Última actualización:
May 29, 2020
Años publicados: 2011, 2014, 2017, 2020
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 isolated hypoparathyroidism is a group of 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 controlling essential aspects of human development and metabolism throughout the lifespan. Parathyroid hormone plays a vital role in regulating the levels of calcium, magnesium, and phosphorus in the blood. Parathyroid hormone deficiency causes low levels of calcium and magnesium in the blood (hypocalcemia) and high levels of phosphorous.
Familial isolated hypoparathyroidism is caused by changes (mutations) in one of several different genes1-4. The first symptoms usually appear in infancy, childhood, or young adulthood. The most common cause of hypoparathyroidism in adults is damage to or removal of the parathyroid glands due to neck surgery.
The symptoms of hypoparathyroidism are predominantly due to low levels of calcium in the blood which lead to neuromuscular irritability and manifested by various symptoms which may include numbness, tingling, spasms (tetany) of the hands, feet, or face, and seizures. Other symptoms include fatigue and muscle weakness. The onset of symptoms of familial hypoparathyroidism is usually during early childhood but can occur at any time from birth to adulthood. Seizures during infancy or childhood may be the first sign of the disorder.
Chronic hypoparathyroidism in childhood may lead to the underdevelopment of the hard-outer layer of the teeth (enamel hypoplasia). Sudden, muscular spasms affecting the larynx (laryngospasm) cause the closure of the upper end of the trachea blocking normal airflow into the lungs. Affected individuals with long-standing hypoparathyroidism may develop calcium deposits in the brain or the kidneys (nephrocalcinosis).
Familial isolated hypoparathyroidism is caused by variants in genes that directly or indirectly control PTH production or secretion. These genetic variants can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern.1
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 by stimulating the release of PTH 1-84.2
The CASR gene is located on the long arm of chromosome 3 (3q13.3-q21). One mutation of the CASR gene can cause autosomal dominant or sporadic (i.e., a new mutation) hypoparathyroidism. The CASR gene directs the formation of 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. Individuals with hypoparathyroidism due to mutations of the CASR gene have diminished parathyroid hormone secretion because the abnormal calcium sensing receptor, also called the calciostat, leads to 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. Another rare form of isolated hypoparathyroidism is caused by variants in the GNA11 gene which encodes the Gα11 protein. This protein is directly related to the intracellular portion of the CaSR receptor signaling.
The GMC2 (glial cells missing, Drosophilia homologue B) gene encodes a transcription factor protein that plays a critical role in the 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.
Mutations of the parathyroid hormone (PTH) gene can cause both autosomal dominant and recessive hypoparathyroidism. A mutation affecting the mature PTH (1-84) peptide has recently been identified in a family with an autosomal recessive form of hypocalcemia and has been demonstrated to impair binding of the mutant PTH peptide with the PTH receptor (PTH1R).3
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.4
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.
The diagnosis of familial isolated hypoparathyroidism is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests should include measurement of intact parathyroid hormone, calcium, phosphorous, and magnesium. Additionally, 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. Molecular genetic testing may confirm the diagnosis of hypoparathyroidism. This is an important first step in identifying hypoparathyroidism in family members.
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.7
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.8,9 Initial studies have shown decreased urinary calcium excretion compared to conventional therapy.10 Long-term 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.11,12 Moreover, insulin pump delivery of PTH 1-34 provides the most physiologic approach to replacement therapy.13,14
The 2002 FDA approved recombinant parathyroid hormone 1-34 (Forteo®, Teriparatide) for the treatment of severe osteoporosis. Forteo has been used off-label for treatment of hypoparathyroidism. 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.14,15
In 2015, the FDA approved the recombinant form of parathyroid hormone 1-84 (Narpara) as an adjunct to conventional therapy in the treatment of individuals with refractory hypoparathyroidism.16,17 In August 2019, Natpara was removed from the market due to safety concerns with the pen injector.
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 website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
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, MD
Pediatric Growth and Nutrition Branch
NICHD, National Institutes of Health
6710 Rockledge Drive MSC 7002
Bethesda, MD 20892-7002
Tel:(301)435-6877
Fax:(301)480-3870
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
1. Mannstadt M, Bilezikian JP, Thakker RV, Clarke BL, Rejnmark L, Mitchell DM, Vokes TJ, Winer KK, Shoback DM. Hypoparathyroidism. Nature Review Disease Primers; Invited Review 2017;
3:17055.
2. Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The Calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nature Reviews Endocrinology
2018;15:333-51.
3. Lee S, Mannstadt M, Guo J, Kim SM, Yi HS, et al. A homozygous PTH 1-84 mutation that impairs PTH/PTHrP receptor activation defies a novel form of hypoparathyroidism. J Bone Miner Res
2015;30,1803-1813.
4. 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.
5. Ferre E, Rose S, Rosensweig S et al. Redefined Clinical Features and Diagnostic Criteria in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy JCI- Insight 2016;
18:1(13).
6. Li D, Streeten E, Chan A, Lwin W et al Exome Sequencing Reveals Mutations in AIRE as a cause of Isolated Hypoparathyroidism. J Clin Endocrinol Metab. 2017; 102:1726-1733
7. Bollerslev, J. et al. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. Eur. J. Endocrinol. 2015;173:G1-G20
8. Rejnmark L, Sikjaer T, Underbjerg L, Mosekilde L, PTH replacement therapy of hypoparathyroidism. Osteoporos Int. 24(5) (2013) 1529-36.
9. Winer KK Advances in the Treatment of Hypoparathyroidism with PTH 1-34. Bone. 2019;120:535-541.
10. Winer KK Yanovski JA, and Cutler, G.B., Jr. Synthetic Human Parathyroid Hormone 1-34 Versus Calcitriol in the Treatment of Hypoparathyroidism: Results of a Short-term Randomized
Trial JAMA 1996; 276, 631-6
11. Winer KK, Ko CW, Reynolds J, Dowdy K, Keil M, Peterson D, Cutler GB Jr, Long-Term Treatment of Hypoparathyroidism: A Randomized Controlled Study Comparing Parathyroid Hormone 1-34
and Calcitirol and Calcium, J. Clin. Endocrinol. Metab. 88 (2003) 4214-4220.
12. Winer KK, Kelly A, Johns A, Zhang B, Dowdy K, Kim L, Reynolds JC, Albert PS, Cutler GB Long-term Parathyroid Hormone 1-34 Replacement Therapy in 14 Children with Hypoparathyroidism
2018 J Pediatr 203;391-9.
13. Winer KK, Fulton K, Albert PS, Cutler G.B. Jr, Twice-Daily Subcutaneous Injections vs. Pump Delivery of PTH 1-34 in the Treatment of Children with Severe Congenital
Hypoparathyroidism, J Pediatr. 165 (2014)556-63.
14. Linglart A, Rothenbuhler A, Gueorgieva I, Lucchini P, Silve C, Bougnères P. Long-term results of continuous subcutaneous recombinant PTH (1-34) infusion in children with refractory
hypoparathyroidism. J Clin Endocrinol Metab. 96(2011):3308-12.
15. Upreti V, Somani S Kotawal N. Efficacy of Teriperitide in Patients with Hypoparathyroidism Indian J. Endocr Metab 2017;21:415-8.
16. 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.
17. Rubin, M.R. et al. Therapy of hypoparathyroidism with PTH(1-84): a prospective six year investigation of efficacy and safety. J. Clin. Endocrinol. Metabol. 2016;101:2742-2750.
INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:146200; Last Update: 05/14/2020. Available at: https://www.ncbi.nlm.nih.gov/omim/146200 Accessed May 290, 2020.
Mayo Clinic for Medical Education and Research. Hypoparathyroidism. Last Update March 14, 2020. Available at: https://www.mayoclinic.com/health/hypoparathyroidism/DS00952 Accessed May 20, 2020.
NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.
Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View report