eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hypoparathyroidism

Paul S Thornton, MB, BCh, MRCPI, Senior Consultant, Division of Endocrinology and Diabetes, Cook Children's Medical Center
Andrea Kelly, MD, Department of Pediatric Endocrinology, Fellow, Children's Hospital of Philadelphia; Michael Willcutts, MD, PhD, Attending Physician, Pediatric Endocrinology, Cook Children's Medical Center
Contributor Information and Disclosures

Updated: Jul 26, 2006

Introduction

Background

Hypoparathyroidism is an inherited or acquired deficiency of the parathyroid hormone (PTH) or its action. PTH secretion by the parathyroid glands (prime regulators of serum calcium concentration) maintains serum calcium within a strict range. Biochemical hallmarks of PTH insufficiency are hypocalcemia and hyperphosphatemia. The hypocalcemia can be quite severe and lead to seizures, stridor, prolonged QTc, and tetany.

Pathophysiology

Mature PTH is an 84–amino acid protein. Production and secretion of PTH are regulated by a G protein–coupled calcium-sensing receptor. Unlike other protein hormones, its production and secretion are stimulated by decreased intracellular calcium concentrations, which reflect serum calcium concentrations. PTH exerts its action through the PTH receptor, which is another member of the G protein–linked receptor family.

The net effects of PTH activity are an increase in serum calcium and a decrease in serum phosphate. PTH acts directly upon bone to stimulate bone resorption and cause calcium and phosphate release. PTH acts directly upon the kidney to decrease calcium clearance and to inhibit phosphate reabsorption. By stimulating renal 1-alpha-hydroxylase activity, PTH increases serum concentrations of 1,25-dihydroxyvitamin D, the active form of vitamin D and, thus, indirectly stimulates calcium and phosphate absorption by the gut through the actions of vitamin D. The phosphaturic effect of PTH offsets the increases of serum phosphate driven by increased bone resorption and GI absorption.

Hypoparathyroidism results in loss of both the direct and indirect effects of PTH on bone, the kidney, and the gut. Calcium and phosphate release from bone is impaired, calcium absorption from the gut is limited, calciuria develops despite hypocalcemia, and retention of phosphate from the urine causes increased plasma phosphate levels.

Frequency

United States

The incidences of idiopathic hypoparathyroidism and pseudohypoparathyroidism (PHP) have not been determined in the United States. Rates following surgical procedures such as thyroidectomy vary depending upon the extent of the surgery and experience of the surgeon.

International

In Japan, a recent survey found the prevalence of idiopathic hypoparathyroidism to be 7.2 cases per million people and the prevalence of PHP to be 3.4 cases per million people.

Mortality/Morbidity

Complications of hypoparathyroidism are largely due to hypocalcemia.

• Neurologic: Hypocalcemia leads to neuromuscular irritability. Affected patients may experience paresthesias, muscle cramping, tetany, or seizures. However, patients can be asymptomatic. Neck muscle cramping can cause dystoniclike neck movements.
• Cardiac: Hypocalcemia causes prolongation of the QTc interval. Affected individuals may be asymptomatic or experience syncope, seizure, or death due to arrhythmias, such as polymorphic ventricular tachycardia.
• Respiratory: Laryngospasm, a form of tetany, can lead to stridor and significant airway obstruction.

Sex

Hypoparathyroidism is equally prevalent in males and females.

Age

Age of onset depends upon the etiology of hypoparathyroidism.

• Newborns may present with hypoparathyroidism, but it can manifest in people of almost any age. Typically, patients with DiGeorge syndrome present during the first few weeks of life. Patients with autoimmune and PTH resistance syndromes tend to present as late as adolescence.
• Transient hypoparathyroidism is common during the first few days of life in preterm infants, infants of mothers with diabetes mellitus, infants of mothers with hypercalcemia, and infants with prolonged delay in parathyroid gland responsiveness.

Clinical

History

Symptoms of hypoparathyroidism can be attributed to hypocalcemia. Symptoms of hypocalcemia include muscle aches, facial twitching, carpopedal spasm, stridor, seizures, and syncope.

Review of the past medical history or symptoms is helpful in determining the etiology of the hypoparathyroidism.

• DiGeorge syndrome, which is one manifestation of the 22q11 deletion syndrome, is associated with recurrent infections related to T-cell abnormalities and conotruncal abnormalities, such as tetralogy of Fallot and truncus arteriosus. Affected individuals may also have a history of speech delay from velopharyngeal insufficiency.
• Familial autoimmune polyglandular syndrome type I (APS I) is associated with chronic mucocutaneous candidiasis and adrenal failure. Other nonendocrine clues to the presence of this autoimmune etiology include vitiligo and dental enamel hypoplasia. Candidal infections of the skin or GI tract that last more than 3 months are considered chronic and are the presenting symptom in 60% of individuals with hypoparathyroidism due to APS I.
• Individuals with PHP type Ia have developmental delay and may have subcutaneous calcifications and disturbances of taste, smell, hearing, and vision.
• A history of radioactive iodine ablation of the thyroid for Grave disease may pre-date the development of acquired hypoparathyroidism by several months.
• Sensorineural deafness, renal dysplasia, and mental retardation are also associated with syndromes that include hypoparathyroidism.

Physical

• Hyperreflexia due to hypocalcemia is common.
  • Trousseau sign is a carpopedal spasm that occurs after a blood pressure cuff around the arm is inflated to the systolic blood pressure for several minutes.
  • Chvostek sign (ie, twitching of facial muscles with tapping on the facial nerve in front of the ear) is a manifestation of neuromuscular irritability. Chvostek sign is present in 25% of healthy adults and in even higher rates in children. Thus, its presence or absence should be documented prior to thyroidectomy.
• Chromosome band 22q11 deletion/velocardiofacial syndrome/DiGeorge syndrome has characteristic physical features, but hypoparathyroidism may be the only immediately recognizable manifestation.
  • Nasal speech can occur from a cleft palate or velopharyngeal insufficiency.
  • Bulbous nasal tip, micrognathia, ear anomalies, and short philtrum are typical facial features but may not be evident in nonwhite children.
  • A heart murmur may signify a conotruncal heart defect.
  • Short stature may be a feature of the genetic syndrome, but in some cases, it is due to hypopituitarism.
• Albright hereditary osteodystrophy (AHO) is the characteristic phenotype of PHP type Ia.
  • Short stature, obesity, round face, short distal phalanges of the thumbs, brachymetacarpals and brachymetatarsals, subcutaneous calcifications, dental hypoplasia, and developmental delay characterize this phenotype.
  • Pseudopseudohypoparathyroidism (PPHP) is characterized by normal calcium homeostasis in the setting of the AHO phenotype.

Causes

Hypoparathyroidism may be transient, genetically inherited, or acquired. Genetically inherited forms arise from defects of parathyroid gland development, defects in the PTH gene, defects in the calcium-sensing receptor gene, defects in PTH action, defects in the autoimmune regulator gene, and genetic syndromes. Acquired hypoparathyroidism may be due to an autoimmune process or may occur after neck irradiation or surgery.

• Transient hypoparathyroidism
  • Transient hypoparathyroidism occurs during the neonatal period. Preterm infants are at increased risk, and as many as 50% of very low birth weight infants may have a deficient surge in PTH that results in hypocalcemia.
  • Ten to 20% of infants of diabetic mothers may be hypocalcemic. These infants may be born prematurely, which is a risk factor for insufficient PTH response. They may have hypomagnesemia from maternal magnesuria complicating glucosuria. Low serum magnesium can impair PTH release and action.
  • PTH secretion is suppressed in the fetus because of high placental transfer of calcium, particularly in the third trimester. With cord clamping, calcium transfer abruptly stops; serum calcium concentrations decrease rapidly, and PTH secretion is triggered. Prolonged delay in PTH responsiveness in some otherwise healthy infants causes transient hypoparathyroidism.
  • Maternal hypercalcemia from hyperparathyroidism can also cause prolonged suppression of PTH secretion in the neonate.
• DiGeorge syndrome (ie, hypoparathyroidism, T-cell abnormalities, cardiac anomalies) is associated with abnormal development of the third and fourth pharyngeal pouches from which the parathyroids derive embryologically and represents an example of a defect in parathyroid gland development. DiGeorge syndrome and velocardiofacial syndrome are variants of the chromosome arm 22q11 microdeletion syndrome.
  • Hypocalcemia associated with a 22q11 microdeletion may be transiently present in infancy but recur later in life, particularly during periods of stress.
  • Hypocalcemia may be the first apparent and, at times, only manifestation of a chromosome arm 22q11.2 microdeletion.
  • Patients with chromosome arm 22q11.2 microdeletion who present with late-onset hypoparathyroidism in adolescence have been described.
• X-linked recessive hypoparathyroidism has been associated with parathyroid agenesis and has been mapped to chromosome arm Xq26-q27, the location of a putative developmental gene.
• Familial cases of hypoparathyroidism due to mutations of the PTH gene located on chromosome arm 11p15 have been identified. These mutations have been both dominantly and recessively inherited.
• Defects in PTH action occur in PHP. The hallmark of PHP is PTH resistance. Three forms of PTH resistance are recognized. These include PHP Ia, PHP Ib, and PHP II. Theoretically, defects in the PTH receptor (also shared by PTH-related peptide or PTHrP) should also be responsible for PTH resistance. Yet, PTH receptor defects are now known to possibly lead to Jansen metaphysial dysplasia and Blomstrand lethal chondrodysplasia. Researchers also hypothesize that bioinactive PTH could cause a hypoparathyroid state.
  • PHP Ia is due to loss-of-function mutations of the subunit of the G protein–coupled calcium-sensing receptor (Gsa). Mutations cause decreased nephrogenous adenosine 3',5'-cyclic adenosine monophosphate (cAMP) response to PTH. These mutations also cause a generalized resistance to other hormones, which act through Gsa and are associated with primary hypogonadism (eg, resistance to luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and primary hypothyroidism resistance to thyroid-stimulating hormone (TSH). Affected individuals have the Albright osteodystrophy phenotype.
  • PPHP describes family members of individuals with PHP Ia who have the AHO phenotype but normal serum calcium homeostasis and normal renal cAMP responsiveness to PTH.
  • Recent work suggests that PHP and PPHP are manifestations of imprinting of the stimulatory G protein defect located on chromosome arm 20q. PPHP results when the defect is inherited from the father. PHP Ia results when the defect is inherited from the mother.
• PHP Ib arises from epigenetic defects in the imprinted gene GNAS, which encodes the alpha subunit of the stimulatory G protein and the NESP55 protein. In the autosomal dominant form, maternally inherited mutations in STX16 have been identified and are thought to disrupt a cis-acting element required for methylation at exon 1A of GNAS. Mutations in the maternally derived NESP55 cause loss of methylation of multiple normally methylated regions on the maternal allele and cause autosomal dominant PHP Ib. Because most of the G protein in the thyroid is thought to be maternally derived, these epigenetic defects may lead to decreased G protein expression, but G protein activity is normal in vitro. Borderline TSH resistance has also been described in some patients, but affected individuals otherwise lack the AHO phenotype.
• The genetic basis of PHP II is unknown. The defect appears to lie downstream of the signal for cAMP generation because PTH causes an increase in urinary cAMP without the phosphaturia that normally accompanies PTH stimulation. Hormone resistance is limited to PTH. PHP II is not associated with the AHO phenotype.
• Polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, also known as APS I, has been linked to mutations of an autoimmune regulator gene located on chromosome band 21q22.3.
  • Patients with hypoparathyroidism of APS I usually present within the first few years of life after the onset of chronic mucocutaneous candidiasis and before the onset of adrenal insufficiency.
  • More than 75% of individuals with APS I develop hypoparathyroidism, more than 85% of patients develop adrenal insufficiency, and 60% of women have ovarian failure.
  • The spectrum of clinical manifestations of APS I is wide. Lifelong monitoring for the development of new components of APS I is indicated.
• The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is associated with partial monosomy of chromosome arm 10p.
• Mitochondrial cytopathies, such as Kearns-Sayre syndrome (ie, external ophthalmoplegia, ataxia, sensorineural deafness, heart block, and elevated cerebral spinal fluid [CSF] protein), are associated with hypoparathyroidism.
• Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome and Kenny-Caffey syndrome have also been associated with hypoparathyroidism. Recently, mutations in the TBCE gene, which encodes a chaperone protein required for alpha tubulin subunit folding, have been identified in both HRD and autosomal recessive Kenny-Caffey syndrome
• Hypoparathyroidism incurred during neck surgery may be transient or permanent depending upon the extent of injury and preservation of the parathyroid glands. The risk varies depending on the series and experience of the surgeon. Parathyroid autotransplantation can be used to preserve parathyroid function.
• Hypoparathyroidism following months of radioactive iodine ablation of the thyroid has been described as more common in treatment of Grave disease than with treatment of thyroid cancer. Radiation to the chest or neck area for cancer is also associated with hypoparathyroidism.
• Parathyroid gland destruction due to deposition of iron (as with hemochromatosis or multiple blood transfusions) or deposition of copper (as with Wilson disease) has been described.
• Autoimmune destruction of the parathyroid glands can be due to the autosomal recessively inherited APS I, which is associated with ectodermal abnormalities and adrenal insufficiency.
• Calcium-sensing receptor mutations represent a resetting of the calciostat and are not considered an etiology of a true hypoparathyroid state. However, patients present with hypocalcemia, inappropriate normal PTH levels, and mild-to-moderate elevations of phosphate levels, and, hence, mimic hypoparathyroidism. Patients may present with hypocalcemia any time from birth to adulthood.
  • Autosomal dominant and sporadic gain-of-function mutations of the Ca²⁺ receptor, a G-protein coupled receptor, cause hypocalcemic hypercalciuria by lowering the serum calcium concentration that is required for PTH secretion and urinary calcium reabsorption.
  • Individuals with Ca²⁺ receptor mutations have PTH concentrations that are within the reference range in the setting of hypocalcemia; they can be asymptomatic or severely affected.
  • These individuals must be differentiated from individuals with true hypoparathyroidism because treatment with vitamin D can cause nephrocalcinosis and renal insufficiency by exacerbating the already high urinary calcium excretion. Therapy with vitamin D should be restricted to symptomatic individuals and should be sufficient enough to relieve symptoms without normalizing serum calcium concentrations. Treatment with hydrochlorothiazide has been shown to be beneficial.

References

• Hypomagnesemia