PROP1 Gene Screening in Patients with Multiple Pituitary Hormone Deficiency Reveals Two Sites of Hypermutability and a High Incidence of Corticotroph Deficiency

Abstract

Alterations of the gene encoding the pituitary transcription factor PROP1 were associated with congenital forms of multiple pituitary hormone deficiencies in several families. Among 23 patients with multiple pituitary hormone deficiencies screened for a PROP1 gene abnormality, nine belonging to eight unrelated families had homozygous PROP1 gene defects. All mutations were located in exon 2 and affected only two different sites: a homozygous AG deletion at codons 99/100/101 (n = 5); homozygous point mutations affecting codon 73: R73C (n = 2) or R73H (n = 1), and a R73C/R99X double-heterozygous mutation (n = 1). R73H and R99X were never described. All patients were born to unaffected parents, and consanguinity was documented in two patients. They had complete GH, LH-FSH, and TSH deficiencies and normal basal levels of PRL. Delayed ACTH deficiency was diagnosed in four of nine patients. At magnetic resonance imaging the anterior pituitary was hypoplastic in seven patients and hyperplastic in two. This study found two novel mutations (R73H and R99X) and underlines the high incidence of PROP1 gene alterations in patients with multiple pituitary hormone deficiencies. A corticotroph deficiency was frequently observed in association with GH, TSH, and gonadotropin deficiencies and should be carefully sought during follow-up.

Novel Mutations in <b><i>HESX1</i></b> and <b><i>PROP1</i></b> Genes in Combined Pituitary Hormone Deficiency

“…Mutations were identified in 15% of all families, and specifically PROP1 mutations were identified in 15% of CPHD families, which is less than in many other studies [17,19,20,22]. Although the cohort is small, this lower rate of PROP1 mutations may result from the patient selection, where several patients had additional clinical characteristics not typical for PROP1 -associated hypopituitarism.…”

“…One of the characteristics is the progressive nature of pituitary hormone deficiencies [17], GH and TSH deficiencies being usually identified in the first decade of life and gonadotropin deficiency being apparent at puberty, with uncertain time of onset, while the function of corticotrophs may either remain normal or become deficient only in the teens or in adulthood [19,20,22]. Furthermore, dynamic changes in pituitary size, ranging from an enlarged pituitary resembling an adenoma to a hypoplastic gland, are specific for PROP1 -associated CPHD [21,22,29]. The novel p.Arg121Thr mutation in PROP1 is located in the third DNA-binding helix that is highly conserved in the DNA-binding homeodomain and was predicted by in silico tools to be damaging.…”

“…PROP1 mutations are implicated in non-syndromic CPHD which includes progressive GH, thyrotropin (TSH), prolactin (PRL) and luteinising hormone (LH)/follicle-stimulating hormone (FSH) deficiencies and in some cases adrenocorticotropin (ACTH) deficiency [17,18,19,20,21,22]. They are the most frequently identified genetic cause of CPHD, being found in some studies in 25-40% of unrelated CPHD patients [17,19,20,22], and are more common in familial cases with a frequency reported to be as high as 29-52.5% [17,19,20,21,23].…”

“…They are the most frequently identified genetic cause of CPHD, being found in some studies in 25-40% of unrelated CPHD patients [17,19,20,22], and are more common in familial cases with a frequency reported to be as high as 29-52.5% [17,19,20,21,23]. …”

Clinical Case Seminar. Peculiar prolactinomas in patients with pituitary developmental gene mutations: from an adult endocrinologist perspective

“…ValletteKasic et al 2001 reported normal baseline prolactin levels in eight of nine patients with PROP1 mutation, while in other studies normal prolactin levels were less frequent. 8,27,28 Lactotroph function may be maintained longer even when other deficiencies develop. 6 During the longitudinal follow-up of patients with PROP1 mutations (from 3-33 years) Bottner et al registered progressive decline of anterior pituitary function.…”