Sandbox:Mazia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Overview

Pseudohypoparathyroidism (PHP) refers to a group of rare endocrine disorders characterized by end organ resistance to the action of parathyroid hormone (PTH), manifestations include hypocalcemia, hyperphosphatemia, and increased serum concentration of PTH.

Development of pseudohypoparathyroidism is the result from multiple genetic mutations involving mainly the GNAS gene.

Historical Perspective

• In 1942, Fuller albright, an American endocrinologist, first discovered pseudohypoparathyroidim. Pseudohypoparathyoroidism is the first hormone resistance syndrome to be discovered.

• In the same year, Albright hereditary osteodystrophy was clinically described together with pseudohypoparathyroidism.

Classification

• Parathyroid hormone resistance is classified based on the measurement of serum and urinary cAMP and phosphate excretion levels after the injection of biologically active PTH into following types:
  • Pseudohypoparathyroidism type I
  • Pseudohypoparathyroidism type II

• Pseudohypoparathyroidism type 1 is further classified into following subtype:
  • Pseudohypoparathyroidism type 1a
  • Pseudohypoparathyroidism type 1b
  • Pseudohypoparathyroidism type 1c.
  • Pseudopseudohypoparathyroidism
• Blomstrand Syndrome is a form of PTH resistance.

Pathophysiology

• Pseudohypoparathyroidism is characterized by end organ resistance to parathyroid hormone.
• Parathyroid hormone effect is mediated by the parathyroid hormone receptor type 1, which acts on a stimulatory guanine-nucleotide–binding (Gs) protein, which is composed of three subunits (α, β, and γ). The GNAS1 gene encodes Gsα subunit that mediates cyclic AMP stimulation by parathyroid hormone and by several other peptide hormones, including thyrotropin.
• Gene mutation results in failure of signal transduction through Gsα inability to activate adenyl cyclase that results in resistance of target tissues to parathyroid hormone evidenced by hypocalcemia and hyperphosphatemia, in the presence of high plasma PTH level.
• Blomstrand's Chondrodystrophy is lethal prenatally characterized by abnormal endochondral bone formation with prematurely occurring mineralization of the cartilaginous bone templates.

Genetics

Genetic mutations associated with parathyroid hormone resistance are discussed below

Type of pseudohyoparathyroidism		Molecular Defect	Origin Of Mutation	Inheritence
Pseudohypoparathyroidism type I	Type 1a	Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs	Maternal	Autosomal dominant
	Type 1b	Familial- heterozygous deletions in STX16, NESP55, and/or AS exons or loss of methylation at GNAS	Maternal	Autosomal dominant
		Sporadic- paternal Uniparental disomy of chromosome 20q in some or methylation defect affecting all four GNAS DMRs	Maternal	Genomic imprinting
	Type 1c	Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs	Maternal	Autosomal dominant
Pseudopseudohypoparathyroidism		Combination of inactivating mutations of GNAS1 and Albright's osteodystrophy	Paternal	Genomic imprinting
Pseudohypoparathyroidism type II		Insufficient data to suggest genetic or familial source	N/A	N/A
Blomstrand chondrodysplasia		Homozygous or heterozygous mutations in PTH receptor	N/A	Autosomal recessive
Acrodysostosis type 1		PRKAR1A germ-line mutation in the encoding gene	N/A	Autosomal dominant
Acrodysostosis type 2		Phosphodiesterase 4D (PDE4D) gene	N/A	Autosomal dominant

Causes

Pseudohypoparathyroidism is caused by mutations involving primarily the GNAS gene that results in end organ resistance to parathyroid hormone.For a complete review of genes involved in pseudohypoparathyroidism click here.

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Epidemiology and Demographics

Prevalence

• In Japan, the prevalence of pseudohypoparathyroidism ranges from a low of 0.26 per 100,000 persons to a high of 0.42 per 100,000 persons with an average prevalence of 0.34 per 100,000 persons.
• In Italy, the estimated prevalence of PHP type 1a, type1b, and PPHP is 1 per 150,000.

Risk Factors

The most potent risk factor in the development of pseudohypoparathyroidism is a positive family history for GNAS mutation.

Screening

There is insufficient evidence to recommend routine screening for pseudohypoparathyroidism.

Complications

Complications that can develop as a result of pseudohypoparathyroidism are

• Seizures (children).
• Hypothyroidism due to associated resistance to thyrotropin.
• Gonadotropin or GHRH resistance.
• Patients may develop hypocalcemia resulting in
  • Paresthesias
  • Muscular cramping
  • Tetany
  • Carpopedal spasm 

• Subcutaneous calcification in neonatal period.

• Reproductive dysfunction is seen in patients with pseudohypoparathyroidism 1a. Women may experience delayed puberty, oligomenorrhea, and infertility.In men decreased Fertility may present with maturation arrest of Testes and cryptorchidism.

• Pseudohypoparathyroidism type 1b patients are at risk of developing tertiary hyperparathyroidism and hyperparathyroid bone disease.  

• Osteopenia and rickets in peudohypoparathyroidism-1a is associated with variable osteoclast responsiveness to parathyroid hormone.

Prognosis

Insufficient data is available to determine the long term outcomes of pseudohypoparathyroidism. In some patients calcium homeostasis adapts to parathyroid hormone resistance resulting in resolution of hypocalcemia while others who do not adapt to parathyroid hormone resistance are managed with lifelong calcium supplementation. Long term levothyroxine is used in patients with associated hypothyroidism.

Diagnosis

Diagnostic Criteria

The diagnosis of pseudohypoparathyroidism Type 1a patients includes:

• Clinical features of Albright hereditary osteodystrophy
• Parathyroid hormone resistance evidenced by
  • Hypocalcemia
  • Hyperphosphatemia
  • Elevated serum concentration of parathyroid hormone
  • Diminished urinary cAMP response after administration of the biosynthetic N-terminal fragment of parathyroid hormone.

History and Symptoms

• A positive family history of pseudohypoparathyroidism is suggestive of the autosomal dominant inheritance.

• The most common symptoms of pseudohypoparathyroidism type 1a include short stature,mental retardation associated with Albright hereditary Osteodystrophy phenotype.

• Common symptoms due to associated hypocalcemia include
  • Paresthesias (peri-oral, extremities)
  • Muscle twitching
  • Carpopedal spasm
  • Seizures
  • Prolonged QT interval
  • Hypotension
  • Arrhythmia.

Physical Examination

• Patients with pseudohypoparathyroidism type1A , type 1c and pseudopseudohypoparathyroidism presents by the second decade of life with characteristic physical features of Albright's hereditary osteodystrophy like:
  • Subcutaneous ossifications
  • Shortening of third, fourth, and fifth metacarpals and metatarsals
  • Round face
  • Frontal bossing
  • Dental hypoplasia

• Pseudohypoparathyroidism Type 1B isolated resistance to parathyroid hormone without the associated clinical features of Albright's osteodystrophy. Mild brachydactyly is seen in some cases.

• Blomstrand's chondrodystrophy presents with short limbs due to characteristic growth impairment.Secondary hyperplasia of the parathyroid glands occurs as a result of associated hypocalcemia.

Laboratory Findings

• The diagnosis of pseudohypoparathyroidism is made by measurement of variations in serum calcium, phosphorus, cAMP and calcitriol and in urinary cAMP and phosphorus excretion helps in assessment of skeletal and renal responsiveness to parathyroid hormone.
• Laboratory findings consistent with the diagnosis of pseudohypoparathyroidism include
  • Hypocalcemia
  • Hyperphosphatemia
  • Elevated serum concentration of parathyroid hormone
  • Diminished urinary cAMP response after administration of the biosynthetic N-terminal fragment of parathyroid hormone
  • Secondary hyperparathyroidism and hyperparathyroid bone disease due to the parathyroid hormone resistance .

• Immunoradiometric assay (IRMA) can be used to measure serum parathyroid hormone concentration.

• Assessment of thyroid function tests, gonadotropin, testosterone, estrogen and insulin like growth factor will help in identification of any associated underlying hormonal dysfunction

Electrocardiogram

An ECG may be helpful in the diagnosis of cardiac dysfunction associated with the pseudohypoparathyroidism. Findings on an ECG suggestive of cardiac dysfunction due to hypocalcemia associated with pseudohypoparathyroidism include prolonged QT interval.

X-ray

An x-ray of the hand may be helpful in the diagnosis of pseudohypoparathyroidism. Findings on an x-ray include short distal phalanx of thumb and short third to fifth metacarpals associated with features of albright hereditary osteodystrophy.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with pseudohypoparathyroidism.

CT scan

Findings on CT scan suggestive of pseudohypoparathyroidism in some patients includes include symmetric calcifications in basal ganglia, perivascular calcifications in soft tissues.

MRI

Findings on brain MRI in pseudohypoparathyroidism Ia patients, particularly those with abnormal neurological examination or developmental delay include Chiari Malformation-Type I .

Other Imaging Findings

There are no other imaging findings associated with psuedohypoparathyroidism.

Other Diagnostic Studies

• Genetic testing may be helpful in the diagnosis of pseudohypoparathyroidism. Analysis of the GNAS1 gene can confirm diagnosis and identify the different variants of PHP. Testing for paternal uniparental isodisomy of chromosome 20q or deletions in STX16 can also help in diagnosis of pseudohypoparathyroidism 1b.

• Gsα defects can be diagnosed by assessment of variations in platelet aggregation responses reflecting a patient's genotype.

• Psuedohypoparathyroidism type 1b associated bone disease can be evaluated with bone mineral density (BMD) testing.

Treatment

Medical Therapy

• The mainstay of treatment for pseudohypoparathyroidism is oral calcium and 1alpha-hydroxylated vitamin D metabolites, such as calcitriol. Other forms of Vitamin D cannot be used as parathyroid hormone resistance in the proximal tubule decreases the efficiency of production of 1,25(OH)2 vitamin D from 25-hydroxyvitamin D.
• The majority of cases of pseudohypoparathyroidism are self-limited and require only supportive care.
• The goal is to maintain serum calcium within the normal range to prevent hypercalciuria and to maintain parathyroid hormone levels within reference range which helps prevent bone remodeling and hyperparathyroid bone disease that can result from elevated parathyroid hormone level.
• Intravenous calcium is recommended for all patients who develop severe symptomatic hypocalcemia. Adult dosage is started 100 mg of elemental calcium (either calcium chloride or calcium gluconate) over 10 to 20 minutes. An additional dose of 100 mg/hr of elemental calcium can be infused if symptoms do not resolve, with close monitoring of calcium levels.Cardiac monitoring may help to guide therapy as rapid infusion of calcium can cause cardiac conduction defects;
•  Parenteral formulations available are calcium chloride and calcium gluconate; a 10-mL ampule of 10% calcium chloride contains 360 mg of elemental calcium, and a 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium.

• For neonates, infants, and children, the recommended initial dose is 0.5-1 mL/kg of 10% calcium gluconate administered over 5 minutes.

Surgery

• Surgery is not the first-line treatment option for patients with psuedohypoparathyroidism.
• Surgical resection of enlarged parathyroid glands is usually reserved for patients that develop tertiary hyperparathyroidism in pseudohypoparathyroidism 1b. Rarely, excision of extraskeletal osteomas is done to relieve associated pressure symptoms in patients.

Primary Prevention

Effective measures for the primary prevention of pseudohypoparathyroidism include genetic counseling in inherited cases.

Secondary Prevention

Monitor therapy with regular serum and urinary calcium measurements.Pseudohypoparathyroidism type 1b patients at an increased risk of developing hyperparathyroidism and hyperparathyroid bone disease should be maintained at sufficient doses of calcium and vitamin D to maintain serum calcium and PTH levels within the normal range. Monitor therapy with regular serum and urinary calcium measurements.

References

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