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Inactivation of the Tumor Suppressor Gene on 11q13 in Brothers with Familial Acrogigantism without Multiple Endocrine Neoplasia Type 1¹

Department of Neurosurgery (S.Y., K.T., M.U.), Toranomon Hospital, Tokyo; Otsuka Department of Clinical and Molecular Nutrition (K.Y., M.I.), and Department of Pathology (T.S.), School of Medicine, The University of Tokushima, Tokushima; Department of Neurosurgery (A.T.), Nihon Medical University, Tokyo, Japan.

Address correspondence and requests for reprints to Dr. Shozo Yamada at: Department of Neurosurgery, Toranomon Hospital, 2–2-2, Toranomon, Minato-ku, Tokyo, 105, Japan.

	Abstract

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Two of three brothers (the second and third brothers) and their uncle (their mother’s brother) presented acrogigantism without multiple endocrine neoplasia type 1 (MEN 1). An invasive macroadenoma was found in the second brother, and it was histologically confirmed as a sparsely granulated GH cell adenoma. Two distinct microadenomas were found in the third brother, and these were histologically diagnosed as a mixed GH cell and PRL cell adenoma and a sparsely granulated GH cell adenoma, respectively. The loss of heterozygosity (LOH) was analyzed in two adenomas (GH cell adenoma from the second brother and a mixed GH cell and PRL cell adenoma from the third brother) by determining microsatellite polymorphisms of DNAs from tumors and patients’ leukocytes. The LOH was found on the chromosome 11q13, whereas LOH was not detected on 1p31-36, 2p, 3p, 4, 5, 6p, 7, 8, 9p21-22, 12p, and 19q13 in both pituitary adenomas examined. The haplotype analysis showed that the same haplotype on 11q13 was found in their mother and the unaffected first brother as well as in the affected uncle and two brothers. The deleted alleles on chromosome 11q13 in the tumors of two affected brothers were, however, restricted to those transmitted from their unaffected father. These data suggest that inactivation of the MEN 1 gene or other tumor suppressor genes on chromosome 11q13 plays an important role for the development of our familial acrogigantism without MEN 1.

	Introduction

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FAMILIAL PITUITARY adenomas are usually presented as a subtype of multiple endocrine neoplasia type 1 (MEN 1) disease. Larsson et al. (1) mapped the MEN 1-susceptibility locus to chromosome 11q13 with linkage analysis. Allelic deletions on chromosome 11 also have been reported in some sporadic pituitary adenomas (2, 3, 4) as well as in a family with MEN 1 (5, 6). In contrast, familial pituitary adenomas in the absence of MEN 1 are rare, and to the best of our knowledge, 43 cases in 19 families have been reported in the literature (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). The genetic background of these pituitary adenomas remains unknown. Here we report the clinical and genetic analysis of two brothers and one uncle with acrogigantism in one pedigree without MEN 1.

	Subjects and Methods

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Case description

The 26-yr-old second brother was referred to our hospital because of his physical stigmata of acrogigantism (height: 205 cm, weight: 118 kg). Endocrine studies showed elevated serum basal GH level (13.1 µg/L) (normal range or NR:< 2.5) and IGF-1 level (115.5 nmol/L) (NR: 18.6–57.2) (20). Serum GH levels were not suppressed by 100 g oral glucose administration and were increased after TRH administration (500 µg, iv) from 17.2 to 31.5 µg/L at 30 min and after GHRH administration (100 µg, iv) from 14.2 to 25.6 µg/L at 30 min. Anterior pituitary hormones were otherwise normal, including serum PRL level (3.8 µg/L) (NR: < 10). Neuroimaging examinations revealed an invasive macroadenoma with an enlarged sella turcica (Fig. 1-A), and transsphenoidal adenomectomy was performed on December 8, 1993.

View larger version (108K): [in this window] [in a new window]   Figure 1. Preoperative gadolinium-enhanced, T1-weighted MRI (coronal view) in the second (A) and the third (B) brother. Note the less enhancing macroadenoma with a slight suprasellar extension and cavernous sinus invasion in the left side (A). MRI showing two different, separated, less enhancing lesions (B). One is located to the left of the midline (an arrowhead) and another is much smaller and is located in the right wing of the pituitary (an arrow).

The 52-yr-old uncle had undergone irradiation to the pituitary for the treatment of acrogigantism at the age of 18. Serum basal GH level was 15 µg/L before irradiation but was normal at 0.6 µg/L with a normal IGF-1 level (24.6 nmol/L) (NR: 13.9–37.1), although he still exhibited a physical stigmata of acrogigantism (height: 187 cm, weight: 92 kg). Magnetic resonance imaging (MRI) showed the enlarged empty sella without any distinct adenoma.

In all three patients mentioned above, the following items in the serum were all within the normal range: calcium was 2.3, 2.4, and 2.4 mmol/L (NR: 2.2–2.6); intact PTH: 2.6, 2.1, 2.2 pmol/L (NR: 2.1–5.6); fasting glucose: 4.7, 4.4, 4.4 mmol/L (NR: 3.9–6.1); insulin: 43.1, 57.0, 40.8 pmol/L (NR: 18.0–72.0); glucagon: 102, 131, 107 ng/L (NR: 40–140); and gastrin: 46.3, 67.2, 60.7 ng/L (NR: 30–150) in the second brother, the third brother, and their uncle, respectively.

In addition, other family members (parents and the first brother) were also studied with their informed consents. Blood samples were taken around 0900 h after an overnight fasting. Serum levels of anterior pituitary hormones, insulin-like growth factor I, calcium, phosphorus, intact PTH, fasting glucose, insulin, glucagon, and gastrin did not indicate the presence of MEN 1 including pituitary adenomas. There was no consanguinity in this family, and no brothers or sisters of the parents showed acrogigantism except for one case of the uncle described above.

Histologic and genetic analysis

Three independent adenoma tissues were obtained, one from the second brother and two from the third brother, and were studied with light microscopy, immunohistochemistry, and electron microscopy. All techniques were performed as described previously (21). Adenoma tissues, one from the second brother and one from the third brother, were kept frozen at -80 C for the analysis of LOH. However, no frozen sample was obtained from the tumor located in the right lateral wing of the pituitary in the third brother because of its small size. DNAs were extracted from two adenoma tissues and blood cells of three brothers, parents, and the uncle with the phenol-chloroform method.

LOH was studied by comparing microsatellite polymorphisms of the tumor DNA with those of leukocyte DNA. The following nine markers closely linked to the MEN 1 locus were analyzed: D11S480, D11S457, D11S449, PYGM, D11S913, D11S1889, D11S987, D11S534, and D11S527 (22). In addition, microsatellite analysis on 1p31-36, 2p, 3p, 4, 5, 6p, 7, 9p21-22, 12p, and 19q13 were also performed. One of each oligonucleotide primer pair was labeled with a 6-FAM fluorescent dye (Perkin Elmer, Foster City, CA). Polymerase chain reaction (PCR) amplification was performed for 30 cycles in a thermal cycler (Astec, Fukuoka, Japan) with 50 ng of genomic DNA as a template in a total volume of 10 µL. Each cycle consisted of denaturation at 95 C for 1 min, annealing at 55–63 C for 1 min, and elongation at 72 C for 1 min. For gel analysis, 0.5 µL internal standards (PRISMTM GENESCAN-350 ROX, Perkin Elmer), 0.5–2 µL PCR products, and 4 µL formamide were mixed and specimens were heated at 95 C for 4 min immediately before gel loading. Gels were composed of 6% acrylamide with 8 mol urea in 90 mmol Tris-borate (pH 8.3) and 2 mmol EDTA. Gel electrophoresis, data collection, and analysis were carried out on a Model 373A DNA sequencer with GENESCAN 672 software (Perkin Elmer). The reduction of allelic intensity in the tumor DNA by greater than 50% compared with the matching leukocyte DNA was considered indicative of LOH.

	Results

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Morphologic findings

The tumor of the second brother was diagnosed as a sparsely granulated GH cell adenoma, showing a chromophobic adenoma with immunopositivity only for GH. In two tumors obtained from the third brother, the adenoma located mainly on the midline was partially eosinophilic and partially chromophobic with immunopositivities for GH and PRL and was diagnosed as a mixed GH and PRL cell adenoma. The other one was chromophobic with immunopositivity only for GH and was diagnosed as a sparsely granulated GH cell adenoma.

LOH on chromosome 11q13

Both adenomas had LOH at D11S457, D11S449, PYGM, D11S534, and D11S527 (Fig. 2 and 3). Patterns of electropherograms shown in Fig. 2 indicated LOH. Microsatellite analysis on 1p31-36, 2p, 3p, 4, 5, 6p, 7, 8, 9p21-22, 12p, and 19q13 confirmed no LOH in these two adenomas examined.

View larger version (38K): [in this window] [in a new window]   Figure 2. Electropherograms of PCR products of D11S457 (A, F), D11S449 (B, G), PYGM (C, H), D11S534 (D, I), and D11S527 (E, J) for leukocytes (W) and the pituitary adenomas (T).Panels A-E and F-J show electropherograms of the second and the third brother, respectively. The ordinate represents the fluorescence signal intensity and the abscissa represents the scan number of detected bands from the start of electrophoresis. The numbers 1 and 2 on each panel indicate the numbers allocated to respective alleles.

View larger version (37K): [in this window] [in a new window]   Figure 3. Haplotype analysis on 11q13 regions. The picture shows part of the pedigree. Healthy uncles and aunts on both father’s and mother’s sides were omitted. The filled symbols indicate affected family members. The haplotype for each individual is depicted along illustrated chromosome segments for D11S480, D11S457, D11S449, PYGM, D11S913, D11S1889, D11S987, D11S534, and D11S527 markers, respectively. The haplotype inferred to be associated with disease transmission is enclosed. An arrow indicates a point of meiotic crossing-over. Results of LOH analysis in the pituitary adenomas from the second and the third brother were also shown. -, LOH; ni, no information because of homozygosity.

Haplotypes on 11q13 of 6 family members were constructed on leukocyte DNAs with the same nine genetic markers. Four distinct haplotypes were identified in the parents (Fig. 3). The haplotype of "212311111" was transmitted from the mother to her three sons and was also found in the affected uncle, although meiotic recombination between the loci of D11S987 and D11S534 was found in the second brother. Interestingly, allelic deletions on chromosome 11q13 found in these tumors occurred only in the allele transmitted from the unaffected father (Fig. 3).

	Discussion

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Although familial acrogigantism generally occurs in pedigrees with MEN 1, our extensive laboratory and endocrine evaluation revealed no evidence of MEN 1 in six examined family members. It was reported that 97% of patients with MEN 1 exhibit primary hyperparathyroidism at the time of clinical detection (23) and that 80% of carriers present the disease by the fifth decade (24). Taken together with the absence of MEN 1 in the 52-yr-old uncle, our case is considered an additional example of familial pituitary adenomas unrelated to MEN 1.

Familial pituitary adenomas unrelated to MEN 1 have been reported (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19), but the form of inheritance has been controversial (12, 13, 18, 19). Pestel et al.(13) reported that only 5 related cases were observed in a pedigree with 233 members and suggested that the mode of inheritance was autosomal dominant with incomplete penetrance. Recently, mutations of the Gs gene were studied in one familial gigantism unrelated to MEN 1, and no point mutations in codon 201 or 227 of the Gs gene were detected (17). This suggests that their non-MEN 1, familial GH cell adenomas did not arise through the activation of the Gs gene.

The MEN 1 consensus region has been mapped within the 3 cM interval between PYGM (centromeric) and D11S460/D11S807 (telomeric) markers (25), although the susceptibility gene itself has not been identified. The combined tumor and pedigree genotype analyses in MEN 1 showed that allele losses at 11q13 region eliminated the wild type allele (1). Linkage analysis data using polymorphic markers on chromosome 11 are limited because of a small number of familial pituitary tumors. Benlian et al.(19) recently reported that their familial acrogigantism had no relation with the MEN 1 gene by segregation analysis. However, the analysis of LOH in tumor DNAs by comparing alleles of patients’ leukocyte DNAs is necessary to establish the role of inactivation of such tumor suppressor genes for tumorigenesis.

This is the first report on the LOH on chromosome 11q13 in familial pituitary adenomas unrelated to MEN 1. Recently, Mulligan et al.(26) have clarified germline mutations in the RET proto-oncogene (MEN2 gene) in familial medullary thyroid carcinomas as well as in families with MEN 2. This suggests that familial medullary thyroid carcinoma is a variant form of MEN 2A. Therefore, the familial acrogigantism could be a variant form of MEN 1. In haplotype analysis, the same haplotype was found not only in the two affected brothers and the uncle, but also in the unaffected first brother and mother. Absence of pituitary adenomas both in the first brother and the mother may suggest the requirement of other genetic changes for tumorigenesis, which may be related to the low penetrance of the disease (13). Allelic deletions on chromosome 11q13 were found in the allele from the unaffected father but not in the allele transmitted from the mother. We concluded that the inactivation of the MEN 1 gene or other tumor suppressor genes on chromosome 11q13 may be playing an important role for the development of familial acrogigantism in our case.

	Acknowledgments

 
We thank Ms. Takako Nakamura, Ms. Nami Furuya, and Mrs. Michie Takahashi for their technical assistance.

	Footnotes

 
¹ This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan, and by a grant from Otsuka Pharmaceutical Factory, Inc., for Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima.

Received March 21, 1996.

Revised July 16, 1996.

Accepted September 13, 1996.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamada, S. Articles by Teramoto, A. Search for Related Content PubMed PubMed Citation Articles by Yamada, S. Articles by Teramoto, A.