Pituitary Magnetic Resonance Imaging and Function in Patients with Growth Hormone Deficiency with and without Mutations inGHRH-R,GH-1, orPROP-1Genes

Abstract

Pituitary stalk interruption and ectopic posterior lobe on magnetic resonance imaging (MRI) are frequently observed in patients with GH deficiency (GHD), but their pathogenesis remains controversial. We performed pituitary stimulation tests, MRI, and studied GH-1, GHRH receptor (GHRH-R), and Prophet of Pit-1 (PROP-1) genes in 76 patients with GHD. Of 33 patients with isolated GHD, 4 had GH-1 deletions and 4 had GHRH-R mutations; of 43 patients with combined pituitary hormone deficiency, 1 had PIT-1 and 5 had PROP-1 mutations. Compared with the 62 patients without mutations, 14 patients with mutations had higher frequency of consanguinity (57 vs. 2%, P < 0.001), familial cases (21 vs. 3%, P < 0.05), and lower frequency of breech delivery or hypoxemia at birth (0 vs. 39%, P < 0.005). On MRI, all patients with mutations had an intact stalk, whereas it was interrupted or thin in 74% without mutations (P < 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations against 13% without mutations (P < 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP-1 and PIT-1 mutations and suggestive of hypothalamic origin in 81% without mutations. Perinatal insults were associated with thin/interrupted pituitary stalk, ectopic posterior lobe, and hypothalamic origin of hormonal deficiencies. In contrast, GH-1, GHRH-R, and PROP-1 mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. We conclude that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiological diagnosis of GHD.

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

“…The patients with EPP showed no mutations in the genes studied (HESX1, LHX4, and PROP1) and this is compatible with the rarity of PTF mutations found in patients with EPP (10,15,20,33,34). Perhaps other developmental genes yet to be identified may be involved in the etiology of EPP, or another pathogenic mechanism could be responsible for this abnormality (35,36).…”

Unusual Phenotypic Features in a Patient with a Novel Splice Mutation in the GHRHR Gene

“…It was thought that patients with a GHRHR molecular defect invariably have anterior pituitary hypoplasia (15,(25)(26)(27)(28)(29), and that GHRHR mutations can be excluded in the absence of this feature because GHRHR is critical for pituitary development and function of somatotroph cells (30)(31). However, patients homozygous for a GHRHR splice site mutation (IVS1 + 1G > A), presumably with molecular consequences identical to those documented in our patients, and with normal anterior pituitary have been reported recently (29).…”

Auxologic parameters and response to 2-year therapy with recombinant human growth hormone in growth hormone deficient children with an ectopic posterior pituitary

“…17,[22][23][24][25][26][27] it should be underlined, however, that normal anatomy of the pituitary does not exclude severe GHD and combined pituitary deficiency, as is found in the case of gene mutations of the pituitary transcription factors, POUF1F and PROP-1. 17,28 The results of this study demonstrate a beneficial effect of rhGH therapy both in patients with normal structure of the pituitary as well as in patients with midline defects of the hypothalamic-pituitary axis, provided that basic auxological criteria for the treatment are fulfilled. Thus, a careful and accurate auxological assessment, and not hypothalamic-pituitary area morphology itself, remains a fundamental criterion for selecting subjects for rhGH therapy.…”