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JCEM Case Reports, 2023, 1, 1–4
https://doi.org/10.1210/jcemcr/luac019
Advance access publication 30 November 2022
Case Report
MEN1 in a Patient With Nonsyndromic Familial
Nonmedullary Thyroid Carcinoma
Lauren A. Fitzgerald,
1
Shelley Williamson,
2
Jawairia Shakil,
1,2,3
and Richard J. Robbins
1,2,3
1
ENMED Program, Texas A&M University, Houston, TX 77030, USA
2
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
3
Weill Cornell Medical College, New York, NY 10021, USA
Correspondence: Richard J. Robbins, MD, Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA. Email: rjrobbins@houstonmethodist.org.
Abstract
Clinical syndromes involving multiple endocrine glands have been well recognized for over a century. Multiple reports describing hereditary
multiple endocrine neoplasia (MEN) syndromes involving pituitary, parathyroid, and pancreatic neuroendocrine tumors have been published.
Differentiated (nonmedullary) thyroid cancer can also present as a hereditary syndrome with or without a specific genetic predisposition. We
report the case of a man with nonsyndromic familial nonmedullary thyroid carcinoma, a pituitary adenoma, hyperparathyroidism, an adrenal
adenoma, and pancreatic adenocarcinoma. Genetic testing did not reveal mutations in the commonly reported genes associated with MEN
syndromes. MEN1 is characterized by endocrine neoplasia in at least 2 of the following glands: pituitary, parathyroid, and the gastro-entero-
pancreatic (GEP) tract. Co-occurrence of MEN1 with familial nonmedullary thyroid carcinoma, however, has not been reported in the medical
literature. This unique case of MEN1 co-existing in a patient with nonsyndromic familial thyroid carcinoma was not associated with any
common MEN syndrome germline mutations.
Key Words: MEN1, acromegaly, familial thyroid cancer, Cushing syndrome
Abbreviations: GEP, gastro-entero-pancreatic; GH, growth hormone; IGF-1, insulin-like growth factor 1; MEN, multiple endocrine neoplasia; Tg, thyroglobulin;
TSH, thyrotropin (thyroid-stimulating hormone).
Received: 12 September 2022. Editorial Decision: 7 November 2022. Corrected and Typeset: 1 December 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For
commercial re-use, please contact journals.permissions@oup.com
Clinical syndromes involving multiple endocrine glands were
recognized as early as 1900 by Erdheim. In 1953, Underdahl
and colleagues from the Mayo Clinic reported a series of pa-
tients with tumors of the pituitary, the parathyroid glands,
and the pancreatic islets [1]. Multiple reports over the next
10 years documented that many of these syndromes were her-
editary [2]. The term multiple endocrine neoplasia (MEN)
was suggested by Steiner in 1968. MEN1 is a syndrome char-
acterized by endocrine neoplasia in at least 2 of the following:
pituitary, parathyroid, and the gastro-entero-pancreatic
(GEP) tract. Additional syndromes that may be related to
the MEN syndromes have been identied as well [3]. We re-
port the case of a man with familial nonmedullary thyroid car-
cinoma, a pancreatic adenocarcinoma, and MEN1 involving
neoplasia in 3 additional endocrine glands.
Case Presentation
A 63-year-old man was referred to our medical center for evalu-
ation of jaundice secondary to a pancreatic mass. The patient
initially presented with painless jaundice. He was then sent
for imaging and a laboratory workup, which revealed a pancre-
atic mass obstructing the biliary tree and an elevated total bili-
rubin of 1.3 mg/dL (22 µmol/L). He had a stent placed
endoscopically to relieve the obstruction and was subsequently
sent to our medical center for further evaluation. His history
was signicant for papillary thyroid carcinoma resected at
age 26 followed by radioiodine remnant ablation. He subse-
quently developed acromegaly at age 51 (insulin-like growth
factor 1 [IGF-1] =776 ng/mL [101 nmol/L]; normal range:
46-219 ng/mL) and had trans-sphenoidal resection of a
13 mm adenoma which stained heavily for immunoreactive
growth hormone (GH). From age 53 to 63 he was on various
somatostatin analogs and/or pegvisomant for excessive GH
production. These were discontinued 2 months prior to his
hospitalization. Additionally, he was diagnosed with type 2
diabetes mellitus at 55 years of age. He also had a history of
recurrent kidney stones.
His family history was signicant for multiple family mem-
bers with endocrine diseases. His mother had a thyroidectomy
for differentiated thyroid carcinoma; one sister had a thyroi-
dectomy for papillary thyroid carcinoma; another sister had
parathyroid carcinoma; and a nephew had papillary thyroid
cancer. His father had a tumor (uncertain histopathology)
blocking the biliary tree with jaundice, and his daughter had
a prolactinoma (Fig. 1).
Physical examination showed central obesity, enlarged
supraclavicular fat pads, an interscapular “buffalo” hump,
and nonpigmented axillary and abdominal striae. There
were no lentigines or hyperpigmented lesions. He had no
facial features suggestive of acromegaly and no masses or
enlarged lymph nodes in the thyroid bed or cervical regions.
Magnetic resonance imaging to characterize his pancreatic
mass also revealed a 1.6-cm right adrenal mass.
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2 JCEM Case Reports, 2023, Vol. 1, No. 1
Endocrinology was consulted for his uncontrolled diabetes
mellitus, history of thyroid and pituitary tumors, hyperpara-
thyroidism, concern for Cushing syndrome, and suspicion for
MEN. He had a 24-hour urine free cortisol that was 120 mcg
(324 nmol [normal range, 10-100 mcg/24 hours]) and an ele-
vated 11 PM salivary cortisol at 2.9 ng/mL (8 nmol/L).
Following a 1-mg overnight dexamethasone suppression test,
his 8 AM cortisol remained at 11 mcg/dL (303 nmol/L) and his
ACTH was suppressed at 2.5 pg/mL (0.55 pmol/L). These nd-
ings, along with the right adrenal mass seen on imaging, sup-
ported the diagnosis of adrenal Cushing syndrome. A neck
ultrasound did not reveal residual thyroid tissue or any other
abnormal masses. He had an elevated corrected calcium level
of 11.6 mg/dL (2.9 mmol/L), a decreased phosphorus level
of 2.2 mg/dL (6.8 mmol/L) and an elevated parathyroid hormone
(PTH) of 135 pg/mL (14.3 pmol/L) upon admission. A SestaMIBI
scan showed no evidence of a parathyroid adenoma. Despite this,
he still had laboratory evidence of hyperparathyroidism as well as
a history of recurrent kidney stones. Thus, 2 previously undiag-
nosed types of endocrine neoplasia were discovered upon this
admission.
Further endocrine workup revealed normal levels of GH,
IGF-1, follicle stimulating hormone, luteinizing hormone, tes-
tosterone, and prolactin. His thyrotropin (thyroid-stimulating
hormone; TSH) was 2.8 mIU/L while on levothyroxine ther-
apy; serum thyroglobulin (Tg) was detectable at 28.9 ng/mL
with negative anti-Tg antibody. Serum calcitonin and carci-
noembryonic antigen levels were within the normal reference
ranges. Gastrin and glucagon levels were also normal.
Screening for carcinoid tumor showed normal range levels of
serotonin, urine 5-hydroxyindoleacetic acid, and chromogra-
nin A. Screening tests for pheochromocytoma were also nega-
tive. Laboratory results are summarized in Table 1.
We performed genetic screening due to his signicant family
history of thyroid cancer and MEN. We tested his white blood
cells for germline mutations in APC, CHEK2, DICER1,
MEN1, PRKAR1A, PTEN, RET, SDHB, SDHD, TP53,
and WRN. None of the common mutations were present in
any of these genes.
Genetic testing was performed using a commercially avail-
able Invitae genetic panel. Identication and conrmation as
needed, of signicant known mutations and their locations,
was carried out using methods established by Invitae [4].
A biopsy of the pancreatic lesion revealed adenocarcinoma.
The patient then underwent a Whipple procedure, with reso-
lution of biliary obstruction and right adrenalectomy with
resolution of hypercortisolemia. Genetic testing of the pan-
creas cancer revealed mutations in TP53, KRAS, and
ERCC2. The patient expired within 1 year due to progressive
pancreas cancer.
Discussion
Our patient had 2 of the 3 most common tumors associated
with MEN1: a GH-secreting pituitary tumor and hyperpara-
thyroidism. Like approximately 10% of MEN1 patients,
Table 1. Serum laboratory evaluation & tumor markers
Analyte Result Normal ranges
Growth hormone 1.87 ng/mL 0.05-3.00 ng/mL
IGF-1 145 ng/mL 46-219 ng/mL
Follicle stimulating hormone 7.2 mIU/mL 1.5-12.4 mIU/mL
Luteinizing hormone 9.2 mIU/mL 1.7-8.6 mIU/mL
Testosterone 311 ng/dL 300-720 ng/dL
Prolactin 14 ng/mL 4-15 ng/mL
TSH 2.8 mIU/L 0.27-4.20 mIU/L
Thyroglobulin 28.9 ng/mL 1.3-31.8 ng/mL
Thyroglobulin auto-antibody <0.9 IU/mL 0.0-4.0 IU/mL
Calcitonin <2.0 pg/mL 0.0-7.5 pg/mL
Serotonin 140 ng/mL 50-220 ng/mL
Chromogranin A 45 ng/mL 0-103 ng/mL
Urine 5-HIAA 3 mg/gCR 0-14 mg/gCR
Gastrin 15 pg/mL 0-100 pg/mL
Dopamine <20 pg/mL 0-20 pg/mL
Epinephrine 25 pg/mL 10-200 pg/mL
Norepinephrine 680 pg/mL 80-520 pg/mL
Metanephrine <10 nmol/L 0.00-0.49 nmol/L
Normetanephrine 0.58 nmol/L 0.00-0.89 nmol/L
CEA 1.4 ng/mL 0.0-3.8 ng/mL
CA 19-9 48 U/mL 0-35 U/mL
Cortisol after DST 11 mcg/dL 6-18 mcg/dL
ACTH after DST 2.5 pg/mL 6-18 pg/mL
Calcium (corrected) 11.6 mg/dL 8.8-10.2 mg/dL
Parathyroid hormone 135 pg/mL 15-65 pg/mL
Phosphorus 2.2 mg/dL 2.4-4.5 mg/dL
Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; ACTH,
adrenocorticotropic hormone; CA 19-9, carbohydrate antigen 19-9; CEA,
carcinoembryonic antigen; DST, 1-mg dexamethasone overnight
suppression test; IGF-1, insulin-like growth factor 1; TSH, thyrotropin
(thyroid-stimulating hormone).
Figure 1. Available family pedigree for the patient (proband) who had
MEN1 and familial nonmedullary thyroid carcinoma. Clinical entities are
shown by color coding in the figure. Circles = females. Squares = males.
Straight lines at 45 degrees through circles or boxes indicate family mem-
bers who have expired.
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JCEM Case Reports, 2023, Vol. 1, No. 1 3
our patient had no clear mutation in the MEN1 gene.
Compared with MEN1 patients who have an MEN1 muta-
tion, genotype-negative MEN1 patients are typically older
and usually have hyperparathyroidism and a pituitary tumor
(most commonly somatotroph adenomas) but rarely develop
a neuroendocrine GEP tumor [5]. Our patient had no evi-
dence of a neuroendocrine tumor of the GEP tract. His gas-
trin and glucagon levels were normal, and he never had
hypoglycemia or a watery diarrhea syndrome. He also had
no clinical features to suggest Carney complex or Cowden
syndrome. Carney complex patients, who often have muta-
tions in the PRKAR1A gene, present with myxomas and tu-
mors of the pituitary, adrenal, and thyroid glands. Cowden
syndrome patients have multiple hamartomas, and may de-
velop cancers of the thyroid, breast, or uterus associated
with mutations in the PTEN tumor suppressor gene. Our pa-
tient had a sister with parathyroid carcinoma; however, he
likewise had no features of hyperparathyroidism-jaw tumor
syndrome or McCune-Albright syndrome. Children with
McCune-Albright syndrome (associated with GNAS1 gene
mutations) often have polyostotic brous dysplasia and
café-au-lait pigmentation and rarely may have acromegaly,
thyroid nodules, and adrenal Cushing syndrome. There
were no other known cases of hyperparathyroidism in his
family.
The patient’s family history meets the denition of familial
nonmedullary thyroid carcinoma [6]. Medullary thyroid car-
cinoma was ruled out based on histopathology reports, and
normal serum calcitonin and carcinoembryonic antigen levels.
His measurable serum Tg could represent regrowth of a thy-
roid remnant 37 years after thyroidectomy without TSH sup-
pression. His neck ultrasound did not reveal any thyroid bed
masses or nodules and there was no lymphadenopathy. Of
course, the measurable serum Tg could also be a result of oc-
cult thyroid cancer metastases, which were not detected by the
multiple imaging studies which he underwent.
Acromegaly can be associated with other benign and malig-
nant tumors. Although many patients with acromegaly have
goiters and thyroid carcinoma, there is no well-described associ-
ation between acromegaly and familial nonmedullary thyroid
carcinoma. Acromegaly is also associated with functional and
morphological abnormalities in the adrenal glands. In 2015,
Ishikawa and colleagues reported a case with many features
similar to our case, most notably that the patient had both acro-
megaly and adrenal Cushing syndrome [7]. Approximately 30%
to 40% of MEN1 patients have functional and nonfunctional
adrenal abnormalities.
The genetic basis of nonsyndromic familial nonmedullary
thyroid carcinoma (NSFNMTC), which our patient ts, has
been a topic of considerable interest in the past 5 years. The
clinical features and secondary neoplasia in probands and
family members have been described [8]. No cases of co-
existence with MEN syndromes have been reported to data.
However, the incidence of pancreas cancer, which occurred
in our patient, seems higher in familial nonmedullary cases
than in those with sporadic differentiated thyroid carcinoma
[9]. Multiple susceptibility genes for nonsyndromic familial
nonmedullary thyroid carcinoma have been identied by
whole-exome sequencing in many unrelated families from
China, Europe, and Japan [10].
Signicant limitations in reporting this case include the in-
ability to obtain pathological tissue from his thyroidectomy
(performed 37 years prior) for genetic testing; and from his
pituitary tumor which was removed 12 years prior. Reports
of his family’s history of endocrine neoplasia also often lack
primary pathological evidence, being derived from interview-
ing multiple family members and old hospital records.
Regarding the genetic testing, Invitae’s deletion/duplication
analysis determines copy number at a single exon resolution
at virtually all targeted exons. However, in rare situations, sin-
gle exon copy number events may not be analyzed due to in-
herent sequence properties or isolated reduction in data
quality. Certain types of variants, such as structural rear-
rangements (eg, inversions, gene conversion events, transloca-
tions, etc.) or variants embedded in sequence with complex
architecture (eg, short tandem repeats or segmental duplica-
tions), may not be detected.
In summary, genetic testing and clinical features in our
MEN1 patient did not suggest a known syndrome (eg,
Carney complex, Cowden syndrome, hyperparathyroidism-
jaw tumor syndrome, or McCune-Albright syndrome).
There are sporadic case reports in the medical literature of
MEN1 with some features like our patient, but none with
familial nonmedullary thyroid carcinoma. It is possible
that features of MEN1 and nonsyndromic familial nonme-
dullary thyroid cancer in 1 individual occurred by chance
alone; however, the presence of a single hereditary genetic
predisposition in this family is also possible. Such a genetic
basis may become evident if future similar cases are
discovered.
Learning Points
• Take a careful family history to rule out hereditary
endocrinopathies
• Review the features of genetic syndromes in familial endo-
crine cases
• Investigate the possibility of MEN in all patients with
acromegaly
• Consider the possibility of functional adrenal tumors in
MEN patients
Funding
This study was supported in part by a grant (to R.J.R.) from
the Golfers Against Cancer organization (https://
golfersagainstcancer.org) and by the Charles and Anne
Duncan Presidential Distinguished Chair.
Author Contributions
All authors were involved in the care of this patient. All au-
thors contributed to the collection of data and construction
of the manuscript. All authors approved the nal draft of
the case report.
Disclosures
None of the authors have any conicts of interest to declare.
Data Availability
The data that support the ndings of this study are available
on request from the corresponding author, RJR.
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4 JCEM Case Reports, 2023, Vol. 1, No. 1
Consent Statement
Retrospective deidentied data review and reporting was ap-
proved by our Institutional Review Board.
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