Endocrine Abstracts

Congenital isolated ACTH deficiency (IAD) is a rare inherited disorder that is clinically and genetically heterogeneous. Patients are characterised by low or absent cortisol production secondary to low plasma ACTH despite the absence of structural pituitary defects and normal secretory indices of other pituitary hormones. When tested, there is often no ACTH response to exogenous CRH. Onset may occur in the neonatal period, but often is first observed in later childhood. Candidate genes include proopiomelanocortin (POMC), prohormone convertase 1 (PC1), corticotropin releasing hormone (CRH) and its receptor (CRH-R1). POMC gene defects have been shown to result in a phenotype of ACTH deficiency combined with red hair and obesity. Recently mutations in the Tpit/Tbx19 gene, a T-box factor selectively expressed in developing corticotroph cells, have been found in cases of early onset IAD. In 2 cases the mutation introduced premature stop codons and in the other two cases the mutation caused amino acid substitutions in the Tpit transcript. Here we report the screening of the Tpit gene in seven patients with IAD, one of which had neonatal onset. Genomic DNA was extracted and the sequences of the 8 Tpit exons and their intron/exon junctions were determined by automated sequencing. No nucleotide changes were observed in exonic sequences. 15 single nucleotide polymorphisms (SNPs) were identified within intronic sequences in the regions analysed. None of these SNPs are predicted to cause a change in the Tpit transcript or splice variations. 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.