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MR Imaging of the Pituitary Gland in Children and Young Adults with Congenital Combined Pituitary Hormone Deficiency Associated with PROP1 Mutations

¹ Department of Pediatrics, Endocrinology Research Center, Moscow 117036, Russia.
² Department of International Health and Radiation Research, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
³ Department of Pediatrics, Nagasaki University School of Medicine, Nagasaki 852-8104, Japan.
⁴ MRI Department, Endocrinology Research Center, Moscow 117036, Russia.

Received April 5, 1999; accepted after revision June 14, 1999.

 
Address correspondence to S. Yamashita.

Supported in part by the Japanese Ministry of Education, Science, Sports and Culture (grants in aid for scientific research 09558072, 0925324, 09042006).

Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
OBJECTIVE. The aim of this study was to clafify the relationship between morphologic changes of the pituitary gland and the genotype of Prophet of Pit-1 (PROP1), a newly discovered gene responsible for congenital combined pituitary hormone deficiency, in a series of eight humans with this disorder.

CONCLUSION. Congenital hypoplasia of the anterior pituitary gland is the most common MR imaging finding in patients with combined pituitary hormone deficiency. Our findings suggest a crucial role for PROP1 in pituitary organogenesis as well as anterior pituitary cell differentiation.

Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The heterogeneity of congenital combined pituitary hormone deficiency in children, including both the genetic basis of the disorder and the clinical phenotype of dwarfism, is now well documented. Investigators have also identified the entire cascade of pituitary transcription factors involved in the distinct temporal and spatial sequence of organogenesis of the anterior pituitary gland—such as PIT1, PROP1, RPX (HESX1), POTX (PTX1), and PLIM—and have determined specific cell lineages in animal models [1].

In humans, specific pituitary transcription factors, POU1F1 and PROP1, are responsible for the combined deficiency of growth hormone, prolactin, and thyroid-stimulating hormone (POU1F1) and of growth hormone, prolactin, thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone (PROP1). A variety of POU1F1 mutations (>10 different types of mutations), leading to different functional abnormalities, has been described to date in children with combined pituitary hormone deficiency. Since February 1998, six different genotypes of PROP1 mutations have been reported in patients with combined pituitary hormone deficiency [2, 3, 4, 5, 6, 7, 8].

The purpose of this study was to evaluate MR imaging findings of the hypothalamus-pituitary region in patients with congenital combined pituitary hormone deficiency caused by PROP1 mutations to clarify the morphologic changes in the pituitary gland that are associated with these mutations.

Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients
Eight patients (six females and two males) with combined pituitary hormone deficiency were included in the study; patients ranged in age from 13 years 9 months to 21 years 6 months. Mutations of PROP1 in these patients have been previously identified and reported by our group [3, 4]. Two types of PROP1 mutations—both of which included common two base-pair deletions in exon 2—were detected in these patients: a homozygous mutation that is caused by the deletion of guanine and adenine at position 296 (i.e., 296delGA/296delGA) and a compound heterozygous mutation that is caused by the deletion of guanine and adenine at positions 149 and 296 (i.e., 149delGA/296delGA). Both mutations result in a frameshift and a substitution of serine with a stop codon at position 109 (i.e., S109X). The predicted protein lacks DNA-binding and transcriptional activation activities [2, 6].

The first group of patients, consisting of three individuals from two families (a 15-year-old boy and his 21-year-old sister [1] and a 19-year-old woman), had the homozygous mutation (i.e., 296delGA). The second group of patients, consisting of five individuals from four families (an 18-year-old woman, 15-year-old girl, 13-year-old boy, 17-year-old girl, and 21-year-old woman [2]), had the heterozygous mutation (i.e., 149delGA/296delGA). These patients had been followed for more than 2 years since the identification of the PROP1 mutations. Clinical and hormonal data of combined pituitary hormone deficiency at the time of MR imaging studies are presented in Table 1. In three of the four young adult females (ages: 19 years, 18 years, and 21 years), hormone levels were determined again at 6 months before MR imaging.

The chronologic age of the patients ranged from 13 years 9 months to 21 years 6 months, whereas the bone age of patients, calculated according to the method described by Greulich and Pyle [9], ranged from 9 to 12 years. All patients had complete deficiency of growth hormone and either complete or partial deficiency of prolactin and thyroid-stimulating hormone that was confirmed by growth hormone stimulation test (insulin, clonidine, growth hormone-releasing hormone, L-dopa) and thyrotropin-releasing hormone stimulation test. Results of long-term follow-up identified the deficiency of gonadotropin (i.e., of luteinizing hormone and follicle-stimulating hormone) in three females (ages: 21 years [1]; 17 years, and 21 years [2]). On reaching a pubertal bone age at a chronologic age of more than 17 years, these patients failed to develop puberty; therefore, estrogen replacement therapy was initiated. Clinical symptoms of hypogonadism were confirmed using the gonadotropin test; findings showed a lack of luteinizing hormone, follicle-stimulating hormone, and estradiol in response to stimulation by gonadotropin-releasing hormone.

It is worth noting that two patients (a 15-year-old boy and 17-year-old girl) with normal blood cortisol levels at first examination subsequently showed low cortisol levels, which were confirmed by hormonal retest. All patients had been treated with L-thyroxine and recombinant growth hormone (Humatrope, Lilly, Indianapolis, IN; Gentropin, Phamacia & Upjohn, Bridgewater, CA; and Norditropin, Novo Nordisk, Bagsvaerd, Denmark) since the time of first examination, although the duration of growth hormone therapy varied among patients.

Evaluation of MR Imaging Findings
After obtaining informed consent from each patient or parent, MR imaging studies were performed using a 1-T scanner (Magnetom Impact; Siemens, Berlin, Germany). Sagittal, coronal, and transverse images were obtained with the following sequence parameters: 330/12 (TR/TE) with a flip angle of 70° for spin-echo and T1-weighted imaging and 5000/119 with a flip angle of 180° for turbo spin-echo and T2-weighted imaging. The thickness was 3 mm with a 0.3-mm intersection gap for sagittal and coronal images, and the thickness was 4 mm with a 0.4-mm intersection gap for transverse images. The field of view was 230 mm and the acquisition matrix size was 256 x 256 pixels. The number of acquisitions for each sequence varied from three to five.

Morphologic and structural characteristics were evaluated around the hypothalamus-pituitary area including the size and structure of the anterior pituitary gland; the location of the posterior pituitary; and the characteristics of the pituitary stalk, hypothalamus, and midline structures. An empty sella was defined as the penetration of the subarachnoid space and cerebrospinal fluid within the sellar cavity. A sella, completely or partly filled with cerebrospinal fluid, was defined as empty in cases of a severely hypoplastic anterior pituitary gland (<2 mm) and as partially empty in cases of a mildly hypoplastic anterior pituitary gland (>2 mm) [10]. Pituitary volume was calculated according to the method described by Di Chiro and Nelson [11].

Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
MR imaging studies revealed abnormal findings in the hypothalamus-pituitary area in all patients. Overall, seven (87.5%) of eight patients showed various degrees of hypoplasia of the anterior pituitary gland; in six of these patients, the anterior pituitary gland was severely hypoplastic, with the sella appearing empty and the upper surface appearing markedly concave (Figs. 1A, 1B, 2, 3, 4A, 4B, 4C). In the seventh patient, a 15-year-old boy, no penetration of cerebrospinal fluid within the sellar cavity was seen, indicating a milder form of hypoplasia of the anterior lobe (Fig. 1A, 1B). The pituitary was small, measuring 3 x 6 x 6 mm (height x width x length) (pituitary volume = 54 mm³). MR imaging findings in another patient from the second group (17-year-old girl) were markedly different from those seen in the other seven patients. In this patient, MR imaging showed the anterior pituitary gland as normal (i.e., as a homogeneous structure) (Fig. 4A, 4B, 4C). The pituitary gland was 7 x 11 x 9 mm (height x width x length) (pituitary volume = 346.5 mm³); moreover, the shape of the anterior pituitary gland in this patient differed from that seen in other patients, with a flat upper surface.

View larger version (114K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —Midsagittal MR images of siblings with congenital combined pituitary hormone deficiency with homozygous PROP1 mutation. Image of 15-year-old boy shows anterior pituitary hypoplasia.

View larger version (103K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —Midsagittal MR images of siblings with congenital combined pituitary hormone deficiency with homozygous PROP1 mutation. Image of 21-year-old sister shows empty sella. Pituitary glands have normal stalk and orthotopic posterior pituitary.

View larger version (115K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2. —19-year-old woman with congenital combined pituitary hormone deficiency and homozygous PROP1 mutation. Midsagittal MR image shows empty sella, normal stalk, and orthotopic posterior pituitary. Note soft-tissue mass in right sphenoidal sinus.

View larger version (124K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3. —21-year-old woman with congenital combined pituitary hormone deficiency and heterozygous PROP1 mutations. Midsagittal MR image shows empty sella, normal stalk, and orthotopic pituitary. Arrow indicates posterior lobe.

View larger version (126K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A. —MR images of siblings with congenital pituitary hormone deficiency with heterozygous PROP1 mutation. Midsagittal image of 13-year-old boy shows empty sella, concave superior surfaces, normal stalk, and orthotopic pituitary.

View larger version (105K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B. —MR images of siblings with congenital pituitary hormone deficiency with heterozygous PROP1 mutation. Midsagittal (B) and coronal (C) MR images of 17-year-old sister shows normal anterior pituitary, flat superior surface, enlarged inferior part of the stalk, and orthotopic posterior pituitary.

View larger version (93K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4C. —MR images of siblings with congenital pituitary hormone deficiency with heterozygous PROP1 mutation. Midsagittal (B) and coronal (C) MR images of 17-year-old sister shows normal anterior pituitary, flat superior surface, enlarged inferior part of the stalk, and orthotopic posterior pituitary.

With regard to the pituitary stalk, MR images showed a clearly normal pituitary stalk in all patients except the 17-year-old girl, in whom the stalk widened up to 2 mm in its inferior portion and appeared to have a density similar to that of the pituitary tissue (Figs. 4B and 4C). In all patients except one, the stalk was located in the middle of the gland. The stalk of a 21-year-old woman was, however, slightly asymmetric. The posterior lobe of the pituitary gland was identified in its normal position—that is, in the posterior part of the sella—in all patients.

Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Findings from examination of large cohorts of children with growth hormone deficiency during the last decade have shown a substantial increase in the proportion of organic forms of growth hormone deficiency with a simultaneous decrease of the idiopathic form. Therefore, reclassification of short stature and of isolated growth hormone deficiency in children must be considered.

MR imaging has become the method of choice for visualization of the pituitary gland and hypothalamic area, diagnosis of growth hormone deficiency, and differential diagnosis of a variety of disorders associated with short stature in children. To this end, the primary mechanisms of the most common MR imaging feature in children with growth hormone deficiency should be identified. A possible mechanism might include severe hypoplasia of the anterior pituitary gland, with empty sella, that is often associated with ectopia of the posterior lobe and either the absence of or hypoplasia of the pituitary stalk. Furthermore, the underlying mechanisms of such pituitary anomalies should also be delineated. Empty sella is considered to be an epiphenomenon of pituitary hypoplasia, a sort of focal dysraphic state, with no evidence of sellar enlargement and primary compression by cerebrospinal fluid. To our knowledge, only two hypotheses have been proposed to explain these MR imaging findings [10, 12]. The first one is that the MR imaging findings result from traumatic stalk abnormalities, which are caused by birth trauma, and from neonatal asphyxia, with subsequent traumatic transection of the stalk. Taking into account the importance of the mode of birth and perinatal events in the causes of concomitant structural defects in the hypothalamus-pituitary region in our patients, we analyzed separately a brief description of the birth data and parental height [3, 4]. All patients except the 18-year-old woman were born at full term, by vaginal delivery with head presentation, and without any evident perinatal problem. There were no birth complications, such as those requiring the use of forceps or vacuum extraction. Two patients (15-year-old boy and 15-year-old girl) had mild asphyxia at birth. Body length and weight at birth were within the normal range for gestational age for all patients.

The second hypothesis stresses the significant role of congenital malformations in both hypothalamus and pituitary development during early embryogenesis. With regard to pituitary transcription factor diseases in humans, the second dysembriogenetic hypothesis provides adequate explanation of MR imaging abnormalities as the primary cause. However, there exist heterogeneous MR imaging findings of the hypothalamus-pituitary area, such as in patients with congenital combined pituitary hormone deficiency with POU1F1 mutations, from a normal pituitary gland to hypoplasia of the anterior pituitary.

Concerning family members with identical PROP1 mutations and congenital combined pituitary hormone deficiency, Wu et al. [2] described a 28-year-old man with a heterozygous mutation (A301G302del/F117I: the deletion of adenine and guanine at positions 301 and 302 with a phenylalanine at position 117 replaced by isoleucine) who had a hypocellular pituitary. Furthermore, Fluck et al. [5] reported the presence of hypoplastic anterior pituitary gland in R120C mutation (a missense mutation with a purine at position 120 replaced by cytosine) seen in two brothers and a sister from one family and in a boy from another family, although his sister had a normal-sized pituitary gland [5].

Recently, unusual results were described in Jamaican and Brazilian patients with combined pituitary hormone deficiency resulting from the homozygous deletion of two base pairs in exon 2 of PROP1 and three siblings from the United States with heterozygosity for this mutation (Parks J et al., presented at the Endocrine Society meeting, June 1998). In these patients, the presence of large sella turcica and the enlargement of the anterior pituitary gland were reported. Moreover, one patient underwent transsphenoidal hypophysectomy and in the excised tissue fibroblast cells were found, suggesting a possible misdiagnosis with pituitary adenoma, craniopharyngioma, or Rathke cleft cyst. Similar data have been reported in three of eight patients from two Dominican families with possibly related mothers who had a homozygous mutation (296delGA) [8]. MR images of these patients, who were of the chronologic age of 17 years 6 months, 26 years 9 months, and 29 years, showed sellar enlargement. Furthermore, Mendonca et al. [12] have recently described MR imaging findings of two females with combined pituitary hormone deficiency that showed a large sellar turcica and an enlarged pituitary anterior lobe with increased signal intensity seen on enhanced T1-weighted MR images [13].

Variable MR imaging findings of the hypothalamus-pituitary area are, thus, not uncommon in patients with congenital combined pituitary hormone deficiency, harboring PROP1 mutations. In our study, such variability of MR imaging findings can be considered from several points of view. First, patients with two different mutations, (i.e., 296delGA/296delGA and 149delGA/296delGA), may exhibit different developmental processes of pituitary organogenesis in spite of similar functional consequences. MR images showed an extremely small anterior pituitary gland, with sellae appearing empty, in the two girls from the first group, and MR images showed less severe anterior hypoplasia in the boy from the first group. In addition, MR images of all three patients from this group, compared with those of patients from the second group, showed other anomalies, including involvement of brain structures in two siblings and an extra mass in the sphenoidal sinus in the third patient.

MR imaging findings were homogenous and showed the anterior pituitary gland to be extremely hypoplastic, as was seen in the first group, in all patients except one from the second group. However, one girl had a normal-sized pituitary with flat superior contour. The height of the anterior pituitary corresponded with that seen in healthy teenage girls, 7-10 mm, and had a spheric appearance. During puberty, there is evidence of a growth spurt in the size of the anterior pituitary, which represents a physiologic hypertrophy and should not be considered as a tumorous process. Although at a chronologic age of 17 years 3 months and a bone age of 12 years, this girl was at Tanner I stage of development on MR imaging and was soon placed on estrogen therapy. Before undergoing MR imaging, she had been treated with recombinant growth hormone injections for 3 years 10 months and L-thyroxine for a similar period. In addition, enlargement of the inferior part of the stalk, similar to the stalk form seen in craniopharyngioma, was observed in this patient. The significance of this finding has not yet been determined. Both groups of patients with PROP1 mutations had orthotopic, normal-sized posterior lobes, confirming that the posterior pituitary is intact in the described form of congenital combined pituitary hormone deficiency.

Another important finding of this study was that siblings from one family with the same PROP1 mutation had different MR imaging findings (15-year-old boy versus 21-year-old woman; 13-year-old boy versus 17-year-old girl). Long-term growth hormone replacement therapy does not seem to induce involution of the anterior pituitary gland, and age-dependent reduction in pituitary size in our study is not obvious because of the relatively short observation period.

In summary, we clarified the heterogeneity of MR imaging findings in young patients with congenital combined pituitary hormone deficiency associated with PROP1 mutations. Our findings included linkage of congenital empty sella. Further studies of a larger population sample are necessary to determine the relationship between heterogeneity of clinical phenotypes and hormonal profile. Furthermore, long-term follow-up studies are important to clarify the relationship between PROP1 mutation and morphologic changes of the hypothalamus-pituitary area detected on MR imaging.

Acknowledgments
 
This study was conducted under a special research agreement between the Institute of Endocrinology, Moscow, and the Nagasaki University School of Medicine.

References

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