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Pituitary Magnetic Resonance Imaging in 15 Patients with Prop1 Gene Mutations: Pituitary Enlargement May Originate from the Intermediate Lobe

First Pediatric Department, Athens University School of Medicine, Aghia Sophia Children’s Hospital (A.V., A.S., S.L., P.X., M.M.-C., I.B., C.D.-V.), Athens, Greece 11527; Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research (A.V.), and Diagnostic Radiology Department, Clinical Center (N.P.), National Institutes of Health, Bethesda, Maryland 20892; Department of Radiology, University of Ioannina School of Medicine (M.A.), Ioannina, Greece 45110; and Department of Endocrinology, Evangelismos Hospital (N.T.), Athens, Greece 10676

Address all correspondence and requests for reprints to: Dr. Catherine Dacou-Voutetakis, First Pediatric Department, Athens University School of Medicine, Aghia Sophia Children’s Hospital, Thivon and Livadias, Goudi 11527, Athens, Greece. E-mail: adacou{at}med.uoa.gr.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Pituitary morphology in patients with Prop1 gene mutations varies. Most patients demonstrate a normal or small pituitary gland. Occasionally, pituitary enlargement of undetermined origin has also been detected. In the present study we use long-term magnetic resonance imaging findings to characterize the morphological abnormalities of the pituitary gland in 15 patients (aged 2.5–45 yr) with combined pituitary hormone deficiency caused by Prop1 gene mutations (GA296del/GA296del in seven, GA296del/A150del in two, A150del/A150del in five, and GA296del/R73H in one patient) and attempt to uncover the origin and nature of the pituitary enlargement. Small pituitary gland was detected in seven patients (25.2 ± 14.4 yr of age), normal pituitary size in three patients (10.2 ± 5.8 yr of age), and pituitary enlargement in five patients (6.5 ± 2.7 yr of age). The pituitary enlargement consisted of a nonenhancing mass lesion interposed between the normally enhancing anterior lobe and the neurohypophysis. The pituitary stalk was displaced anteriorly, whereas the neurohypophysis was orthotopic, displaying a normal signal. Spontaneous regression of the mass lesion with normalization of the pituitary stalk position was observed in three patients. Our data indicate that although a small pituitary gland is usually observed in older subjects, a significant number of young patients with Prop1 gene mutations demonstrate pituitary enlargement with subsequent regression. The distinct magnetic resonance imaging characteristics of the pituitary enlargement in our patients in conjunction with pertinent data from Prop1-deficient mice suggest that the mass causing the pituitary enlargement most likely originates from the intermediate lobe.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
DURING MAMMALIAN PITUITARY organogenesis, distinct cell populations emerge from a common primordium. The expression of transcription factors (Ptx1/2, Rpx, Lhx3/ Lhx4, Prop1, and Pit-1) in a distinct, spatial, and temporal pattern results in precursor proliferation, cell lineage determination, and terminal differentiation of the distinct cell phenotypes (1, 2, 3, 4, 5).

The Prophet of the Pit-1 (Prop1) gene is a tissue-specific, paired-like, homeodomain transcription factor expressed in the anterior pituitary during the early stages of pituitary ontogenesis. The 226-amino acid protein encoded by the Prop1 gene plays an essential role in the evolution of pituitary cells secreting GH, prolactin (PRL), TSH, LH, and FSH. Inactivating mutations of the Prop1 gene lead to GH, PRL, TSH, LH, and FSH deficiencies of variable degree and age of onset (6, 7, 8). Low serum dehydroepiandrosterone sulfate values have also been reported in the presence of a normal pituitary-adrenal axis (9), and in certain cases, late-onset ACTH deficiency has been detected (10, 11, 12, 13).

The pituitary morphology in patients with the Prop1 gene defect varies, most patients demonstrating a small or normal size anterior pituitary gland (14). However, anterior pituitary enlargement or adenoma has been reported in certain cases and constitutes a puzzling finding of undetermined origin (7, 15). The pituitary stalk and neurohypophysis have been described as normal in all reported cases.

In the present communication we report long-term imaging data of pituitary abnormalities detected in 15 patients with Prop1 gene defects in conjunction with a brief review of the literature on pertinent animal and human data in an attempt to uncover their origin and nature.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Fifteen patients of Greek origin (eight females and seven males) with combined pituitary hormone deficiency (CPHD) and diverse mutations of the Prop1 gene were included in the study. Their age ranged from 2.5–45 yr (mean, 16 ± 13.3 yr) at the time of the initial magnetic resonance imaging (MRI). Both hormonal and imaging studies herein presented form part of our diagnostic and follow-up routines. For the molecular studies, informed consent was obtained from the parents of the children and from the patients themselves if they were older than 18 yr. The institutional review board approved all parts of the study.

Pituitary MRI

The MRI protocol consists of pre- and postcontrast T1-weighted spin echo scans with TR/TE 500 /20 msec and slice thickness 3- and 0.3-mm gap. Sagittal T2-weighted spin echo scans were also obtained with TR/TE 2500/90 msec. The maximum vertical height of the pituitary gland was measured in a midline sagittal scan. The pituitary gland was considered small if the maximum height was less than –2 SD and enlarged if the maximum height was greater than 2 SD compared with normal for age values (16, 17).

Genomic analysis of the Prop1 gene

DNA was extracted from peripheral blood using the QIAmp DNA Blood Mini Kit (Qiagen, Hilden, Germany). Each of the three exons of the Prop1 gene was PCR-amplified. PCR was performed in a 50-µl reaction mixture containing 100 ng DNA, 25 µl Promega Mastermix (Promega Corp., Madison, WI), and 25 pmol of each primer. The following pairs of primers were used: exon 1: sense primer, 5'-GAGCTGCGGAAGCAGAGAAATCTCA-3'; antisense primer, 5'-AGAGGTAACTGTCTCACATCCCCAC-3'; exon 2: sense primer, 5'-CACTGAGCGCAATCCCGGGAC-3'; antisense primer, 5'-GAGATGAGGCCTGTGTCTGGTGA-3'; and exon 3: sense primer, 5'-CTCTTGTCATTGGAGTAGGGTGTCA-3'; antisense primer, 5'-CAGACTTCCTCCACTAATCACCCCA-3'. The PCR amplification reaction consisted of one cycle at 94 C for 3 min, followed by 35 cycles of 30 sec at 94 C, 30 sec at 56 C, and 1 min at 72 C, and one cycle of 5 min at 72 C. The PCR products were cleaned with the QIAquick PCR purification kit (Qiagen). The double-stranded PCR products of each exon were directly sequenced employing the Thermo Sequenase core sequencing kit on the VISTRA DNA Sequencer 725 (Amersham Pharmacia Biotech, Little Chalfont, UK) using the following primers: exon 1, 5'-CCAAGGGGTGCTCCAGTC-3' (sense); exon 2: 2F', 5'-TGGTCCAGCACCGAGGAG-3' (sense); and 2S: 5'-TGCCCAACATTCTATGATAGC-3' (antisense); and exon 3: 3S1, 5'-GTGGGCTCTGATGTGGTTC-3' (sense); and 3S2, 5'-CACCACCACCACCAGTGACCTG-3' (sense).

Hormonal studies

Originally, serum TSH, T₄, PRL, LH, and FSH were determined using commercially available RIA kits. Since 1995, serum TSH and PRL were determined using microparticle enzyme immunoassay technology (IMX, Abbott Laboratories, Chicago, IL), and serum T4 was determined using fluorescence polarization immunoassay technology (IMX, Abbott Laboratories). LH and FSH were determined by chemiluminescence using the Chiron diagnostics kit (Chiron Corp., Emeryville, CA). Since 1999, serum TSH, T₄, PRL, LH, and FSH were determined using the automated chemiluminescence system (ACS 180, Bayer Diagnostics Europe Ltd., Dublin, Ireland). GH was originally determined using commercially available RIA kits. Since 1992, GH was determined by immunoradiometric assay (kit from CIS Bio-International, Gif-sur-Yvette, France) and the chemiluminescence immunoassay (Nichols Advantage, Nichols Institute Diagnostics, San Juan Capistrano, CA).

GH was assessed using two provocative tests in each patient (glucagon- and L-dihydroxyphenylalanine-induced or insulin-induced hypoglycemia). GH was considered low if peak values during provocative testing were less than 10 µg/liter. The GnRH test was carried out after iv administration of 100 µg synthetic GnRH. Blood samples for LH and FSH determinations were obtained before and 30 and 60 min after GnRH administration. Gonadotropin deficiency was diagnosed if no response of LH and FSH to GnRH was observed at the age of expected puberty.

	Results

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MRI data

In three patients (age, 10.2 ± 5.8 yr), the size and morphology of the pituitary gland were normal for age. A small pituitary gland was observed in seven (age, 25.2 ± 14.4 yr; Fig. 1A), and pituitary enlargement was found in five (age, 6.5 ± 2.7 yr) patients (Fig. 1, B and C). The mean age of the patients with small and enlarged pituitary glands is depicted in Fig. 2. In all but one patient with a small pituitary gland, the pituitary parenchyma enhanced homogeneously on the postcontrast scans. In this patient, two small (1-mm diameter) cyst-like lesions, with signal characteristics similar to cerebrospinal fluid, were observed between the anterior and posterior lobes of the gland. In addition, a nodule with isosignal to the gray matter, measuring 1.5 mm, was observed in the inferior portion of the pituitary stalk (Fig. 1D). On a follow-up MRI carried out 2 yr later, the cystic lesions had resolved, but the nodule was unchanged (data not shown).

View larger version (128K): [in this window] [in a new window]   FIG. 1. A, 12.5-yr-old girl with CPHD caused by a homozygous Prop1 gene mutation (A150del/A150del). The midsaggital T1-weighted image demonstrates a small pituitary gland and a normal pituitary stalk. B, 9.25-yr-old boy with CPHD caused by a homozygous Prop1 gene mutation (A150del/A150del). The midsagittal post contrast T1-weighted scan shows a nonenhancing, space-occupying lesion (black arrow) interposed between the anteriorly displaced adenohypophysis (white arrowhead) and the neurohypophysis. The pituitary stalk is still visible when entering the mass. C, Same patient as in B; coronal contrast-enhanced, T1-weighted scan demonstrating the nonenhancing mass lesion and the midline position of the pituitary stalk. D, 15-yr-old girl with CPHD caused by a homozygous Prop1 gene mutation (GA296del/GA296del). The midsagittal T1-weighted scan shows: a) cyst-like lesions (black arrows) located between the adenohypophysis and the neurohypophysis, and b) a nodule with isosignal to the gray matter at the inferior part of the pituitary stalk (white arrowhead). The cystic lesions had resolved on an MRI carried out 2 yr later. E, Boy with CPHD caused by a homozygous Prop1 gene mutation (GA296del/GA296del). At 7.25 yr of age, a midsagittal T1-weighted scan showed pituitary enlargement. A space-occupying lesion was interposed between the adenohypophysis and the neurohypophysis. The anterior lobe and the pituitary stalk were anteriorly displaced. F, Same patient as in E at 9.8 yr of age. A midsagittal T1-weighted scan showed regression of the pituitary enlargement and normalization of the pituitary stalk position.

View larger version (14K): [in this window] [in a new window]   FIG. 2. Mean age of patients with enlarged and small pituitary glands. The pituitary gland was considered enlarged if the maximum height was greater than 2 SD, and small if the maximum height was less than –2 SD, compared with normal for age values.

In all subjects studied, the neurohypophysis was orthotopic and exhibited a normal bright signal on precontrast scans. In all cases, the pituitary stalk was visible in its entire length. The MRI findings, the genotypes, and the normal values of pituitary height for the corresponding age groups (16, 17) are shown in Table 1.

The Prop1 gene mutations detected in the 15 patients were as follows: GA296del/GA296del in seven patients, GA296del/A150del in two patients, A150del/A150del in five patients, and GA296del/R73H in one patient (Table 1).

Hormonal values at presentation and follow-up are shown in Table 2. The values of total T₄ listed are without L-T₄ therapy. In all patients, GH and TSH deficiencies were detected. Basal PRL values were low in 11 of 15 patients. In patients older than 14 yr, LH and FSH deficiencies were also documented by the absence of secondary sex characteristics and the lack of response of gonadotropins to GnRH stimulation.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Prop1 gene mutations result in CPHD, which includes GH, PRL, TSH, LH, and FSH deficiencies (2, 5, 18). In a subset of these patients, ACTH insufficiency develops as a relatively late manifestation (10, 11, 12, 13). In addition, low values of dehydroepiandrosterone sulfate have been observed in the presence of a normal pituitary-adrenal axis (9). Molecular defects of the Prop1 gene are found in almost 50% of familial cases of CPHD (5, 18, 19). Therefore, in patients with CPHD and in the absence of neoplasia, the diagnosis of Prop1 gene defects must be considered, especially if low PRL values are detected (2).

In patients with idiopathic hypopituitarism, a small sella turcica and small pituitary gland are expected. This was demonstrated by the report of Underwood et al. (20), who found lower than normal sellar volume on skull radiographs in 34 patients with idiopathic hypopituitarism. Contrary to these findings, Parks et al. (21, 22) reported large sella turcica and pituitary enlargement in patients with hypopituitarism associated with the GA296del mutation of the Prop1 gene. As reported, one of these patients had suprasellar extension of the pituitary mass and underwent surgery. The histopathology revealed amorphous material with occasional fibroblasts (22). Since that original report other researchers have detected enlarged pituitary gland in some patients with Prop1 gene defects (7, 13, 21, 23, 24, 25).

In subjects with Prop1 gene defects, the development and differentiation of most hormone-secreting pituitary cells are interrupted at an early stage of their ontogenesis; hence, a small pituitary gland is expected on MRI. Consequently, the finding of pituitary enlargement in previously reported cases and in our own series is paradoxical. Interestingly, pituitary enlargement was recently described in a patient with CPHD due to mutations in LHX3 (26). The phenomenon of pituitary enlargement is even more puzzling in light of reports showing spontaneous regression of the pituitary mass in some patients with Prop1 gene defects (7, 25). This regression could be attributed to apoplexy or cell apoptosis resulting in a small pituitary gland and a partially empty sella. Apoptosis may be the result of incomplete cell differentiation, prolonged absence of transcription factors that are physiologically expressed throughout life, and lack of vital communication and signal exchange between the remaining pituitary cells (27).

In our study an enlarged pituitary gland was found in five of 15 patients, a relatively high incidence by comparison with published data (Table 3) (4, 7, 8, 10, 11, 12, 13, 14, 15, 21, 22, 23, 24, 25, 28, 29, 30). This may be related to the lower age at MRI in our patients. The mean age of our subjects with pituitary enlargement was 6.5 ± 2.7 yr (Fig. 2). In this age group (i.e. <10 yr), five of seven patients had pituitary enlargement. These findings indicate that most patients with a Prop1 gene defect might exhibit pituitary enlargement early in life, which later results in a small pituitary, as was the case in three of the five patients in our study group (Fig. 1, E and F). The timing of regression varies, since pituitary enlargement has been reported even in adult patients (Table 3).

In the present study the MRI revealed a pituitary space-occupying lesion interposed between the anterior lobe and the neurohypophysis in the five patients with pituitary enlargement. The mass displaced the adenohypophysis anteriorly and was isosignal to the anterior pituitary gland on precontrast T1- and T2-weighted images. Rathke’s pouch cysts and intrasellar cystic craniopharyngiomas (31, 32) may also present as space-occupying lesions interposed between the anterior and posterior lobes of the pituitary. However, both demonstrate signal characteristics on T1- and T2-weighted scans typical for fluid (31, 32). Pituitary adenomas differ in location from the mass lesions of these five patients. Specifically, they are located in the anterior lobe surrounded, at least in part, by a normally enhancing pituitary parenchyma (33). Intrasellar germinomas are extremely rare and enhance intensely (31). Moreover, the above-mentioned lesions, with the exception of Rathke’s pouch cysts, do not regress spontaneously as does pituitary enlargement in some Prop1-deficient patients (Fig. 1F) (7, 25). The small cysts detected in one of our patients with small pituitary (Fig. 1D) may represent an evolutionary step toward intermediate lobe regression (34). The eventual disappearance of these cystic lesions supports this assumption. Hence, the MRI characteristics of the pituitary mass in our patients favor the concept that the pituitary mass may originate from the intermediate lobe.

The intermediate lobe of human hypophysis is well developed in fetal life, its involution starting during the third trimester of pregnancy. Later in life, a distinct intermediate lobe is lacking in humans. At the end of fetal development the pituitary cleft becomes obliterated allowing physical contact between the anterior and the intermediate lobes. The cells of the intermediate lobe migrate and are incorporated into the anterior lobe (34, 35, 36). The role of Prop1, if any, in these evolutionary events is not apparent. Studies in the animal model of Prop1 gene defects (Ames dwarf mouse) offer a satisfactory interpretation of the observed pituitary enlargement and support our thesis on the origin of the pituitary mass from the intermediate lobe in patients with Prop1 gene defects. These data are briefly outlined.

The anterior lobe of the pituitary gland develops from an invagination of the oral ectoderm, known as Rathke’s pouch (37, 38, 39, 40, 41, 42, 43, 44, 45). The pituitary transcription factor Prop1 is activated on embryonic d 10 (e10) and is essential for the determination of the dorsal and caudomedial pituitary cell types, namely somatotrophs, lactotrophs, and thyrotrophs. It is also important for complete differentiation of the gonadotrophs, which reside in the most ventral aspect of the developing anterior pituitary. Prop1 normally represses dorsal growth and activates ventral expansion and cell specification in the pituitary primordium (42). Prop1 is also required for Pit-1 gene activation (40, 41, 42) and down-regulation of the transcriptional repressor Rpx, which becomes rapidly extinct after e12.5 (37).

In Prop1-deficient mice (Ames dwarf), Rpx expression persists until e17.5, and the Pit-1 gene is not activated, resulting in deficiency of GH, PRL, and TSH and reduced LH and FSH levels (37, 43, 44). Although the pituitary gland size of the adult Ames dwarf mouse is significantly reduced (as in most adult humans with the Prop1 gene defect), abnormal dorsal expansion of the pituitary primordium is observed and is probably due to a lack of the physiological ventral migration of the pituitary lineage precursor cells. Part of the dorsal overgrowth can be attributed to the expansion of the prospective intermediate lobe. This expanded intermediate lobe consists of the normally residing proopiomelanocortin (POMC)-expressing cells and an increased number of POMC-negative cells (42). A dorsal expansion of incompletely differentiated pregonadotrophs also occurs and seems to outflank, invade, and dislocate the prospective intermediate lobe, possibly contributing to the enlargement (42). This cascade of events can be attributed not only to the lack of Prop1 and Pit-1 expression, but also to the lack of Rpx repression, because in transgenic animals, failure to extinguish the expression of Rpx after e12.5 results in pituitary dysmorphogenesis similar to that found in the Ames dwarf (45).

The synthesis of the presented data, namely the MRI findings in our patients and pertinent animal data, support our theory that pituitary enlargement encountered in humans with the Prop1 gene defect originates from the intermediate lobe and may contain, among other precursors, normally residing POMC-secreting cells, POMC-negative cells, and invading pregonadotrophs. An alternative and quite attractive hypothesis for the interpretation of the pituitary enlargement is that in humans with Prop1 gene defects, the involution of the intermediate lobe (normally occurring in postnatal life) is delayed. The latter gives the impression of a pituitary mass that persists for a variable time in different patients.

Apart from the theoretical interest of the present data as concerns the mechanism involved in the phenomenon of pituitary enlargement in Prop1 gene mutations, there are practical implications as well. The possibility of a Prop1 gene defect must always be considered in the differential diagnosis of a pituitary mass detected in patients with CPHD, especially in the presence of low PRL values. The characteristics of this mass, as described above, allow the differentiation from pituitary adenoma, craniopharyngioma, germinoma, or Rathke pouch cyst.

	Footnotes

 
Abbreviations: CPHD, Combined pituitary hormone deficiency; e, embryonic d; MRI, magnetic resonance imaging; POMC, proopiomelanocortin; PRL, prolactin.

Received October 9, 2003.

Accepted February 18, 2004.

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