TBX19 – Congenital Isolated ACTH Deficiency

This summary reviews the association between TBX19 and congenital isolated adrenocorticotropic hormone deficiency (CIAD). Multiple independent case reports from 2017 to 2019 provide strong clinical evidence for a causative role of TBX19 mutations in CIAD. Several unrelated probands, including familial cases, have been identified with compound heterozygous or homozygous mutations in TBX19, establishing an autosomal recessive inheritance pattern (PMID:28458651, PMID:29858850, PMID:31057487, PMID:31998673). This genetic evidence, combined with clear segregation data, supports a strong gene-disease association.

Genetic analyses have revealed a diverse variant spectrum in TBX19. Among the reported mutations is the recurrent variant c.856C>T (p.Arg286Ter), which has been found in multiple families. The inheritance has been confirmed as autosomal recessive with additional affected relatives identified in segregating pedigrees. Besides nonsense mutations, other variant classes including frameshift and splice-site alterations contribute to the overall pathogenic spectrum.

Patients with TBX19 mutations typically present with isolated ACTH deficiency characterized by low cortisol and ACTH levels. The clinical phenotype is notable for recurrent lower respiratory tract infections, hypoglycemia, seizures, and occasionally cholestasis. These overlapping symptoms have been consistently reported across case studies and multi‐patient analyses, providing a robust clinical framework for diagnosis.

Functional studies have established that TBX19 mutations result in loss of function, primarily through impaired transcription of the pro-opiomelanocortin (POMC) gene. In vitro assays such as luciferase reporter analyses and splicing assays demonstrate that mutations like the synonymous change causing aberrant splicing and the c.856C>T (p.Arg286Ter) variant lead to non‑functional truncated proteins. These findings corroborate the clinical observations by linking molecular deficiency to the CIAD phenotype.

While a few studies have explored TBX19 in contexts beyond CIAD, the convergence of genetic and experimental evidence in CIAD cases minimizes any conflicting interpretations. The consistent documentation of TBX19 loss‑of‑function in affected individuals reinforces its clinical utility in diagnosing congenital isolated ACTH deficiency.

In summary, the robust evidence for TBX19 mutations causing CIAD—spanning clinical case reports, segregation analyses, and functional assessments—supports its use as a reliable diagnostic biomarker. Key take‑home message: TBX19 mutation testing should be integrated into the workup for patients with isolated ACTH deficiency to ensure prompt diagnosis and appropriate management.

References

• Frontiers in endocrinology • 2017 • A Novel TBX19 Gene Mutation in a Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Presenting with Recurrent Respiratory Tract Infections PMID:28458651
• Hormones (Athens, Greece) • 2018 • A rare cause of neonatal hypoglycemia in two siblings: TBX19 gene mutation PMID:29858850
• Frontiers in endocrinology • 2019 • A Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Caused by Two Novel Mutations in the TBX19 Gene PMID:31057487
• Frontiers in pediatrics • 2019 • Congenital Isolated ACTH Deficiency Caused by TBX19 Gene Mutation: A Family Report PMID:31998673
• Endocrinology, diabetes & metabolism case reports • 2021 • Missplicing due to a synonymous, T96= exonic substitution in the T‑box transcription factor TBX19 resulting in isolated ACTH deficiency PMID:34564059

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