Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations

J Clin Endocrinol Metab. 2012 Mar;97(3):E486-95. doi: 10.1210/jc.2011-1659. Epub 2011 Dec 14.


Context: Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTH and cortisol levels and preservation of all other pituitary hormones. This condition was poorly defined before we identified TPIT, a T-box transcription factor with a specific role in differentiation of the corticotroph lineage in mice and humans, as its principal molecular cause.

Objective: We have enlarged our series of IAD patients to better characterize the phenotype and the genotype of this rare disease.

Design: Each exon of the TPIT gene was amplified and sequenced in IAD patients without any identified cause. A functional analysis of each new TPIT mutation was performed.

Results: We described the largest series of 91 IAD patients and identified three distinct groups: neonatal onset complete or partial IAD or late onset IAD. We did not identify any TPIT mutation in patients with partial or late-onset IAD. However, we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD. These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers. We identified nine new mutations: four missense, one one-nucleotide deletion, three splice-site mutations, and one large deletion. TPIT mutations lead to loss of function by different mechanisms, such as non-sense-mediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects.

Conclusion: TPIT mutations are responsible for two thirds of neonatal-onset complete IAD but can not be detected in partial or late-onset IAD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenocorticotropic Hormone / deficiency*
  • Adrenocorticotropic Hormone / genetics
  • Adult
  • Child
  • Child, Preschool
  • Female
  • Genetic Diseases, Inborn / genetics*
  • Genotype
  • Homeodomain Proteins / genetics*
  • Humans
  • Hypothalamic Diseases / genetics*
  • Male
  • Phenotype
  • T-Box Domain Proteins / genetics*


  • Homeodomain Proteins
  • T-Box Domain Proteins
  • TBX19 protein, human
  • Adrenocorticotropic Hormone