TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency

Objective: Congenital isolated ACTH deficiency (IAD) is a rare inherited disorder that is clinically and enetically heterogeneous. Patients are characterised by low or absent cortisol production secondary to low plasma ACTH despite normal secretion of other pituitary hormones and the absence of structural pituitary defects. Onset may occur in the neonatal period, but may first be observed in later childhood. Recently, mutations in the TPIT gene, a T-box factor selectively expressed in developing corticotroph cells, have been found in cases of early-onset IAD. Design: Here we report the screening of the TPIT gene in seven patients with IAD, four of whom had neonatal onset. Methods: Genomic DNA was extracted and the sequences of the 8 TPIT exons and their intron/exon junctions were determined by automated sequencing. Results: Two siblings with early-onset IAD were both compound heterozygotes for mutations in exons 2 and 6. The missense mutation (Met86Arg) in exon 2 within the T-box (or DNA binding domain) is predicted to disrupt DNA binding. A frameshift mutation in exon 6 (782delA) introduces a premature stop codon and is likely to lead to a non-functional truncated protein. No nucleotide changes were observed in exonic sequences in the other two early- or the three later-onset cases. Fifteen single nucleotide polymorphisms that were not predicted to change the TPIT transcript were also detected. Conclusions: These findings provide a further illustration of the genetic heterogeneity of IAD and are highly suggestive of one or more other genes being implicated in this disorder. © 2004 Society of the European Journal of Endocrinology.