A Lifetime of Hypercalcemia and Hypercalciuria,Finally Explained
Thomas P. Jacobs, Martin Kaufman, Glenville Jones, Rajiv Kumar,Karl-Peter Schlingmann, Sue Shapses, and John P. Bilezikian
Division of Endocrinology (T.P.J., J.P.B.), Department of Medicine, College of Physicians and Surgeons,Columbia University, New York, New York 10032; Department of Biomedical and Molecular Sciences(M.K., G.J.), Queen’s University, Kingston, Ontario, Canada K7L 3N6; Nephology Research (R.K.),Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota55902; Department of General Pediatrics (K.-P.S.), University Children’s Hospital, 48129 Munster,Germany; and School of Environmental and Biological Sciences (S.S.), Rutgers University, NewBrunswick, New Jersey 08901
Context: Hypercalcemia, hypercalciuria, and recurrent nephrolithiasis are all common clinical prob-lems. This case report illustrates a newly described but possibly not uncommon cause of this pre-senting complex.
Objective: We report on a patient studied for over 30 years, with the diagnosis finally made withmodern biochemical and genetic tools.
Design and Setting: This study consists of a case report and review of literature conducted in aUniversity Referral Center.
Patient and Intervention: A single patient with hypercalcemia, hypercalciuria, and recurrent neph-rolithiasis was treated with low-calcium diet, low vitamin D intake, prednisone, and ketoconazole.
Main Outcome Measure: We measured the patient’s clinical and biochemical response to inter-ventions above.
Results: Calcium absorption measured by dual isotope absorptiometry was elevated at 37.4%.Serum levels of 24,25-dihydroxyvitamin D were very low, as measured in two laboratories (0.62ng/mL [normal, 3.49 � 1.57], and 0.18 mg/mL). Genetic analysis of CYP24A1 revealed hom*ozygousmutation E143del previously described. The patient’s serum calcium and renal function improvedmarkedly on treatment with ketoconazole but not with prednisone.
Conclusions: Chronic hypercalcemia, hypercalciuria, and/or nephrolithiasis may be caused by mu-tations in CYP24A1 causing failure to metabolize 1,25-dihydroxyvitamin D. (J Clin EndocrinolMetab 99: 708–712, 2014)
Hypercalcemia, a common medical condition, is causedmost often by primary hyperparathyroidism or ma-
lignancy. Hypercalcemia due to increased intestinal ab-sorption of calcium is much less common, but is usuallycaused by abnormalities in ingestion or metabolism of vi-tamin D or its biologically active form, 1,25-dihydroxyvi-tamin D, and much less commonly by ingestion of large
amounts of calcium together with absorbable alkali, the“milk alkali syndrome.” Although it was originally be-lieved that the hypercalcemia of vitamin D intoxicationmight be mediated by the renal conversion of some pro-portion of the elevated level of 25-hydroxyvitamin D to1,25-dihydroxyvitamin D (1), recent data from theCYP27B1-knockout mouse lacking the ability to make
ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2014 by the Endocrine SocietyReceived October 15, 2013. Accepted December 30, 2013.First Published Online January 13, 2014
Abbreviations: IIH, idiopathic infantile hypercalcemia; nl, normal.
S P E C I A L F E A T U R E
C l i n i c a l C a s e S e m i n a r
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1,25-dihydroxyvitamin D suggest that toxicity is due tothe effects of very high 25-hydroxyvitamin D levels (2).The hypercalcemia of sarcoidosis, of some other granu-lomatous diseases, and of certain lymphomas is due to theaccelerated 1�-hydroxylation of 25-hydroxyvitamin D bygranulomatous macrophages or neoplastic lymphocytes(3, 4). A third mechanism of vitamin D-mediated hyper-calcemia, only recently discovered, is a genetic mutation inthe CYP24A1 enzyme that is responsible for the inactiva-tion of 1,25-dihydroxyvitamin D by its metabolism to1,24,25-dihydroxvitamin D (5). We describe a patientwith chronic hypercalcemia mediated by inappropriatelyhigh levels of 1,25-dihydroxyvitamin D caused by an in-activating mutation in this gene. Although exceedinglyrare, it is possible that with wider recognition of this eti-ology, more cases will be discovered.
Case Report
This 73-year-old university professor, born in Greece tononconsanguineous parents, suffered “leg weakness” as achild that resolved as he grew older. First symptomatic ofkidney stones in his early 20s, he was admitted to Colum-bia University Medical Center a decade later with recur-rent right renal calculi. The serum calcium was elevated,between 10.7 and 11.5 mg/dL, and phosphorus (4.0 mg/dL), blood urea nitrogen (21.5 mg/dL), and 24-hour urinecalcium (269 mg) were all normal. Because reliable mea-surements of PTH were not available at this time, and thusdid not yet have diagnostic utility, the patient underwentneck exploration and 3 years later mediastinal explorationin an effort to find and excise abnormal parathyroid tissue.Histological findings of these two operations includedonly two normal parathyroid glands, remnants of the thy-mus, and chronic lymphadenitis. Hypercalcemia per-sisted, and virtually all PTH levels before and after thesetwo operations were at or below the lower limit of theassay, with serum calcium levels persistently in the rangeof 11.0 to 13.2 mg/dL. Further evaluation at age 44 con-firmed persistent hypercalcemia (11.7 mg/dL) and the fol-lowing: phosphorus, 2.7 mg/dL; creatinine, 1.7 mg/dL;24-hour urine calcium (three determinations), 508, 288,and 360 mg (normal [nl], �300 mg); with 24-hour urinehydroxyproline, 19 and 18 mg/d (nl, 14.9–43.7 mg/d).Angiotensin converting enzyme level was normal, and theKveim test was negative. Serum 1,25-dihydroxyvitamin Dwas 38 pg/mL. Treatment with oral prednisone 30 mg/dfor 1 week did not reduce the serum calcium. A percuta-neous, transiliac bone biopsy with quantitative static anddynamic histomorphometry showed normal values of tra-becular bone volume, cortical width, percentage osteoid,
osteoid width, extent of tetracycline uptake, percentageresorption surface, and osteoclast presence. At age 53, hisionized calcium level was 5.92 mEq/L (nl, �5.3 mEq/L);with osteocalcin, 13.4 ng/mL (nl, 8–52 ng/mL); bone-spe-cific alkaline phosphatase activity, 9.5 �g/L (nl, 5.9–27.8�g/L); 24-hour urine N-telopeptide, 22.8 nmol BCE/mmol creatinine (nl, �86); 25-hydroxyvitamin D, 25 ng/mL; and 1,25-dihyroxyvitamin D, 74 pg/mL (nl, 15–60pg/mL). A PTHrP level was 0.4 pmol/L (nl, �1.3 pmol/L).A bone mineral density test showed T-scores of �0.6 inL1–4, �1.1 in total hip, and �2.9 in the 1/3 radius, eachmeasurement having changed by �0.6%, �0.3%, and�10.5%, respectively, in comparison with 8 years earlier.A bone density measurement at age 73 showed values onlyslightly lower.
At age 72, he was hospitalized with fatigue and confu-sion after his dose of hydrochlorothiazide was increasedfrom 25 to 100 mg/d for worsening hypertension. Theserum calcium had risen to 15.8 mg/dL, creatinine to 4.3mg/dL, and phosphorus to 3.6 mg/dL. The 25-hydroxyvi-tamin D level was 20 ng/mL, and the 1,25-dihydroxyvi-tamin D was 48 pg/mL. With iv saline hydration and pred-nisone (50 mg/d), the serum calcium fell to 11.5 mg/dL.Two weeks later, he experienced low-grade fever andpoorly localized pains in his back and shoulders. Hiserythrocyte sedimentation rate test was 110 mm/h. For apresumptive diagnosis of polymyalgia rheumatica, he wasstarted on prednisone 20 mg/d. The 1,25-dihydroxyvita-min D was 75 pg/mL. Symptoms did not improve, and theserum calcium rose again to 15 mg/dL. Prednisone wasincreased to 60 mg/d, and he was started on ketoconazole200 mg twice a day. The prednisone was rapidly taperedto 10 mg/d, and after 3 weeks on ketoconazole the serumcalcium fell to 10.3 mg/dL. In 3 months, his calcium hadfallen to 10.2 mg/dL, with 1,25-dihydroxyvitamin D of 44pg/mL. Ten months later, his calcium level was 10.6 mg/dL, creatinine was 2.62 mg/dL, and 1,25-dihydroxyvita-min D was 25 pg/mL. The patient has no siblings or chil-dren and knows of no difficulties with calcium or renalstones in his parents, although a deceased maternal cousinwas said to have had a “calcium problem.”
Methods
Assays for all routine laboratory data, including PTH,25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, andPTHrP, were done in a variety of different clinical labo-ratories. Calcium absorption studies were performed us-ing a dual stable isotope technique (6). The initial assay for24,25-dihydroxyvitamin D was performed at the MayoClinic (Rochester, MN) under Dr Rajiv Kumar (7). The
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second assay for 24,25-dihydroxyvitamin D was per-formed at the laboratory of Dr Glenville Jones at Queen’sUniversity (Kingston, Ontario, Canada). Serum 25-hy-droxyvitamin D and 24,25-dihydroxyvitamin D weremeasured in 100-�L serum samples by liquid chroma-tography tandem mass spectrometry with a Waters XevoTQ-S instrument after DMEQ-TAD derivitization. Deu-terated standards were used to quantitate the vitamin Dmetabolites. Results are expressed as a ratio of 25-hy-droxyvitamin D3 to 24,25-dihydroxyvitamin D3. Geneticanalysis was performed at the laboratory of Dr Karl PeterSchlingmann at Wilhelms-University (Munster, Ger-many) (5). Written informed consent was given by thepatient for the genetic analysis.
Results
True fractional calcium absorption in this patient was37.4%, with published values for normal males of 21.9 �1.7% to 27.4 � 1.8% (8). The serum concentration of24,25-dihyroxyvitamin D measured initially before thepatient’s episode of severe hypercalcemia was very low at0.62 ng/mL (nl, 3.49 � 1.57 ng/mL when 25-hydroxyvita-min D levels are 15–50 ng/mL) at a time when the patient’sserum calcium was 11.4 mg/dL and 25-hydroxyvitamin Dwas 23 ng/mL. Serum level of 24,25-dihydroxyvitamin Dmeasured subsequently was confirmed to be low at 0.18 ng/mL. The ratio of 25-hydroxyvitamin D to 24,25-dihy-droxyvitamin D on this specimen was 169, a value that rep-resents the highest ratio ever measured in that laboratory. Atthat time, the serum 25-hydroxyvitamin D was 30 ng/mL,and calcium was 12.1 mg/dL. Genetic analysis of CYP24A1revealed a hom*ozygous mutation E143del previously de-scribed by Schlingmann et al (5), Streeten et al (9), andDauber et al (10).
Discussion
In the 1950s in the United Kingdom, an epidemic of in-fantile hypercalcemia, hypercalciuria, and nephrocalcino-sis was observed after the introduction of vitamin D rec-ommendations up to 4000 IU/d for these young children(11). The diagnosis of idiopathic infantile hypercalcemia(IIH) was coined, and the epidemic subsided when recom-mended doses of vitamin D were reduced to the previouslevel, 500 IU/d. Because most infants tolerated the higherlevels without difficulty, some observers felt that the chil-dren who became ill had an unusual sensitivity to vitaminD (12), although the mechanism was unclear and occa-sional sporadic cases of IIH continued to be observed overthe coming years. With the explosion of knowledge in
vitamin D metabolism in the 1970s, it became clear thatboth 1,25-dihydoxyvitamin D, the active form of vitaminD, and its precursor, 25-hydroxyvitamin D, were primar-ily metabolized by CYP24A1 (24-hydroxylase), an en-zyme activity that resulted in a five-step process to the sidechain-truncated, inactive product, calcitroic acid (13). ACYP24A1-null mouse model was developed by St-Arnaudet al (14), exhibiting a phenotype with hypercalcemia andnephrocalcinosis and resulting in 50% lethality at wean-ing. Survivors lacking CYP24A1 demonstrated very de-layed clearance of 1,25-dihydroxyvitmin D from theblood, liver, and kidney; reduced expression of 25-hy-droxyvitamin D 1-� hydroxylase; higher levels of 25-hy-droxyvitamin D in blood and other tissues; and no for-mation of 24,25-dihydroxyvitamin D. Keratinocytes fromthese mice failed to synthesize calcitroic acid from 1,25-dihydroxyvitamin D (15).
In 2010, Nguyen et al (16) reported 20 infants withhypercalcemia, hypercalciuria, and low levels of PTH. Se-rum levels of 1,25-dihydroxyvitamin D were high-normalor frankly elevated, and levels of 25-hydroxyvitamin Dwere normal. Analysis of the promoter sequences of fourgenes important in vitamin D metabolism in 17 patientsand 12 family members showed only an excess of Klothominor alleles in the hypercalcemic patients when com-pared with 195 control subjects. Evaluation of 24-hydrox-ylase activity in the fibroblasts of one patient showeddetectable 24,25-dihydroxyvitamin D under basal condi-tions, but no increase after exposure to 1,25-dihydroxyvi-tamin D. Patients treated with ketoconazole, a broad-spectrum cytochrome P450 inhibitor known to blocksynthesis of 1,25-dihydroxyvitamin D (17, 18), normal-ized their serum calcium levels sooner than patients nottreated. The following year, Schlingmann et al (5) reportedsix patients with IIH from four families and four youngpatients with vitamin D intoxication after receiving a sin-gle oral dose of ergocalciferol 600 000 IU. Analysis ofthree genes (CYP27B1, FGF23, and KL) important in cal-cium metabolism resulted in discovery of no functionallymeaningful mutations, but analysis of CYP24A1 revealedfive different mutations present in either hom*ozygous orcompound heterozygous form, which resulted in altera-tions in amino acid residues that are highly conserved invitamin D-metabolizing enzymes. Recreation of the mu-tations in the wild-type human gene and in vitro transfec-tion of the mutant genes into V79–4 host cells resulted instable or transient expression of CYP24A1, with no mea-surable expression of 24-hydroxylase activity in all butone construct, which expressed only 5.3% of wild type (5).In 2012, Tebben et al (19) reported a family in whichaffected members had hypercalcemia, hypercalciuria,nephrolithiasis, and elevated levels of 1,25-dihydroxyvi-
710 Jacobs et al Hypercalcemia and 24-Hydroxylase Deficiency J Clin Endocrinol Metab, March 2014, 99(3):708–712
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tamin D. Sequencing of the CYP24A1 gene carried out inthe proband and seven family members in three genera-tions showed two canonical splice junction mutations inthe CYP24A1 gene. Analysis of family members showed aphenotype associated with one or both mutations, sug-gesting autosomal dominant transmission with partialpenetrance of the trait. Treatment with ketoconazole 200mg every 8 hours for 2 months led to normalization ofserum and urine calcium and serum 1,25-dihydroxyvita-min D, and previously decreased concentrations of PTHincreased into the normal range (19). Streeten et al (9)reported a 47-year-old man who presented with nephroli-thiasis at age 19 but was discovered at age 39 to be hyper-calcemic and hypercalciuric with suppressed PTH, elevatedlevels of 25-hydroxyvitamin D and 1,25-dihydroxyvitaminD, and low levels of 24,25-dihydroxyvitamin D. Sequencingof CYP24A1 revealed the E143del mutation also present inour patient (9).
The patient described in this report appears to representthe longest course of chronic hypercalcemia and hyper-calciuria due to a mutation in CYP24A1. This syndromeappears to be compatible with a long and healthy life,although with obvious high risk for calcium urolithiasisand nephrocalcinosis. His presentation is different fromthat of the adult patient reported by Tebben et al (19) inthat his bone mineral density is well above average andrising with age, possibly representing a lifetime of expo-sure of skeletal tissues to low levels of PTH (20) and highlevelsof calciumand1,25-dihydroxyvitaminD.His serumcalcium rose rapidly in response to an escalation of hisdose of hydrochlorothiazide, a medication known to re-duce renal calcium excretion (21), suggesting that patientswith this syndrome are at risk from exposure to thiazidediuretics as well as to calcium supplements and vitamin D.They may also be at special risk from exposure to othermedical conditions or medications known to reduce renalcalcium excretion (eg, renal failure) or to cause hypercal-cemia through accelerated bone resorption. His elevatedserum calcium did not respond to glucocorticoids, unlikemany patients with other causes of hypercalcemia associ-ated with elevated levels of 1,25-dihydroxyvitamin D, butit did appear to respond to the administration of keto-conazole in a modest dose, presumably because of theeffect of ketoconazole on the metabolism of 1,25-dihy-droxyvitamin D (18, 22). A great many patients with cal-cium nephrolithiasis appear to absorb and excrete dietarycalcium at abnormally high rates and have serum 1,25-dihydroxyvitamin D levels in the normal or mildly ele-vated range (23, 24). It remains to be determined whetherinborn or acquired abnormalities of vitamin D metabo-lism play a part in their predilection to stone formation.This case also illustrates that a mutation in this gene
should be considered in the context of long-standing, un-explained hypercalcemia associated with normal or ele-vated 1,25-dihydroxyvitamin D and kidney stones.
Acknowledgments
Address all correspondence to: Thomas P. Jacobs, MD, Collegeof Physicians and Surgeons, 630 West 168th Street, New York,NY 10032. E-mail: [emailprotected]. Address reprint re-quests to: Dr Thomas P. Jacobs, Room 210, Herbert Irving Pa-vilion, 161 Fort Washington Avenue, New York, NY 10032.
S.S. is supported by National Institutes of Health GrantAG12161.
Disclosure Summary: T.P.J., M.K., R.K., K.-P.S., S.S., andJ.P.B. have nothing to declare. G.J. is a consultant and memberof Scientific Advisory Board of OPKO Renal (Miami, Florida)and has access to a liquid chromatography tandem mass spec-trometry instrument provided by Waters Corp (Milford,Massachusetts).
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