Chinese Medical Journal 2009;122(13):1495-1500 1495

Original article
Diagnosis and surgical treatment of multiple endocrine neoplasia
ZHOU Guang-wen, WEI Yao, CHEN Xi, JIANG Xiao-hua, LI Xiao-ying, NING Guang and LI Hong-wei

Keywords: multiple endocrine neoplasia; surgical treatment; diagnosis; gene

Background Multiple endocrine neoplasia (MEN) is relatively rare. But more patients could be found by detailed
examination. We discuss the diagnosis and surgical treatment of MEN.
Methods The clinical data of 95 MEN cases were retrospectively analyzed. There were 30 cases of MEN1 including 19
cases from 6 families. The MEN1 gene mutation was detected in 81.48% of cases admitted after 1997. There were 22
cases of primary hyperparathyroidism (PHPT), 10 cases of enteropanceatic tumor including 9 cases of insulinoma, 15
cases of pituitary adenoma, 9 cases of adrenal adenoma, 2 cases of thymic carcinoid. Two patients had 4 glands
involved, 3 patients had 3 glands involved, 16 patients had 2 glands involved, and 6 patients had only one gland involved.
Three patients had neither clinical symptoms nor biochemical changes, and was diagnosed by MEN1 gene mutation. Six
patients presented with nephrolithasis and 6 patients had impaired pancreatic endocrine function. There were 60 cases of
MEN2a and 5 cases of MEN2b. 58 cases of MEN2a belongs to 19 kindreds. All MEN2a patients but one presented RET
gene mutation in codon 634, and all MEN2b cases had mutation in codon 918. 48 cases of MEN2a had thyroid masses
with elevated calcitonin levels. 27 patients had pheochromocytoma including 12 cases of multiple foci and 5 malignancy.
13 patients presented with hyperparathyroidism. 5 MEN2b patients had medullary thyroid carcinoma and mucosal
ganglioneuromatosis with Marfanoid. Among them, 3 patients had bilateral pheochromocytoma.
Results In MEN1, subtotal parathyroidectomy was performed in 12 patients with PHPT and one patient received
parathyroid adenoma enucleation. Insulinomas were enucleated in 4 patients. Two patients underwent thymus tumor
extirpation. Total thyroidectomy with bilateral dissection of regional lymph nodes was performed in 16 patients with
MEN2a and nodule enucleation was performed in 9 patients. Twenty two MEN2a patients underwent pheochromocytoma
enucleation including bilateral adrenal resection in 10 cases. 5 MEN2b patients underwent total thyroidectomy with
bilateral lymph node dissection. Among them, 3 cases underwent bilateral adrenal operations.
Conclusions MEN varies in symptoms. Germline mutation test is helpful in establishing a diagnosis. Surgical
management should be aimed at the improvement of life quality in MEN1 and prevention of the fetal tumors in MEN2.
Chin Med J 2009;122(13):1495-1500

M ultiple endocrine neoplasia (MEN) is an inherited

disease that presents with hyper functioning of
many endocrine glands. MEN is subdivided into MEN1
male proband and his brother and sister.

There were 60 MEN2a patients, including 15 males and

and MEN2 (MEN2a and MEN2b). The morbidity of
MEN1 was reported as 1 per 30 000 abroad, but only tens
of cases have been reported nationally until now. About
five hundred kindreds1 of MEN2 have been reported
overseas, but the cases in our country have not exceeded
50. Herein, we report 95 MEN cases diagnosed and
collected from 1974 to 2008.
METHODS
Patients
Between 1974 and 2008, 30 MEN1 and 65 MEN2
patients were diagnosed and collected.
There were 20 men and 10 women in MEN1 with 19
cases belonging to six kindreds. Kindred one was a male
proband and her sister, father and her fathers sister;
kindred two was a female proband and her daughter;
kindred three was a female and her mother and daughter;
kindred four was a female proband and her father and
sister; kindred five was a female proband and her mother,
brother and son of her brother; and kindred six was a
45 females. Fifty eight cases belonged to 19 kindreds.
One representative kindred was a female proband and her
brother and son. Others included cousins, daughters, and
the granddaughter of a cousin (Figure). Five MEN2b
patients included 4 males and 1 female. No family history
was identified in these patients.
Clinical diagnosis
Information regarding clinical symptoms and family
history of the MEN1 patients including primary
hyperparathyroidism (PHPT), pancreatic endocrine
tumors, pituitary tumors, and adrenal gland tumors was
DOI: 10.3760/cma.j.issn.0366-6999.2009.13.004
Department of Surgery (Zhou GW, Wei Y, Chen X and Li HW),
Department of Endocrine and Metabolism (Jiang XH, Li XY and
Ning G), Ruijin Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China
Correspondence to: Dr. CHEN Xi, Department of Surgery, Ruijin
Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai 200025, China (Fax: 86-21-64333548. Email: cc_vrai
@yahoo.com.cn)
Drs. ZHOU Guang-wen and WEI Yao contributed equally to this
work.
1496 Chin Med J 2009;122(13):1495-1500

screening was performed by detecting blood calcitonin,

Figure. The stemma of one representative MEN2a patient
collected. Blood glucose, blood calcium, parathyroid
hormone (PTH), growth hormone (GH), prolactin (PRL),
adrenocorticotrophic hormone (ACTH), blood and urine
free cortisol, blood insulin and gastrin were all included
in routine laboratory examination. Ultrasonography of the
neck and abdominal part were also performed. In cases
with an obvious diagnosis of MEN, additional diagnostic
tests involving magnetic resonance (MR) of the skull,
computed tomography (CT) or methoxyisobutyl isonitrile
(MIBI) of the neck and chest, and CT or MR of the
abdomen were performed to further characterize the
involved glands. A clinical diagnosis of MEN1 was made
when two or more glands were involved including the
pancreas, pituitary and parathyroid glands.
In patients suspected of having medullary thyroid
carcinoma (MTC) and pheochromocytoma, the family
history and symptoms must be collected in detail. MEN2
blood calcium, parathyroid hormone (PHT),
metanephrine, methoxyepinephrine and 24-hour urine
catecholamine. At the same time, ultrasonography of the
thyroid, parathyroid, and adrenal glands was performed.
If multiple subcutaneous nodules on the lips or apex of
the tongue were identified, a biopsy was performed.
Patients were diagnosed with MEN2a if MTC and
pheochromocytoma were identified, but diagnosed with
MEN2b if MCT and mucosal ganglioneuromatosis with
Marfanoid were identified. In patients with a clear
diagnosis of MEN2, neck CT and MIBI isotope scanning
and abdominal CT and MIBI should be performed to
localize the lesion in order to determine the optimal
strategy for surgical management. If MEN2 patients have
PHPT, MIBI isotope scanning should be done.
Germline mutation test
Twenty seven patients who were diagnosed with MEN1
after 1997 underwent MEN1 gene sequence detection.
Nine exons located in 11q13 were detected. When the
diagnosis of MEN1 was clear in the proband, sequence
detection should be performed in the first degree relatives
to confirm the clinical diagnosis in the presenting patient,
to identify new patients, and to create a pedigree. For the
fifty nine patients diagnosed with MEN2a after 1997,
sequence detection of exons 10 and 11 of RET oncogene
was performed and exon 16 of RET in patients with
MEN2b. Just like the MEN1 patients, sequence detection
in affected patients and first degree relatives was
performed to obtain a definite gene diagnosis.

Table 1. Localization of tumors in MEN-1 patients

Age Sex Parathyroid Pituitary Pancreas Others
28 M PTH ACTHoma
32 F PRLoma Insulinoma
45 F HPT Adenoma
21 F HPT PRLoma Adrenal hyperplasia
76 F HPT PRLoma Thyroid nodule
37 F PRLoma Insulinoma
55 M HPT Adenoma Aldosteronoma
26 M PRLoma,GH adenoma Insulinoma
45 F PTH Adrenal hyperplasia
38 M Thymic carcinoma
21 F Insulinoma
43 F HPT Adenoma Insulinoma, gastrinoma with hepatic metastasis Thyroid adenoma, ovary teratoma
18 F Adrenal hyperplasia
43 F HPT Insulinoma Adrenal hyperplasia, ovary mucinous cystadenoma
40 M HPT Insulinoma
66 F HPT
7 F Adrenal hyperplasia
52 F HPT PRLoma Thyroid nodule
24 F Adrenal hyperplasia
37 F HPT PRLoma Insulinoma Thyroid nodule, dermatofibromalipoma,
32 F HPT Pancreas tumor Thymic carcinoma, ACTH dependent cushing syndrome
63 M PTH Thyroid tumor
30 F HPT Glucagonoma Thyroid nodule
32 F HPT Insulinoma
18 F HPT PRLoma, ACTHoma
27 M PTH Pancreas tumor
40 F HPT ACTHoma
43 M HPT Adenoma Lipoma, dermatofibroma
50 M HPT Adrenal nodule
45 F HPT PRLoma Adrenal hyperplasia
Chinese Medical Journal 2009;122(13):1495-1500 1497

Table 2. Clinical characteristics of probands in 19 families with MEN2a

MTC PCC HPT
No. Sex
Yes/No Localization (half/ bilateral) Yes/No Localization (half/ bilateral) Yes/No Localization (half/ bilateral)
1 M Yes Bilateral Yes Half No
2 F Yes Bilateral Yes Bilateral No
3 F Yes Bilateral Yes Bilateral No
4 F Yes Bilateral Yes Half No
5 M Yes Half Yes Bilateral No
6 M Yes Bilateral Yes Bilateral Yes Half
7 M Yes Bilateral Yes - No
8 F Yes Half Yes Bilateral No
9 F Yes Bilateral Yes Half Yes Half
10 F Yes Bilateral Yes Half No
11 M Yes Bilateral Yes Half No
12 F Yes Bilateral Yes Half No
13 F Yes Half Yes Bilateral Yes Bilateral
14 M Yes Bilateral Yes Bilateral Yes Half
15 F Yes Bilateral Yes Half No
16 F Yes Bilateral Yes Half No
17 M Yes Bilateral Yes Half No
18 F Yes Bilateral Yes Half No
19 F Yes Bilateral Yes Half Yes Half

Clinical manifestations Nine of fifteen pituitary adenoma patients had elevated

In all the 30 MEN1 patients, four glands were involved in
two cases, three glands were involved in three cases, two
glands were involved in sixteen cases, and one gland was
involved in six cases. Three carriers had no symptoms or
biochemical changes (Table 1). Eleven cases had kidney
stones and nine cases had hypoglycemia, peptic ulcer, or
diabetes mellitus as their initial symptoms. Four cases
presented with obesity and amenorrhea, symptoms of
Cushings syndrome and two patients with thymus tumors
presented with respiratory distress as the primary
complaint. In addition, four cases discovered by genetic
screening were completely asymptomatic.
There were twenty two cases with parathyroid gland
involvement in the 30 MEN1 patients. All MEN1 patients
had an elevated PHT level. The PHT was 5 times the
upper limit in twelve cases, eight cases had levels 510
times higher than normal, one case had levels 12 times
higher, and another one was 27 times higher. Ninteen of
twenty two cases had raised blood calcium of which
twelve cases were 0.250.5 mmol/L higher than normal,
and seven cases were higher but within 0.25 mmol/L of
normal. The blood calcium levels of another three cases
discovered by genetic screening were at the higher end of
the normal limit. Twelve of twenty two cases were
confirmed by pathology and eleven patients had multiple
glands with pathologic changes.
The nine cases of insulinoma all had a Whipple triad,
insulin/glucose ratio (I/G) of >0.3, and all were confirmed
by pathology except the 2 patients refusing operation.
One of these cases was diagnosed with multifocal
insulinoma in the body and tail of the pancreas and the
tumors infiltrated the blood vessels. One case had
multiple gastrinomas combined with hepatic metastasis. A
30-year-old female diabetic patient had a five fold
increase in glucagon, but it did not reach the diagnostic
level of glucagonoma. Since there was a suspected mass
in the tail of the pancreas, she was followed-up closely.
PRL levels. One of these cases also had elevated GH
levels and another case also had elevated ACTH levels.
There are two ACTHoma and four nonfunctional pituitary
adenomas. Nine patients had adrenal gland involvement.
Of these, eight were diagnosed with adrenocortico-
hyperplasia and one was an aldosteronoma. There were
also two cases diagnosed with thymus carcinoid and two
had lipoma with dermatofibroma.
Calcitonin levels were examined in fifty seven patients of
MEN2a and were elevated in all patients except one.
Forty eight cases of them had thyroid masses. They were
diagnosed as medullary thyroid carcinoma (MTC).
Twenty seven MEN2a patients had pheochromocytoma of
which 12 had multiple foci and 5 were malignant.
Thirteen patients presented hyperparathyroidism and 12
patients were asymptomatic (Table 2). Except probands,
most MEN2a patients were found by family member
screening.
All MEN2b patients were diagnosed as MTC
pathologically with mucosal ganglioneuromatosis and
Marfanoid. Three of them suffered from bilateral
pheochromocytomas.
Gene mutation
Among patients who accept MEN1 tumor suppressor
gene sequencing, twenty two patients (81.48%) were
found having heterozygosis mutations. Fifty nine MEN2a
patients (98.33%) had a mutation of codon 634, exon 11
of RET located on 10q11.2. In all MEN2b patients, the
mutation was located on codon 918, exon 16 of RET.
Operation indication
Medical therapy, surgical therapy, or conservative
follow-up of the case are all options when managing
MEN1 patients. Exploration and parathyroidectomy were
performed when symptoms of PHPT or severe
hypercalcemia presented. Clear insulinomas were
1498
indicated to operation.
Thyroidectomy was advised for all MEN2 patients. If the
pathology confirms the presence of lymph node
metastases secondary to the MTC then radical neck
lymph node resection should be performed. The
parathyroid glands should be explored during operation
and resected if they are enlarged. In cases with
concomitant pheochromocytoma, the adrenal tumor
should be resected first and the neck operation should
only be performed once adrenal gland function has
normalized.
RESULTS
Treatment and outcome of MEN1 patients
Twelve of twenty-two cases with parathyroid gland
involvement accepted surgical management. One patient
had a single adenoma enucleated and eleven had subtotal
parathyroidectomy. One of these patients continued to
experience a mild hypercalcemia post-operatively. Three
patients rejected surgery due to their advanced age and
one was excluded due to poor overall health following the
thymus carcinoma operation. Four patients with
parathyroid gland involvement had no treatment because
they were asymptomatic or had normal blood calcium
levels. Two patients planned to have intervention.
Four of nine cases diagnosed with insulinomas underwent
enucleation. Pancreatic neck resection with
pancreaticoenterostomy was performed in one patient.
One patient accepted distal pancreas resection with
splenectomy. Both cases recovered well. One case with
multiple gastrinomas located in the pancreas and
duodenum underwent gastrinoma enucleation, insulinoma
enucleation and hepatic tumor biopsy. This patient was
managed medically post-surgically to control symptoms.
One patient chosen diet therapy and close follow-up due
to unclear tumor localization. The relatives of one
demented patient refused any treatment and the patient
died of secondary epilepsy six years later.
Three of fifteen pituitary adenoma patients underwent
adenoma enucleation and others controlled their
symptoms medically. In the nine patients with adrenal
gland involvement, one aldosteronoma patient and two
adrenocorticohyperplasia patients received tumor
enucleation and one patient took radiotherapy after
operation. Two cases of thymus carcinoid underwent
thymus enucleation. One case recurred three years later
and the patient died of vena cava obstruction syndrome.
The other case survived two years post-operatively with
additional radiotherapy and chemotherapy.
Treatment and outcome of MEN2 patients
Total thyroidectomy with bilateral dissection of the
regional lymph nodes was performed in sixteen patients
of MEN2a and nodule enucleations were performed in
nine patients who had persistently elevated calcitonin
Chin Med J 2009;122(13):1495-1500
levels. Enlarged parathyroid glands were resected at the
same time and the pathologic diagnosis was hyperplasia.
The average age of patients receiving thyroidectomy was
36.507.93 years. Twenty two MEN2a patients
underwent adrenal gland enucleation including ten
patients who underwent bilateral adrenal resection.
There were five MEN2b patients treated with a total
thyroidectomy with bilateral lymph node dissection.
Pathological examination showed that the bilateral MTC
was accompanied by metastases to local lymph nodes.
The average age of those receiving operation was
18.09.0 years. Three MEN2b patients underwent
bilateral adrenal gland operation.
DISCUSSION
MEN is a neoplastic syndrome with an autosomal
dominant inheritance. The virulent gene of MEN1 is
localized on chromosome 11q13 as determined by gene
linkage analysis. It is a tumor suppressor gene,2
comprised of a 9.2 kb segment of genomic DNA
consisting of 10 exons coding a 610 amino acid nuclear
protein termed menin.3 Menin is a 67 kDa protein and
interacts with a diverse group of transcription factors and
co-regulators, including JunD, NF-B, PEM, Smad3, and
mSin3A-histone deacetylase. As such, menin has been
hypothesized to play a role in the regulation of gene
transcription, DNA replication, and cell cycle control.4-8
The mutation of the RET proto-oncogene leads to
abnormal differentiation of the neural crest cells. The
RET gene is located on 10q11.2. For MEN2a, the most
common mutation is codon 634, exon 11 of RET, but it is
on codon 918, exon 16 of RET in MEN2b. It has also
been reported that mutations occur on codons 611, 618,
620, 768, 790, 791, 804, 883, 891, and 922 as well as
exons 10, 11, 13, 14, 15, 16 of RET.9,10 We have found
eight new MEN kindreds and 18 new MEN cases since
genetic squencing has become available for the first
degree relatives of MEN patients. Among them, four
patients (three MEN1 and one MEN2a) had neither
clinical symptoms nor biochemical changes. To date, our
group has identified eight types of MEN1 gene mutation
and the mutations on codons 634 and 918 of RET.
Genetic mutation testing is useful for diagnosis of MEN
and facilitations the identification of patients in high-risk
group earlier in the course of disease.
MEN1 can present with more than twenty kinds of
combinations of different endocrine or nonendocrine
tumors. At present, there is no simple definition that
covers all the clinical symptoms of the cases and kindreds
that have been diagnosed with MEN.11 In general,
considering the parathyroid and pituitary and pancreas, if
two or more of these glands have pathological changes
either simultaneously or successively, then MEN1 should
be suspected. Ninety percent of MEN1 patients have
PHPT and the parathyroid gland is always the first gland
to be involved. These patients primarily present with
Chinese Medical Journal 2009;122(13):1495-1500
hyperplasia. Wang et al12 reported that approximately
78.9% of MEN1 patients had PHPT. In our patients
database, the parathyroid gland was involved in about
three-fourths of the patients and PHPT was the primary
complaint in more than one-third of the MEN1 patients.
Clinical symptoms were the same as reported.13
Meanwhile 40% patients suffered from gastrinoma and
20% patients suffered from insulinoma. In our study,
more than one-third of patients had insulinomas, but only
one case had a gastrinoma. Other enteropancreatic
endocrine tumors included nonfunctional islet cell tumor,
glucagonoma, somatostatinoma and vasoactive intestinal
peptide tumor. The incidence of pituitary tumor is about
20%25%. These tumors have the ability of secreting
PRL, GH, and ACTH, so patients should be symptomatic
although asymptomatic patients also present. The
incidence of thymus carcinoid, bronchus carcinoid,
adrenocortical tumor and pheochromocytoma is 2%, 2%,
25%, and 1% respectively.
The earliest and most common pathological change in
MEN2 patients is MTC. Ninety five percent of patients
have MTC, 50% have pheochromocytoma, and
20%30% have PHPT in MEN2a. There can also be
megacolon of the newborn and dermabryoamyloidosis. In
MEN2b, all the patients could get MTC, and 50% get
pheochromocytoma. Additional complaints include dental
ulcer, mucosal ganglioneuromatosis and Marfanoid. In
the early stage of MTC, especially during the estrin phase
of C cell, most patients have no symptoms frequently
leading to misdiagnosis. When there are apparent nodules
in the neck, regional metastasis is common. A 23-year-old
woman in our group presented with lateral cervial lymph
nodes metastasis despite the fact that the tumor in the
thyroid was only 0.6 cm in diameter. Thus, it is important
to measure blood calcitonin levels in patients with thyroid
nodules and obtain a complete family and case history.
In MEN1 patients, surgery is mainly provided to address
parathyroid gland changes, pancreatic endocrine tumors,
and carcinoids. Indications for surgery include PHPT
with markedly elevated blood calcium levels, insulinoma,
and thymus carcinoid. Prolactionomas can generally be
treated medically with such drugs as Ergolactin; however,
some functional tumors such as somatotropinoma,
ACTH-secreting tumors, and even nonfunctional tumors
that compress on nerves should also be resected. Surgery
for parathyroid tumors is mainly performed to alleviate
the hypercalcemia and to improve life quality.
Unfortunately, the recurrence rate is high. During surgery,
the four glands must be explored carefully and extra
glands should be looked for. In some medical center,
parathyroidectomy and partial gland autotransplantation
are recommended.12,13 Trans-cervical subtotal
thymectomy is also recommended during the initial neck
operation to prevent thymus carcinoid.4 However,
subtotal parathyroidectomy is the main treatment in
China.14 Carcinoid is the only fatal tumor in MEN1. For
patients with thymus carcinoid, a thymectomy should be
1499
performed involving complete resection of the tumor, the
thymus and mediastinal lymph nodes.
Most enteropancreatic endocrine tumors can be cured
surgically, especially insulinomas. It is important to
identify multiple tumors. The value of surgery in curing
gastrinomas is still controversial because most cases
present with multiple small tumors and curative excision
is likely not possible. Proton pump inhibitors and
somatostatin analogs effectively control symptoms. Due
to hypercalcemia stimulating gastrin secretion, resection
of gastrinomas should followed the calcemia returning to
normal.
The goal of surgically managing MEN2 patients is to
prevent and cure fatal tumors such as MTC and tumors of
the adrenal medulla. MTC is the main cause of mortality
in MEN2 patients. In our group, the average age that
MEN2a patients underwent thyroidectomy was
36.507.93 years and 18.09.0 years in MEN2b. And
most patients presented local lymph nodes metastasis at
the time of operation. It is therefore extremely important
for MEN2 patients to have early and total thyroidectomy.
In MEN2, since the type of gene mutation is strongly
related to clinical phenotype,15 there is an international
consensuse that total thyroidectomy should be performed
according to the result of genetic analysis. Specifically,
patients with a mutation of codons 883, 918, or 922
should have the operation within 6 months after birth,
mutations in codons 611, 618, 620, or 634 should be
operated on within 5 years of birth, and patients with
mutations in codons 60, 768, 790, 804, or 891 should be
operated on by age of 10 years.5 But it would take some
time to make this concept becoming more acceptable
domestically. For patients diagnosed with MTC, total
thyroidectomy with bilateral lymph nodes dissection
should be carried out16 and the parathyroid glands should
be explored at the same time. Pheochromocytoma must
be excluded preoperatively or a hypertensive crisis can
lead to death. Since pheochromocytomas can recur or
occur in multiples, repeated and bilateral surgical
explorations are indicated while maintaining the function
of the adrenal cortex.
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(Received November 17, 2008)
Edited by JI Yuan-yuan