NORD gratefully acknowledges 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.
Familial iFamilial 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 affected individuals of congenital hypoparathyroidism is usually during early childhood, but can occur any time from birth to adulthood. In some patients, seizures during infancy or childhood may be the first sign of the disorder.
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 and in various other parts of the body including the kidney, bone, and intestinal tract 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. Individuals with hypoparathyroidism due to mutations of the CASR gene have diminished parathyroid hormone secretion because of the faulty sensing of elevated levels of blood calcium even when the calcium levels are abnormally low. This disordered calcium sensing leads to excessive calcium excretion in the urine and, in many, kidney damage.
Mutations of the autoimmune regulator gene (AIRE) gene cause a recessive form of hypoparathyroidism called autoimmune polyglandular failure type 1 (APS1), also called autoimmune polyendocrinopahy candidiasis ectodermal dystrophy (APECED). In this disease, hypoparathyroidism is usually the first of multiple autoimmune endocrine disorders to appear.
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 by 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.
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. Urine calcium and magnesium levels are elevated in this disorder.
In some cases, molecular genetic testing can confirm the diagnosis of hypoparathyroidism. For example, it can identify characteristic genetic mutations in the calcium receptor or mutations in the AIRE gene to diagnose APS1.
Treatment is aimed at raising calcium levels high enough to provide symptom relief without causing abnormally high levels of calcium excretion in the urine (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. Many individuals receive a combination of shorter and longer acting vitamin D analogs.
Patients with hypoparathyroidism are encouraged to eat foods high in calcium such as dairy products, breakfast cereals, fortified orange juice and green, leafy vegetables.
PTH Replacement Therapy
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 by Winer et al has shown the use of an insulin pump to deliver PTH 1-34 provides the most physiologic approach to 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.
In 2015, the FDA approved the recombinant form of parathyroid hormone 1-84 (Narpara) as an add on to conventional therapy in the treatment of individuals with refractory hypoparathyroidism. Two single center studies and a multicenter randomized controlled study of daily subcutaneous PTH 1-84 vs. placebo injections showed PTH 1-84 given as a single daily injection maintained serum calcium levels in the normal range and reduced the need for calcitriol and calcium supplements.
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: www.centerwatch.com.
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for additional information about familial isolated hypoparathyroidism:
Karen Winer, M.D.
Pediatric Growth and Nutrition Branch
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
6710 Rockledge Drive MSC 7002
Bethesda, MD 20892-7002
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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Bollerslev, J. et al. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. Eur. J. Endocrinol. 2015;173:G1-G20.
Mannstadt, M. et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised phase 3 study. Lancet Diabetes Endocrinol. 2014;1:275-83.
Winer, K.K., Fulton, K., Albert, P.S.,Cutler, G.B. Effects of pump versus twice-daily injection delivery of synthetic human PTH 1-34 in the treatment in children with severe congenital hypoparathyroidism J. Pediatr. 2014;165:556-563.
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