Inherited endocrinopathies: an update

Inherited endocrinopathies, including multiple endocrine neoplasia type 1 (MEN-1), multiple endocrine neoplasia type 2 syndromes (MEN-2A, MEN-2B, familial medullary thyroid carcinoma), and inherited syndromes with pheochromocytoma (von Hippel–Lindau disease, neurofibromatosis type 1, others), comprise a heterogeneous group of cancer susceptibility syndromes that affect one or more components of the endocrine system. During the past several years, novel findings regarding genotype–phenotype correlation have highlighted the importance of establishing a genetic diagnosis in the treatment of these diseases. Here, we present a case-based review of recent advances in the genetics, diagnosis and management of inherited endocrinopathies.     

Genotype-phenotype correlation in multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma. The specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. Offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. Earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses.     

RET Proto-Oncogene and Thyroid Cancer

TheRET proto-oncogene has not only conclusively been identified as responsible for the three subtypes of the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN-2) but also shown to be involved in the molecular evolution of sporadic medullary and papillary thyroid carcinoma as well as Hirschsprung’s disease. A variety of recent studies have elucidated the pathophysiological mechanisms leading to neoplastic disease and we now understand that dominant activating germline mutations lead to MEN-2A, MEN-2B, and familial MTC; somatic mutations to sporadic medullary thyroid carcinoma;RET rearrangements to papillary thyroid carcinoma; and inactivating alterations to Hirschsprung's disease. The clinical significance, however, ofRET alterations especially in sporadic thyroid tumors is still controversial and therapeutic concepts in MEN-2 gene carriers only start to emerge. This article is a short summary of the recent findings on the structure and physiology of theRET proto-oncogene and its role in familial and sporadic thyroid cancer. This article was presented in part at the Endocrine Pathology Society Companion Meeting of the USCAP in Orlando, FL, March 1, 1997.     

The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience

An important question facing physicians who care for families with multiple endocrine neoplasia type 2a is whether prospective screening to detect early abnormalities of the thyroid, parathyroid, or adrenal glands favorably influences the ultimate course of the disease. An 18-year study of a large family has allowed us to examine the effect of early treatment on the clinical course of the disease. Of 22 patients who underwent thyroidectomy for early C-cell abnormalities, 19 remained free of detectable medullary thyroid carcinoma according to all criteria, at a mean of 11 years after thyroidectomy. None of the 22 patients had evidence of parathyroid disease either at the time of surgery or after a mean follow-up of 10 years. Prospective screening for adrenal medullary abnormalities by means of measurement of 24-hour urinary epinephrine excretion and the ratio of urinary epinephrine to norepinephrine was predictive of pheochromocytoma in 10 of 11 patients (with a false negative result in one patient) but was not useful in diagnosing adrenal medullary hyperplasia. We conclude that regular, prospective screening and early treatment of the manifestations of multiple endocrine neoplasia can prevent metastasis of medullary thyroid carcinoma and the morbidity and mortality caused by pheochromocytoma.     

Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes,related sporadic tumours,and Hirschsprung disease

The RET proto-oncogene codes for a receptor tyrosine kinase thought to play a role in the development of neural crest and its derivatives. Mutations in the RET proto-oncogene have been found in patients with the multiple endocrine neoplasia type 2 syndromes (MEN 2), the related sporadic tumours medullary thyroid carcinoma and pheochromocytoma, and familial and sporadic Hirschsprung disease, a syndrome of congenital absence of enteric innervation. Germline mutations in one of eight codons within RET cause the three subtypes of MEN 2, namely, MEN 2A, MEN 2B, and familial medullary thyroid carcinoma. Somatic mutation in an overlapping group of nine codons have been found in a proportion of sporadic medullary thyroid carcinoma and pheochromocytoma. In contrast to MEN 2, approximately 25% of patients with Hirschsprung disease have germline mutations scattered throughout the length of RET. Hum Mutat 9:97–109, 1997. © 1997 Wiley-Liss, Inc.     

Multiple endokrine Neoplasien Typ 2

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome with the major components medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Due to the clinical course three distinct subtypes are distinguished, MEN 2A, MEN 2B and familial medullary thyroid carcinoma. The disease is caused by germ-line mutations of the RET proto-oncogene and the localization of these mutations correlates with the onset of the development of medullary thyroid carcinoma, which is crucial for the clinical course and outcome of the disease. It therefore has a substantial influence on the clinical management of the affected patients and their relatives. This review summarizes the morphology and clinic of MEN 2-associated tumors and their respective precursor lesions.     

Cholecystitis, cholelithiasis, and ganglioneuromatosis of the gall bladder: an unusual presentation of MEN type 2b.

A 40 year old man with multiple endocrine neoplasia type 2b (MEN 2b) presented with cholecystitis caused by gall stones. Twenty four years earlier, he had had a partial thyroidectomy for a cold nodule. At his initial presentation MEN 2b with medullary carcinoma of the thyroid had not been made. This was diagnosed while investigating his gall bladder symptoms and he was found to have asymptomatic residual medullary thyroid carcinoma and bilateral adrenal phaeochromocytomas. The cholecystectomy specimen contained several mixed calculi and extensive ganglioneuromatosis with large, prominent nerves containing ganglion cells in the gall bladder wall.     

Serum calcitonin in thyroid disorders and in pheochromocytoma kindred

Serum calcitonin was determined by RIA in 59 healthy subjects (Group 1), 49 randomly selected patients with treated or untreated thyroid disorders (Group 2), and in 12 kindred of a pheochromocytoma index case (Group 3). Although most subjects in Group 2 had normal calcitonin levels, there were significant (p less than 0.001) differences between all three groups. Of the five patients in Group 2 with high serum calcitonin, one had medullary cancer of the thyroid, one had multiple endocrine neoplasia, one had acromegaly, and two remained undiagnosed. Increased serum calcitonin levels were also found in seven of 12 normotensive relatives of a patient with pheochromocytoma. It is therefore concluded that high serum calcitonin levels in patients with thyroid disorders strongly suggest the presence of C-cell neoplasia or medullary cancer of the thyroid.     

RET codon 609 mutations: a contribution for better clinical managing

Medullary thyroid carcinoma currently accounts for 5-8% of all thyroid cancers. The clinical course of this disease varies from extremely indolent tumors that can go unchanged for years to an extremely aggressive variant that is associated with a high mortality rate. As many as 75% of all medullary thyroid carcinomas are sporadic, with an average age at presentation reported as 60 years, and the remaining 25% are hereditary with an earlier age of presentation, ranging from 20 to 40 years. Germline RET proto-oncogene mutations are the genetic causes of multiple endocrine neoplasia type 2 and a strong genotype-phenotype correlation exists, particularly between a specific RET codon mutation and the (a) age-related onset and (b) thyroid tumor progression, from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, to nodal metastases. RET mutations predispose an individual to the development of medullary thyroid carcinomas and can also influence the individual response to RET protein receptor-targeted therapies. RET codon 609 point mutations are rare genetic events belonging to the intermediate risk category for the onset of medullary thyroid carcinoma. A large genealogy resulting in a less aggressive form of medullary thyroid carcinoma is associated with the high penetrance of pheochromocytoma and has been reported in the literature. In this short review article, we comment on our previous report of a large multiple endocrine neoplasia type 2A kindred with the same Cys609Ser germline RET mutation in which, conversely, the syndrome was characterized by a slightly aggressive, highly penetrant form of medullary thyroid carcinoma that was associated with low penetrance of pheochromocytoma and primary hyperparathyroidism.     

Adrenal medullary hyperplasia: A clinicopathologic study of four cases

This study presents the clinicopathologic findings in four new cases of adrenal medullary hyperplasia. The patients presented with episodic hypertension frequently associated with palpitations headache, and diaphoresis. All four had elevated urinary catecholamine levels during attacks, and were thought clinically to have a pheochromocytoma. In each case laparotomy revealed a diffusely enlarged adrenal gland without a discrete tumor. Histologic examination of the adrenals demonstrated a diffuse or diffuse and nodular expansion of the medulla confirmed by morphometric study. Of the four patients, three underwent unilateral and one bilateral adrenalectomy. Two patients who underwent unilateral adrenalectomy have been free of symptoms for three years. Thus, it would appear that adrenal medullary hyperplasia may occur unilaterally or asynchronously in the two glands. The bilaterally adrenalectomized patient has had persistent attacks, suggesting that the stimulus to adrenal medullary hyperplasia may possibly affect other chromaffin tissues. On the basis of our cases and a review of the literature, we propose the following criteria for the diagnosis of adrenal medullary hyperplasia: a clinical history of episodic attacks suggesting pheochromocytoma (generally with associated increased urinary catecholamine levels), an adrenal gland showing diffuse expansion of the medulla into the alae or tail of the gland with or without nodule formation, a medulla composed of enlarged cells with or without pleomorphism, and, most important, an increased medulla/cortex ratio, together with an increased calculated medullary weight asddetermined by morphometric analysis.     

How familial cancer genes and environmentally induced oncogenes have changed the endocrine landscape.

The gene responsible for MEN-2, the ret proto-ocogene, has elucidated mechanisms of endocrine tumorigenesis. Activating mutations of this transmembrane tyrosine kinase receptor represent the first known example of an inherited oncogene. This knowledge has altered our approach to affected patients by allowing in utero screening and prophylactic thyroidectomy rather than provocative testing and morphologic analysis of C cell hyperplasia--will it result in eradication of medullary carcinoma of thyroid? The lessons from Chernobyl taught us how radiation can induce chromosomal rearrangements that involve the same gene. This has led to a better understanding of papillary thyroid carcinoma and provides a novel immunohistochemical marker that widens our diagnostic armamentarium.     

Adrenal medullary hyperplasia. A morphometric analysis in patients with familial medullary thyroid carcinoma.

The syndrome of familial medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia is inherited as an autosomal dominant trait, and is characterized by development of bilateral and multicentric thyroidal and adrenal medullary tumors. One of the earliest manifestations of adrenal medullary hyperfunction in patients with this syndrome is an increased ratio of epinephrine to norepinephrine in urine. In order to define the morphologic correlates of these early catecholamine abnormalities in a large kindred with familial MTC, a morphometric analysis based on a point-counting system to asses adrenal medullary volume was undertaken. These studies clearly revealed adrenal medullary hyperplasia as reflected by a two- to three-fold increase in medullary volume and weight as compared to age- and sex-matched controls. The increase in total medullary mass resulted from diffuse and multifocal modular proliferations of adrenal medullary cells primarily within the head and body regions of the glands. These results support the hypothesis that the pheochromocytomas in patients with familial MTC may, in fact, represent extreme degrees of nodular hyperplasia of the medulla.     

Integrated DNA-based/biochemical screening for early diagnosis of multiple endocrine neoplasia type 2A (MEN2A)

Multiple endocrine neoplasia type 2A (MEN2A), a subtype of MEN2, is characterized by medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism. A Han Chinese pedigree with MEN2A was investigated following confirmation of the proband''s diagnosis by pathological findings and DNA/biochemical screening. DNA samples from 4 other family members were collected and exon 5, 8, 10, 11, 13, 16 and 18 of the RET proto-oncogene were sequenced and then analyzed. A missense mutation of TGG (Trp) to TGC (Cys) at codon 634 (the classic MEN2A mutation) in exon 11 of the RET gene was detected in 3 family members, including the proband. Sequencing data were compared with the human gene mutation database. Elevated serum calcitonin level was detected initially; medullary thyroid carcinoma was revealed in the 3 cases and adrenal pheochromocytoma was also found in the proband. Elective operations were successfully performed on the adrenal and thyroid glands because of pheochromocytoma and medullary thyroid carcinoma. Our case study confirms that integrated DNA-based/biochemical screening is crucial for early diagnosis of MEN2A and is helpful in the screening of their relatives. In addition, DNA-based screening may occasionally uncover a previously unknown RET sequence.     

— AN AUTOPSY CASE —

A diagnosis of the heritable disorder Sipple's syndrome was made in a Japanese male aged 28 years. The coexistence of bilateral pheochromocytomas, bilateral medullary thyroid carcinomas and secondary hyperplasia of parathyroid was confirmed at the time of autopsy. Pancreatic islets were hyperplastic with marked proliferation of A and D cells. Transition of the ductal cell to the islet, i.e. 'nesidioblatosis' was observed. There was no proliferation of B cells, but a retention of B cell granules, a manifestation of suppressed secretion of insulin attributed to the overproduction of catecholamines was evident. In the stomach, numerous petechial hemorrhages and proliferation of gastrin cells were found. The pathogenesis of changes in the pancreatic islets and stomach is discussed from the viewpoint of hormonal disorders induced by pheochromocytoma and medullary thyroid carcinoma such as are found in Sipple's syndrome. ACTA PATH. JAP. 27: 739˜748,1977.     

Multiple endocrine neoplasia type 2A: an unusual clinical presentation and association with renal dysplasia

We report what we believe to be the first case of a patient with multiple endocrine neoplasia type 2A (MEN 2A) and renal dysplasia associated with an RET 634 mutation. The proband presented at the age of 29 with medullary thyroid carcinoma (MTC), bilateral pheochromocytomas, and primary hyperparathyroidism. Screening of family members identified the syndrome in his father. Both the proband and his father carry RET 634 germline mutation resulting in cysteine to arginine amino acid substitution. The proband had a left nephrectomy at the age of 10 years. Histologic examination of the resected kidney revealed severe dysplasia. His father had normal renal tract on ultrasonography. The proband's clinical presentation was unusual, and initially thought to be an atypical pneumonia. Surgical management after pharmacologic alpha- and beta-blockage consisted of bilateral adrenalectomy, total thyroidectomy, and subtotal parathyroidectomy as a single procedure.     

Sipple's syndrome with peculiar changes in pancreatic islets--an autopsy case.

A diagnosis of the heritable disorder Sipple's syndrome was made in a Japanese male aged 28 years. The coexistence of bilateral phenochromocytomas, bilateral medullary thyroid carcinomas and secondary hyperplasia of parathyroid was confirmed at the time of autopsy. Pancreatic islets were hyperplastic with marked proliferation of A and D cells. Transition of the ductal cell to the islet, i.e. "nesidioblatosis" was observed. There was no proliferation of B cells, but a retention of B cell granules, a manifestation of suppressed secretion of insulin attributed to the overproduction of catecholamines was evident. In the stomach, numerous petechial hemorrhages and proliferation of gastrin cells were found. The pathogenesis of changes in the pancreatic islets and stomach is discussed from the viewpoint of hormonal disorders induced by pheochromocytoma and medullary thyroid carcinoma such as are found in Sipple's syndrome.     

Extensive ganglioneuromatosis of gallbladder

A case of extensive ganglioneuromatosis (GN) of gallbladder is presented. A 38-year-old man presented with a hepatic hilar mass (? ~ 48 mm) and gall stones. He had undergone total thyroidectomy for medullary thyroid carcinoma 8 years earlier. The hepatic hilus tumor, which had been clinically suspected to be a lymph node metastasis from the medullary thyroid carcinoma, was found to be pheochromocytoma. The gallbladder, resected with a clinical diagnosis of cholelithiasis, showed extensive transmural GN despite a grossly normal appearance. Taking into account the past history, the patient was diagnosed as having multiple endocrine neoplasia 2b (MEN2b)-associated GN of gallbladder and ectopic pheochromocytoma. As GN of gallbladder in MEN2b has been rarely reported, the histological findings are described in detail and a brief review of literature is carried out.     

Multiple endocrine neoplasia: the Chilean experience

Multiple endocrine neoplasia (MEN) types 1 and 2 are genetic diseases that are inherited as autosomal traits. The major clinical manifestations of multiple endocrine neoplasia type 1 include the so-called "3 P's": parathyroid, pituitary, and pancreatic tumors, including gastroenteroneuroendocrine tumors. Genetic testing can be performed on patients and the potential carriers of the menin gene mutation, but the genotype-phenotype correlation in multiple endocrine neoplasia type 1 is less straightforward than multiple endocrine neoplasia type 2. Most likely, the main advantage of genetic testing in MEN1 is to exclude from further studies those who are negative for the genetic mutation if they belong to a family with a known history of MEN1. In Chile, we started with rearranged during transfection proto-oncogene genetic testing (MEN2) 15 years ago. We carried out a prophylactic total thyroidectomy to prevent medullary thyroid carcinoma in a three-year-old girl who presented with microscopic medullary thyroid carcinoma. More than 90% of the individuals who tested positive using a genetic test achieved a biochemical cure compared with only 27% of patients who receive a clinical diagnosis. Mutations are mainly located in exon 11; the most common is C634W, rather than C634R. Hypertensive crisis was the cause of death in three patients, and extensive distant metastases occurred in nine (including two patients with multiple endocrine neoplasia type 2B) of 14 patients. Earlier recognition of medullary thyroid carcinoma and the other features of the disease, especially pheochromocytoma, will improve the survival rate of patients with multiple endocrine neoplasia.     

Clinical features and mutations of RET proto-oncogene in a pedigree affected with type 2A multiple endocrine neoplasia北大核心CSCD

Objective To investigate the clinical features and mutations of RET proto-oncogene in a pedigree affectedwith multiple endocrine neoplasia type 2A (MEN 2A). Methods Clinical data of the family members was collected.Genomic DNA from peripheral blood leukocytes were extracted and subjected to PCR amplification. Exons 8, 10,11, 13, 14, 15, 16 of the RET gene was sequenced. Results A missense mutation p. C634W was detected in 8members from the family. Among them, 3 were diagnosed with pheochromocytoma, 1 with medullary thyroidcarcinoma, 1 with medullary thyroid carcinoma and pheochromocytoma, 1 with medullary thyroid carcinoma andhyperparathyroidism. One member was found with thyroid enlargement but refused further examination, and another one was identified as carrier of the RET gene mutation. Conclusion A p. C634W mutation has been detected in afamily affected with MEN2A, in which most carriers have developed clinical symptoms. RET mutation detectionshould be routinely performed for families affected with MEN2A.     

The importance of multiple endocrine neoplasia syndromes in differential diagnosis

Summary In the differential diagnosis of endocrine symptoms, the autosomal dominant multiple endocrine neoplasia (MEN) syndromes are rare but important. We found seven index cases of MEN-I in 176 patients with adenomas of the anterior pituitary and 26 patients with primary hyperparathyroidism. Of 23 cases of medullary thyroid carcinoma and eight cases of pheochromocytoma, 14 patients are classified as MEN-IIa and one as MEN-IIb. Family screening identified six MEN-I and seven MEN-II cases among 32 individuals examined. Because of autosomal dominant inheritance and sometimes-delayed manifestation of the complete syndrome, screening of healthy and affected family members should be repeated at least every other year.