A Rare Cause of Adrenal Insufficiency – Isolated ACTH Deficiency Due to TBX19 Mutation: Long-Term Follow-Up of Two Cases and Review of the Literature

Abstract

• Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare disorder that can cause severe hypoglycemia, convulsions, and prolonged cholestatic jaundice. • Mutations in TBX19 are responsible for 65% of neonatal onset IAD which can result in 25% mortality in the neonatal period if not treated. • Further cases or functional analyses are needed for genotype-phenotype correlations of the mutations described thus far. Novel Insights • TBX19 deficiency is a rare cause of adrenal insufficiency; there is limited knowledge about this lifethreatening disease and we wanted to increase awareness of it. • We present 2 patients, 1 with a novel and 1 with a reported mutation. • Data on long-term follow-up of IAD patients are scarce. We present our experience with the long-term follow-up and growth patterns of 2 patients with TBX19 mutation. • Low bone mineral density, dysmorphic features, Chiari type 1 malformation, and sparse pubic hair were important and interesting features in our patients.

A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin

“…This point is noteworthy because four recently reported cases were diagnosed in older children, up to 5 years of age. However, the medical history of these patients (repeated hospitalizations and hydrocortisone treatment) suggests that IAD symptoms were already present before 1 year of age ( 5 – 7 , 10 ).…”

“…However, since autosomal recessive diseases are typically associated with consanguinity, other genetic defects cannot be excluded. Extrapituitary malformations, including a Chiari I malformation ( 1 , 5 ) and microcephaly ( 5 ), have been reported in other cases of TBX19 mutation. One of our patients had scaphocephaly (1/4) and two had cardiac valve defects (a bicuspid aortic valve, mitral regurgitation).…”

“…Avoiding decompensation and repeated severe hypoglycemic or hyponatremic episodes is essential for the outcomes of these children, especially in the first years of life. Indeed, one of the main consequences of undiagnosed adrenal crises and inadequately adjusted hydrocortisone treatment in IAD due to TBX19 mutations is cognitive impairment ( 2 , 4 , 5 , 20 ). Early diagnosis, close clinical monitoring in specialized centers and multiple therapeutic education sessions for parents are critical to avoid brain damage.…”

“…Since the description in 2012 of a series of 91 IAD patients with 21 pathogenic variants ( 1 ), 13 other mutations have been described in patients with IAD, mostly as individual cases, and six further mutations have been reported in public databases (ClinVar, LOVD, HGMD) ( 5 – 16 ). TBX19 mutations are distributed across all exons other than exon 8 and all types of pathogenic variants have been described, including missense and truncating mutations (nonsense or indel frameshifts, larger deletions of one or several exons, or intronic mutations affecting splicing), in homozygous or compound heterozygous state.…”

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.…”