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Patient with Persistent Lactation and Recurrent Hypercalcemia
Qing H. Meng, Elizabeth A. Wagar
DOI: 10.1373/clinchem.2014.234849 Published October 2015
CASE DESCRIPTION
An 18-year-old woman presented with persistent bilateral lactation, excess
body weight, and recurrent hypercalcemia. At age 13 years, before
menarche, she developed 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
resection 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
hormone replacement therapy, including desmopressin acetate [a synthetic
analog of antidiuretic hormone (ADH)], conjugated estrogen (Premarin),
growth hormone (Humatrope), and bromocriptine. A year later, she
developed recurrent kidney stones and was diagnosed with primary
hyperparathyroidism. She was also found to have multiple thyroid nodules.
She underwent a 4-gland parathyroidectomy with left forearm autograft and
total thyroidectomy. She had had transient hypoparathyroidism following
parathyroidectomy, soon afterward she experienced 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 examination revealed an obese young woman in distress, with leg
swelling and unbalanced gait. Her pulse was 91 beats per 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 vaginal and groin region.
The evaluation at our institution included laboratory investigations (Table
1), imaging, and histologic studies.
An adrenocorticotropic hormone (ACTH) stimulation test (1 μg
cosyntropin) showed a peak cortisol concentration of 18.7 μg/dL (reference
interval >20 μg/dL). Complete blood cell count showed microcytic
hypochromic anemia.
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?
DISCUSSION
MRI revealed a recurrent and progressive pituitary tumor. Histologic review
of the resected pituitary tumor confirmed an adenoma positive for prolactin
by immunohistochemistry. Endoscopic ultrasound showed multiple cysts
measuring 4 mm or less in the pancreatic genu/body and tail. A nodular area
of 4.6 × 6.3 mm in the genu/body of the pancreas suggested a pancreatic
neuroendocrine tumor. Histologic examination of the fine-needle aspiration
biopsy sample from this lesion confirmed pancreatic neuroendocrine tumor
with low-grade and mild reactive atypia (i.e., islet cell tumor).
The patient's history, physical examination findings, and results from
laboratory, imaging, and pathologic investigations suggested a diagnosis of
multiple endocrine neoplasia type 1 (MEN1) with pituitary adenoma,
primary hyperparathyroidism, and pancreatic neuroendocrine tumors. She
was tested for multiple endocrine neoplasia 1 (MEN1) gene mutation at
another institution, and the results of this test were reportedly positive. Her
clinical course was complicated by central adrenal insufficiency,
hypothyroidism, hypogonadism, and growth hormone deficiency that
developed
following
transsphenoidal
resection
of
the
pituitary
macroadenoma. Central adrenal insufficiency was diagnosed based on the
low cortisol and inappropriately low ACTH in the face of hypocortisolism.
The ACTH stimulation test, also referred to as the cosyntropin test, helps to
differentiate
primary
and
secondary
adrenal
insufficiency.
Under
cosyntropin stimulation, little or no increase in cortisol concentrations
indicates primary adrenal insufficiency. Patients with secondary adrenal
insufficiency usually show a blunted response to cosyntropin but
occasionally have a normal response with basal ACTH concentrations within
or below the reference interval. Testing with use of a 250-μg dose of
cosyntropin is intended to examine only the maximum adrenocortical
capacity, and this high dose overrides any more partial loss of cortisol
secretion. Testing with a 1-μg dose of cosyntropin is more sensitive and
accurate than use of the 250-μg dose of cosyntropin in detecting partial
adrenal insufficiency, in particular secondary adrenal insufficiency resulting
from pituitary tumors or chronic glucocorticoid treatment. A direct
corticortropin-releasing hormone stimulation test can help to detect
secondary adrenal insufficiency. Although thyroid tumors are found in
patients with MEN1, as seen in this case, it has been suggested that the
association of thyroid abnormalities may be incidental and not significant.
This patient's pancreatic neuroendocrine tumors, gastrinoma (ZollingerEllison syndrome) and insulinoma (hyperinsulinemia), are typical of MEN1.
She also exhibited skin manifestations of MEN1, such as angiofibromas.
MEN1 is an autosomal dominant inherited syndrome characterized by the
occurrence of tumors involving 2 or more principal endocrine glands,
including parathyroid, pancreatic endocrine tissues, and pituitary (1, 2).
Other endocrine and nonendocrine neoplasms typical of MEN1 include
carcinoid tumors, bronchial endocrine tumors, skin tumors (angiofibromas,
collagenomas, lipomas, melanomas), central nervous system tumors
(meningiomas, ependymonas, schwannomas), and smooth muscle tumors
(3). Most of the MEN1-associated tumors are benign, although malignancy
does occur occasionally. The prevalence of this disease is uncertain, but the
incidence has been estimated from autopsy studies to be 0.25% (2). MEN1 is
caused by mutations in the MEN1 gene located on chromosome 11q13,
consisting of 10 exons, that encodes a 610–amino acid nuclear protein,
menin (1, 4, 5). Menin is believed to be involved in many important cellular
processes such as cell cycle regulation, transcriptional control, cell division,
and genomic stability; however, the precise role of menin in tumorigenesis
remains to be established. No correlation has been observed between
genotype and MEN1 phenotype (1). Because there was no family history of
endocrine disorders in this case, this presentation likely represents a de novo
mutation. The occurrence of de novo mutations appear in 10% of all patients
with MEN1 (2).
A diagnosis of MEN1 is established by the occurrence of 2 or more primary
MEN1-associated endocrine tumors, the occurrence of MEN1-associated
tumors in a first-degree relative of a patient with a clinical diagnosis of
MEN1, or identification of a germline MEN1 mutation in an asymptomatic
individual who has not yet developed serum biochemical or radiological
abnormalities indicative of tumor development (2, 6). The diagnosis of
MEN1 is often delayed. The interval between the appearance of symptoms
and the diagnosis of MEN1 varies from several to dozens of years (6).
Failure to recognize multiple clinical manifestations of MEN1 is a common
reason for the delayed diagnosis. Primary hyperparathyroidism is the most
common and usually the earliest clinical abnormality of MEN1 (95%),
followed by pancreatic endocrine tumors (40%–70%) and pituitary
adenomas (30%–40%) (2, 7). All individuals in whom MEN1 is suspected
should be screened with measurements of serum calcium and parathyroid
hormone (PTH) concentrations. Other biochemical measurements such as
insulin, proinsulin, glucagon, prolactin, gastrin, insulin-like growth factor-1
(IGF-1), pancreatic 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 symptoms 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 estimated at 1–10 per 100 000
inhabitants (9), and in most of the cases the tumors may be benign (as
compared to malignant), the disease itself is not benign and can be fatal.
Therefore, early identification and diagnosis is critical to asymptomatic
individuals who should benefit from treatment. A careful family history 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 similar 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 hyperparathyroidism 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 damage to the hypothalamus or pituitary
gland during pituitary surgery. It is characterized by increased urine output
and decreased urinary osmolality and specific gravity due to decreased
secretion of ADH. Her plasma calcium concentrations remained only
slightly high. Vitamin D deficiency may reduce the severity of
hypercalcemia but accentuate the increase in PTH. She also received
ergocalciferol as treatment of vitamin D deficiency. Her gastroesophageal
reflux disease, which resulted from the gastrinoma, 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, including carcinoids, pheochromocytomas,
neuroblastomas, medullary thyroid carcinomas, some pituitary tumors, and
functioning and nonfunctioning islet cell tumors. The effects of proton pump
inhibitor–induced elevation of chromogranin A are correlated with the dose
and prolongation of the treatment of proton pump inhibitors.
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,
pancreatic islet cells, or pituitary gland, with or without other endocrine and
nonendocrine neoplasms. Primary hyperparathyroidism is the most common
feature 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 measured as screening
tests for individuals in whom MEN1 is suspected. Other biochemical
measurements assessing the function of endocrine organs in combination
with imaging studies are beneficial for early detection and diagnosis of
MEN1.