Familial Combined Pituitary Hormone Deficiency Caused by <i>PROP-1</i> Gene Mutation

Abstract

Background: Mutations of the prophet of PIT-1 (PROP-1), a paired-like homeodomain transcription factor which is responsible for early embryonic pituitary development, have recently been reported as a cause of combined pituitary hormone deficiency. Methods: We describe the phenotype, long-term auxological data and MRI findings in two families with 4 affected members, all of whom have a mutation of the PROP-1 gene. GH, TSH, PRL, LH and FSH were completely deficient in all patients. Results: ACTH deficiency was not diagnosed until the 3rd or 4th decades of life. Pituitary MRI showed an empty sella in 2 subjects, but unspecific tissue accumulation resembling a pituitary mass lesion in another patient. The affected boy from family II who was continuously treated with all the necessary hormones reached the familial target height. However, the 3 subjects in family I were only treated sporadically (GH treatment lasting from 1 to 3 years). Conclusion: Despite this insufficient therapy, final height was in the lower normal range. Longitudinal growth continued up to the age of 40 years in these subjects.

Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects

“…Only two of seven adult patients required cortisol substitution in early adulthood. Therefore, the prevalence, age of onset and clinical significance of late-onset ACTH deficiency in patients with PROP1 gene defects remains a matter of controversy (17,23,26,27). From our data and published data, it may be concluded that late-onset ACTH deficiency may develop during the third or fourth decade of life in some affected individuals.…”

“…In those patients not diagnosed and treated in time, growth retardation progressed, leading to a mean height SDS of 2 4.1 at 5 years of age. The question of when GH deficiency manifests in patients with PROP1 gene defects is a matter of controversy (17,26,27). This longitudinal study indicates that growth retardation starts earlier than previously suggested, calling for initiation of GH therapy at young age.…”

Mutations and Pituitary Morphology in a Series of 82 Patients with <i>PROP1</i> Gene Defects

“…Thus, we included Czech patients from a population-based testing for genetic causes of pituitary insufficiency in childhood and adulthood [6], as well as pediatric and adult patients from Germany [16], Poland, Lithuania, and Russia. The study cohort was also complemented by several adult patients who originated from Austria [14]. Ethical review board approval was obtained, and all applicable regulatory requirements in the participating countries were followed.…”

“…The true nature, prevalence, and natural development of pituitary masses due to PROP1 mutations have so far been studied only in limited cohorts of patients [3,4,5,13,14,15,16,17,18,19]; therefore, we aimed to establish a representative group of affected patients allowing more detailed analysis over the lifespan.…”

PROP-1 Gene Mutation (R120C) Causing Combined Pituitary Hormone Deficiencies with Variable Clinical Course in Eight Siblings of One Jewish Moroccan Family

“…The hypothalamic-pituitary-adrenal axis of the 2 older sisters was intact. Although overt ACTH deficiency is uncommon in patients carrying PROP-1 mutations, studies have shown a tendency towards partial ACTH and cortisol deficiencies with age in some of them [4, 10, 11, 12, 13]. The hormonal insufficiency was not linked with the R120C mutation or other PROP-1 mutations, but was attributed either to the accumulation of amorphous material in the pituitary gland or to progressive apoptosis of the corticotropes due to lack of signals from other pituitary cell lineages.…”