Clinical Chemistry 61:11
13281332 (2015)
A Patient with Persistent Lactation and Recurrent
Hypercalcemia
Qing H. Meng1* and Elizabeth A. Wagar1
CASE DESCRIPTION
An 18-year-old woman presented with persistent bilat-
eral lactation, excess body weight, and recurrent hyper-
calcemia. At age 13 years, before menarche, she devel-
oped bilateral milk discharge from her breasts. The
lactation continued and, at age 16 years, she experienced
increasingly frequent headaches and visual field changes;
her prolactin concentration was noted to be 2400
ng/mL. A year later, she underwent transsphenoidal re-
section of a pituitary macroadenoma. After the surgery,
she developed panhypopituitarism and central diabetes
insipidus (DI).2 She was treated with levothyroxine (T4)
for secondary hypothyroidism and received other hor-
mone replacement therapy, including desmopressin ace-
tate [a synthetic analog of antidiuretic hormone (ADH)],
conjugated estrogen (Premarin), growth hormone (Hu-
matrope), and bromocriptine. A year later, she developed
recurrent kidney stones and was diagnosed with primary
hyperparathyroidism. She was also found to have multi-
ple thyroid nodules. She underwent a 4-gland parathy-
roidectomy with left forearm autograft and total thyroid-
ectomy. She had had transient hypoparathyroidism
following parathyroidectomy, soon afterward she experi-
enced recurrent primary hyperparathyroidism with
nephrocalcinosis and pyelonephritis.
She came to our hospital to seek further evaluation
and treatment. She had continued to gain weight and had
developed depression and anxiety. She also reported joint
pain, fatigue, blurry vision, loss of appetite, dyspnea,
polyuria, and insomnia. She reported occasional diarrhea
but no significant flatulence. There was no pertinent
family history of endocrine disorders. Physical examina-
tion revealed an obese young woman in distress, with leg
swelling and unbalanced gait. Her pulse was 91 beats per
1
Department of Laboratory Medicine, The University of Texas MD Anderson Cancer
Center, Houston, TX.
* Address correspondence to this author at: Department of Laboratory Medicine, The
University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 37, Hous-
ton, TX 77030-4009. Fax 713-792-4793; e-mail qhmeng@mdanderson.org.
Received October 16, 2014; accepted February 12, 2015.
DOI: 10.1373/clinchem.2014.234849
2015 American Association for Clinical Chemistry
2
Nonstandard abbreviations: DI, diabetes insipidus; T4, levothyroxine; ADH, antidiuretic
hormone; ACTH, adrenocorticotropic hormone; MEN1, multiple endocrine neoplasia
type 1; PTH, parathyroid hormone; IGF-1, insulin-like growth factor-1.
1328
Clinical Case Study
QUESTIONS TO CONSIDER
1. What diagnosis does this constellation of laboratory
results and clinical symptoms suggest?
2. What other disorders may be seen with this primary
disease?
3. What genetic testing would be indicated?
minute and blood pressure was 113/67 mmHg. Findings
of the cardiovascular and respiratory examination were
unremarkable. Multiple skin tags and nodules were
noted over the trunk and abdomen and around her vag-
inal and groin region. The evaluation at our institution
included laboratory investigations (Table 1), imaging,
and histologic studies. An adrenocorticotropic hormone
(ACTH) stimulation test (1 g cosyntropin) showed a
peak cortisol concentration of 18.7 g/dL (reference in-
terval 20 g/dL). Complete blood cell count showed
microcytic hypochromic anemia.
DISCUSSION
MRI revealed a recurrent and progressive pituitary tu-
mor. Histologic review of the resected pituitary tumor
confirmed an adenoma positive for prolactin by im-
munohistochemistry. Endoscopic ultrasound showed
multiple cysts measuring 4 mm or less in the pancre-
atic genu/body and tail. A nodular area of 4.6 6.3
mm in the genu/body of the pancreas suggested a pan-
creatic neuroendocrine tumor. Histologic examina-
tion of the fine-needle aspiration biopsy sample from
this lesion confirmed pancreatic neuroendocrine tu-
mor with low-grade and mild reactive atypia (i.e., islet
cell tumor).
The patients history, physical examination find-
ings, and results from laboratory, imaging, and patho-
logic investigations suggested a diagnosis of multiple
endocrine neoplasia type 1 (MEN1) with pituitary ad-
enoma, primary hyperparathyroidism, and pancreatic
neuroendocrine tumors. She was tested for multiple
endocrine neoplasia 1 (MEN1) gene mutation at an-
other institution, and the results of this test were re-
portedly positive. Her clinical course was complicated
by central adrenal insufficiency, hypothyroidism, hy-
 Clinical Case Study

dose of cosyntropin in detecting partial adrenal insuf-

Table 1. Patients laboratory results. ficiency, in particular secondary adrenal insufficiency
resulting from pituitary tumors or chronic glucocorti-
Reference
Test Result interval
coid treatment. A direct corticortropin-releasing hor-
mone stimulation test can help to detect secondary
PTH, intact, pg/mL 986 980 adrenal insufficiency. Although thyroid tumors are
Calcium, mg/dL 10.6 8.410.2 found in patients with MEN1, as seen in this case, it
25-hydroxyvitamin-D, 15 30100 has been suggested that the association of thyroid ab-
ng/mL normalities may be incidental and not significant. This
Prolactin, ng/mL 92.2 4.823.30 patients pancreatic neuroendocrine tumors, gastri-
Growth hormone, ng/mL <0.01 0.013.61 noma (Zollinger-Ellison syndrome) and insulinoma
IGF-1, ng/mL 50 117321 (hyperinsulinemia), are typical of MEN1. She also ex-
Insulin, mIU/mL 105 2.029.1 hibited skin manifestations of MEN1, such as
Proinsulin, pmol/L 300 320
angiofibromas.
MEN1 is an autosomal dominant inherited syn-
Thyroid-stimulating <0.01 0.274.20
hormone, IU/mL drome characterized by the occurrence of tumors involv-
ing 2 or more principal endocrine glands, including para-
Free T4, ng/dL 0.99 0.931.70
thyroid, pancreatic endocrine tissues, and pituitary
Follicle-stimulating <0.1 3.512.5
hormone, mIU/mL (1, 2 ). Other endocrine and nonendocrine neoplasms
typical of MEN1 include carcinoid tumors, bronchial
Luteinizing hormone, <0.7 1.011.4
mIU/mL endocrine tumors, skin tumors (angiofibromas, collag-
Estradiol, pg/mL 29 15350
enomas, lipomas, melanomas), central nervous system
tumors (meningiomas, ependymonas, schwannomas),
ACTH, pg/mL <5 546
and smooth muscle tumors (3 ). Most of the MEN1-
Cortisol, g/dL 2.0 4.322.4
associated tumors are benign, although malignancy does
Chromogranin A, ng/mL 1263 93 occur occasionally. The prevalence of this disease is un-
Pancreatic polypeptide, 343 249 certain, but the incidence has been estimated from au-
pg/mL topsy studies to be 0.25% (2 ). MEN1 is caused by mu-
Gastrin, pg/mL 584 <100 tations in the MEN1 gene located on chromosome
Sodium, mmol/L 142 136146 11q13, consisting of 10 exons, that encodes a 610
Osmolality, mOsm/kg 301 289308 amino acid nuclear protein, menin (1, 4, 5 ). Menin is
Urine osmolality, mOsm/kg 255 500850 believed to be involved in many important cellular pro-
Urine specic gravity 1.005 1.0051.030 cesses such as cell cycle regulation, transcriptional con-
trol, cell division, and genomic stability; however, the
precise role of menin in tumorigenesis remains to be es-
tablished. No correlation has been observed between ge-
pogonadism, and growth hormone deficiency that de- notype and MEN1 phenotype (1 ). Because there was no
veloped following transsphenoidal resection of the pi- family history of endocrine disorders in this case, this
tuitary macroadenoma. Central adrenal insufficiency presentation likely represents a de novo mutation. The
was diagnosed based on the low cortisol and inappro- occurrence of de novo mutations appear in 10% of all
priately low ACTH in the face of hypocortisolism. The patients with MEN1 (2 ).
ACTH stimulation test, also referred to as the cosyn- A diagnosis of MEN1 is established by the occur-
tropin test, helps to differentiate primary and second- rence of 2 or more primary MEN1-associated endo-
ary adrenal insufficiency. Under cosyntropin stimula- crine tumors, the occurrence of MEN1-associated tu-
tion, little or no increase in cortisol concentrations mors in a first-degree relative of a patient with a
indicates primary adrenal insufficiency. Patients with clinical diagnosis of MEN1, or identification of a
secondary adrenal insufficiency usually show a blunted germline MEN1 mutation in an asymptomatic indi-
response to cosyntropin but occasionally have a nor- vidual who has not yet developed serum biochemical
mal response with basal ACTH concentrations within or radiological abnormalities indicative of tumor de-
or below the reference interval. Testing with use of a velopment (2, 6 ). The diagnosis of MEN1 is often
250-g dose of cosyntropin is intended to examine delayed. The interval between the appearance of symp-
only the maximum adrenocortical capacity, and this toms and the diagnosis of MEN1 varies from several to
high dose overrides any more partial loss of cortisol dozens of years (6 ). Failure to recognize multiple clin-
secretion. Testing with a 1-g dose of cosyntropin is ical manifestations of MEN1 is a common reason for
more sensitive and accurate than use of the 250-g the delayed diagnosis. Primary hyperparathyroidism is

Clinical Chemistry 61:11 (2015) 1329

Clinical Case Study
the most common and usually the earliest clinical ab-
normality of MEN1 (95%), followed by pancreatic
endocrine tumors (40%70%) and pituitary adeno-
mas (30% 40%) (2, 7 ). All individuals in whom
MEN1 is suspected should be screened with measure-
ments of serum calcium and parathyroid hormone
(PTH) concentrations. Other biochemical measure-
ments such as insulin, proinsulin, glucagon, prolactin,
gastrin, insulin-like growth factor-1 (IGF-1), pancre-
atic polypeptide, and chromagranin A may be helpful
in making the diagnosis (8 ). Genetic testing for
MEN1 mutation is recommended for individuals in
whom MEN1 is suspected, whether they have symp-
toms or not (1, 2, 9 ). Imaging studies such as x-rays
and scans of the pituitary, thyroid, and abdomen may
be done at initial diagnosis of the carrier state and
periodically for tumor surveillance or if clinical signs
develop. Whereas the prevalence of MEN1 is esti-
mated at 110 per 100 000 inhabitants (9 ), and in
most of the cases the tumors may be benign (as com-
pared to malignant), the disease itself is not benign and
can be fatal. Therefore, early identification and diag-
nosis is critical to asymptomatic individuals who
should benefit from treatment. A careful family his-
tory and thorough clinical, biochemical, pathologic,
and imaging investigations should be considered in
any individual suspected of MEN1. The treatment for
each type of MEN1-associated tumor is generally sim-
ilar to that for the same tumor occurring in non-
MEN1 patients. However, the treatment outcomes for
MEN1-associated tumors are not as successful as those
for non-MEN1 patients because of the complexity and
multiorgan involvement of this disease (2 ).
Although hypoparathyroidism may occur following
extensive parathyroidectomy, recurrent hyperparathy-
roidism following parathyroid surgery is not uncommon
in MEN1. Patients who undergo successful subtotal
parathyroidectomy frequently experience recurrence of
hyperparathyroidism within 15 years (1, 10 ). Her central
DI, a feature of panhypopituitarism, was caused by dam-
age to the hypothalamus or pituitary gland during pitu-
itary surgery. It is characterized by increased urine output
and decreased urinary osmolality and specific gravity due
to decreased secretion of ADH. Her plasma calcium con-
centrations remained only slightly high. Vitamin D defi-
ciency may reduce the severity of hypercalcemia but
accentuate the increase in PTH. She also received ergo-
calciferol as treatment of vitamin D deficiency. Her gas-
troesophageal reflux disease, which resulted from the gas-
trinoma, responded quite well to the proton pump
inhibitor esomeprazole. Proton pump inhibitors also
may cause false elevation of chromogranin A, a useful
diagnostic marker for neuroendocrine neoplasms, in-
cluding carcinoids, pheochromocytomas, neuroblasto-
mas, medullary thyroid carcinomas, some pituitary tu-
1330 Clinical Chemistry 61:11 (2015)
POINTS TO REMEMBER
MEN1 is an autosomal dominant inherited disorder. It
is characterized by the development of 2 or more
endocrine-tumors of the parathyroid glands, pancre-
atic islet cells, or pituitary gland, with or without
other endocrine and nonendocrine neoplasms. Pri-
mary hyperparathyroidism is the most common fea-
ture of MEN1.
MEN1 mutations and other genes have been identified
as associated with MEN1. MEN1 germline mutation
testing is recommended for screening and diagnosis of
MEN1.
Serum calcium and PTH concentrations should be mea-
sured as screening tests for individuals in whom MEN1
is suspected. Other biochemical measurements assess-
ing the function of endocrine organs in combination
with imaging studies are beneficial for early detection
and diagnosis of MEN1.
A diagnosis of MEN1 can be established by clinical,
familial, or genetic criteria or by a combination of these
criteria.
mors, and functioning and nonfunctioning islet cell tumors.
The effects of proton pump inhibitorinduced elevation of
chromogranin A are correlated with the dose and prolonga-
tion of the treatment of proton pump inhibitors.
Author Contributions: All authors confirmed they have contributed to the
intellectual content of this paper and have met the following 3 requirements: (a)
significant contributions to the conception and design, acquisition of data, or
analysis and interpretation of data; (b) drafting or revising the article for intel-
lectual content; and (c) final approval of the published article.
Authors Disclosures or Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.
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practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol
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MR, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1.
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5. Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjold M. Multiple endocrine
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due to phenocopies: lessons from multiple endocrine neoplasia type 1 (MEN1). Hum
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7. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Guidelines
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8. de Laat JM, Pieterman CR, Weijmans M, Hermus AR, Dekkers OM, de Herder WW, et
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Commentary
Shruti M. Gandhi1,2* and Eric S. Nylen1,2
Multiple endocrine neoplasia syndromes are rare and
seldom encountered even in subspecialty clinics de-
spite diligent evaluations. As this fascinating case illus-
trates, uncovering a case with such a syndrome leads to
a complexity of endocrinopathy challenges that con-
veys several important lessons.
Although authoritative textbooks and guidelines
emphasize that MEN1 patients initially present with
hyperparathyroidism, their illness occasionally debuts
as an insulinoma or prolactinoma. Typically, these
prolactinomas are macroadenomas that are multiple
and invasive, rendering them more challenging to
cure. Additionally, being cognizant of the cutaneous
manifestations of MEN1 is important for early recog-
nition with high diagnostic sensitivity and specificity.
In this case, multiple skin tags and nodules were noted
over the trunk, abdomen, and groin. The characteris-
tic skin lesions in MEN1 (in order of appearance)
1
Department of Endocrinology, DC VA Medical Center; 2 Department of Endocrinology,
George Washington University, Washington, DC.
* Address correspondence to this author at: George Washington University, 50 Irving St.,
N.W., Department of Endocrinology, DC VA Medical Center, Washington, DC 20422.
E-mail shruti1019@gmail.com.
Received April 18, 2015; accepted April 24, 2015.
DOI: 10.1373/clinchem.2015.240630
2015 American Association for Clinical Chemistry
Commentary
Roger L. Bertholf*
In some respects, treating endocrine disorders can be like
flying a helicopter. A helicopter pilot uses 3 essential con-
Department of Pathology and Laboratory Medicine, University of Florida College of Medi-
cine, Jacksonville, FL.
* Address correspondence to the author at: Department of Pathology and Laboratory Med-
Clinical Case Study
9. Lassen T, Friis-Hansen L, Rasmussen AK, Knigge U, Feldt-Rasmussen U. Primary hy-
perparathyroidism in young people. When should we perform genetic testing for
multiple endocrine neoplasia 1 (MEN1)? J Clin Endocrinol Metab 2014;99:39837.
10. Pieterman CR, van Hulsteijn LT, den Heijer M, van der Luijt RB, Bonenkamp JJ, Her-
mus AR, et al. Primary hyperparathyroidism in MEN1 patients: a cohort study with
longterm follow-up on preferred surgical procedure and the relation with genotype.
Ann Surg 2012;255:1171 8.
include angiofibromas, collagenomas, cafe-au-lait ma-
cules, lipomas, confetti-like hypopigmented macules,
and multiple gingival papules. Interestingly, these cu-
taneous proliferative lesions are manifestations of in-
activated menin.
The diagnosis of MEN1 focuses on the culprit mu-
tation of the menin gene, which is typically familial.
However, sporadic mutations, as in this case, have been
described in 10% of cases. Nevertheless, some of these
may be familial because complete medical pedigrees are
not always available. Interestingly, sporadic MEN1 mu-
tations may be transmitted to the next generation and
such de novo mutations from the parent increase the risk
in children of the next generation, requiring early clinical
and biochemical evaluation.
This case exemplifies the unexpected presentation of
endocrinopathies that a single patient with MEN1 may
present with. Early recognition and diagnosis of this syn-
drome may be of value in improving quality of life, out-
come, and prognosis.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 require-
ments: (a) significant contributions to the conception and design, acquisi-
tion of data, or analysis and interpretation of data; (b) drafting or revising
the article for intellectual content; and (c) final approval of the published
article.
Authors Disclosures or Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.
trols to maintain stable flight: the throttle, which controls
icine, University of Florida Health Science Center, Jacksonville, 655 West 8th St., Jack-
sonville, FL 32209. E-mail roger.bertholf@jax.u.edu.
Received April 16, 2015; accepted April 24, 2015.
DOI: 10.1373/clinchem.2015.240622
2015 American Association for Clinical Chemistry
Clinical Chemistry 61:11 (2015) 1331