Pediatric Hypoparathyroidism Clinical Presentation

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 very 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 insufficiency. 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 pseudohypoparathyroidism (PHP) type Ia are obese, have short stature and short fourth and fifth metacarpal/metatarsal, and may have subcutaneous calcifications and disturbances of taste, smell, hearing, and vision. Patients also have mental retardation and developmental delay. Other endocrine abnormalities, such as TSH resistance, could be associated findings.

• A history of radioactive iodine ablation of the thyroid for Grave disease may predate the development of acquired hypoparathyroidism by several months. However, it could be sooner in those patients who underwent thyroid surgery.

• Sensorineural deafness, renal dysplasia, and mental retardation are also associated with syndromes that include hypoparathyroidism.

See the list below:

• Hyperreflexia due to hypocalcemia is common.

  • Trousseau sign is a carpopedal spasm that occurs after a blood pressure cuff around the arm is inflated above the systolic blood pressure for several minutes.

  • Chvostek sign (ie, twitching of ipsilateral facial muscles with tapping on the facial nerve in front of the ear and just below the zygomatic bone) is a manifestation of neuromuscular excitability. 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 growth hormone deficiency.

• PHP is an uncommon metabolic disorders characterized by biochemical hypoparathyroidism (ie, hypocalcemia and hypophosphatemia), and PTH resistance.

• Albright hereditary osteodystrophy (AHO) is the characteristic phenotype of PHP type Ia and Ic.

  • 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.

Hypoparathyroidism may be transient, genetically inherited, or acquired. Genetically inherited forms arise from defects of parathyroid gland development, defects in the parathyroid hormone (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 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.

  • Hypocalcemia is noted in 10-20% of infants of diabetic mothers. 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, absence of thymus gland [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. Several cases of chromosome 10p deletion have also been reported in which affected individuals have some features of DiGeorge 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.

• Autosomal recessive forms of hypoparathyroidism have been shown to be caused by rare homozygous mutations in the genes encoding pre-pro-PTH or glial cell missing B (GCMB). ^[2]

• Autosomal dominant forms of hypoparathyroidism could be due to a dominant negative GCMB muation. ^[3]

• Defects in PTH action occur in PHP. The hallmark of PHP is PTH resistance. Four forms of PTH resistance are recognized. These include PHP Ia, Ib, Ic and 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.

  • 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.

  • PHP Ic: Patient will have similar features to PHP Ia except they do not have a demonstrable defect in Gs alpha subunit mutation. The nature of the lesion in such patients is unclear, but it could be related to some other general component of the receptor-adenylyl cyclase system, such as catalytic unit. Alternatively, these patients could have functional defects of Gs (or Gi) that do not become apparent in the assays presently available.

  • PHP II: Patients with PHP II have normal physical appearance. There is no association with 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. 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 (CaSR) 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 active vitamin D (calcitriol) can cause nephrocalcinosis and renal insufficiency by exacerbating the already high urinary calcium excretion. Therapy with calcitriol 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. In addition, PTH therapy could be effective in correcting serum and urine calcium and the phosphate levels in this disorder. ^[4]