The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No.

11, 3113–3128
https://doi.org/10.1210/clinem/dgab504
Mini-Review

Mini-Review

Rare Causes of Hypercalcemia: 2021 Update

Yasaman Motlaghzadeh,1 John P. Bilezikian,2 and Deborah E. Sellmeyer1

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1
Stanford University School of Medicine, Division of Endocrinology, Gerontology and Metabolism,
Palo Alto, CA 94305, USA; and 2Division of Endocrinology, Department of Medicine, Vagelos College of
Physicians and Surgeons, Columbia University, New York, NY 10032, USA
ORCiD number: 0000-0003-4571-1386 (D. E. Sellmeyer).

Abbreviations: 1,25-OH2D, 1,25-dihydroxyvitamin D; ATRA, all-trans-retinoic acid; PTHrP, PTH-related protein; SCFN,
subcutaneous fat necrosis; SLE, systemic lupus erythematosus.
Received: 11 June 2021; Editorial Decision: 2 July 2021; First Published Online: 8 July 2021; Corrected and Typeset:
28 July 2021.

Abstract
Context: Primary hyperparathyroidism and malignancy are the etiologies in 90% of cases
of hypercalcemia. When these entities are not the etiology of hypercalcemia, uncommon
conditions need to be considered. In 2005, Jacobs and Bilezikian published a clinical
review of rare causes of hypercalcemia, focusing on mechanisms and pathophysiology.
This review is an updated synopsis of rare causes of hypercalcemia, extending the
observations of the original article.
Evidence Acquisition: Articles reporting rare associations between hypercalcemia and unusual
conditions were identified through a comprehensive extensive PubMed-based search using
the search terms “hypercalcemia” and “etiology,” as well as examining the references in the
identified case reports. We categorized the reports by adults vs pediatric and further categorized
the adult reports based on etiology. Some included reports lacked definitive assessment of
etiology and are reported as unknown mechanism with discussion of likely etiology.
Evidence Synthesis: There is a growing understanding of the breadth of unusual causes
of hypercalcemia. When the cause of hypercalcemia is elusive, a focus on mechanism
and review of prior reported cases is key to successful determination of the etiology.
Conclusions: The ever-expanding reports of patients with rare and even unknown
mechanisms of hypercalcemia illustrate the need for continued investigation into the
complexities of human calcium metabolism.
Key Words: hypercalcemia, 1,25 dihydroxyvitamin D, PTHrP, ectopic PTH, calcitriol

In 2005, Jacobs and Bilezikian published a clinical re- development for a number of potentially key factors has
view of rare causes of hypercalcemia, focusing on mech- progressed and become more widely available, allowing
anisms and pathophysiology (1). Since that time, assay better characterization of the etiology of hypercalcemia

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in USA
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.
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3114  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

in unusual settings. Additionally, a considerable number Reports in Adults

of rare cases of hypercalcemia have since been reported
Hypercalcemia mediated by elevated levels of
including some new mechanisms such as ingestion of non-
1,25-dihydroxyvitamin D
alkali calcium compounds. In this review, we present an
updated compendium of rare causes of hypercalcemia, ex- Hypercalcemia associated with elevated levels of
tending the observations of the original article and pro- 1,25-dihydroxyvitamin D has been described in patients
viding a guide for clinicians who evaluate hypercalcemia with granulomatous diseases, such as sarcoidosis, tuber-
in atypical settings. culosis, and some systemic fungal infections (Table 1). The
Hypercalcemia is a relatively common clinical mechanism for hypercalcemia in granulomatous diseases
problem and virtually always signifies an underlying is attributed to unregulated 1-alpha-hydroxylase expres-
disorder. Among the etiologies of hypercalcemia, pri- sion by activated macrophages within the granulomas,
leading to increased conversion of 25-hydroxyvitamin

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mary hyperparathyroidism and malignancy are the
most common, accounting for more than 90% of D to 1,25-OH2D. Hypercalcemia has occurred in pa-
cases. Other causes of hypercalcemia, such as vitamin tients with granulomatosis with polyangiitis (9, 10) with
D intoxication, granulomatous disorders, cosmetic in-
jections, thyrotoxicosis, adrenal insufficiency, milk- Table 1. Hypercalcemia mediated by elevated levels of
alkali syndrome, medications, familial hypocalciuric 1,25-dihydroxyvitamin D
hypercalcemia, and immobilization amount to less than Granulomatous/macrophage disorders that rarely cause
10% of all causes of hypercalcemia. Considering rare 1,25-dihydroxyvitamin D-mediated hypercalcemia
etiologies is important, nevertheless, when primary Granulomatosis with polyangiitis (9-11)
hyperparathyroidism or malignancy does not account Common variable immunodeficiency (12)
for the hypercalcemia. In this review, we summarize the Giant cell myocarditis (13)
reports of unusual etiologies of hypercalcemia, which Malakoplakia (14)
Necrobiotic xanthogranuloma (15)
are not typically listed in the literature or in many re-
Rosai-Dorfman disease (16)
views. In most of these cases, an etiology is defined. We
Palisaded neutrophilic and granulomatous dermatitis (17)
also included reports with unknown mechanisms and Granulomatous slack skin disease (18)
some that were published before the wide availability Acute granulomatosis pneumonia (19)
of current assays for investigating hypercalcemia, in Hepatic granulomatosis (20)
particular, 1,25-dihydroxyvitamin D (1,25-OH 2D) Bacille Calmette-Guerin therapy (21)
measurement. This review, thus, is an updated and Crohn disease (22-24)
Pneumocystis jirovecii pneumonia (25-28)
comprehensive review of rare causes of hypercalcemia
Immune reconstitution inflammatory syndrome (29-31)
in children and adults (1-7).
Gastrointestinal stromal tumor (32-34)
Idiopathic hypereosinophilic syndrome (35)
Cat scratch fever (36)
Methods Foreign material
Talc-induced granulomatous (37)
We included case reports identified through a compre- Silicone (38-41)
hensive extensive PubMed-based search using the search Polymethylmethacrylate (42)
terms “hypercalcemia” and “etiology,” as well as exam- Paraffin oil injections (43)
ining the references in the identified case reports. The Mineral oil injections (44)
search included the time frame from 2005 (the publica- Particle disease (45)
Nephrogenic systemic fibrosis (46)
tion date of the original Jacobs and Bilezikian review)
Lipid pneumonia (47)
through January 2021. We excluded common forms of
Acromegaly (48)
hypercalcemia, in particular, hyperparathyroidism, malig- 8-Cl-cAMP therapy (50)
nancy, and calcium-sensing receptor antibody/mutations, Mutations in CYP24A1 (51-59)
even if they occurred in patients with unusual medical Likely 1,25-dihydroxyvitamin D mediated (not confirmed)
conditions (8). We categorized the reports by adults vs Allopurinol-induced granulomatous hepatitis (60)
pediatric and further categorized the adult reports based Eosinophilic granuloma (61)
on etiology. Some included reports lacked definitive as- Mycobacterium avium complex in AIDS (62)
Chronic berylliosis (63)
sessment of etiology and are reported as unknown mech-
Paraffin granulomatosis (64)
anism with discussion of likely etiology.
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 3115

improvement in serum calcium and 1,25-OH2D levels in Hypercalcemia in patients with Crohn disease has been
1 patient treated with cyclophosphamide and glucocortic- reported on at least 4 occasions, of which 2 had granu-
oids (11). Hypercalcemia has also been described in a pa- lomas on bowel biopsy (22). Three of the cases responded
tient with biopsy-proven noncaseating renal granulomas in to glucocorticoid therapy (22, 23) and 1 to infliximab
the setting of common variable immunodeficiency (12) and (24). Although still rare, there have been increasing re-
in another case with giant cell myocarditis (13). Both pa- ports of hypercalcemia presenting in association with
tients responded to glucocorticoid therapy. Malakoplakia, pneumocystis infections in renal transplant recipients.
a rare disease of nongranulomatous macrophage infiltra- This finding has been attributed to increased conversion of
tion, has also been associated with 1,25-OH2D–mediated 25-hydroxyvitamin D to 1,25-OH2D by activated macro-
hypercalcemia (14). This finding has been attributed to ab- phages in inflamed tissue (25-28). Three patients with his-
normal 1-alpha-hydroxylase activity in the malakoplakia tory of HIV also developed hypercalcemia with elevated

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cell. Necrobiotic xanthogranuloma, a chronic granuloma- 1,25-OH2D in the setting of immune reconstitution inflam-
tous disease primarily involving the skin, has been reported matory syndrome in patients with mycobacterium tuber-
in association with hypercalcemia and inappropriately ele- culosis (29, 30) and Mycobacterium avium complex (31).
vated levels of 1,25-OH2D. Glucocorticoid therapy was Hypercalcemia has been reported in 3 patients with
effective in controlling the hypercalcemia and reducing the gastrointestinal stromal tumors. Direct tumor production
1,25-OH2D levels (15). One patient with Rosai-Dorfman of 1,25-OH2D or the 1-alpha-hydroxylase enzyme resulting
disease, a rare disorder of massive lymphadenopathy re- in conversion of 25-hydroxy vitamin D to 1,25-OH2D is
sulting from proliferation of histiocytes in lymph nodes, the putative mechanism in gastrointestinal stromal tumor-
was found to have hypercalcemia and increased serum related hypercalcemia (32-34). A patient with idiopathic
1,25-OH2D levels. Immunohistochemistry in this case re- hypereosinophilic syndrome accompanied by eosinophilic
vealed increased expression of 1-alpha-hydroxylase by myocarditis was found to have hypercalcemia with an
histiocytes. Treatment with oral prednisolone decreased elevated 1,25-OH2D level. Glucocorticoid therapy im-
the serum levels of 1,25-OH2D and normalized the serum proved hypercalcemia and 1,25-OH2D level promptly (35).
calcium level (16). Palisaded neutrophilic and granuloma- Identical male twins with cat scratch disease were found to
tous dermatitis, a benign inflammatory dermatosis, was have hypercalcemia and hypercalciuria with elevated 1,25-
reported to cause 1,25-OH2D–mediated hypercalcemia. OH2D levels. Treating the bacterial infection normalized
Using immunohistochemistry, granuloma and epi- the serum and urinary calcium concentrations in both
dermal cells were found to be 1-alpha-hydroxylase posi- cases (36).
tive (17). Granulomatous slack skin disease, a rare T-cell Introduction of foreign material into the human body
lymphoproliferative disorder, led to hypercalcemia with can lead to a granulomatous inflammatory reaction.
elevated 1,25-OH2D in a 19-year-old man (18). Tissue ana- Hypercalcemia with concurrently elevated 1,25-OH2D
lysis demonstrated 1-alpha-hydroxylase activity limited has been reported in patients with talc-induced granu-
to the basal layer of the epidermis in unaffected skin, but lomatous pneumoconiosis pneumonia (37), in 4 cases of
overexpression of 1-alpha-hydroxylase in dermal granu- granulomatous reaction to silicone injections (38-41) and
lomata as well as basal epidermal cells in affected skin. 2 cases of polymethylmethacrylate injections (42). Paraffin
Hypercalcemia with elevated 1,25-OH2D has been de- oil (43) and mineral oil injections (44) causing sclerosing
scribed in acute granulomatous pneumonitis, a rare com- paraffinomas have also been reported to cause cosmetic
plication of methotrexate therapy. Hypercalcemia and injection-induced hypercalcemia with elevated 1,25-OH2D.
1,25-OH2D levels improved with glucocorticoid treatment Shredded foreign body particulates from a failed pros-
(19). Hypercalcemia has been reported in 4 patients on thetic joint generating a local inflammatory response, an
chronic hemodialysis with hepatic granulomatosis of un- entity known as particle disease, has been reported as a
known etiology. These patients had inappropriately normal cause of 1,25-OH2D–mediated hypercalcemia. Biopsy of
PTH levels, possibly secondary to accumulation of inactive the inflammatory mass in this case demonstrated activated
PTH fragments, but the high-normal 1,25-OH2D levels macrophages and foreign body granuloma. Hypercalcemia
are suggestive of production of 1,25-OH2D by the hepatic responded promptly to therapy with glucocorticoids (45).
granulomas. Hypercalcemia in these cases also responded In some case reports, the increase in 1,25-OH2D has not
promptly to glucocorticoid therapy (20). Granulomatous been associated with a granulomatous process. For example,
hepatitis in the setting of a systemic reaction to Bacillus nephrogenic systemic fibrosis associated with the adminis-
Calmette-Guérin therapy for bladder cancer has also been tration of gadolinium-containing contrast in patients with
associated with significant hypercalcemia and elevated renal insufficiency, has been found to cause hypercalcemia
1,25-OH2D (21). with elevated 1,25-OH2D. This finding has been attributed
3116  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

to increased 1-alpha-hydroxylase activity in the nephrogenic (Table 2). Because milk-alkali syndrome is estimated to be
systemic fibrosis lesions (46). Lipid pneumonia has also the third most common cause of hypercalcemia (66), we
been associated with recurrent hypercalcemia and elevated only included rare instances of this syndrome. Milk-alkali
levels of 1,25-OH2D (47). Hypercalcemia with elevated syndrome has been reported in a 64-year-old woman sec-
1,25-OH2D has been reported in 2 cases of acromegaly ondary to chewing approximately 30 pieces of nicotine-
(48). Animal studies have shown that GH can directly ac- substitute gum daily for several years after she stopped
tivate 1-alpha-hydroxylase in the kidney (49). Complete smoking. Each piece of gum was found to contain 94 mg
resection of tumor resulted in biochemical remission of of elemental calcium, giving her a daily calcium intake,
acromegaly and normalization of calcium and 1,25-OH2D through this source alone, of about 2820 mg. The patient
(48). Hypercalcemia associated with elevated levels of 1,25- was concurrently drinking large amounts of carbonated
OH2D has been described in patients with advanced solid water. Her calcium level was17.7 mg/dL on admission and

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malignancies in the setting of an experimental use of cAMP normalized after 3 days with hydration, IV bisphosphonate
analog (8-Cl-AMP) (50). Although elevated 1,25-OH2D administration, and calcitonin (67). A 59-year-old man
is usually from excess production, inactivating mutations who presented with severe hypercalcemia on 2 occa-
in CYP24A1, the enzyme responsible for the metabolism sions, subsequently admitted to ingesting a household
of 1,25-OH2D can lead to hypercalcemia by reducing its cleanser containing a large amount of calcium carbonate.
breakdown. These patients typically have a history of unex- Hypercalcemia resolved after the patient discontinued
plained hypercalcemia for years, along with hypercalciuria, ingesting the product (68). Similarly, a 41-year-old woman
nephrolithiasis, and nephrolithiasis (51-59). Although this with a known major depressive disorder presented with
cause of hypercalcemia is becoming more widely recog- hypercalcemia after intentionally ingesting 250 mL of li-
nized, it is still the subject of case reports and is thus in- quid calcium fertilizer containing 237 g of calcium (69).
cluded in this review. Milk- alkali syndrome has also been reported in 3 patients
Other cases of hypercalcemia have been reported in from Taiwan after chewing betel nuts along with oyster
rare settings associated with granulomatous or mast cells shell powder that was used to neutralize the bitter taste of
disorders, but without 1,25-OH2D measurements. For ex- the betel nuts (70, 71). Two patients who attempted suicide
ample, hypercalcemia was reported in a 62-year-old man with buffered aspirin tablets developed hypercalcemia,
with allopurinol-induced granulomatous hepatitis. In this presumably because of the associated intake of calcium
case, the hypercalcemia and elevated hepatic enzymes carbonate (72). Hypercalcemia has also been reported in a
were further evident with the addition of furosemide. nurse after surreptitious ingestion of large amounts of cal-
Hypercalcemia improved after discontinuation of both cium carbonate with a thiazide diuretic (73). Similarly, a
allopurinol and furosemide and treatment with gluco- woman with an eating disorder developed hypercalcemia
corticoids (60). requiring hospitalization on 3 occasions after consuming
Hypercalcemia responsive to glucocorticoid therapy a massive amount of cheese with concurrent dehydration
has been reported in association with eosinophilic granu- and metabolic alkalosis caused by vomiting and thiazide
loma (61). Hypercalcemia has also been described in a pa- diuretic use (74).
tient with AIDS and Mycobacterium avium (62). Chronic
berylliosis complicated by granulomatous pneumonitis in
Table 2. Hypercalcemia from excess calcium intake
2 patients was associated with hypercalcemia that resolved
spontaneously after several months (63). A 63-year-old Milk alkali
man with multiorgan failure and widespread granuloma- Nicotine replacement chewing gum (67)
tous lesions developed hypercalcemia 28 years after a par- Household cleanser (CaCO3) ingestion (68)
affin mammoplasty (64). Although these cases (60-64) did Liquid calcium fertilizer (CaCO3) intoxication (69)
Oyster shell calcium in betel nut chewing (70, 71)
not report 1,25-OH2D measurements, we have described
Overdose with buffered aspirin (72)
them in this section because of the granulomas and the like-
Munchausen syndrome (73)
lihood for a similar etiology through the ectopic produc- Massive cheese ingestion (74)
tion of 1,25-OH2D. Other calcium compounds
Calcium alginate dressing for extensive toxic epidermal
necrolysis (75)
Hypercalcemia from excess calcium intake Calcium sulfate beads impregnated with antibiotics (76)
Commercial moisture absorber ingestion (77)
Milk-alkali syndrome secondary to ingestion of large
Instant heat pack ingestion (78)
amounts of calcium and absorbable alkalis is defined by
Extensive burns caused by heated CaCl2 solution (79)
hypercalcemia, renal failure, and metabolic alkalosis (65)
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 3117

Hypercalcemia has also been reported in other rare Table 3. Hypercalcemia caused by PTH-related protein
occasions secondary to excessive non-alkali calcium ab-
Benign tumors
sorption. For example, an 87-year-old Chinese man with Giant pilomatricoma (84, 85)
allopurinol-induced toxic epidermal necrolysis developed Intestinal and uterine leiomyoma (83, 86, 87)
hypercalcemia after using a large quantity of calcium al- Ovary (88)
ginate dressing as part of his treatment (75). In a study Kidney (89)
evaluating complications of antibiotic-eluting absorbable Benign pheochromocytoma (90, 91)
Sarcoidosis (92)
calcium sulfate beads in 15 patients with periprosthetic
Systemic lupus erythematosus (93-95)
joint infection, 3 patients developed hypercalcemia during
HIV-associated lymphadenopathy (96)
the follow-up period (76). A 31-year-old man with history Pregnancy/lactation related
of pervasive developmental disorder presented with se- Humeral hypercalcemia of pregnancy (99)

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vere hypercalcemia (serum total calcium 20.7 mg/dL) and Massive mammary hyperplasia during pregnancy (100-102)
metabolic acidosis after intentionally ingesting 300 mL During late pregnancy and lactation in hypoparathyroidism
of commercial moisture absorber solution containing (103-105)
300 g of calcium chloride (77). Similarly, a 35-year-old
man developed hypercalcemia and gastric necrosis after
ingesting 3 topical hot packs in an attempt to be removed uptake throughout the lungs (94). Hypercalcemia with
from jail. The hot packs were given to him for back pain, elevated levels of PTHrP has also been reported in a
and each contained 90% to 97% calcium chloride (78). young woman with SLE presenting with pleural effusions
Hypercalcemic crisis has also been reported in a young and lymphedematous bilateral breast enlargement (95).
man with extensive burns caused by a heated CaCl2 so- A 63-year-old man with HIV-associated lymphadenop-
lution (79). athy developed recurrent hypercalcemia and was found
to have positive staining for PTHrP and its mRNA in a
cervical lymph node (96).
Hypercalcemia caused by PTH-related protein PTHrP is produced physiologically in fetal and ma-
Hypercalcemia associated with PTH-related protein ternal tissues but excessive production in the placenta and
(PTHrP) secretion has been described mostly in malig- mammary glands can cause hypercalcemia (97, 98). Rarely,
nant tumors and is known as a major cause of humeral PTHrP-mediated hypercalcemia has been reported in the
hypercalcemia of malignancy (80-82) (Table 3). However, setting of pregnancy, delivery, and lactation.
it rarely has been reported in the setting of benign diseases A 28-year-old pregnant woman developed severe
(83). Three patients with pilomatrixoma, a cutaneous be- hypercalcemia on the first postpartum day with a markedly
nign appendage tumor that commonly occurs on the face increased serum level of PTHrP. The serum levels of calcium
and extremities, were found to have PTHrP-mediated and PTHrP both normalized after administration of saline and
hypercalcemia (84, 85). Hypercalcemia and elevated pamidronate (99). Another young woman presented in the
PTHrP have been reported in benign intestinal (86) and 15th week of pregnancy with massive enlargement of breasts
uterine leiomyomas (83, 87), benign ovarian tumor (88), and was found to have severe hypercalcemia, suppressed PTH,
renal adenoma (89), and pheochromocytomas (90, 91). and an elevated level of PTHrP. Treatment with bromocriptine
Surgical removal of the benign tumor normalized the serum suppressed PTHrP and normalized serum calcium levels (100).
calcium level in these cases. A 25-year-old pregnant woman with massive mammary hyper-
A 67-year-old man with sarcoidosis was found to plasia accompanied by severe hypercalcemia responded to bi-
have hypercalcemia with elevated levels of PTHrP. lateral mastectomy (101). Immunostaining of the breast tissue
Bone marrow granulomas stained positively for revealed PTHrP reactivity limited to myoepithelial cells, with
PTHrP and treatment with glucocorticoids normalized none evident in normal breast tissue (102). Hypercalcemia has
hypercalcemia and the PTHrP level (92). A patient with also been reported during 2 pregnancies of a patient with low
systemic lupus erythematosus (SLE) with multiorgan in- PTH levels. In the second pregnancy, PTHrP level remained
volvement and diffuse lymphadenopathy presented with elevated for several months after delivery (103). Another pa-
hypercalcemia and a high circulating PTHrP concentra- tient with hypoparathyroidism developed hypercalcemia with
tion. Immunohistology of biopsied lymph nodes revealed elevated PTHrP while lactating. Hypercalcemia in this case
PTHrP expression (93). Similarly, a 39-year-old woman responded to the withdrawal of calcium and calcitriol supple-
with SLE developed PTHrP-mediated hypercalcemia ac- ments, whereas PTHrP levels remained elevated (104). There
companied by ectopic calcinosis in subcutaneous tissue is an additional case report of similar findings in 2 pregnant
of both hands. Interestingly, bone scan showed intense patients from 1969; however, no PTHrP measurements were
3118  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

done (105). Based on these reports, patients with hypopara- PTH levels normalized after surgical resection of the tumor
thyroidism on pharmacologic doses of vitamin D appear to be in all 3 cases.
at increased risk for hypercalcemia during pregnancy and lac- Hypercalcemia associated with high PTH level has been
tation. Calcium should be monitored closely in these patients reported in 3 patients with pancreatic neuroendocrine
who may need a reduction in vitamin D intake until breast tumors. In 2 of these cases with liver metastases, chemo-
feeding is completed. therapy resulted in a decrease in the pancreatic mass, PTH,
and calcium levels (115, 116). In the first case, there was no
family history suggestive of multiple endocrine neoplasia
Hypercalcemia caused by ectopic PTH type 1, and neck imaging did not demonstrate any para-
Malignancy-associated hypercalcemia with elevated PTH thyroid abnormalities. PTH and serum calcium levels re-
is rare, with few reports over the past decades (Table 4). sponded to treatment of the neuroendocrine tumor. In the

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For example, A 25-year-old man with acute myeloblastic second case, neck exploration did not identify a parathyroid
leukemia developed hypercalcemia associated with in- adenoma; sestamibi scanning showed uptake in the liver
appropriately elevated levels of PTH on 6 occasions in con- at the site of metastases. Similarly, a 41-year-old man with
junction with relapses of his disease. The in vitro studies pancreatic neuroendocrine tumor developed hypercalcemia
were remarkable for production of PTH by leukemic cells later during his disease. A PTH level was not checked,
(106). Hypercalcemia caused by ectopic PTH has also been but several tumor cells were found to be positive for PTH
reported in 2 patients with hepatocellular carcinoma (107, (117). At autopsy, the parathyroid glands were normal.
108). Elevated PTH was found in hepatic venous sampling A 73-year-old woman with a clinical and biochemical
and decreased after embolization of the tumor in the first profile characteristic of primary hyperparathyroidism but
report (107). Similarly, 2 patients with small cell lung cancer normal sestamibi scan was found to have a neuroendocrine
were found to have hypercalcemia associated with elevated tumor in the neck. Surgical resection of the mass resulted
PTH levels in the tumor extract and in vitro studies (109, in normalization of the PTH level within 10 minutes (118).
110). Bronchogenic lung cancer has also been reported to Additionally, papillary thyroid cancer (119), squamous
cause hypercalcemia in the setting of ectopic PTH secre- cell carcinoma of tonsil (120), pheochromocytomas (121),
tion. Surgical resection of the tumor resulted in a reduction nasopharyngeal rhabdomyosarcoma (122), and thymoma
in serum calcium and PTH levels in this patient (111). (123) have all been associated with hypercalcemia in the
Ectopic PTH secretion by ovarian tumor cells has been setting of ectopic PTH secretion.
reported in 3 cases. A 33-year-old woman with ovarian
non-small cell neuroendocrine carcinoma was found to
have severe hypercalcemia with elevated serum level of Hypercalcemia caused by PTH and PTHrP
PTH. The poorly differentiated cells of the tumor stained There have been few case reports of hypercalcemia due to
positive for PTH (112). Similarly, a 74-year-old woman tumors producing both PTH and PTHrP (Table 5). Although
with persistent hypercalcemia after resection of 3.5 para- PTH and PTHrP interact with a common receptor, there is
thyroid glands, was found to have ovarian carcinoma. no cross-reactivity in their current assays. This makes it pos-
DNA amplification and rearrangement in the regulatory sible to clearly distinguish between PTH-mediated, PTHrP-
region of the PTH gene was demonstrated in tumor tissue mediated, and ultra-rare situations where both appear to
(113). A young woman with small cell carcinoma of the be etiologic in hypercalcemia. A 30-year-old man with per-
ovary had a similar presentation (114). Serum calcium and sistent hypercalcemia and normal level of PTH was found
to have a substernal parathyroid adenoma. He underwent
Table 4. Hypercalcemia caused by ectopic PTH parathyroidectomy with pathology remarkable for oxyphil
adenoma that stained positive for PTH and PTHrP (124).
Acute myeloblastic leukemia (106)
Similarly, a 73-year-old man with a history of primary
Hepatocellular carcinoma (107, 108)
Lung cancer (109-111)
Ovarian cancer (112-114) Table 5. Hypercalcemia caused by concurrent secretion of
Pancreatic neuroendocrine tumor (115-117) PTH and PTH-related protein
Neuroendocrine tumor in the neck (118)
Papillary thyroid cancer (119) Substernal oxyphil parathyroid adenoma (124)
Squamous cell carcinoma of tonsil (120) Transitional cell carcinoma (125)
Bilateral pheochromocytomas (121) Pancreatic neuroendocrine tumor (126)
Metastatic nasopharyngeal rhabdomyosarcoma (122) Gastric carcinoma (127)
Thymoma (123) Neuroectodermal tumor (128)
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 3119

hyperparathyroidism presented with recurrent hypercalcemia Hypercalcemia in a 31-year-old postpartum patient

6 years after removal of a parathyroid adenoma. He was found with acute interstitial granulomatous nephritis was at-
to have large retroperitoneal mass. Computed tomography- tributed to use of omeprazole (137). The 1,25-OH2-D
guided biopsy of the mass demonstrated metastatic, poorly levels were not reported; however, PTH was low and
differentiated transitional cell carcinoma immunopositive angiotensin-converting enzyme level was elevated. The
for PTH and PTHrP (125). A poorly differentiated neuro- patient’s serum calcium and renal function responded to
endocrine tumor of the pancreas has also been associated discontinuation of omeprazole and treatment with gluco-
with hypercalcemia and elevated levels of PTH and PTHrP. corticoids. In 60 patients with theophylline toxicity, 11
Staining of the tumor cells was positive for PTH in this case developed hypercalcemia with normal PTH levels sug-
(126). Similar findings have been reported in metastatic gas- gesting impaired parathyroid gland sensitivity to ionized
tric cancer (127) and neuroectodermal tumor (128). calcium (138). Hypercalcemia developed among patients

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in a surgical intensive care unit receiving high doses of
human GH, although other factors such as parenteral nu-
Hypercalcemia rarely caused by medications trition and immobilization may have also had a role (139).
Common medications such as thiazide diuretics, lithium, Long-term parenteral nutrition caused hypercalcemia in
and excessive intake of vitamin D, vitamin A, or cal- several patients; this effect was resolved in 1 small study
cium can result in hypercalcemia. Rarely, other medica- by removal of vitamin D from nutritional solutions (140).
tions have been associated with hypercalcemia (Table 6). Hypercalcemia, arthritis, and lytic bone lesions occurred
A 24-year-old woman with acute promyelocytic leukemia shortly after the third dose of recombinant hepatitis B virus
treated with all-trans-retinoic acid (ATRA) developed vaccine in a 44-year-old man (141). Bone biopsy demon-
hypercalcemia while concurrently on voriconazole (129). strated increased bone resorption and his clinical symp-
Hypercalcemia was attributed to the inhibition of cyto- toms responded to antiresorptive therapies. A significant
chrome P450 function by voriconazole when used con- increase in serum calcium also has been reported in cases
comitantly with ATRA. Similarly, a 38-year-old man with with manganese poisoning (142).
acute promyelocytic leukemia developed hypercalcemia
from the interaction of ATRA and itraconazole treatment
(130). Foscarnet can lead to hypocalcemia through its che- Hypercalcemia of unknown mechanisms
lating effect, but in 3 case reports has been associated with In some reported cases of hypercalcemia, the mechan-
hypercalcemia. A 4-month-old infant with severe combined isms are unclear, either because they were published be-
immunodeficiency disease and 2 adult patients with AIDS fore widespread availability of accurate and helpful assays
all developed hypercalcemia during foscarnet therapy for (eg, PTH, PTHrP, vitamin D metabolites), or where the
cytomegalovirus infection (131, 132). There are 4 case re- mechanism could not be defined despite measurements
ports of denosumab discontinuation leading to rebound of these factors (Table 7). Hypercalcemia has rarely been
hypercalcemia. Hypercalcemia with elevated markers of reported in patients with adrenal insufficiency. For ex-
bone remodeling has been reported in all cases, including a ample, a 47-year-old woman with a history of unilateral
10-year-old boy being treated for giant cell tumor, 2 women adrenalectomy developed hypercalcemia after long-term
being treated for oncologic indications, and a 67-year-old
woman being treated for osteoporosis. In 1 of the women
Table 7. Hypercalcemia from unknown mechanisms
receiving oncologic doses of denosumab, FGF23 was ele-
vated during the time of hypercalcemia (133-136). Unusual presentations of adrenal insufficiency (142-149)
Acute renal failure secondary to rhabdomyolysis (150-153)
Table 6. Hypercalcemia rarely caused by medications Burn patients (154)
Mycobacterium leprae (155, 156)
Voriconazole/itraconazole used concomitantly with all-trans- Cryptococcal meningitis in AIDS (157)
retinoic acid (129, 130) Cytomegalic virus infection in AIDS (158)
Foscarnet (131, 132) Rheumatoid arthritis (159, 160)
Discontinuation of denosumab (133-136) Scabies (161)
Omeprazole in acute interstitial nephritis (137) Nocardia asteroides pericarditis (162)
Theophylline toxicity (138) Diffuse osteoclastosis (163)
GH (139) Advanced chronic liver disease (164)
Parenteral nutrition (140) Type 1 Gaucher disease with acute pneumonia (165)
Hepatitis B vaccination (141) Lymphedema in systemic lupus erythematosus (166)
Manganese toxicity (142) Lymphadenopathy with high IL-6 (167)
3120  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

use of licorice as laxative and stopping her corticosteroid Hypercalcemia has been observed in a 40-year-old man
replacement therapy. Administration of hydrocortisone and with scabies. Biopsy of an axillary lymph node was remark-
zoledronic acid was associated with improvement in her able for nonspecific inflammation but no granuloma. 1,25-
clinical picture and normalization of serum calcium (143). OH2D was not measured in this case (161).
Hypercalcemia associated with adrenal crisis was also de- A 34-year-old woman with a history of hypoparathyr-
scribed in a patient with psoriasis after abrupt withdrawal oidism developed hypercalcemia associated with Nocardia-
of topical and oral glucocorticoids (144). Similarly, a induced pericarditis. Hypercalcemia responded to successful
45-year-old man with PTH-independent hypercalcemia was treatment of the infection (162). Another young woman
found to have adrenal histoplasmosis complicated by ad- with bone pain was found to have focal osteolysis and
renal insufficiency (145). Hypercalcemia has been reported hypercalcemia associated with normal PTH and PTHrP.
in isolated ACTH deficiency (146), medroxyprogesterone Treatment with glucocorticoids improved the symptoms,

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acetate withdrawal (147), and glucocorticoid withdrawal but the patient subsequently died of severe hypercalcemia.
after surgical intervention for Cushing syndrome (148). Histologic evaluation of these lesions was remarkable for in-
A 57-year-old woman developed hypercalcemia secondary tense osteoclastic resorption, without malignant cells (163).
to adrenal insufficiency in the setting of partial hypopituit- In 10 patients with advanced liver disease, hypercalcemia
arism and pyelonephritis (149). was reported in association with mild azotemia and sup-
Transient hypercalcemia has been observed in patients pressed or low-normal PTH levels (164). Hypercalcemia
with acute renal failure secondary to rhabdomyolysis, par- has also been reported in a 35-year-old woman with type
ticularly during the recovery phase of the disease. In all of I Gaucher disease and acute pneumonia. This was attrib-
these cases, serum PTH and 1,25-OH2D levels were low uted to activation of osteoclasts by proinflammatory cyto-
(150-153). Hypercalcemia in this syndrome has been at- kines (165). Hypercalcemia associated with lymphedema
tributed to remobilization of the calcium from the dam- in patients with SLE has also been described in the set-
aged muscles into the extracellular space (150, 151). In a ting of normal PTHrP levels. It has been suggested that
retrospective cohort study of 73 burn-injury intensive care autoantibodies may be responsible for hypercalcemia via
unit admissions, 22 (30%) developed hypercalcemia. Acute cross-reacting with an activating the PTH receptor (166).
renal failure was more frequent in hypercalcemic patients. Finally, a 24-year-old man with diffuse musculoskeletal pain
Hydration and mobilization resulted in normalization of and lymphadenopathy was found to have hypercalcemia,
calcium in most cases (154). hyperphosphatemia, and elevated serum alkaline phos-
Hypercalcemia in granulomatous diseases such as sar- phatase activity. Further evaluation revealed diffuse uptake
coidosis and tuberculosis is typically 1,25-OH2D mediated, of radionuclide on a bone scan, high urinary N-telopeptide
but the exact mechanism in patients with leprosy is unclear. excretion, and a serum interleukin-6 level that was 100
A 78-year-old man with borderline tuberculoid leprosy and times higher than normal. Treatment with intravenous
type I lepra reaction developed hypercalcemia associated pamidronate resulted in symptomatic and biochemical im-
with normal levels of PTH and 1,25-OH2D (155). Similarly, provement (167). Many of the cases in which no specific
another patient with leprosy complicating rheumatoid arth- mechanism could be identified have features suggesting in-
ritis was found to have hypercalcemia in association with crease bone resorption as the underlying etiology, similar to
low levels of 1,25-OH2D. In this case, hypercalcemia re- the presumed mechanism in cases of hypercalcemia associ-
sponded to treatment with dapsone and prednisone (156). ated with immobilization. By categorizing these individuals
A 24-year-old man with AIDS developed hypercalcemia as- whose mechanism is not known, it is evident that there are
sociated with cryptococcal meningitis. Workup in this pa- probably many different mechanisms in these various situ-
tient was remarkable for low PTH, PTHrP, and 1,25-OH2D ations all leading to osteoclast activation but most likely via
(157). Similarly, 2 patients with AIDS and diffuse cyto- different provocative intermediaries.
megalovirus infection were found to have hypercalcemia
associated with a low PTH level (158). Hypercalcemia has
also been reported in 2 cases of rheumatoid arthritis (RA). Diseases occurring in childhood
A 60-year-old woman with RA developed hypercalcemia Hypercalcemic disorders in children are less frequently
in association with suppressed PTH and increased bone re- seen than in adults (Table 8). They are classified as PTH-
sorption on bone scan (159). Similarly, a boy with juvenile dependent or PTH-independent and as congenital or
RA and persistent hypercalcemia was found to have serum acquired. Here, we summarize the reports of unusual eti-
activity that stimulated bone resorption in vitro and was ologies of hypercalcemia seen nearly exclusively in young
neutralized by an interleukin-1 receptor antagonist (160). children and infants.
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 3121

Table 8. Diseases occurring in childhood nephrocalcinosis has also been reported in infants with
congenital lactase deficiency. Although the mechanism of
Heritable diseases of childhood
Jansen osteodystrophy (168-170)
hypercalcemia is not well known, it improves with lactose-
Hypophosphatasia (171, 172) free diet (176).
Williams-Beuren syndrome (173) Hypercalcemia likely secondary to excessive calcium
Primary oxalosis (175) supplementation has been described in 4 patients with
Congenital lactase deficiency (176) Down syndrome (177, 178). Short syndrome, a rare auto-
Down syndrome (177, 178) somal dominant disorder characterized by short stature,
SHORT syndrome (179)
hyperextensibility of joints, and teething delay, has also
Sotos syndrome (180, 181)
been associated with hypercalcemia and nephrocalcinosis
Incontinentia pigmenti (182)
Blue diaper syndrome (183) (179). Similarly, transient hypercalcemia has been re-

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Posttransplant hypercalcemia in osteopetrosis (184, 185) ported in infants with Sotos syndrome because of 5q35
Acquired diseases of childhood microdeletions (180, 181). A 19-month-old boy with
Renal tubular acidosis (186-189) incontinentia pigmenti developed persistent hypercalcemia
Phosphate depletion in severe prematurity (190) that was attributed to eosinophilia-associated extrarenal
Subcutaneous fat necrosis of the newborn (192, 193) overactive 1-alpha-hydroxylase, but this was not confirmed
Infantile hypothyroidism (194)
by measurement of 1,25-OH2D level (182). Hypercalcemia
Pediatric granulomatous arthritis (195)
Talc pleurodesis (196)
has also been reported in infants with blue diaper syn-
Ketogenic diet for seizure disorder (197) drome, a rare genetic disorder characterized by the incom-
Ovarian dysgerminoma (198) plete intestinal breakdown of tryptophan (183). Post-bone
Metastatic alveolar rhabdomyosarcoma (199) marrow transplant hypercalcemia has been described in
Benign congenital mesoblastic nephroma (200) 3 patients with osteopetrosis (184, 185). Treatment with
denosumab normalized the serum calcium levels in 2 of the
Abbreviation: SHORT, short stature, hyperextensibility of joints and/
cases (185).
or hernia (inguinal), ocular depression, Rieger anomaly, and teething delay.

Heritable diseases of childhood Acquired diseases of childhood

Jansen metaphyseal chondrodysplasia, a rare autosomal Primary infantile renal acidosis known as Lightwood
dominant disease, is characterized by short-limbed dwarfism syndrome has been associated with hypercalcemia in
and severe PTH-independent hypercalcemia associated with infancy and early childhood (186-188). A 21-day-old
constitutive activation of the PTH/PTHrP receptor (168- male hospitalized for severe hypercalcemia was diag-
170). Hypophosphatasia is characterized by defective bone nosed with distal renal tubular acidosis. Hypercalcemia
mineralization and deficiency in alkaline phosphatase ac- in this patient had not resolved by age 4 years (189).
tivity because of mutations in the gene for tissue-nonspecific Hypercalcemia associated with hypophosphatemia has
alkaline phosphatase. Hypercalcemia most likely results been reported in extremely low birthweight infants.
from impaired bone mineralization in conjunction with Serum calcium levels normalized in theses infants when
normal osteoclastic bone resorption (171, 172). phosphate supplements were added to expressed breast
Williams-Beuren syndrome is a rare autosomal dom- milk and IV nutrition (190). The hypercalcemia was at-
inant neurodevelopmental disorder, causing elfin-like fea- tributed to phosphate depletion syndrome, which has
tures, short stature, developmental delay, connective tissue been reported only in laboratory animals, not in humans
abnormalities, and hypercalcemia (173). Although infantile (191). The authors postulate that, in the face of a low
hypercalcemia is a well-known feature of Williams-Beuren phosphate intake and immature kidneys, bone resorption
syndrome, the defined mechanism of hypercalcemia, was increased to provide phosphorus to the systemic cir-
which often resolves by age 4 years, is unclear (174). culation, which also mobilized skeletal calcium (190).
Hypercalcemia has been reported in a child with primary Treatment with phosphorus supplements normalized
oxalosis, a rare congenital disorder with widespread depos- both serum phosphorus and calcium. Although not meas-
ition of calcium oxalate crystals throughout the body. The ured in this study and not postulated by the authors, ele-
patient had undergone both renal and liver transplants and vated 1,25-OH2D would have been expected in response
developed recurrent hypercalcemia with lytic bone lesions. to the hypophosphatemia and could have contributed to
Bone biopsy demonstrated oxalate crystals associated with hypercalcemia.
macrophages and evidence of excessive bone resorption Subcutaneous fat necrosis (SCFN) of the newborn
(175). Hypercalcemia associated with hypercalciuria and is a rare, self-limiting panniculitis mostly presenting
3122  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

within the first few weeks after birth associated with Table 9. Pseudohypercalcemia
several perinatal complications including hypoxia and
High serum albumin (201)
meconium aspiration. Hypercalcemia is a rare but ser- Thrombocythemia (202)
ious complication of SCFN and is associated with low Calcium binding to M proteins (203-207)
levels of PTH. The most accepted theory for patho-
genesis of hypercalcemia in SCFN is elevated levels of
to the release of calcium in vitro from platelets (202).
1,25-OH2D secondary to a granulomatous inflammatory
Monoclonal proteins can lead to pseudohypercalcemia,
process (192, 193). Mild hypercalcemia has also been
thought to result from abnormal calcium binding by the
described in infants with congenital hypothyroidism
paraprotein. This has been described in 2 patients with
both before and during early months of treatment with
Waldenstrom macroglobulinemia resulting from IgM
levothyroxine. Hypercalcemia in untreated children with
kappa (203, 204) as well as in patients with IgG kappa

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hypothyroidism has been ascribed to increased sensi-
(205) and IgG lambda (206) paraproteins. In a patient
tivity to vitamin D leading to increased intestinal calcium
with multiple myeloma, a calcium-binding IgG lambda
absorption (194).
monoclonal protein was demonstrated to have a binding
1,25-OH2D–mediated hypercalcemia has been reported
capacity of 4 mol of calcium/mol of IgG that completely
in a 4-year-old girl with pediatric granulomatous arthritis
accounted for the hypercalcemia (207).
that corrected with anti-inflammatory medications (195).
Similarly, a male infant developed severe hypercalcemia with
elevated levels of 1,25-OH2D following talc pleurodesis for Conclusion
recurrent peritoneal dialysis-related hydrothorax (196).
Hypercalcemia is a relatively common clinical problem
Hypercalcemia associated with low PTH and 1,25-OH2D
and understanding its etiology is key to devising a suc-
has been described in 3 children on a ketogenic diet for re-
cessful treatment strategy. The most common causes of
fractory seizures. The mechanism of hypercalcemia in these
hypercalcemia, primary hyperparathyroidism, and malig-
cases is unknown but is consistent with increased bone re-
nancy, are usually evident from the clinical scenario and
sorption and urinary calcium excretion (197).
laboratory measurement of PTH, PTHrP, and vitamin D
Humeral hypercalcemia of malignancy is rare in chil-
analytes. It is important for clinicians to be aware of rare
dren and is mostly a result of PTHrP secretion by the tumor.
etiologies that should be considered when these 2 most
However, other tumor-related mechanisms have rarely been
common causes are not present. In this review, we have
reported. A 10-year-old girl with ovarian dysgerminoma
summarized the reports of unusual etiologies which are not
developed severe 1,25-OH2D–mediated hypercalcemia that
typically listed in the literature. Even as the number and
resolved 2 weeks after chemoembolization of the tumor
diversity of reports of rare causes of hypercalcemia have
(198). A 14-year-old male with metastatic alveolar rhabdo-
grown and the availability of specialized assays has ex-
myosarcoma presented with hypercalcemia and elevated
panded, the mechanism of hypercalcemia in many of these
PTH level. Imaging did not reveal any parathyroid abnor-
reports remains unknown, illustrating well our incomplete
mality, and calcium level normalized following chemo-
understanding of how calcium metabolism can be de-
therapy (199). Finally, PTHrP-mediated hypercalcemia
ranged. Elucidation of heretofore unknown mechanisms of
in the setting of benign tumor has been reported in 2 in-
hypercalcemia, an aspirational goal for the field, will help
fants with benign congenital mesoblastic nephroma. Serum
to optimize diagnosis and treatment of these unusual cases
PTHrP level normalized following resection of the tumors
of hypercalcemia.
and immunohistochemical staining of tumor cells was posi-
tive for PTHrP (200).
Acknowledgments
In Memoriam: The authors acknowledge the contributions of Dr
Pseudohypercalcemia
Thomas P. Jacobs, in whose memory this paper is dedicated. He was
Pseudohypercalcemia is defined as elevated total serum the inspiration for the original article in 2005 on this topic and for
calcium in the presence of a normal ionized serum cal- this update.
Funding: None.
cium level (Table 9). Normally, about one-half the serum
calcium concentration is bound to albumin; therefore,
in patients with elevated serum albumin level, mild
Additional Information
hypercalcemia may be observed (201). Hypercalcemia
Correspondence: Deborah E. Sellmeyer, MD, Stanford Univer-
has been reported in 2 patients with essential thrombo-
sity School of Medicine, Division of Endocrinology, Gerontology
cythemia in which serum calcium levels fluctuated with and Metabolism, 300 Pasteur Dr., M/C 5103, Palo Alto, CA 94305.
changes in platelet counts. Hypercalcemia was attributed Email: [email protected].
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 3123

Disclosures: The authors declare that they have no relevant dis- histological evidence of extrarenal calcitriol overproduction.
closures. Intern Med. 2014;53(24):2783-2787.
Data Availability: Data sharing is not applicable to this article 17. Kono M, Hasegawa T, Nagai S, et al. Palisaded neutrophilic and
as no datasets were generated or analyzed during the current study. granulomatous dermatitis as a novel cause of hypercalcemia: a
case report. Medicine (Baltimore). 2017;96(21):e6968.
18. Karakelides H, Geller JL, Schroeter AL, et al. Vitamin D-mediated
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