Adrenocorticotrope deficiency with clinical evidence for late onset in combined pituitary hormone deficiency caused by a homozygous 301-302delAG mutation of the PROP1 gene.

Combined pituitary hormone deficiency (CPHD) can be caused by mutation of the pituitary transcription factors POU1F1 or PROP1. More recently mutations in the HESX1, the LHX3 and LHX4 transcription factor genes have also been described as a cause in patients with CPHD. In most patients the disorder is characterized by an impaired production of GH, TSH, PRL and gonadotropins. In some cases of CPHD adrenocorticotropin deficiency is also present. We report the progressive CPHD and its molecular etiology in a woman with CPHD presenting with first symptoms of ACTH/cortisol deficiency at the age of 48 years. The 49 year old patient's initial symptoms were growth retardation at the age of 2 years and symptoms of hypothyroidism at the age of 5 years. The patient never entered puberty spontaneously. No familial history of delayed puberty, growth retardation or other symptoms of CPHD were present. At the age of 48 years the patient presented with the first symptoms of hypocortisolism such as recurring hypoglycaemias and hyponatriaemia with coma. Cortisol, ACTH, TSH, fT3, fT4 and GH as well as LH, FSH and PRL were measured in basal conditions. GH, cortisol and ACTH were also measured in response to an Insulin Tolerance Test. Molecular analysis was performed by PCR amplification and sequencing of exon 1-3 of the PROP1 gene. The patient had insufficiencies of TSH, LH, FSH and GH. PRL was normal. Serum cortisol was low and basal ACTH was normal. However, there were no responses of cortisol, ACTH and GH to hypoglycaemia. Magnetic resonance imaging showed a hypoplastic anterior pituitary lobe. Direct sequencing revealed a homozygous 2 base-pair deletion 301-302delAG in exon 2 of the PROP1 gene. This case suggests that in patients with CPHD ACTH producing cells may be involved at a rather late age.