Missed diagnosis of MEN – 2B

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*Resident (Endocrinology), +,#Classified Specialist (Medicine & Endocrinology), **Senior Advisor (Medicine & Endocrinology), Army
Hospital (Research & Referral), Delhi Cantt – 10.
Received : 07.01.10; Accepted : 15.04.10 E-mail : mkgargs@gmail.com
CR 6138 10mju25 - 3rd proof
Case Report
Missed Diagnosis of Multiple Endocrine Neoplasia
Type 2 B
G Abhay*, Lt Col MK Dutta+, Lt Col R Pakhetra#, Col MK Garg**
MJAFI 2010; 66 : 00-00
Key Words : Multiple endocrine neoplasia; Pheaochromocytoma; Hyperparathyroidism; Thyroid carcinoma
Introduction
Multiple endocrine neoplasias (MEN) are autosomal
dominant hereditary cancers which have their
origin in hormone secreting glands [1]. These produce
specific syndromes due to the hormones secreted. Also
these hormones act as tumour markers which can be
used in screening and follow up. MEN have been
classically classified as MEN 1 (primary
hyperparathyroidism (PHPT), pituitary adenomas,
pancreatic islet cell tumours), MEN-2A (medullary
thyroid carcinoma (MTC), pheochromocytoma, PHPT)
and MEN-2B (MTC, pheochromocytoma, Marfanoid
habitus, mucocutaneous neuromas). At times these
syndromes have overlapping or additional features. We
report a case of MEN-2B which has many unusual
features.
Case Report
A 31 year old lady, born out of a second degree
consanguineous marriage reported to a gynaecologist for
evaluation of primary infertility. During evaluation, an
ultrasound of pelvis was ordered. When this was being
performed she told the radiologist that she was operated for
a ‘Pheo’ in past. When the probe was placed on the abdomen
a mass in the left suprarenal region was seen. She was referred
to the endocrine department for further evaluation. She gave
history of unprovoked episodic giddiness, sweating and
palpitations of five years duration. On examination she had
multiple neuromas on the conjunctiva, lips, tongue, trunk
and extremities (Fig. 1). Her height was 151 cm, upper segment
to lower segment ratio was 0.9, arm span was 150 cm and she
weighed 37 kg. She didn’t have marfanoid habitus. She had
tachycardia, collapsing pulse and her blood pressure was
150/110 mm of Hg with significant postural fall (30 mmHg).
Slit lamp examination demonstrated thickened corneal nerves
(Fig. 2). Her systemic examination was normal. Twelve years
back when she was being evaluated for pain in the right
upper quadrant of abdomen, was found to have a hydatid
cyst in the liver. She was taken up for surgical removal of the
same. When the abdomen was opened a huge right suprarenal
mass was seen and the operation deferred. Further evaluation
confirmed a diagnosis of pheochromocytoma (24 hour urinary
vanillyl mandelic acid (VMA) level was 4.2 mg/day). A well
encapsulated pheochromocytoma measuring 18 cm X 11 cm
X 5 cm weighing 675 g was removed at a later date. At the age
of four years she was evaluated by an ophthalmologist for
bilateral swellings in eyelid margins. Biopsy report from the
tissue was inconclusive. With this history a diagnosis of
pheochromocytoma was made and possibility of MEN-2B
kept.
Her haemoglobin was 10.3 mg/dl, BUN – 8.0 mg/dl,, serum
creatinine – 0.7 mg/dl,, total bilirubin 0.6 mg/dl,, total protein
– 6.6 g/dl,, albumin – 4.2 g/dl,, SGOT/SGPT – 30/35 U/l, serum
calcium - 10.3 mg/dl, (9.0 – 11.0), inorganic phosphorous – 2.9
mg/dl, (2.5-4.5), alkaline phosphatise 70 U/l.
Pheochromocytoma was confirmed biochemically. The 24
hour urinary metanephrines was 6931.12 µg (52.00-341.00),
and normetanephrine was 13550.5 µg (88.00-444.00). Serum
calcitonin was 847.0 pg/ml (<11.50), serum carcinoembryonic
antigen (CEA) level -68.26 ng/ml (<3.0), parathormone ( iPTH)-
199.40 pg/ml (15.00-68.30), T3 – 1.2 ng/ml (0.9 – 2.6), T4 –
101.3 nmol/l (60 – 160) and thyroid stimulating hormone (TSH)
1.7 µIU/ml (0.3- 6.5). Computed tomography (CT) scan of
abdomen showed a left suprarenal mass consistent with
pheochromocytoma (Fig. 3). Ultrasonography of neck showed
a well defined hetero echoic lesion seen in right lobe of thyroid
measuring 1.6 cm X 1.0 cm X 0.93 cm with calcification within
the lesion, the left lobe and isthmus were normal. Fine needle
aspiration cytology (FNAC) was consistent with medullary
thyroid carcinoma. Bone scan showed no skeletal metastases.
Colonoscopy showed no ganglioneuromas. Radiograph of
hip and pelvis was normal.
Patient was started on α blockade (prazosin 1mg thrice
daily to start with and gradually increased to 2 mg 6 hourly).
Once adequately blocked, volume expansion was done and β
blocker added (propranolol 40 mg thrice daily). After adequate
preparation patient underwent left adrenalectomy for

MJAFI, Vol. 66, No. 3, 2010
2Abhay et al
Fig. 3 : CT scan abdomen showing characteristic
pheochromocytoma lesion – heterogeneous adrenal
masses. Panel A shows right sided lesion which was
removed twelve years back and panel B shows left sided
lesion which was successfully removed.
Fig. 4 : Histopathological examination of specimen
from left adrenal showing cells in nest and
trabaculae separated by thin vascular stroma
consistent with pheochromocytoma.
Fig. 6 : Histopathological examination
of specimen from parathyroid showing
hyperplasia.
Fig. 5 : Histopathological examination of
specimen from medullary thyroid carcinoma
in right lobe of thyroid showing amyloid
interspersed between tumour cells.
Normal
Adrenal
tissue
Capsule
Tumour
Amyloid
Fig. 1 : Shows subconjuctival neuromas.
Fig. 2 : Slit lamp examination shows thickened corneal nerves
(white lines).
A
B
pheochromocytoma. Postoperative period was uneventful and
she received hydrocortisone and fluodrocortisone
replacement as she now had bilateral adrenalectomy status.
Peroperative findings didn’t show evidence of megacolon or
neuromas on the intestinal wall. At a later date she underwent
total thyroidectomy and central lymph node clearance.
Parathyroid exploration was carried out and the glands were
removed. Biopsy reports confirmed pheochromocytoma (Fig.
4), MTC (Fig. 5) and parathyroid hyperplasia (Fig. 6). She
was started on thyroxine replacement. On second
postoperative day she developed spontaneous carpopedal
spasm secondary to hypoparathyroidism and was managed
with α-calcidiol and calcium supplements.
Discussion
MEN-2B (MIM 162300) is a very rare syndrome
with incidence of about 1 in 1 million [2]. MEN-2B is
also called Wagenmann-Froboese or mucosal neuroma
syndrome. It accounts for 5% of cases of MEN-2. It is
transmitted as autosomal dominant trait but a significant
number of cases represent new mutations. About 95%
of MEN-2B are caused due to a specific germline
mutation in RET proto oncogene on chromosome 10q.
MEN-2B syndrome is usually diagnosed at a mean age
of 11.5 years [3]. Our patient was diagnosed at an age
of 31 years. The hallmark of this disease is the
occurrence of mucocutaneous neuromas especially on

MJAFI, Vol. 66, No. 3, 2010
Missed Diagnosis of Multiple Endocrine Neoplasia Type 2 B 3
the tongue and subconjuctival areas. Infact the
subconjuctival neuromas are amongst the earliest
manifestations of this disease [4]. In this patient her
mother had noticed swellings in the eyelid margins at
birth and she was evaluated by an ophthalmologist at
the age of four years, however diagnosis was missed.
These neuromas are an important clue to underlying
MEN-2B. Thickened corneal nerves can be appreciated
on slit lamp examination. Intestinal gangliomatosis is
found in nearly all patients [5]. The earliest presentation
in a child could be constipation or intestinal obstruction
secondary to the neuromas and manifest before
extraintestinal endocrine manifestations. Our patient
didn’t have this finding on colonoscopy and direct
visualisation of the intestine during operation.
The next common component is MTC which can have
an onset as early as first year of life [6]. In contrast to
MEN-2A in which MTC has an indolent course in 80%
of cases, in MEN-2B MTC has a very aggressive course
and is rarely curable. These hereditary MTC are typically
bilateral. MTC initially presents with diarrhoea, having
about 10 – 20 stools per day which are voluminous in
contrast to islet cell tumors. These tumours are located
at the junction of upper and middle third of thyroid lobes
incoherent with the maximum density of c – cells in this
area. It was unusual that our patient of MTC was
asymptomatic and diagnosed at the age of 30 years, she
was in stage II and the tumour was localised to right
lobe of thyroid.
Pheochromocytoma occurs in 50% of patients with
MEN-2B [7]. They present at around 30 years. It was
unusual that our patient presented with
pheochromocytoma at the age of 19 years. About half
of the tumours are bilateral and >50% of patients who
have had unilateral adrenalectomy develop a
pheochromocytoma in the contralateral gland within a
decade [7]. Our patient also developed
pheochromocytoma in contralateral gland after the first
surgery. The pheochromocytoma differs from the
sporadic and other familial pheochromocytoma in that
they secrete predominantly epinephrine. This could be
explained by the enzyme phenylethanolamine N-
methyltransferase (PNMT) being positively regulated
by RET proto oncogene leading to increased methylation
of norepinephrine to epinephrine. Clinically this
biochemical finding can be observed in the form of
relative lack of hypertension and predominance of α
adrenergic symptoms [3]. It is interesting to note that
pheochromocytoma in our patient probably secreted
predominantly norepinephrine as evidenced by markedly
elevated urinary normetanephrine compared to
metanephrine levels and also had hypertension.
PHPT is very rare in MEN-2B [8]. These patients
have a normal calcium levels. Histologically the
parathyroid glands are normal in most of the patients
but hyperplasia can be seen occasionally [9]. The glands
don’t exhibit the normal involution with the increasing
age. Our patient had asymptomatic normocalcemic
PHPT which is yet to be reported. This could be due to
either initial stage of HPHT or vitamin D deficiency.
Vitamin D levels were not measured in our patient;
however her serum alkaline phosphatase was normal.
The complete syndrome with mucosal neuromas,
pheochromocytoma and MTC occurs in only 50% of
the cases [3]. Generally, pheochromocytoma is the first
clinical manifestation of the disease in 25% of cases
(after MTC in 40%); in 35% of cases, MTC and
pheochromocytoma are diagnosed at the same time.
Treatment consists of removal of pheochromocytoma
first, if present, followed by that of MTC and removal
of parathyroid gland and implantation in the forearm.
As 50% of patients are found to have
pheochromocytoma bilaterally the trend now is to
perform cortex sparing adrenalectomy. In our patient
genetic studies for RET proto oncogene could not be
performed due to local constraints. Family screening
has been advised.
Conflicts of Interest
None identified
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