Causes and Differential Diagnosis of Hypocalcemia - J-Stage

Endocrine Journal 2008, 55 (5), 787–794

PERSPECTIVE

Causes and Differential Diagnosis of Hypocalcemia —Recommendation Proposed by Expert Panel Supported by Ministry of Health, Labour and Welfare, Japan— SEIJI FUKUMOTO, NORIYUKI NAMBA*, KEIICHI OZONO*, MIKA YAMAUCHI**, TOSHITSUGU SUGIMOTO**, TOSHIMI MICHIGAMI***, HIROYUKI TANAKA#, DAISUKE INOUE##, MASANORI MINAGAWA###, ITSURO ENDOµ AND TOSHIO MATSUMOTOµ Division of Nephrology & Endocrinology, Department of Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan *Department of Pediatrics, Osaka University Graduate School of Medicine, 2-15 Yamadaoka, Suita, Osaka 525-0871, Japan **Department of Endocrinology/Metabolism and Hematology/Oncology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 650-0017, Japan ***Department of Bone and Mineral Research, Osaka Medical Centre for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan #Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikada-cho, Okayama, Okayama 700-8558, Japan ##Third Department of Medicine, Teikyo University School of Medicine Ichihara Hospital, 3426-3 Anesaki, Ichihara, Chiba 299-0111, Japan ###Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan µDepartment of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, 2-50-1 Kuramoto-Cho, Tokushima, Tokushima 770-8503, Japan

Abstract. Serum calcium (Ca) level is maintained within a narrow range mainly by actions of parathyroid hormone (PTH) and 1,25-dihydroxyvitmain D [1,25(OH)2D]. While it is not rare to encounter hypocalcemia in clinical practice, there is currently no practical guideline for the differential diagnosis of hypocalcemia. We therefore propose flowcharts for the differential diagnosis of hypocalcemia and hypoparathyroidism, especially PTH-deficient hypoparathyroidism in which many genetic or other causes have been identified recently. Hypocalcemia can be divided into two categories, hypocalcemia with low serum phosphate level, and one with normal to elevated serum phosphate level. Deficient actions of 1,25(OH)2D, loss of Ca into urine, and deposition of Ca in bone or soft tissues are main causes of hypocalcemia with low to low normal serum phosphate level. Hypocalcemia with high normal to high serum phosphate level includes chronic renal failure and hypoparathyroidism. Hypoparathyroidism is subdivided into PTH-deficient hypoparathyroidism and pseudohypoparathyroidism. Recent investigations identified several causes of PTH-deficient hypoparathyroidism, including genetic abnormalities and parathyroid autoantibodies, which should be differentiated from idiopathic hypoparathyroidism. Physical and laboratory findings, the time of the onset of diseases and accompanying illness can be clues for identifying causes of PTH-deficient hypoparathyroidism. Key words: Hypocalcemia, Hypoparathyroidism, Parathyroid hormone, 1,25-dihydroxyvitamin D (Endocrine Journal 55: 787–794, 2008)

HYPOCALCEMIA causes symptoms and sings such Received: March 11, 2008 Accepted: March 19, 2008 Correspondence to: Dr. Seiji FUKUMOTO, Division of Nephrology & Endocrinology, Department of Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

as numbness, tetany and convulsion. In addition to such symptomatic hypocalcemia, hypocalcemia is frequently observed in medical practice even when patients are asymptomatic. However, there is currently no practical guideline for the differential diagnosis of hypocalcemia. Serum calcium (Ca) level is maintained within a narrow range at least in part by actions

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Fig. 1.

Flowchart for the differential diagnosis of hypocalcemia.

of two Ca-regulating hormones, parathyroid hormone (PTH) and 1,25-dihydroxyvitmain D [1,25(OH)2D]. These hormones increase serum Ca level through their actions on bone, kidney and intestine, and impaired actions of either of these two hormones are major causes of hypocalcemia. Hypoparathyroidism refers to a group of diseases characterized by deficient actions of PTH. Hypoparathyroidism caused by impaired PTH secretion, except for those with known primary causes such as postoperative hypoparathyroidism, has been classified as “idiopathic” hypoparathyroidism. However, recent clinical, biochemical and genetic analyses identified many causes for the impairment of PTH secretion, and extracted several diseases from this “idiopathic” hypoparathyroidism. Such recent advancement made it necessary to establish a new classification of hypoparathyroidism. Based on these backgrounds, the expert panel supported by the Ministry of Health, Labour and Welfare of Japan addressed two issues: First, to propose a flowchart for the differential diagnosis of hy-

pocalcemia which can be used in clinical practice and second, to present a new classification of hypoparathyroidism by summarizing recent findings.

Pathogenesis and differential diagnosis of hypocalcemia (Fig. 1) Extracellular Ca is maintained by intestinal Ca absorption, renal Ca reabsorption and dynamic equilibrium between extracellular Ca and hydroxyapatite in bone. About one half of serum Ca is bound to albumin and other proteins, and only ionized Ca is biologically active. Therefore, it is necessary to correct serum Ca according to serum albumin in the presence of hypoalbuminemia in order to evaluate serum Ca level. While several methods for the correction of serum Ca have been proposed, we recommend the formula by Payne because of its simplicity and therefore suitability for clinical use [1]. PTH increases serum Ca by stimulating osteoclastic bone resorption, distal tubular

CAUSES AND DIFFERENTIAL DIAGNOSIS OF HYPOCALCEMIA

Ca reabsorption and indirectly intestinal Ca absorption through enhancing 1,25(OH)2D production. On the other hand, the increase of serum Ca suppresses PTH secretion through its action on Ca-sensing receptor (CASR) on the plasma membrane of parathyroid cells. Binding of Ca to CASR activates several intracellular signaling pathways and inhibits PTH secretion [2]. In addition, PTH reduces serum phosphate level by suppressing proximal tubular phosphate reabsorption. Therefore, excess actions of PTH cause hypercalcemia and hypophosphatemia while deficient actions of PTH result in hypocalcemia and hyperphosphatemia. Excess actions of 1,25(OH)2D increases intestinal Ca and phosphate absorption, and may cause hypercalcemia without hypophosphatemia. Deficient actions of 1,25(OH)2D reduce intestinal Ca and phosphate absorption with secondary hyperparathyroidism, resulting in hypocalcemia and hypophosphatemia. Based on these actions of PTH and 1,25(OH)2D, hypocalcemia can be divided into two categories, hypocalcemia with high normal or elevated serum phosphate level and hypocalcemia with low normal to reduced serum phosphate level. It should be noted that serum phosphate levels are high during childhood [3], and age of patients should be taken into account to assess serum phosphate levels. Hypocalcemia with high normal to elevated serum phosphate level includes hypoparathyroidism and renal failure. Renal failure can be diagnosed by assessing glomerular filtration rate. Hypoparathyroidism is divided into diseases caused by deficient PTH secretion and those by resistance to PTH, pseudohypoparathyroidism. In patients with pseudohypoparathyroidism, PTH secretion increases in response to hypocalcemia. Therefore, PTH-deficient hypoparathyroidism and pseudohypoparathyroidism can be discriminated by intact PTH levels [4]. The classification and differentiation of pseudohypoparathyroidism was reported previously [5]. Briefly, pseudohypoparathyroidism is divided into two categories, type I and type II. Pseudohypoparathyroidism type I is characterized by impaired renal tubular cyclic AMP (cAMP) production and excretion in response to exogenous PTH. Pseudohypoparathyroidism type I is further divided into type Ia and Ib. Type Ia is caused by mutations in the coding region of GNAS1 gene which encodes guanine nucleotide binding protein alpha stimulating activity polypeptide 1 (Gsα) [6], and type Ib is considered to be caused by impaired expression of Gsα protein in renal proximal tubules due to

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aberrant imprinting of GNAS1 gene. Although detailed description of the mechanism of these diseases is beyond the scope of this review, several deletions in the upstream promoter region of GNAS1 gene are reported in patients with familial pseudohypoparathyroidism type Ib [7–9]. In pseudohypoparathyroidism type II, while exogenous PTH can increase cAMP excretion, phosphaturic action of PTH is impaired. Although the cause of pseudohypoparathyroidism type II is unclear, many of the reported cases of pseudohypoparathyroidism type II are associated with renal tubular damages or under treatment with drugs including anticonvulsant which can impair the metabolism of vitamin D [10–12]. Therefore, it is questionable whether pseudohypoparathyroidism type II should be listed as a disease entity. The second arm of hypocalcemia includes diseases caused by deficient actions of 1,25(OH)2D, loss of Ca into urine and deposition of Ca in bone or other soft tissues. Deficient actions of 1,25(OH)2D cause rickets and osteomalacia characterized by impaired mineralization of bone. Growth retardation and bowing of lower extremities are main problems in rickets while bone pain and muscle weakness are predominant symptoms of patients with osteomalacia. Besides these clinical features, reduced bone mineral density, high alkaline phosphatase and hypophosphatemia suggest the presence of rickets/osteomalacia. Serum 25-hydroxyvitamin D [25(OH)D] level reflects the nutritional status of vitamin D. Rickets/osteomalacia due to vitamin D deficiency does not usually occur with serum 25(OH)D level over 15 ng/ml in adults. However, it should be noted that requirement of vitamin D differs with age, and 25(OH)D level over 15 ng/ml cannot exclude the possibility of vitamin D deficiency in children with high vitamin D requirement. Vitamin D dependency type I is caused by inactivating mutations in CYP27B1 gene encoding 25(OH)D1α-hydroxylase [13], and type II by vitamin D receptor gene [14]. These two diseases can be differentiated by serum 1,25(OH)2D levels. In patients with vitamin D dependency type I, serum 1,25(OH)2D is low because of the impairment in the production of 1,25(OH)2D. In contrast, serum 1,25(OH)2D is usually high in patients with vitamin D dependency type II due to a resistance to 1,25(OH)2D actions.

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Fig. 2. Causes and differential diagnosis of PTH-deficient hypoparathyroidism. Numbers in parentheses indicate the respective ones in OMIM.

Causes of and diagnosis of PTH-deficient hypoparathyroidism (Fig. 2) Impaired secretion of PTH can be induced secondarily by causes such as surgical removal of parathyroid glands, radiation, replacement of parathyroid glands by malignant cells or granulomatous tissues, deposition of metals and maternal hypercalcemia in neonates. These causes can be diagnosed from clinical history. In cases without such causes, physical and laboratory findings, the time of the onset of diseases and accompanying illness can be clues for identifying causes of PTH-deficient hypoparathyroidism. Most cases of hypoparathyroidism caused by genetic abnormalities develop clinical manifestations in neonates or infants. A group of diseases are characterized by their association of developmental defects with PTH-deficient hypoparathyroidism. DiGeorge syndrome is caused by chromosomal deletion of 21q11.2 region [15, 16]. This region contains several genes including TBX1.

Although haploinsufficiency of TBX1 gene is shown to be responsible for the development of cardiovascular abnormalities of DiGeorge syndrome, it is not known whether TBX1 gene is responsible for the development of hypoparathyroidism. Hypoplasia of parathyroid glands and thymus, and cardiac outflow tract defects are main components of this syndrome. In addition, facial dysmorphism such as low set ear, micrognathia and slanting eyes are described. However, symptoms and signs are variable. The diagnosis of DiGeorge syndrome is confirmed by demonstrating a deletion of the responsible chromosomal region by fluorescent in situ hybridization. GATA3 is a member of zinc finger transcription factors. It has been shown that haploinsufficiency of GATA3 gene results in a disease characterized by hypoparathyroidism, sensorineural deafness and renal disease (HDR syndrome) [17, 18]. These phenotypes, especially renal dysplasia, are again variable among patients. However, mutations in GATA3 have not been reported in patients with isolated hypo-


parathyroidism [18]. Therefore, mutations in GATA3 gene should be suspected in patients with hypoparathyroidism together with hearing disturbance and/or renal insufficiency. Tubulin-specific chaperon E (TBCE) gene encodes a protein which is necessary for proper folding of tubulin subunits. Inactivating mutations in TBCE gene result in hypoparathyroidismretardation-dysmorphism (HRD) syndrome especially in Middle Eastern populations [19]. Several mitochondrial disorders also cause hypoparathyroidism with various neuromuscular and metabolic abnormalities [20–22]. A group of hypoparathyroidism is associated with hypomagnesemia. PCLN1 gene encodes a protein called paracellin-1 which is expressed at tight junctions of renal tubular cells in ascending limb of Henle. In this segment, divalent cations such as Ca and magnesium (Mg) are reabsorbed through paracellular route driven by positive charge in the lumen. Paracellin-1 is required for this paracellular reabsorption of Mg and Ca. Therefore, inactivating mutations in PCLN1 gene cause hypomagnesemia due to renal Mg wasting [23]. In addition to the impaired reabsorption of Ca by mutations in PCLN1 gene, hypomagnesemia in itself causes hypoparathyroidism as discussed below. TRPM6 gene is identified as a responsible gene for a disease called hypomagnesemia with secondary hypocalcemia. TRPM6 protein belongs to a family of the long transient receptor potential channel (TRPM). It is expressed in the intestine and kidney, but the primary defect of this disease is believed to be an impairment of Mg absorption from the intestine [24]. Several genes were shown to be responsible for a disease named familial isolated hypoparathyroidism by Online Mendelian Inheritance of Man (OMIN). In patients with activating mutations in CASR gene, CASR is activated and therefore PTH secretion is suppressed by lower extracellular Ca than that in healthy controls [25, 26]. In addition, activation of CASR in renal tubular cells enhances Ca excretion into urine at least in part by reducing the positive charge in the lumen of ascending loop of Henle, and thus suppressing paracellular reabsorption of Ca and Mg in this segment. Therefore, activating mutations of CASR result in hypocalcemia with low PTH level and relative hypercalciuria, although the diagnostic criteria of hypercalciuria for this disease have not been established. As speculated from the actions of CASR in renal tubular cells, some patients with activating mutations of CASR

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exhibit hypomagnesemia. Furthermore, it has been reported that some activating mutations of CASR cause Bartter’s syndrome in addition to hypoparathyroidism [27, 28]. There are several genes responsible for Bartter’s syndrome. Bartter’s syndrome type 1 and 2 are caused by inactivating mutations of genes coding for a transporter and a channel that are required for the production of the positive charge in the lumen of ascending limb of Henle. Therefore, it is speculated that some activating mutations of CASR cause Bartter’s syndrome by reducing the positive charge in the lumen. Bartter’s syndrome caused by mutations of CASR gene is classified as Batter’s syndrome type 5. Several mutations in PTH gene are reported in patients with PTH-deficient hypoparathyroidism [29–31]. These mutations replace amino acids in the signal sequence or impair mRNA splicing. Theoretically, it is possible that mutations in PTH gene produce inactive PTH protein resulting in hypocalcemia with high PTH levels. Such clinical entity has been called pseudoidiopathic hypoparathyroidism. While there are several reports describing patients presenting these clinical manifestations using old PTH assays [32], no mutation in PTH gene has been so far reported that results in impaired action of this hormone. GCM2 encodes a protein called glial cells missing-2, which is an essential transcription factor for the development of parathyroid glands. Thus, mutations in this gene seem to result in congenital hypoparathyroidism [33–35]. Sry-Box 3 (SOX3) gene is a candidate for X-linked recessive hypoparathyroidism, but this has not been definitely proven [36]. Autoimmune polyendocrine syndrome type 1 is caused by mutations in autoimmune regulator (AIRE) gene [37, 38], although hypoparathyroidism does not appear in neonates or infants. Antibodies to CASR are shown to be responsible for hypoparathyroidism in autoimmune polyendocrine syndrome type 1 at least in some patients [39]. Similarly, acquired hypoparathyroidism can be caused by activating antibodies to CASR [40, 41]. In addition, NACHT leucine-richrepeat protein 5 (NALP5) has been identified to be another parathyroid autoantigen in patients with autoimmune-polyendocrine syndrome type 1 [42]. The function of this protein and the consequence of antibodies to NALP5 remain to be clarified. Hypomagnesemia causes both impaired secretion and action of PTH [43]. Severe hypomagnesemia is usually associated with hypocalcemia with low PTH

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level. However, some patients with hypomagnesemia show hypocalcemia with high PTH levels while the mechanism of the resistance to PTH has not been well explained. Therefore, hypomagnesemia should be always kept in mind as a possible cause of hypocalcemia. Because hypokalemia is frequently associated with hypomagnesemia [44], it is necessary to measure serum Mg level in patients presenting both hypocalcemia and hypokalemia. Hypocalcemia usually develops by severe hypomagnesemia, as low as 1 mg/dl or below.

Concluding remarks Recent progress in the identification of causes for PTH-deficient hypoparathyroidism has made it inappropriate to call all PTH-deficient hypoparathyroidism as “idiopathic” hypoparathyroidism. Here, we propose a new classification of hypoparathyroidism and a flow chart for differential diagnosis of hypocalcemia as a practical clinical guideline. We hope that these classification and flow chart become useful for clinical diagnosis and treatment of patients with hypocalcemia and hypoparathyroidism. However, more and more genetic causes of PTH-deficient hypoparathyroidism will be determined and less and less patients will be classified as idiopathic hypoparathyroidism in the future. We expect that we will have to revise the list of these diseases in a near future.

Acknowledgements This work was supported by Ministry of Health, Labour and Welfare, Japan.

References 1. Payne RB, Carver ME, Morgan DB (1979) Interpretation of serum total calcium: effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual. J Clin Pathol 32: 56–60. 2. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366: 575–580.

3. Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, Minagawa M, Sugimoto T, Yamauchi M, Michigami T, Matsumoto T (2008) Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients-Proposal of diagnostic criteria using FGF23 measurement-. Bone 42: 1235– 1239. 4. Okazaki R, Matsumoto T, Furukawa Y, Fujimoto Y, Niimi H, Seino Y, Fujita T, Nagataki S, Ogata E (1992) Serum intact parathyroid hormone concentration measured by a two-site immunoradiometric assay in normal subjects and patients with various parathyroid disorders. Endocrinol Jpn 39: 115–120. 5. Yamamoto M, Furukawa Y, Konagaya Y, Sohn HE, Tomita A, Fujita T, Ogata E (1989) Human PTH(1–34) infusion test in differential diagnosis of various types of hypoparathyroidism: an attempt to establish a standard clinical test. Bone Miner 6: 199–212. 6. Patten JL, Johns DR, Valle D, Eil C, Gruppuso PA, Steele G, Smallwood PM, Levine MA (1990) Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med 322: 1412–1419. 7. Bastepe M, Frohlich LF, Hendy GN, Indridason OS, Josse RG, Koshiyama H, Korkko J, Nakamoto JM, Rosenbloom AL, Slyper AH, Sugimoto T, Tsatsoulis A, Crawford JD, Juppner H (2003) Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest 112: 1255–1263. 8. Bastepe M, Frohlich LF, Linglart A, Abu-Zahra HS, Tojo K, Ward LM, Juppner H (2005) Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet 37: 25–27. 9. Linglart A, Gensure RC, Olney RC, Juppner H, Bastepe M (2005) A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am J Hum Genet 76: 804–814. 10. Matsuda I, Takekoshi Y, Tanaka M, Matsuura N, Nagai B, Seino Y (1979) Pseudohypoparathyroidism type II and anticonvulsant rickets. Eur J Pediatr 132: 303–308. 11. Kruse K, Kracht U, Gopfert G (1982) Response of kidney and bone to parathyroid hormone in children receiving anticonvulsant drugs. Neuropediatrics 13: 3– 9. 12. Yamada K, Tamura Y, Tomioka H, Kumagai A, Yoshida S (1984) Possible existence of anti-renal tubular plasma membrane autoantibody which blocked parathyroid hormone-induced phosphaturia in a patient with pseudohypoparathyroidism type II and Sjogren’s syndrome. J Clin Endocrinol Metab 58: 339–343.


13. Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, O’Malley BW (1988) Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 242: 1702– 1705. 14. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, Hasegawa Y, Niimi H, Yanagisawa J, Tanaka T, Kato S (1998) Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 338: 653–661. 15. Lindsay EA, Vitelli F, Su H, Morishima M, Huynh T, Pramparo T, Jurecic V, Ogunrinu G, Sutherland HF, Scambler PJ, Bradley A, Baldini A (2001) Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410: 97–101. 16. Merscher S, Funke B, Epstein JA, Heyer J, Puech A, Lu MM, Xavier RJ, Demay MB, Russell RG, Factor S, Tokooya K, Jore BS, Lopez M, Pandita RK, Lia M, Carrion D, Xu H, Schorle H, Kobler JB, Scambler P, Wynshaw-Boris A, Skoultchi AI, Morrow BE, Kucherlapati R (2001) TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104: 619–629. 17. Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K (2000) GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406: 419–422. 18. Ali A, Christie PT, Grigorieva IV, Harding B, Van Esch H, Ahmed SF, Bitner-Glindzicz M, Blind E, Bloch C, Christin P, Clayton P, Gecz J, GilbertDussardier B, Guillen-Navarro E, Hackett A, Halac I, Hendy GN, Lalloo F, Mache CJ, Mughal Z, Ong AC, Rinat C, Shaw N, Smithson SF, Tolmie J, Weill J, Nesbit MA, Thakker RV (2007) Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum Mol Genet 16: 265– 275. 19. Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loeys B, Zecic A, Mortier G, Gregory S, Sharony R, Kambouris M, Sakati N, Meyer BF, Al Aqeel AI, Al Humaidan AK, Al Zanhrani F, Al Swaid A, Al Othman J, Diaz GA, Weiner R, Khan KT, Gordon R, Gelb BD (2002) Mutation of TBCE causes hypoparathyroidismretardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nat Genet 32: 448–452. 20. Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S, et al. (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 320: 1293–

793

1299. 21. Dionisi-Vici C, Garavaglia B, Burlina AB, Bertini E, Saponara I, Sabetta G, Taroni F (1996) Hypoparathyroidism in mitochondrial trifunctional protein deficiency. J Pediatr 129: 159–162. 22. Seneca S, De Meirleir L, De Schepper J, Balduck N, Jochmans K, Liebaers I, Lissens W (1997) Pearson marrow pancreas syndrome: a molecular study and clinical management. Clin Genet 51: 338–342. 23. Simon DB, Lu Y, Choate KA, Velazquez H, AlSabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP (1999) Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285: 103–106. 24. Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R, Sheffield VC (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31: 171–174. 25. Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG (1994) Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet 8: 303–307. 26. Pearce SH, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, Brown EM, Thakker RV (1996) A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med 335: 1115–1122. 27. Vargas-Poussou R, Huang C, Hulin P, Houillier P, Jeunemaitre X, Paillard M, Planelles G, Dechaux M, Miller RT, Antignac C (2002) Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. J Am Soc Nephrol 13: 2259–2266. 28. Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T (2002) Association between activating mutations of calciumsensing receptor and Bartter’s syndrome. Lancet 360: 692–694. 29. Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM (1990) Mutation of the signal peptideencoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest 86: 1084–1087. 30. Parkinson DB, Thakker RV (1992) A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet 1: 149–152. 31. Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S (1999) A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroid-

794

FUKUMOTO et al.

ism. J Clin Endocrinol Metab 84: 3792–3796. 32. Nakano T, Masuoka H, Hamaguchi K, Takezawa H (1987) Pseudoidiopathic hypoparathyroidism: report of a case and review of the literature in Japan. Jpn J Med 26: 226–229. 33. Ding C, Buckingham B, Levine MA (2001) Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest 108: 1215–1220. 34. Baumber L, Tufarelli C, Patel S, King P, Johnson CA, Maher ER, Trembath RC (2005) Identification of a novel mutation disrupting the DNA binding activity of GCM2 in autosomal recessive familial isolated hypoparathyroidism. J Med Genet 42: 443–448. 35. Thomee C, Schubert SW, Parma J, Le PQ, Hashemolhosseini S, Wegner M, Abramowicz MJ (2005) GCMB mutation in familial isolated hypoparathyroidism with residual secretion of parathyroid hormone. J Clin Endocrinol Metab 90: 2487–2492. 36. Bowl MR, Nesbit MA, Harding B, Levy E, Jefferson A, Volpi E, Rizzoti K, Lovell-Badge R, Schlessinger D, Whyte MP, Thakker RV (2005) An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism. J Clin Invest 115: 2822–2831. 37. Finnish-German APECED Consortium (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 17: 399–403. 38. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F,

39.

40.

41.

42.

43.

44.

Shimizu N (1997) Positional cloning of the APECED gene. Nat Genet 17: 393–398. Gavalas NG, Kemp EH, Krohn KJ, Brown EM, Watson PF, Weetman AP (2007) The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 92: 2107–2114. Li Y, Song YH, Rais N, Connor E, Schatz D, Muir A, Maclaren N (1996) Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 97: 910– 914. Kifor O, McElduff A, LeBoff MS, Moore FD, Jr., Butters R, Gao P, Cantor TL, Kifor I, Brown EM (2004) Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 89: 548–556. Alimohammadi M, Björklund P, Hallgren A, Pöntynen N, Szinnai G, Shikama N, Keller M, Ekwall O, Kinkel S, Husebye E, Gustafsson J, Rorsman F, Peltonen L, Betterle C, Perheentupa J, Akerström G, Westin G, Scott H, Holländer G, Kämpe O (2008) Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med 358: 1018–1028. Garty R, Alkalay A, Bernheim JL (1983) Parathyroid hormone secretion and responsiveness to parathyroid hormone in primary hypomagnesemia. Isr J Med Sci 19: 345–348. Whang R, Whang D, Ryan M (1992) Refractory potassium repletion. A consequence of magnesium deficiency. Arch Intern Med 152: 40–45.