Combined pituitary hormone deficiency (CPHD) with adult-onset corticotropin deficiency but without evidence for PROP-1 or HESX1 mutations
F Hammer1, S Hahner1, B Allolio1 & W Arlt1,2
Combined pituitary hormone deficiency (CPHD) denotes impaired production of growth hormone (GH) and of one or more other pituitary trophic hormones. Distinct subtypes of CPHD have been shown to be due to mutations in different homeobox transcription factors, which are involved in pituitary development and organogenesis. So far, only PROP-1 and HESX1 mutations have been associated with CPHD comprising corticotropin deficiency. Here we report two patients with a novel form of CPHD, presenting as late onset adrenal insufficiency. The first patient, a 61-year-old man, complained about fatigue and nausea gradually increasing over the last few months. He was of short stature (152 cm), had underdeveloped genitalia (G1) with complete absence of axillary and pubic hair (PH1), and a high-pitched voice. The second patient, a 67-year-old woman, presented with severe fatigue, nausea and recent onset of vomiting. On examination her height was 124 cm, she had a complete lack of axillary and pubic hair (PH1), and a history of primary amenorrhea. In both cases, hormonal evaluation revealed growth hormone deficiency, hypogonadotropic hypogonadism, mild secondary hypothyroidism and secondary adrenal insufficiency (cortisol increased from 1.0 to 11.0 and 1.0 to 4.2 micrograms per decilitre, respectively after corticotropin stimulation). However, baseline prolactin was within the normal range. MRI scans of the hypothalamic-pituitary region revealed pituitary hypoplasia without other gross abnormalities. PCR amplification and direct exon-by-exon sequencing of the homeobox transcription factors PROP-1 and HESX1 did not show any mutations in the coding region nor in the adjacent exon-intron-junction splicing sites. In conclusion, we identified a new entity of CPHD, which is defined by early onset of GH and gonadotropin deficiencies, normal serum prolactin, thyrotropin deficiency, followed by manifestation of secondary adrenal insufficiency during late adulthood. The underlying genetic defect leading to this form of CPHD remains to be elucidated.