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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 12 4776-4780
Copyright © 2000 by The Endocrine Society

Original Studies

Pituitary Macroadenoma in a 5-Year-Old: An Early Expression of Multiple Endocrine Neoplasia Type 11

Constantine A. Stratakis, Debra H. Schussheim, Samuel M. Freedman, Margaret F. Keil, Svetlana D. Pack, Sunita K. Agarwal, Monica C. Skarulis, Robert J. Weil, Irina A. Lubensky, Zhengping Zhuang, Edward H. Oldfield and Stephen J. Marx

Developmental Endocrinology Branch, National Institute of Child Health and Human Development (C.A.S., M.F.K.); Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (D.H.S., S.K.A., M.C.S., S.J.M.); Laboratory of Pathology, National Cancer Institute (S.D.P., I.A.L., Z.Z.); and Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke (R.J.W., E.H.O.), National Institutes of Health, Bethesda, Maryland 20892; and Pediatric Specialty Center (S.M.F.), Joe DiMaggio Children’s Hospital, Hollywood, Florida 33021

Address correspondence and requests for reprints to: Constantine A. Stratakis, M.D., Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, MSC1862, 10 Center Drive, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov


   Abstract
Top
 Abstract
Introduction
 Case report
 Materials and Methods
 Results
 Discussion
 References
 
Multiple endocrine neoplasia type 1 (MEN 1) is associated with parathyroid, enteropancreatic, pituitary, and other tumors. The MEN1 gene, a tumor suppressor, is located on chromosome 11. Affected individuals inherit a mutated MEN1 allele, and tumorigenesis in specific tissues follows inactivation of the remaining MEN1 allele. MEN 1-associated endocrine tumors usually become clinically evident in late adolescence or young adulthood, as high levels of PTH, gastrin, or PRL. Because each of these tumors can usually be controlled with medications and/or surgery, MEN 1 has been regarded mainly as a treatable endocrinopathy of adults. Unlike in MEN 2, early testing of children in MEN 1 families is not recommended. We report a 2.3-cm pituitary macroadenoma in a 5-yr-old boy with familial MEN 1. He presented with growth acceleration, acromegaloid features, and hyperprolactinemia. We tested systematically to see whether his pituitary tumor had causes similar to or different from a typical MEN 1 tumor. Germ line DNA of the propositus and his affected relatives revealed a heterozygous point mutation in the MEN1 gene, which leads to a His139Asp (H139D) amino acid substitution. The patient had no other detectable germ-line mutations on either MEN1 allele. DNA sequencing and fluorescent in situ hybridization with a MEN1 genomic DNA sequence probe each demonstrated one copy of the MEN1 gene to be deleted in the pituitary tumor and not in normal DNA, proving MEN1 "second hit" as a tumor cause. Gs{alpha} mutation, common in nonhereditary GH-producing tumors, was not detected in this tumor. We conclude that this pituitary macroadenoma showed molecular genetic features of a typical MEN 1-associated tumor. This patient represents the earliest presentation of any morbid endocrine tumor in MEN 1. A better understanding of early onset MEN 1 disease is needed to formulate recommendations for early MEN 1 genetic testing.


   Introduction
Top
 Abstract
 Introduction
Case report
 Materials and Methods
 Results
 Discussion
 References
 
FAMILIAL MULTIPLE ENDOCRINE neoplasia type 1 (MEN 1) is an autosomal dominant disorder with variable expression characterized by tumors of the parathyroids, enteropancreas, anterior pituitary, and other tissues. The MEN1 gene, which is located on chromosome 11q13, was recently identified (1). Individuals affected by MEN 1 inherit an MEN1 inactivated allele; tumorigenesis in specific tissues follows inactivation of the remaining normal allele. MEN 1 is regarded as an endocrinopathy presenting in young adulthood (2).

We report clinical, genetic, and laboratory findings of a 5-yr-old boy with familial MEN 1 and a mammosomatotroph pituitary macroadenoma. This patient represents the earliest morbid presentation of tumor in MEN 1.


   Case report
Top
 Abstract
 Introduction
 Case report
Materials and Methods
 Results
 Discussion
 References
 
A 5-yr-old boy presented to his physician with worsening headaches over 1 yr, coarsening facial features, and accelerated growth. Despite height below the 5th percentile since birth (at 3 yr of age the bone age was 2 yr old), beginning 18 months before presentation, the patient had rapid growth acceleration (13 cm per year) and proportionate weight gain. Cranial magnetic resonance imaging revealed a pituitary macroadenoma with erosion of the sella floor and compression of the optic chiasm (Fig. 1Go, A and B). PRL levels were elevated to 1600 ng/mL (normal range, 1–11), and insulin-like growth factor I (IGF-I) levels were 84 nmol/L (650 ng/mL; normal range, 51–288); IGF-binding protein-3 levels were normal (3.3 mg/L; normal range, 1.5–3.4). Other studies of anterior pituitary function were significant for secondary hypothyroidism (thyroid-stimulating hormone, 0.14 uIU/mL; free T4, 0.9 ng/mL; normal ranges, 0.4–4.6 and 1–1.9, respectively). Replacement levothyroxine was prescribed. Treatment with bromocriptine was initiated, and the dosage was increased gradually to 10 mg daily. On therapy, however, there was incomplete suppression of PRL secretion (values ranged from 105–435 ng/mL) and the tumor size increased.



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  		Figure 1. Coronal (left) and sagittal (right) T1-weighted magnetic resonance images. A nonhomogenous enhancing tumor (shown by the arrows) is seen displacing normal pituitary tissue upward and to the left. There is probable cavernous sinus invasion bilaterally.

 
The patient was referred to the NIH at the age of 51/2 yr. A family history of MEN 1 was apparent. The father had been diagnosed in his 20s with primary hyperparathyroidism. Two paternal aunts were affected with parathyroid disease, and one had undergone transsphenoidal surgery for a prolactinoma at age 51. There was no consanguinity between the parents of the propositus.

Physical examination revealed a tall, overweight (>95th percentile), normotensive child with coarsened facial features, broadened nose, and prominent ear cartilage. There was no gynecomastia or galactorrhea. Testes were slightly enlarged bilaterally, measuring 5 cc (normal range, 1–2). Visual field testing was grossly normal.

While the patient was taking 15 mg daily of bromocriptine, PRL levels ranged from 150–200 ng/mL. Overnight serial sampling of GH (average levels of 5.6 ng/mL) showed complete loss of pulsatility, and GH was not suppressible by oral glucose tolerance testing.

The patient underwent transsphenoidal surgery, but complete excision of the macroadenoma was not possible because of extensive invasion of the left cavernous sinus. PRL levels declined after surgery by ~50% but increased gradually thereafter to their preoperative levels. The patient responded to pergolide (100 µg nightly), which was subsequently changed to cabergoline (Dostinex, 500 µg weekly) with PRL levels less than 100 ng/mL. Because of high GH levels (4–7 ng/mL) postoperatively, somatostatin analog (octreotide acetate) treatment was added to his regimen (Sandostatin LAR, 5 mg monthly), to which IGF-I levels responded with a decrease to 9.9 nmol/L (76 ng/mL; normal range, 2–118); spot GH levels decreased to less than 1 ng/mL, and IGF-binding protein-3 levels remained in the normal range (3.5 mg/L).

Because of his early presentation of a pituitary tumor, during each of the follow-up visits, the patient was also screened for possible hyperparathyroidism and hypergastrinemia; PTH, total and ionized calcium, and fasting gastrin levels have been normal to this date.


   Materials and Methods
Top
 Abstract
 Introduction
 Case report
 Materials and Methods
Results
 Discussion
 References
 
Tissue processing and characterization

The patient and his relatives were studied according to protocols approved by NIDDK and NICHD Institutional Review Boards and informed consent was obtained. Tissue from the patient’s pituitary tumor was collected at surgery. Tissue slices were snap frozen at 70 C, simultaneously processed for culture, and fixed in formalin for histological analysis.

For light microscopy and immunocytochemistry, sections were stained with hematoxylin and eosin, periodic acid-Schiff, and the Gordon-Sweet silver reticulin stain. The avidin-biotin-peroxidase complex technique was used to localize GH and PRL and to stain for ACTH, TSH, LH, FSH, and {alpha}-subunit of glycoprotein hormones.

DNA extraction

Normal DNA was obtained from peripheral blood lymphocytes for germ-line mutation testing and restriction digests. Single-step DNA extraction was performed by standard methods (Qiagen, Inc., Valencia, CA). Tumor DNA was extracted from frozen tissue in a 0.7-mL solution of 50 mM Tris (pH 8.0), 100 mM EDTA, 100 mM NaCl, 1% SDS, and 0.5 mg/mL proteinase K. Samples were subsequently extracted four times in phenol/chloroform, precipitated with ethanol, and resuspended in 1x TE [50 mM Tris-HCl and 1 mM EDTA (pH 8.0)]. Simultaneously, touch preparations were performed from frozen tumor for fluorescent in situ hybridization (FISH) analysis (3).

MEN 1, GNAS1 mutation screening, and MEN1 allelic deletion analysis

The MEN1 gene contains 10 exons (with the first exon untranslated) and extends across 9 kb (1). PCR-single strand conformation polymorphism (SSCP) analysis was performed to amplify exons 2–10 from tumor and normal DNA, as described previously (4). Each amplicon was screened by SSCP analysis for the presence of an aberrant band in tumor DNA compared with normal DNA. After detection of a variant allele on the SSCP gel, tumor and normal DNA were reamplified by PCR. The PCR products were directly sequenced (Cyclin Sequencing Kit; Perkin-Elmer Corp.), and the normal and tumor DNA sequences were compared. Peripheral blood DNA from MEN 1 patients of other families with known germ-line mutations in each exon (5) was run in parallel with each assay gel as a positive control. The patient’s tumor DNA was also screened for activating point mutations in exons 8 and 9 of the GNAS1 gene, including Arg201 and Gln227 (6). Sequencing to exclude any GNAS1 mutation, as described previously (7), followed SSCP.

FISH on frozen specimens was performed following protocols as described elsewhere (3, 8). The probe was cosmid c10B11 containing MEN1 gene, which was labeled by nick translation with digoxigenin-11-dUTP (Roche Molecular Biochemicals, Indianapolis, IN) for 2.5 h at 15 C. A chromosome 11-specific centromeric {alpha}-satellite probe labeled with biotin-16-dUTP (Oncor, Gaithersburg, MD) was used for chromosome identification. Hybridization signals were scored using a Carl Zeiss Axiophot2 (Carl Zeiss, Inc., Thornwood, NY) fluorescence microscope equipped with a Sensys CCD camera (Photometrics). Fluorescence images were automatically captured and merged using IPLab Spectrum software (Scananalytics, Inc., Fairfax, VA) on a PowerPC 8500/150.


   Results
Top
 Abstract
 Introduction
 Case report
 Materials and Methods
 Results
Discussion
 References
 
Histology showed a pituitary adenoma invading the medial wall of the left cavernous sinus. The reticulin structure of the tumor tissue was distorted, and there was preservation of the reticulin structure of normal surrounding pituitary tissue. Immunoperoxidase stains performed on the paraffin sections showed the individual tumor cells to be positive for both PRL and GH and negative for ACTH, TSH, LH, FSH, and {alpha}-subunit of glycoprotein hormones, consistent with a mammosomatotroph adenoma.

In germ line DNA of the propositus, a C-to-G point mutation was identified in exon 2 of the MEN1 gene (cDNA position 525), which leads to a His139Asp (H139D) amino acid substitution in menin (4). This matched the germ-line mutation detected in the patient’s living affected relatives. No other germ-line mutation was found in the propositus. The unaffected mother and sister did not have the mutation. The mutated sequence abolished a restriction site (ApaI); thus, independent confirmation of the "mutation status" was obtained by restriction enzyme analysis in all available members. GNAS1 gene mutation analysis in the tumor did not detect any sequence changes.

FISH was performed with a probe containing the MEN1 genomic DNA sequence. In tumor cells one copy of the MEN1 gene was found to be deleted, demonstrating "allelic loss" for the MEN1 locus (Fig. 2Go). SSCP and sequencing analysis of tumor tissue detected a mutation in exon 2 of the MEN1 gene identical to that in the germ line and no heterozygosity for the normal allele, establishing by a second criterion that the normal allele had been lost in the tumor.



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  		Figure 2. FISH of the patient’s pituitary tumor cells demonstrates only one copy of MEN1 (red signal) in all cells, reflecting loss of one allele at the MEN1 locus. Green signals represent the chromosome 11 {alpha}- satellite probe. All cells have extensive losses of one chromosome 11 that include the {alpha}-satellite region. The inset shows a pituitary tumor cell from another patient that has two copies of chromosome 11, identified by all four signals.

 

   Discussion
Top
 Abstract
 Introduction
 Case report
 Materials and Methods
 Results
 Discussion
References
 
We describe a MEN 1-related mammosomatotroph adenoma presenting at an unusually young age. Like many hereditary tumors, MEN 1 typically presents earlier than sporadic tumors of the same tissue type. The age disparity at presentation is striking for MEN 1-related hyperparathyroidism (3rd vs. 6th decade in sporadic cases), but less pronounced for gastrinoma and insulinoma (4th vs. 5th decade in each) (9). By contrast, there has been no apparent age difference for the onset of MEN 1-associated and sporadic prolactinoma (4th decade) (10, 11, 12).

In fact, pituitary tumors, which occur in 10–30% of symptomatic MEN 1 cases (13), are considered rare in pediatric and adolescent patients with MEN 1 (14), as they are in the general pediatric population. These adenomas account for less than 2% of all intracranial tumors in childhood (15) and 3.6–6% (16, 17) of all pituitary adenomas treated surgically. In a large series reviewing 2230 patients with pituitary adenoma only 1.4% occurred in patients 11 yr or younger, and of those only 16% and 6% secreted PRL and GH, respectively (14). In these patients, among the 136 patients younger than 20 yr old, adrenocorticotropic hormone-releasing adenomas were the most common tumors before puberty, and prolactinomas were most common during and after puberty (14).

FISH analysis, performed on this patient’s pituitary tumor tissue, confirmed MEN1 wild-type "allelic loss" on chromosome 11 (second hit). Although a significant incidence of loss of heterozygosity on chromosome 11 has been reported for sporadic parathyroid and enteropancreatic endocrine tumors (26–38%; Refs. 18, 19, 20) and 19–93% (Refs. 4, 21 , and 22 , respectively), the incidence is estimated to be much lower (0–18%) in sporadic pituitary adenomas (22, 23, 24). Small inactivating mutations (first hits) of the MEN1 gene also seem to be rare in sporadic tumors of the pituitary gland, occurring in only 0–5% of cases (18, 24, 25). Therefore, in this patient, a germ-line MEN1 mutation and MEN1 gene wild-type allelic loss provide strong evidence that this is not an incidental, rare, unrelated macroadenoma in a patient with MEN1, but a tumor caused by inactivation of both copies of the MEN1 gene.

The mutation described here (H139D) is a missense mutation similar to one third of the MEN1 germ-line or somatic mutations identified, to date (26). The same mutation has been reported in a sporadic parathyroid adenoma (27). This same mutation was analyzed in the study that described the functional consequences of MEN1 mutations (28). Like several other missense mutants between amino acids 139 and 142, this one (H139D) resulted in a loss of menin binding to junD and loss of menin-inhibition of junD-activated transcription. The H139D mutation did not differ from other genetic defects in the MEN1 gene that had a typical clinical phenotype. Overall, there is no obvious clustering of missense mutations in the MEN1 gene and, in general, both somatic and germ-line mutations show a remarkably similar distribution within the MEN1 messenger RNA sequence (2). Interestingly, too, in our patient’s family, there was no other early onset or unusual MEN 1 phenotype. Therefore, at this time, no clear genotype-phenotype correlation has emerged from the molecular elucidation of MEN 1 in extended kindreds (26, 29, 30, 31) or in this patient.

The unusually early presentation of our patient raised the question of whether other, additional genetic defects contributed to this tumor. Somatic point mutations in the GNAS1 gene (Arg201 and Gln227) that encode the {alpha}-chain of G- stimulatory protein have been identified in approximately one third of sporadic GH-secreting pituitary tumors (7, 32). However, in our patient’s tumor no such GNAS1 mutations were identified, although other GNAS1 changes cannot be excluded. Similarly, changes in other genes are possible; in fact, these are common in many benign endocrine tumors (33).

The age of clinical onset of treatable MEN 1-related tumors is an important factor in formulating biochemical and DNA screening recommendations. Hyperparathyroidism is usually the earliest and most common endocrine expression. In several studies, hypercalcemia was an almost universal finding at the time of MEN 1 diagnosis (10, 34, 35). Clinically evident hyperparathyroidism in MEN 1 has been reported at ages 5 and 7 yr (36) and several times at age 8 (10, 29, 37). However, no morbidity has been reported from early hyperparathyroidism in MEN 1. MEN 1-associated prolactinomas have been reported previously in children ages 10–13 yr old (38, 39, 40). Likewise, GH-producing adenomas in MEN 1 have been described in early adolescence (40). Gastrinoma, the other defining feature of MEN 1, has not been seen earlier than age 12 in MEN1 (Jensen, R. C., unpublished data) (36, 37, 39). MEN 1-associated insulinoma has been described as early as age 6 (34, 41). All or most of these prior reports of early onset endocrinopathy have been anecdotal. This case is the earliest MEN 1-related morbidity seen in our series of 85 MEN 1 kindreds with 565 known affected members (our unpublished data) and, to our knowledge of other reported cases, represents the earliest morbid presentation of tumor in MEN 1.

Prospective biochemical or molecular screening at a very early age may have had an influence on the clinical course of this unusual case. Clinical signs and symptoms of excessive GH and PRL are often ambiguous and difficult to detect, especially in young, rapidly growing children. Presumably, early genetic identification of MEN1, followed by periodic biochemical screening, could have identified the tumor before clinical presentation.

Identification of the MEN1 gene was first achieved by positional cloning (1), and mutation testing is now available at several centers. The ability to test asymptomatic children for diseases like MEN 1 and MEN 2 raises ethical and legal issues. Genetic testing at an early age has been advocated for MEN 2 because it is characterized by thyroidal C cell tumors with high malignant potential and may present at a young age with aggressive malignant tumors (42). RET gene analysis can result in a recommendation for early thyroidectomy to prevent or cure cancer (42). RET gene testing is perhaps the most clear example of early intervention for cancer based on mutation testing, with general recommendations to test and intervene before age 1, specifically in MEN 2B (43). MEN1 gene testing would not regularly result in major therapeutic interventions and timely medical benefit. Therefore, MEN1 gene testing has not been routinely advocated in individuals younger than 18 yr of age, after which a legally independent and informed choice could be made (12, 44). However, the recognition of significant morbidity from MEN 1 at young ages, as described here, should prompt reconsideration of this position.

In summary, we found no additional explanation for the unusually early development of this MEN 1-related mammosomatotroph adenoma in this 5-yr-old patient, representing the youngest age of morbid MEN 1 presentation reported thus far. A better understanding of early onset MEN 1 disease is needed to formulate recommendations for early MEN 1 testing.


   Footnotes
 
1 Presented in part at the Annual Meeting of the Society of Pediatric Research, 1998, and at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, 2000. Back

Received May 15, 2000.

Revised August 30, 2000.

Accepted September 6, 2000.


   References
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 Abstract
 Introduction
 Case report
 Materials and Methods
 Results
 Discussion
 References
 

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B. Verges, F. Boureille, P. Goudet, A. Murat, A. Beckers, G. Sassolas, P. Cougard, B. Chambe, C. Montvernay, and A. Calender
Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study
J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 457 - 465.
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M. L. Brandi, R. F. Gagel, A. Angeli, J. P. Bilezikian, P. Beck-Peccoz, C. Bordi, B. Conte-Devolx, A. Falchetti, R. G. Gheri, A. Libroia, et al.
CONSENSUS: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2
J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5658 - 5671.
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