature termination that was predicted to result in a non-functional truncated protein. The second was a nonsense C-to-T transition in exon 6 of the TBX19 gene, resulting in an arg286-to-ter mutation (dbSNP: rs74315376). Both parents were heterozygous for one of the mutations.ConclusionHere, we presented a new mutation in the TBX19 gene in a patient with CIAD who presented with recurrent respiratory tract infections. This expands the mutation spectrum in this disorder. To conclude, adrenal insufficiency should be considered in patients with unexplained recurrent infections to prevent a delay in diagnosis.

Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency

“…The initial descriptions of the disease reported homogeneous phenotypic features for patients with TBX19 mutations. However, as we learn more about the disease, different genotype–phenotype relationships have been observed with presentations such as recurrent respiratory infections as well as Chiari type 1 malformation, tall stature and dysmorphic features ( 6 , 7 ). Differences in presentations emphasise the need for genetic characterisation as unrecognised and untreated congenital IAD can be life-threatening.…”

A Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Caused by Two Novel Mutations in the TBX19 Gene

“…Reference values for routine laboratory testing of ACTH and cortisol are about 1.6–13.9 pmol/L and 193.2–690 nmol/L, respectively (3, 10, 11). In three recent cases, ACTH and cortisol levels in the plasma were very low, which were lower than lower limit of the reference value and perfectly consistent with routine laboratory test (3, 11). In our case, the plasma level of cortisol was <25.7 nmol/L, which is less than the lower limit of reference value.…”

“…CIAD can result in 20% mortality in the neonatal period if unrecognized (2). CIAD is an autosomal recessive inherited disease that is caused by homozygous or compound heterozygous mutations in the TBX19 (MIM 604614) (3). The protein of TBX19 , located on chromosome 1q24, is a member of T-box family, which has crucial roles throughout development (4).…”

Development of the Pituitary Gland

“…The progenitors of the hormone-secreting cell types proliferate ventrally from the pouch between E12.5-17. 5 and populate what will form the anterior lobe Ward et al, 2006). The remnants of the dorsal portion of the pouch will form the intermediate lobe, whilst the lumen of the pouch remains as the pituitary cleft, separating the intermediate from the anterior lobe (Rizzoti and Lovell-Badge, 2005).…”

“…The authors concluded that patients with unexplained recurrent infections should be tested for adrenal insufficiency to prevent a delay in diagnosis and possible fatal consequences (Akcan N et al, 2017). (Budry et al, 2012).…”