Familial Isolated Hypoparathyroidism
NORD is very grateful to Karen K. Winer, MD, National Institutes of Health, National Institute of Child Health and Human Development, NIH, /Pediatric Growth and Nutrition Branch, for assistance in the preparation of this report.
Synonyms of Familial Isolated Hypoparathyroidism
- CASR-related hypoparathyroidism
- GCM2-related hypoparathyroidism
- PTH-related hypoparathyroidism
- X-linked recessive hypoparathyroidism
Familial isolated hypoparathyroidism is a group of extremely rare genetic disorders characterized by parathyroid glands that do not produce or secrete enough parathyroid hormone to maintain normal mineral balance. The parathyroid glands are part of the endocrine system, the network of glands that regulate the chemical processes within the body. Parathyroid hormone plays a vital role in regulating the levels of calcium and phosphorus in the blood. Parathyroid hormone deficiency causes low levels of calcium in the blood (hypocalcemia) and high levels of phosphorous.
The most common cause of hypoparathyroidism is damage to or removal of the parathyroid glands due to neck surgery. Hypoparathyroidism can also be caused by autoimmunity and can occur in association with a number of different underlying disorders such as autoimmune polyglandular syndrome type 1 (APS-1). Familial isolated hypoparathyroidism is caused by mutations to one of several different genes.
The symptoms of hypoparathyroidism are predominantly due to low levels of calcium in the blood which leads to a variety of symptoms including fatigue, muscle weakness, twitching and cramping of the extremities, or spasms of the hands, feet, arms, or face (tetany). The onset of symptoms in cases of congenital hypoparathyroidism is usually during early childhood, but can occur any time from birth to adulthood. In some cases, seizures during infancy or childhood may be the first presenting sign.
Chronic hypoparathyroidism in childhood may affect the teeth including the underdevelopment of the hard outer layer of the teeth (enamel hypoplasia). Sudden, muscular spasms affecting the larynx (laryngospasm) causes closure of the upper end of the trachea and prevents air form reaching the lungs. Affected individuals may develop calcium deposits (calcifications) in the brain or the kidneys (nephrocalcinosis). Fluctuations in serum calcium lead to neuromuscular irritability which may result in numbness, tingling, and cramping of the extremities or seizures. Chronic hypoparathyroidism may also lead stone formation in the kidney or collecting ducts (nephrolithiasis).
Familial isolated hypoparathyroidism is caused by mutations to one of several different genes. These genetic mutations can be inherited as an autosomal dominant, autosomal recessive or X-linked recessive trait.
Parathyroid hormone (PTH) is produced and secreted by the four parathyroid glands that surround the thyroid gland in the neck. PTH is cleaved from a precursor peptide, pre-pro PTH, to an 84-amino acid single-chain peptide hormone (PTH 1-84), which is stored in the parathyroid glands' secretory granules. The calcium-sensing receptor (CaSR) is a structure on parathyroid cells that responds to low or declining blood calcium levels, which leads to the release of PTH 1-84.
The CASR gene creates a protein that is found in the parathyroid-producing cells of the parathyroid gland. The CASR gene is located on the long arm of chromosome 3 (3q13.3-q21). Heterozygous mutations of the CaSR gene can cause autosomal dominant or sporadic (i.e., a new mutation) hypoparathyroidism.
Mutations of the parathyroid hormone (PTH) gene can cause both autosomal dominant and recessive hypoparathyroidism.
The GMC2 (glial cells missing, Drosophilia homologue B) gene encodes a protein that is thought to play a critical role in normal development of the parathyroid glands. Individuals with hypoparathyroidism due to mutations of the GCM2 gene may have residual, yet extremely low, activity of parathyroid hormone. The GCM2 gene is located on the short arm of chromosome 6 (6q24.2). This mutation has been identified in several families with isolated hypoparathyroidism.
X-linked recessive hypoparathyroidism is caused mutations of a gene located on the long arm (q) of the X chromosome (Xq26-q27). This gene plays a critical role in the development of the parathyroid glands.
Familial isolated hypoparathyroidism, with the exception of the X-linked form, affects males and females in equal numbers. The X-linked form affects males almost exclusively. The exact incidence and prevalence of these disorders in the general population is unknown. Some mild cases may go unrecognized, making it difficult to determine the true frequency of these disorders.
Symptoms of the following disorders can be similar to those of familial isolated hypoparathyroidism. Comparisons may be useful for a differential diagnosis.
Hypoparathyroidism can occur as an acquired condition usually through damage caused by neck surgery for another condition (post-surgical hypoparathyroidism). Hypoparathyroidism can also be caused by autoimmunity as in autoimmune polyglandular failure. (For more information on these other forms of hypoparathyroidism, choose "hypoparathyroidism" as your search term in the Rare Disease Database.)
Hypoparathyroidism can also develop as part of a larger syndrome such as chromosome 22q11.2 deletion syndrome, Barakat syndrome (hypoparathyroidism - sensorineural deafness - renal disease), Kenney-Caffey disease, Sanjad-Sakati syndrome (hypoparathyroidism - retardation - dysmorphism), autoimmune polyendocrine syndrome type I or lymphedema-hypoparathyroidism syndrome. It can also occur as part of certain mitochondrial disorders such as Kearns-Sayre syndrome or MELAS syndrome. In some cases, hypoparathyroidism may occur in association with Wilson disease (due to copper accumulating in the parathyroid glands) or hemochromatosis (due to iron accumulating in the parathyroid glands). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Albright's hereditary osteodystrophy is a rare disorder characterized by the resistance to parathyroid hormone. Unlike hypoparathyroidism, in which there are abnormally low levels of functional parathyroid hormone, individuals with Albright's hereditary osteodystrophy produce enough parathyroid hormone, but the the response to the hormone is not normal. . This referred to as PTH resistance. There are three main subtypes - pseudohypoparathyroidism 1a and 1b and pseudohypoparathyroidism II. All forms of Albright's hereditary osteodystrophy are extremely rare. Common symptoms include abnormalities of the bone and teeth, behavioral problems, cognitive deficits and short stature.
A diagnosis of familial isolated hypoparathyroidism is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests should include an intact parathyroid hormone level, calcium, phosphorous, and magnesium. The measurement of urine mineral levels is important to identify the unusual clinical presentation associated with a heterozygous activating CaSR mutation resulting in familial hypercalciuric hypocalcemia.
In some cases, molecular genetic testing can confirm the diagnosis of hypoparathyroidism. For example, it can identify characteristic genetic mutations in the calcium receptor.
Treatment is aimed at raising calcium levels high enough to provide symptom relief without causing abnormally high levels of calcium (hypercalciuria). Vitamin D analogs and calcium supplements are the conventional FDA approved therapy for all forms of hypoparathyroidism. The main form of active vitamin D used for individuals with hypoparathyroidism is 1,25 OH vitamin D3, calcitriol. Two other synthetic forms of vitamin D that are often used are cholecalciferol and dihydrotachysterol. These forms of vitamin D have a longer duration of action than calcitriol. Some individuals receive a combination of shorter and longer acting vitamin D analogs.
Some individuals with hypoparathyroidism may be encouraged to eat foods high in calcium such as dairy products, breakfast cereals, fortified orange juice and green, leafy vegetables.
Thiazide diuretics may be used off-label to treat mild post-surgical hypoparathyroidism toenhance calcium absorption in the kidneys. A low sodium diet, however, is required for thiazides to have their effect on the kidney.
A synthetic human N-terminal fragment of PTH (PTH 1-34), with full biological activity, has been used as an investigational hormonal replacement therapy of chronic hypoparathyroidism over the past two decades. Initial studies have shown decreased urinary calcium excretion compared to conventional therapy. Three-year randomized controlled studies in both adults and children comparing PTH 1-34 with conventional therapy have demonstrated both safety and efficacy of twice daily PTH injections. A recent study has shown the use of pump therapy provides the closest approach to physiologic PTH replacement therapy.
The 2002 FDA approval of the recombinant form of parathyroid hormone 1-34 (Forteo®, Teriparatide) for the treatment of severe osteoporosis has allowed this therapy to be used off-label for treatment of hypoparathyroidism both in the US and in Europe. Many individuals with hypoparathyroidism worldwide have reported improvement in their symptoms when treated with teriparatide, which is usually given as an injection under the skin (subcutaneously) once or twice a day.
Researchers are also studying a recombinant form of parathyroid hormone 1-84 (NPSP558) for the treatment of individuals with hypoparathyroidism. Initial studies have shown that every other day treatment with PTH 1-84 in combination with calcitriol and calcium, significantly reduced the need for clacitriol and calcium supplements in individuals with hypoparathyroidism.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about familial isolated hypoparathyroidism:
Karen Winer, M.D.
Pediatric Growth and Nutrition Branch
National Institute of Child Health and Human Development, NIH
Building 6100, Room 4B11
Bethesda, MD 20892-7510
Familial Isolated Hypoparathyroidism Resources
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Rejnmark L, Sikjaer T, Underbjerg L, Mosekilde L. TH Replacement Therapy of Hypoparathyroidism. Osteoporosis Int. 2013;24:1529-1536.
Winer KK, Zhang B, Shrader JA, Peterson D, Smith M, Albert PS, Cutler GB Synthetic Human Parathyroid Hormone 1-34 Replacement Therapy: A Randomized Crossover Trial Comparing Pump Versus Injections In The Treatment Of Chronic Hypoparathyroidism. J Clin Endocrinol Metab. 2012 ;97(2):391-9.
Sikjaer T, Rejnmark L, Rolighed L, et al. The effect of adding PTH (1-84) to conventional treatment of hypoparathyroidism- A randomized, placebo controlled study. J Bone Miner Res. 2011;26:2358-2370.
Rubin MR, Sliney J Jr, McMahon DJ, Silverberg SJ, Bilezikian JP. Therapy of hypoparathyroidism with intact parathyroid hormone. Osteoporos Int. 2010;21:1927-1934.
Winer KK, Sinaii N, Reynolds J, et al. Long-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium. J Clin Endocrinol Metab. 2010;95:2680-2688.
Shoback D. Hypoparathyroidism. N Engl J Med. 2008;359:391-403.
Angelopoulos NG, Goula A, Tolis G. Sporadic hypoparathyroidism treated with teriparatide: a case report and literature review. Exp Clin Endocrinol Diabetes. 2007;115:50-54.
Baumber L, Tufarelli C, Patel S, et al. Identification of a novel mutation disrupting the DNA binding activity of GCM2 in autosomal recessive familial isolated hypoparathyroidism. J Med Genet. 2005;42:443-448.
Bowl MR, Nesbit MA, Harding B, et al. An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism. J Clin Invest. 2005;115:2822-2831.
Thomee C, Schubert SW, Parma J, et al. Rapid communication. GCMB mutation in familial isolated hypoparathyroidism with residual secretion of parathyroid hormone. J Clin Endocrinol Metab. 2005;90:2487-2492.
Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: A randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab. 2003;88:4214-4220.
Ding C, Buckingham B, Levine MA. Familial isolated hypoparathyroidism caused by a mutation in the gene for transcription factor GCMB. J Clin Invest. 2001;108:1215-1220.
Lienhardt A, Bai M, Lagarde JP, et al. Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab. 2001;86:5313-5323.
Winer KK, Yanovski JA, Sarani B, Cutler GB Jr. A randomized, crossover trial of once-daily vs twice-daily human parathyroid hormone 1-34 in the treatment of hypoparathyroidism. J Clin Endocrinol Metab. 1998;83:3480-3486.
Winer KK, Yanovski JA, Cutler GB Jr. Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism: Results of a randomized crossover trial. JAMA. 1996;276:631-636.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:146200; Last Update: 08/12/2013. Available at: http://www.ncbi.nlm.nih.gov/omim/146200 Accessed March 25, 2014.
Mayo Clinic for Medical Education and Research. Hypoparathyroidism. Oct. 24, 2012. Available at: http://www.mayoclinic.com/health/hypoparathyroidism/DS00952 Accessed March 25, 2014.
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Report last updated: 2014/04/01 00:00:00 GMT+0
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