Volume 21, Issue 3, September 2005

Table of Contents 21-3

Congenital ACTH Deficiency, Hypoglycemia and TPIT Gene Mutations

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Over the past decades congenital pituitary hormone deficiencies have been described in humans; corresponding animal models were also developed. Quite a number of transcription factor mutations have been reported. Of these, TPIT is the most cell-restricted transcription factor controlling the terminal differentiation of the corticotrophs. Mutations of the TPIT gene in humans are associated with congenital ACTH deficiency.

This is the first large report of a neonatal-onset form of congenital isolated ACTH deficiency (IAD). The authors described a series of patients (n=27) from 21 unrelated families. TPIT gene mutations, all of which affected coding sequences, were found in only 17 of the 27 patients. Ten different mutations were identified and their distribution indicated a recessive mode of transmission. It was also shown by functional studies of 4 missense mutations that there was a defect in the transcriptional ability with loss of DNA binding, a mechanism inducing a loss of function. The 10 remaining cases belonged to 8 different families who were consanguineous or had evidence of hereditary transmission of IAD.

In the group carrying TPIT gene mutations the diagnosis was made before the age of 2 years. Severe hypoglycemia led to the diagnosis of IAD. Furthermore, 11 out of 17 neonates presented prolonged neonatal cholestatic jaundice. These symptoms were suppressed by cortisol replacement therapy. Adrenarche did not occur at time of puberty. In patients without mutations the clinical picture was the same, however, there were some cases with milder disease who had evidence of some ACTH secretion, but it was insufficient to avoid hypoglycemia.

Therefore, congenital IAD, regardless of the molecular findings, presented with a homogeneous clinical phenotype. Consanguinity was observed in 5 of 13 families. Compound heterozygotes were also present, indicating that mutant alleles may be more frequent than expected in the population. It was concluded that the subgroup of IAD patients without mutations should be further investigated for loss-of-function of other genes.

Vallette-Kasic S, Brue T, Pulichino AM, et al. Congenital isolated adrenocorticotrophin deficiency: An underestimated cause of neonatal death, explained by TPIT gene mutations. J Clin Endocrinol Metab. 2005;90:1323−1331.

Editor’s Comment: This group, led by Drouin, presented their first paper in 2001 on TPIT, a pituitary cell restricted T-box factor, showing that mutations in this gene were associated with neonatal IAD.^1,2 These researchers now report that a large number of patients and families (some followed-up until puberty) showed lack of adrenarche. The presenting symptoms are characteristic of profound neonatal cortisol deficiency combining hypoglycemia and cholestatic jaundice. Thus, this entity should be considered in the array of causes of early adrenal insufficiency and be considered a neonatal emergency, easily controlled by cortisol treatment. The more puzzling issue is the group of patients who have no mutations in the coding sequence of the TPIT gene. However, their clinical presentation and management were not different.

Another issue is the severity of hypoglycemia causing neonatal death or mental retardation in survivors. Death occurred in 5 infants belonging to 5 families regardless of the presence of TPIT mutations. Therefore, congenital ACTH deficiency should be rapidly recognized. In affected families prenatal diagnosis should be performed, as in other genetic diseases with adrenal hypoplasia, by measuring maternal serum estriol levels during the third trimester of pregnancy.

In addition, it is of interest that a late onset form of IAD has been described with a presentation of cortisol deficiency without skin hyperpigmentation during childhood.³ In these cases, mutation of the TPIT gene could not be found. Here again, other genes contributing to this lineage differentiation and to ACTH secretion may be involved. We do not know whether these cases are somehow related to the early congenital form without identified mutations.

Raphaël Rappaport, MD

References - (linked to )

1. Lamolet B, Pulichino AM, Lamonerie T, et al. Cell. 2001;104:849−859.
2. Pulichino AM, Vallette-Kasic S, Couture C, et al. Genes Dev. 2003;17:711−716.
3. Metherell LA, Savage MO, Dattani M, et al. Eur J Endocrinol. 2004;151:463−465.

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