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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 4142-4145
Copyright © 2004 by The Endocrine Society

Comment

Pheochromocytoma and Medullary Thyroid Carcinoma: A New Genotype-Phenotype Correlation of the RET Protooncogene 891 Germline Mutation

Camilo Jimenez, Mouhammed Amir Habra, Su-Chen Eileen Huang, Adel El-Naggar, Suzanne E. Shapiro, Douglas B. Evans, Gilbert Cote and Robert F. Gagel

Departments of Endocrine Neoplasia and Hormonal Disorders (C.J., M.A.H., S.-C.E.H., G.C., R.F.G.), Surgical Oncology (S.E.S., D.B.E.), and Pathology (A.E.-N.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Robert F. Gagel, The University of Texas MD Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, 1515 Holcombe Boulevard, Unit 435, Houston, Texas 77030. E-mail: rgagel{at}mdanderson.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Prior experience in kindreds with a codon 891 RET protooncogene mutation indicates that carriers of this mutation develop only hereditary medullary thyroid carcinoma without evidence of other manifestations of multiple endocrine neoplasia type 2. In this paper, we report the first documented case in which medullary thyroid carcinoma and pheochromocytoma were clinically expressed in members of a family affected by the codon 891 RET mutation. Genetic analysis of the RET protooncogene in this family revealed an exon 15 missense mutation at codon 891 that resulted in a serine to alanine amino acid substitution. These findings indicate that patients with this mutation should be screened for pheochromocytoma.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE RET PROTOONCOGENE was discovered in 1985 as a result of the rearrangement of this gene during DNA extraction (1). Linkage analysis in kindreds with multiple endocrine neoplasia (MEN) type 2A (MEN2A) led to the identification of mutations of the RET protooncogene in this syndrome (2, 3, 4, 5). In 1993, activating mutations of the RET protooncogene were identified in all variants of MEN type 2 (MEN2): MEN2A (6, 7), familial medullary thyroid carcinoma (FMTC) (8), and MEN type 2B (MEN2B) (9, 10). MEN2A is a syndrome defined by the appearance of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia (11). MEN2A is caused by mutations in codons 609, 611, 618, 620, 630, 634, 635, 637, 790, and 804 of RET (12) (Table 1Go). Mutation of codon 634 constitutes 80–90% of causes of MEN2A, and it is the most common mutation associated with pheochromocytoma (12). MEN2B differs from MEN2A in that it is typically associated with an earlier onset and more aggressive forms of MTC, pheochromocytoma, the presence of mucosal neuromas of the gastrointestinal tract, and a marfanoid body habitus (13). RET mutations in MEN2B have been found to occur primarily in regions encoding the tyrosine kinase (TK) domain of the RET protooncogene in codons 883 and 918 (10, 14, 15, 16). Although the 918 mutation has been found in 95% of patients with MEN2B, it represents only 5% of all RET mutations (9, 10, 17). FMTC is a heritable form of MTC without the other phenotypic features of MEN2 (18). Mutations in codons 609, 611, 618, 620, 630, 790, and 804 have been found in association with MEN2A and FMTC (Table 1Go). Mutations in codons 532, 533, 768, 791, and 891, although rare, have been exclusively associated with FMTC (12, 19). Therefore, the identification of a RET protooncogene mutation in codons 532, 533, 768, 791, and 891 has been used to rule out a diagnosis of MEN2A, eliminating the need to screen for pheochromocytomas and primary hyperparathyroidism.


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  		TABLE 1. Mutations associated with MEN2 and variants

 

   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
A 27-yr-old white woman (Fig. 1Go, III-7) was referred to our institution for further assessment of a thyroid nodule. The patient had presented with symptoms of hypothyroidism in 2002 and was found to have a firm, mobile, 1-cm right midthyroid nodule. Fine-needle aspiration results at another institution suggested a benign colloid nodule. Her family history indicated that her father (II-5) developed a hypertensive crisis at 52 yr of age after an automobile accident. A right pheochromocytoma was found, and he underwent a laparoscopic cortical-sparing adrenalectomy at another institution with no complications, confirming the diagnosis (Fig. 2Go). One year later, a thyroid nodule was discovered during his routine physical examination. Fine-needle aspiration of this nodule was positive for MTC, and he underwent total thyroidectomy with a radical left neck dissection revealing MTC with involvement of regional lymph nodes. Although his family history did not indicate any obvious endocrine tumors, a genetic analysis for RET protooncogene mutations in exons 10, 11, and 16 was performed; however, no causative mutation was found.



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  		FIG. 1. Pedigree of the family with codon 891 RET mutation.

 


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  		FIG. 2. A photomicrograph of hematoxylin- and eosin-stained slide displaying organoid cellular architecture, granular cytoplasm, and vascular stroma characteristic of pheochromocytoma.

 
Because of the father’s diagnosis of MEN2A, it was recommended that the patient undergo examination of previously untested exons 13, 14, and 15 in the RET protooncogene. A mutation was found at exon 15, codon 891, TCG mutated to GCG resulting in a serine to alanine amino acid change. Upon genetic confirmation of the mutation, biochemical studies for MEN2A were done and revealed a mildly elevated calcitonin level of 6.1 ng/liter [6.1 pg/ml; reference range, <4.6 ng/liter (<4.6 pg/ml)], normal serum calcium level of 2.175 mmol/liter [8.7 mg/dl; reference range, 2.1–2.55 mmol/liter (8.4–10.2 mg/dl)], normal PTH level of 60 ng/liter [60 pg/ml; reference range, 10–65 ng/liter (10–65 pg/ml)], and normal 24-h urine levels of catecholamines and metanephrines.

The patient underwent a total thyroidectomy with central (level VI) neck dissection. Histopathology revealed a 1-mm focus of MTC within the right thyroid lobe with multifocal C cell hyperplasia in a background of Hashimoto’s thyroiditis in both thyroid lobes. Seventeen lymph nodes were negative for tumor. After surgery, calcitonin values remained normal with no evidence of pheochromocytoma or hyperparathyroidism after 1 yr of follow-up.

After written informed consents were obtained, blood samples were collected from the patient, her father, and other relatives according to an Institutional Review Board protocol. DNA was then extracted from peripheral blood leukocytes using a QIAGEN Dnesy Tissue kit (QIAGEN, Valencia, CA). PCR amplification was performed on affected individuals and included unaffected normal controls. Restriction enzyme-based analysis was performed as previously described (20).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subsequent analyses of the family members revealed autosomal dominant transmission of the codon 891 mutation in the patient’s sister (III-6), father (II-5), one uncle (II-1), and two cousins (III-2 and IV-1) (Fig. 1Go). The uncle (II-1) had a total thyroidectomy at age 55 yr. His pathology specimen showed C cell hyperplasia but no evidence of MTC. The other mutation carriers (III-2, III-6, and IV-1) were asymptomatic, and physical examinations did not show any evidence of abnormality. Also, they did not have any biochemical evidence of pheochromocytoma or hyperparathyroidism as confirmed by normal urine and plasma catecholamines and metanephrines and normal serum calcium and intact PTH values. They have been scheduled for total thyroidectomy. Two family members had died: one (II-3) of metastatic colon carcinoma at age 49 yr and the other (III-3) of an undetermined cause shortly after birth.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The RET protooncogene encodes a cell surface TK receptor that modulates specific intracellular signaling pathways involved in the development of the nervous and neuroendocrine systems (21, 22). This receptor has a large extracellular domain, a single transmembrane region, and a cytoplasmic TK domain. The extracellular domain has a cadherin ligand-binding site, which is important for cell-to-cell signaling, and a cysteine-rich region, which is important for receptor dimerization (23). The intracellular TK domain initiates a phosphorylation cascade that modulates cell proliferation and apoptosis. In the last decade, advances in genetic testing of the RET protooncogene have allowed physicians to characterize more than 95% of the activating germline mutations responsible for MEN2A, FMTC, and MEN2B syndromes in different regions of this gene (12). After analyzing different families affected with these mutations, it became clear that specific mutations had a clinical expression of MEN2A/FMTC and other variants (e.g. cutaneous lichen amyloidosis and Hirschsprung’s disease) or MEN2B, indicating a genotype-phenotype correlation and the necessity for periodic and careful screening for associated conditions (i.e. MTC, pheochromocytoma, and hyperparathyroidism) (17). Thus, the RET codon in which the mutation occurs and the clinical features within the family should be carefully analyzed when planning the treatment (24, 25, 26). Risk for MTC can then be evaluated based on the codon in which the RET mutation occurs with stratification of risk into one of three levels based on this information (24). This genetic information can also be used to assess risk for pheochromocytoma. Individuals with RET mutations in codons 609, 611, 618, 620, 630, 634, 790, V804L, or 918 should be screened routinely for pheochromocytoma (24).

A mutation at codon 891 was previously believed to be associated solely with intermediate-risk FMTC (20, 27, 28). However, we report a pheochromocytoma in a patient with a codon 891 mutation, proving that patients with this mutation have a predisposition for MEN2A. We were not completely surprised by this finding because one of our previously reported cases of MTC associated with a codon 891 mutation also had corneal nerve thickening (20), a condition that has generally been associated with MEN2A or MEN2B (29).

Like other intermediate-risk mutations, it is unclear how often these patients should be subjected to biochemical testing for pheochromocytoma and at what age total thyroidectomy should be performed in these gene carriers. Recently, the EUROMEN Study Group analyzed 207 gene carriers of RET mutations who underwent early thyroidectomy based on the results of genetic testing (30). Only six patients in this study had mutations in codon 891 and MTC, one as early as 13 yr of age. Of interest, all mutations that have been previously associated with pheochromocytoma demonstrated on average an earlier onset of MTC. Given this recently identified association of codon 891 mutation with pheochromocytoma, our findings suggest that carriers of this mutation could benefit from earlier total thyroidectomy.

When there is a clinical suspicion of MEN2 syndrome, we emphasize the importance of screening exons 13, 14, and 15 of the RET protooncogene for rare mutations when initial evaluation for more common mutations in exons 10, 11, and 16 is negative. As this case illustrates, pheochromocytoma should be considered a possibility in patients with rare mutations where experience with the clinical phenotype is limited.


   Footnotes
 
C.J. and M.A.H. hold joint Endocrinology, Diabetes, and Metabolism Fellowships at The University of Texas MD Anderson Cancer Center (Houston, TX) and Baylor College of Medicine (Houston, TX).

Abbreviations: FMTC, Familial MTC; MEN, multiple endocrine neoplasia type; MTC, medullary thyroid carcinoma; TK, tyrosine kinase.

Received January 12, 2004.

Accepted April 13, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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