Combined pituitary hormone deficiency (including ACTH deficiency) due to genetic pituitary abnormalities is rare. ACTH and cortisol deficiency have been described in patients with multiple pituitary hormone deficiencies due to mutations in the PROP-1 (Prophet of Pit-1) gene, even though PROP-1 is not expressed in corticotropes. The onset of cortisol deficiency, which may be severe, ranges from childhood to late adulthood [ 2-5 ]. Mutations in other transcription factors involved in early pituitary development (HESX1, LHX4) also can result in variable degrees of hypopituitarism that include ACTH deficiency [ 6,7 ]. (See "Causes of hypopituitarism", section on 'Genetic diseases' .)
Buss et al. (2007) identified a heterozygous 1254G-T transversion in the SERPINA6 gene, resulting in the D367N substitution, in a 22-year-old Swiss male patient with severe muscle fatigue, usually after stressful events. Extensive biochemical and endocrine analysis showed decreased serum CBG and increased serum cortisol in response to ACTH or catecholamine administration. Investigation of other family members showed that the mutation occurred de novo on the paternal allele. Buss et al. (2007) proposed that SERPINA6 deficiency may act as an autosomal dominant disorder with incomplete penetrance, although a second pathogenic mutation could not be excluded.