Understanding the Causes of Hypoparathyroidism
by Dr Michael Levine (USA)
The term hypoparathyroidism refers to a group of disorders in which the relative or absolute deficiency of PTH leads to hypocalcemia and hyperphosphatemia. We have recently discovered a defect in a novel gene that is required for the embryological development of parathyroid glands in a patient with severe autosomal recessive hypoparathyroidism. Based on this finding, we have initiated a research program to evaluate this gene in patients with early-onset (i.e., before 1 year of age) hypoparathyroidism. Although mutations in this gene are a cause of autosomal recessive hypoparathyroidism, it is possible that unusual mutations could cause autosomal dominant hypoparathyroidism. Patients who are interested in participating in this research study should contact Dr. Michael A. Levine, Pediatric Endocrinology at Johns Hopkins, 410.955.6463 or email: firstname.lastname@example.org.
To place this gene defect into perspective, below I discuss the many and varied causes of hypoparathyroidism.
Surgery is the most common cause of acquired hypoparathyroidism. Hypoparathyroidism may occur after parathyroid or thyroid surgery or after radical surgery for laryngeal or esophageal carcinoma (1). The resulting hypoparathyroidism can be transient or permanent, and sometimes may not develop for many years (2). The degree of hypoparathyroidism may be more profound after treatment of laryngeal cancer with surgery plus radiotherapy than with surgery alone (3). A chronic state of "decreased parathyroid reserve" (2) may exist in some patients who manifest hypocalcemia only when mineral homeostasis is stressed further by other factors such as pregnancy, lactation, or illness. Permanent hypoparathyroidism is unusual after an initial neck exploration for primary hyperparathyroidism and develops in less than 1-2% of patients. The incidence is greatly increased with repeated neck surgery for recurrent or persistent hyperparathyroidism, after subtotal parathyroidectomy for parathyroid hyperplasia, or when an inexperienced operator performs surgery.
The incidence of permanent hypoparathyroidism after thyroid surgery varies widely, and reflects the underlying thyroid lesion, the extent of surgery, and the experience of the surgeon.
Radiation and Drugs
In contrast to many other endocrine tissues, the parathyroid glands are particularly resistant to damage by a great many toxic agents. The administration of radioactive iodine for the treatment of benign or malignant thyroid disease or for the deliberate induction of hypothyroidism has only rarely caused permanent, symptomatic hypoparathyroidism. Similarly, external beam radiation appears to have little or no effect on parathyroid gland function. Parathyroid tissue is remarkable resistance to most chemotherapeutic or cytotoxic agents, with the notable exceptions of asparaginase, which causes parathyroid necrosis, and ethiofos, a radio- and chemoprotector that causes reversible inhibition of PTH secretion (4,5). The most common toxic agent to affect parathyroid function is alcohol (6). Transient hypoparathyroidism has been associated with ingestion of large quantities of alcohol and may be related to either direct effects of alcohol on the parathyroids or through induction of hypomagnesemia (5,7,8).
Infiltrative disease of the parathyroids
Infiltrative processes that affect the parathyroid gland can diminish the ability of the gland to secrete PTH. Idiopathic hemochromatosis and chronic transfusion therapy are often associated with significant deposition of iron in the parathyroid glands (9). A similar pathophysiological process has been described in one patient with Wilson disease and increased copper storage who developed symptomatic hypoparathyroidism (10). Pathologic involvement of the parathyroid glands can also occur in metastatic neoplasia, miliary tuberculosis, amyloidosis, and sarcoid, but clinical hypoparathyroidism rarely occurs in these conditions.
Magnesium deficiency and excess
This situation is most commonly encountered in obstetric practice when high-dose magnesium infusions are used for the treatment of toxemia or premature labor, and likely reflects the ability of elevated serum levels of magnesium to stimulate calcium-sensing receptors expressed by parathyroid cells and thereby inhibit PTH secretion (11-13). Hypocalcemia is more often a manifestation of magnesium depletion (14). Symptomatic hypocalcemia frequently occurs in patients with magnesium depletion due to chronic alcoholism (5) or burn injury (15), and is also a feature of Gitelman syndrome (16,17) as well as other forms of hereditary renal or intestinal hypomagnesemia (18).
Autoimmune hypoparathyroidism may occur alone or in association with additional features, including mucocutaneous candidiasis and adrenal insufficiency, as a component of the autoimmune polyglandular syndrome type 1 (APS-1) (19). APS-1 may be sporadic or familial with an autosomal recessive inheritance pattern (20). By contrast, the autoimmune polyglandular syndrome type 2 (APS-2) is characterized by adult-onset adrenal insufficiency associated with insulin-dependent diabetes mellitus and thyroid disease, and is believed to be polygenic with apparent autosomal dominant inheritance. The APS-1 syndrome is typically considered as a clinical triad of hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis (HAM), but many affected patients have additional autoimmune features (below). The syndrome is generally first recognized in early childhood, although a few individuals have developed the condition after the first decade of life. The clinical onset of the three principal components of the syndrome typically follows a predictable pattern, in which mucocutaneous candidiasis first appears at a mean age of 5 years, followed by hypoparathyroidism at a mean age of 9 years and adrenal insufficiency at a mean age of 14 years (19). Patients may not manifest all three components of the clinical triad. On the other hand, some patients will develop additional features, such as alopecia, keratoconjunctivitis, malabsorption and steatorrhea, gonadal failure, pernicious anemia, chronic active hepatitis, thyroid disease, and insulin-requiring diabetes mellitus. Enamel hypoplasia of teeth is also common, and appears to be unrelated to hypoparathyroidism (21). The presence of these additional defects in patients with APS-1 has led to the suggestion that a more inclusive term be used to describe the syndrome: "autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy" (APECED) (20,22). Antibodies directed against the parathyroid, thyroid, and adrenal glands are present in many patients (23) and a T cell abnormality has been described (24). The presence of organ-specific autoantibodies may not correlate well with the clinical findings. In those cases that have been examined pathologically, complete parathyroid atrophy or destruction has been demonstrated. In some patients, treatment of hypoparathyroidism has been complicated by apparent vitamin D "resistance," possibly related to coexistent hepatic disease or steatorrhea, or both. The molecular defect in patients with APS-1 has been identified, thus facilitating genetic diagnosis of the syndrome. The APS-1 gene is termed AIRE for autoimmune regulator.
Isolated hypoparathyroidism, in which PTH deficiency is not associated with other endocrine disorders or developmental defects, is usually sporadic, but it may occur on a familial basis. The age of onset is generally within the first decade, although hypocalcemia may not be first discovered until later in adult life.
There is a high incidence of parathyroid antibodies in patients with isolated idiopathic hypoparathyroidism, and some cases may be examples of autoimmune hypoparathyroidism or represent incomplete expression of the APS-1 syndrome (above). Some patients may possess antibodies that inhibit the secretion of PTH (25) rather than cause parathyroid gland destruction (26). In other cases that have been examined pathologically, fatty replacement (27) or atrophy with fatty infiltration and fibrosis (28) has been described.
Isolated hypoparathyroidism may be sporadic or familial, with inheritance of PTH deficiency by autosomal dominant, autosomal recessive, or X-linked modes of transmission (29). The age at onset covers a broad range (1 month to 30 years), but the condition is most commonly diagnosed during childhood. Moreover, it is not unusual in familial cases to discover affected adult relatives who have few if any symptoms of hypocalcemia. Parathyroid antibodies are absent. As the preproPTH gene is located at 11p15, molecular genetic studies of familial isolated hypoparathyroidism have focused on kindreds in which inheritance of hypoparathyroidism is consistent with an autosomal mode of transmission. Defects in the preproPTH gene are an uncommon cause of isolated hypoparathyroidism. New insights into the molecular pathology of hypoparathyroidism have come from the recent cloning and characterization of the cDNA (30) and gene (31) encoding the calcium-sensing receptor, the cell surface protein that determines the calcium "set-point" of the parathyroid cell and thereby controls calcium-sensitive secretion of PTH. Mutations in the calcium sensing receptor gene that lead to gain of function have been identified in many kindreds with autosomal dominant hypocalcemia, a syndrome associated with low serum levels of PTH (32,33). In other cases, linkage of hypocalcemia to the chromosomal locus for the calcium-sensing receptor (3q21-24) has provided indirect evidence for the involvement of this gene with familial hypoparathyroidism (34). Subsequent studies have identified similar activating mutations of the calcium-sensing receptor gene in many patients with sporadic hypoparathyroidism. These results suggest that mutation of calcium-sensing receptor gene may be the most common cause of genetic hypoparathyroidism.
Familial hypoparathyroidism can also be inherited as an X-linked disorder that is of course unrelated to specific defects in the preproPTH gene on chromosome 11 (35). These results imply that the defective gene or genes in this syndrome may be important for parathyroid cell development or function. The early onset of hypocalcemia in affected individuals, and the apparent inability to identify parathyroid tissue in a single patient with this disorder at autopsy (29), are consistent with a role for this genetic locus in the embryological development of the parathyroid glands (see below).
Developmental Disorders of the Parathyroid Gland
Hypoparathyroidism may result from agenesis or dysgenesis of the parathyroid glands. The most well described examples of parathyroid gland dysembryogenesis are the DiGeorge and velocardiofacial syndromes, in which maldevelopment of the third and fourth branchial pouches is frequently associated with congenital absence of not only the parathyroids but also the thymus. Because of thymic aplasia, T-cell-mediated immunity is impaired, and affected infants have an increased susceptibility to recurrent viral and fungal infections. Despite the emphasis on thymus dysgenesis in these syndromes, clinically significant immune defects occur in very few patients. The basic embryological defect is inadequate development of the facial neural crest tissues that results in maldevelopment of branchial pouch derivatives, producing characteristic facial and aorto-cardiac anomalies. Most cases of DiGeorge syndrome are sporadic, but familial occurrence with apparent autosomal dominant inheritance has been described (36,37).
Molecular mapping studies have demonstrated an association between the syndrome and deletions involving 22ql1.2 (DGSI) (38-42) in the great majority of patients with DiGeorge syndrome, but deletions at a second locus at l0p13, termed DGSII, have been found in some patients (43-45). Microdeletions in 22q11 can be readily identified by fluorescent in situ hybridization (FISH), but similar molecular testing for the 10p13 microdeletion is not widely available.
Recent studies have identified a novel gene that is required for development of the parathyroid glands. This gene is a transcription factor, but the genes that are regulated by this factor are presently unknown. Targeted inactivation of this gene in transgenic mice leads to complete absence of the parathyroid glands and severe hypoparathyroidism. We have recently discovered a family with severe early-onset hypoparathyroidism in which affected members are homozygous for defects in this gene. Thus, we propose that defective expression of this gene is a cause of autosomal recessive hypoparathyroidism. It is uncertain whether dominant negative mutations in this transcription factor can lead to autosomal dominant hypoparathyroidism. We have now initiated a research program to analyze this gene for defects in patients with early-onset (i.e., before age 1 year) hypoparathyroidism, and would like to recruit patients to join our study.
1. Isaacson, S.R. 1980. Hypocalcemia in surgery for carcinoma of the pharynx and larynx. Otolaryngol.Clin.North Am. 13:181-191.
2. Wade, J., P. Fourman, and L. Deane. 1965. Recovery of parathyroid function in patients with "transient" hypoparathyroidism after thyroidectomy. Br J Surg 52:493
3. Thorp, M.A., N.S. Levitt, S. Mortimore, and S. Isaacs. 1999. Parathyroid and thyroid function five years after treatment of laryngeal and hypopharyngeal carcinoma. Clin Otolaryngol. 24:104-108.
4. Attie, M.F., M.D. Fallon, B. Spar, and et al. 1985. Bone and parathyroid inhibitory effects of S-2(3-aminopropylamino)ethylphosphorothioic acid. J.Clin.Invest. 75:1191
5. Hermans, C., C. Lefebvre, J.P. Devogelaer, and M. Lambert. 1996. Hypocalcaemia and chronic alcohol intoxication: transient hypoparathyroidism secondary to magnesium deficiency. [Review] [31 refs]. Clin.Rheumatol. 15:193-196.
6. Manfredini, R., L. Bariani, B. Bagni, A.R. Cavallini, M. Gallerani, R. Salmi, M. Pasin, E. Cecchetti, M. Rosini, F. Franceschini, and et al. 1992. Hypoparathyroidism in chronic alcohol intoxication: a preliminary report. Riv.Eur.Sci.Med.Farmacol. 14:293-296.
7. Laitinen, K., R. Tahtela, and M. Valimaki. 1992. The dose-dependency of alcohol-induced hypoparathyroidism, hypercalciuria, and hypermagnesuria. Bone Miner. 19:75-83.
8. Laitinen, K., C. Lamberg-Allardt, R. Tunninen, S.L. Karonen, R. Tahtela, R. Ylikahri, and M. Valimaki. 1991. Transient hypoparathyroidism during acute alcohol intoxication. N.Engl.J.Med. 324:721-727.
9. Anonymous. 1995. Multicentre study on prevalence of endocrine complications in thalassaemia major. Italian Working Group on Endocrine Complications in Non-endocrine Diseases. Clin.Endocrinol.(Oxf). 42:581-586.
10. Carpenter, T.O., D.L. Carnes, Jr., and C.S. Anast. 1983. Hypoparathyroidism in Wilson's disease. N.Engl.J.Med. 309:873-877.
11. Cruikshank, D.P., G.M. Chan, and D. Doerrfeld. 1993. Alterations in vitamin D and calcium metabolism with magnesium sulfate treatment of preeclampsia. Am.J.Obstet.Gynecol. 168:1170-1176.
12. Cholst, I.N., S.F. Steinberg, P.J. Tropper, H.E. Fox, G.V. Segre, and J.P. Bilezikian. 1984. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N.Engl.J.Med. 310:1221-1225.
13. Mayan, H., A. Hourvitz, E. Schiff, and Z. Farfel. 1999. Symptomatic hypocalcaemia in hypermagnesaemia-induced hypoparathyroidism, during magnesium tocolytic therapy--possible involvement of the calcium-sensing receptor. Nephrol.Dial.Transplant. 14:1764-1766.
14. Fatemi, S., E. Ryzen, J. Flores, D.B. Endres, and R.K. Rude. 1991. Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism. J.Clin.Endocrinol.Metab. 73:1067-1072.
15. Klein, G.L. and D.N. Herndon. 1998. Magnesium deficit in major burns: role in hypoparathyroidism and end- organ parathyroid hormone resistance. Magnes.Res. 11:103-109.
16. Bianchetti, M.G., A. Bettinelli, J.P. Casez, E. Basilico, M.G. Metta, I. Spicher, C. Santeramo, M. Bigoni, and P. Jaeger. 1995. Evidence for disturbed regulation of calciotropic hormone metabolism in gitelman syndrome. J.Clin.Endocrinol.Metab. 80:224-228.
17. Bettinelli, A., E. Basilico, M.G. Metta, P. Borella, P. Jaeger, and M.G. Bianchetti. 1999. Magnesium supplementation in Gitelman syndrome. Pediatr.Nephrol. 13:311-314.
18. Meij, I.C., K. Saar, L.P. van den Heuvel, G. Nuernberg, M. Vollmer, F. Hildebrandt, A. Reis, L.A. Monnens, and N.V. Knoers. 1999. Hereditary isolated renal magnesium loss maps to chromosome 11q23. Am J Hum.Genet 64:180-188.
19. Neufield, R.B., N. Maclaren, and R. Blizzard. 1981. Two types of autoimmune Addison's disease associated with differeent polyglandular autoimmune syndromes. Medicine 60:355
20. Ahonen, P. 1985. Autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin.Genet. 27:535-542.
21. Perniola, R., G. Tamborrino, S. Marsigliante, and C. De Rinaldis. 1998. Assessment of enamel hypoplasia in autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED). J Oral Pathol.Med. 27:278-282.
22. Ahonen, P., S. Myllarniemi, I. Sipila, and J. Perheentupa. 1990. Clinical variation of autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy (APECED) in a series of 68 patients. N.Engl.J.Med. 322:1829-1836.
23. Blizzard, R.M., D. Chee, and W. Davis. 1966. The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism. Clin.Exp.Immunol. 1:119-128.
24. Verghese, M.W., F.E. Ward, and G.S. Eisenbarth. 1981. Lymphocyte suppressor activity in patients with polyglandular failure. Hum.Immunol. 3:173-179.
25. Posillico, J.T., J. Wortsman, S. Srikanta, G.S. Eisenbarth, L.E. Mallette, and E.M. Brown. 1986. Parathyroid cell surface autoantibodies that inhibit parathyroid hormone secretion from dispersed human parathyroid cells. J.Bone Miner.Res. 1:475-483.
26. Brandi, M.L., G.D. Aurbach, A. Fattorossi, R. Quarto, S.J. Marx, and L.A. Fitzpatrick. 1986. Antibodies cytotoxic to bovine parathyroid cells in autoimmune hypoparathyroidism. Proc.Natl.Acad.Sci.U.S.A. 83:8366-8369.
27. Drake, T.G., F. Albright, and W. Bauer. 1934. Chronic idiopathic hypoparathyroidism: report of 6 cases with autopsy findings in one. Ann.Intern.Med. 12:1751
28. Treusch, J.V. 1962. Idiopathic hypoparathyroidism: follow-up study including autopsy findings of a case previously reported. Ann.Intern.Med. 56:484
29. Thakker, R.V. 1996. Molecular basis of PTH underexpression. In Principles of Bone Biology. J.P. Bilezikian, L.G. Raisz, and G.A. Rodan, editors. Academic Press, San Diego. 837-851.
30. Brown, E.M., G. Gamba, D. Riccardi, M. Lombardi, R. Butters, O. Kofor, A. Sun, M.A. Hediger, J. Lytton, and S.C. Hebert. 1993. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 366:575-580.
31. Pollak, M.R., E.M. Brown, Y.W. Chou, S.C. Hebert, S.J. Marx, B. Steinmann, T. Levi, C.E. Seidman, and J.G. Seidman. 1993. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75:1297-1303.
32. Pearce, S.H., C. Williamson, O. Kifor, M. Bai, M.G. Coulthard, M. Davies, N. Lewis-Barned, D. McCredie, H. Powell, P. Kendall-Taylor, E.M. Brown, and R.V. Thakker. 1996. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor [see comments]. N.Engl.J.Med. 335:1115-1122.
33. Bai, M., S. Quinn, S. Trivedi, O. Kifor, S.H.S. Pearce, M.R. Pollak, K. Krapcho, S.C. Hebert, and E.M. Brown. 1996. Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor. J.Biol Chem. 271:19537-19545.
34. Finegold, D.N., M.M. Armitage, M. Galiani, T.C. Matise, M.R. Pandian, Y.M. Perry, R. Deka, and R.E. Ferrell. 1994. Preliminary localization of a gene for autosomal dominant hypoparathyroidism to chromosome 3q13. Pediatr.Res. 36:414-417.
35. Mumm, S., M.P. Whyte, R.V. Thakker, K.H. Buetow, and D. Schlessinger. 1997. mtDNA analysis shows common ancestry in two kindreds with X- linked recessive hypoparathyroidism and reveals a heteroplasmic silent mutation. Am.J.Hum.Genet. 60:153-159.
36. Rohn, R.D., M.S. Leffell, P. Leadem, and et al. 1984. Familial third-fourth pharyngeal pouch syndrome with apparent autosomal dominant transmission. J Pediatr 105:47
37. Raatikka, M., J. Ropola, L. Tuteri, and et al. 1981. Familial third and fourth pharyngeal pouch syndrome with truncus arteriosus: DiGeorge syndrome. Pediatrics 67:173
38. de la Chapelle A., R. Herra, M. Kiovisto, and P. Aula. 1981. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum.Genet. 57:253
39. Kelley, R.I., F.H. Zackai, and B.S. Emanuel. 1982. The association of the DiGeorge anomalad with partial monosomy of chromosome 22. J Pediatr 101:197
40. Driscoll, D.A., M.L. Budarf, and B.S. Emanuel. 1991. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet 50:924
41. Greig, F., E. Paul, J. DiMartino-Nardi, and P. Saenger. 1996. Transient congenital hypoparathyroidism: resolution and recurrence in chromosome 22q11 deletion. J.Pediatr. 128:563-567.
42. Hur, H., Y.J. Kim, C.I. Noh, J.W. Seo, and M.H. Kim. 1999. Molecular genetic analysis of the DiGeorge syndrome among Korean patients with congenital heart disease. Mol.Cells 9:72-77.
43. Monaco, G., C. Pignata, E. Rossi, and et al. 1991. DiGeorge anomaly associated with 10p deletion. Am J Med Genet 19:215
44. Lai, M.M.R., P.N. Scriven, C. Ball, and A.C. Berry. 1992. Simultaneous partial monosomy 10p and trisomy 5q in a case of hypoparathyroidism. J Med Genet 29:586
45. Daw, S.C., C. Taylor, M. Kraman, K. Call, J. Mao, S. Schuffenhauer, T. Meitinger, T. Lipson, J. Goodship, and P. Scambler. 1996. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat.Genet 13:458-460.