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

Pseudohypoparathyroidism is characterized by end-organ resistance to the parathyroid hormone. Patients have a low serum calcium and high phosphate, but the parathyroid hormone level is appropriately high. Pseudohypoparathyroidism type 1a presents with the characteristic phenotypic appearance of Albright’s hereditary osteodystrophy. Pseudohypoparathyroidism type 1b lacks the physical appearance of type 1a, but is biochemically similar. The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but is biochemically normal. There are three types of pseudohypoparathyroidism, type 1a, type 1b and type 2. All forms of pseudohypoparathyroidism are very rare and are caused by abnormal genes. Usual signs and symptoms include numbness, tetany, seizures, cataracts and dental problems. Patients with pseudohypoparathyroidism type 1a, which is also called Albright’s hereditary osteodystrophy, may show signs of short stature. Blood tests of minerals, genetic testing and head MRI may help diagnose the disorder. Treatment for pseudohypoparathyroidism includes taking calcium carbonate and vitamin D supplements to normalize blood levels of calcium and phosphorus.

In 1942, Fuller albright, an American endocrinologist, first discovered pseudohypoparathyroidim and associated clinical features of Albright hereditary osteodystrophy.

Pseudohypoparathyroidism is classified based on the measurement of serum and urinary cAMP and phosphate excretion levels after the injection of biologically active parathyroid hormone into pseudohypoparathyroidism type I and pseudohypoparathyroidism type II. Pseudohypoparathyroidism type 1 may be classified into type 1a, type 1b, and type 1c.

Pseudohypoparathyroidism is characterized by end-organ resistance to parathyroid hormone. Gene mutation results in failure of signal transduction. Blomstrand’s chondrodystrophy results in intrauterine death and is characterized by abnormal endochondral bone formation with prematurely occurring mineralization of the cartilaginous bone templates. Acrodysostosis patients have resistance to parathyroid hormone with normal calcium and phosphorus, in addition to resistance thyroid-stimulating hormone and growth hormone releasing hormone.

Pseudohypoparathyroidism is caused by mutations involving primarily the GNAS gene that results in end organ resistance to parathyroid hormone.

Pseudohypoparathyroidism can be differentiated from other causes of increased parathyroid hormone (PTH) and parathyroid hormone resistance like Blomstrand chondrodysplasia, acrodysostosis, hypomagnesemia, hypoparathyroidism and hyperparathyroidism.

The worldwide incidence and prevalence of pseudohypoparathyroidism is unknown. 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 Pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type1b, and pseudopseudohypoparathyroidism is 0.67 per 100,000

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

There is insufficient evidence to recommend routine screening for pseudohypoparathyroidism.

Patients with pseudohypoparathyroidism type Ia have an increased rate of other endocrine abnormalities (such as hypothyroidism and hypogonadism). Complications of hypocalcemia associated with pseudohypoparathyroidism may include seizures and other endocrine problems, leading to decrease libido and delayed sexual development, fatigue, and obesity.

Pseudohypoparathyroidism diagnosis is mainly a clinical diagnosis. The confirmatory diagnostic study of choice for pseudohypoparathyroidism is genetic testing.

A positive family history of pseudohypoparathyroidism is suggestive of the autosomal dominant inheritance. The most common symptoms of pseudohypoparathyroidism type 1a include short stature, short limbs, mental retardation associated with Albright hereditary osteodystrophy phenotype.

Patients with pseudohypoparathyroidism type1a, type 1c and pseudopseudohypoparathyroidism present by the second decade of life with characteristic physical features of Albright’s hereditary osteodystrophy. 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.

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.

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.

Findings on an x-ray include short distal phalanx of thumb and short third to fifth metacarpals associated with features of Albright hereditary osteodystrophy. Findings on an x-ray of hand in acrodysostosis, include shortened metacarpals with cone epiphyses. In acrodysostosis the spine may also be affected by loss of caudal widening of interpedicular distance, which may correlate with stenosis of the spinal canal. Findings on CT scan suggestive of pseudohypoparathyroidism in some patients includes include symmetric calcifications in basal ganglia, perivascular calcifications in soft tissues. MRI in pseudohypoparathyroidism Ia patients may include Chiari Malformation-Type I.

Other diagnostic studies include genetic testing, platelet aggregation testing for Gsα defects and bone densitometry testing.

The mainstay of treatment for pseudohypoparathyroidism is oral calcium and 1 alpha-hydroxylated vitamin D analogs, 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. Intravenous calcium is recommended for all patients who develop severe symptomatic hypocalcemia.

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.

Effective measures for the primary prevention of pseudohypoparathyroidism include genetic counseling in inherited cases. Secondary prevention of measures in pseudohypoparathyroidism includes regular serum and urinary calcium measurements monitoring.

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

In 1942, Fuller albright, an American endocrinologist, first discovered pseudohypoparathyroidim and associated clinical features of Albright hereditary osteodystrophy.

• In 1942, Fuller albright, an American endocrinologist, first discovered pseudohypoparathyroidim. Pseudohypoparathyoroidism is the first hormone resistance syndrome to be discovered.^[1]

• In the same year, Albright hereditary osteodystrophy was clinically described together with pseudohypoparathyroidism.^[2]

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

Pseudohypoparathyroidism is classified based on the measurement of serum and urinary cyclic adenosine monophosphate (cAMP) and phosphate levels after injection of biologically active parathyroid hormone into the suspected patient.

Pseudohypoparathyroidism is classified based on the measurement of serum and urinary cAMP and phosphate excretion levels after injection of biologically active parathyroid hormone. The following are the different types of pseudohypoparathyroidism:^[1]

• 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

Other forms of parathyroid hormone resistance include :

• Blomstrand syndrome
• Acrodysostosis type 1 
• Acrodysostosis type 2 

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

Pseudohypoparathyroidism is characterized by end-organ resistance to parathyroid hormone. Gene mutation results in failure of signal transduction. Blomstrand’s chondrodystrophy results in intrauterine death and is characterized by abnormal endochondral bone formation with prematurely occurring mineralization of the cartilaginous bone templates. Acrodysostosis patients have resistance to parathormone with normal calcium and phosphorus, in addition to resistance thyroid-stimulating hormone and growth hormone releasing hormone.

• Pseudohypoparathyroidism is characterized by end-organ resistance to parathyroid hormone.^[1][2]
• Parathyroid hormone (PTH) 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 Gs-α 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 in the prenatal period characterized by abnormal endochondral bone formation with prematurely occurring mineralization of the cartilaginous bone templates.
• Patients with acrodysostosis have:
  • Resistance to parathyroid hormone
  • Resistance to thyroid-stimulating hormone
  • Resistance to growth hormone releasing hormone

Genetic mutations associated with parathyroid hormone resistance are discussed below ^{[3][4][5][6][7][8]}

On gross pathology, enlarged parathyroid glands occur as a result of associated hypocalcemia.

On microscopic histopathological analysis, secondary hyperplasia of the parathyroid glands occurs as a result of associated hypocalcemia.

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

Pseudohypoparathyroidism is caused by mutations involving primarily the GNAS gene that results in end organ resistance to parathyroid hormone.

• Pseudohypoparathyroidism is caused by mutations that result in end-organ resistance to parathyroid hormone like:^[1]
  • Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs
  • Familial-heterozygous deletions in STX16, NESP55, and/or AS exons or loss of methylation at GNAS
  • Sporadic-paternal uniparental disomy of chromosome 20q in some or methylation defect affecting all four GNAS genes
  • Combination of inactivating mutations of GNAS1 and Albright’s osteodystrophy
• For a complete review of genes involved in pseudohypoparathyroidism and associated parathyroid hormone, resistance click here

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

Pseudohypoparathyroidism can be differentiated from other causes of increased parathyroid hormone( PTH) and parathyroid hormone resistance like Blomstrand chondrodysplasia, acrodysostosis, hypomagnesemia, hypoparathyroidism and hyperparathyroidism.

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

All types of pseudohypoparathyroidism and associated parathyroid resistance syndromes are rare diseases.

• 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.^[1]
• In Italy, the estimated prevalence of Pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type1b, and pseudopseudohypoparathyroidism is 0.67 per 100,000.^[2]

• Patients with pseudohypoparthyroidism type 1a and type 1c present in the second decade with physical features of Albright’s hereditary osteodystrophy.^[2]
• Neonatal screening can detect patients with severe hypoparathyroidism in severe cases.^[2]

• There is no racial predilection to pseudohypoparathyroidism.

• The prevalence and incidence of pseudohypoparathyroidism is more common in women than in men.

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

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

The most potent risk factor in the development of pseudohypoparathyroidism is a positive family history for GNAS mutation. For more information regarding GNAS mutation click here.

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

There is insufficient evidence to recommend routine screening for pseudohypoparathyroidism.

There is insufficient evidence to recommend routine screening for pseudohypoparathyroidism.

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

Patients with pseudohypoparathyroidism type Ia have an increased rate of other endocrine abnormalities (such as hypothyroidism and hypogonadism). Complications of hypocalcemia associated with pseudohypoparathyroidism may include seizures and other endocrine problems, leading to decreased sexual drive and delayed sexual development, fatigue, and increased weight.

• If left untreated, patients with pseudohypoparathyroidism type1a, type 1c and pseudopseudohypoparathyroidism present 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
  • Obesity
  • Frontal bossing
  • Dental hypoplasia
• If left untreated, pseudohypoparathyroidism type 1b patients at an increased risk of developing hyperparathyroidism and hyperparathyroid bone disease as a result of long-term elevation in parathyroid hormone.

Complications that can develop as a result of pseudohypoparathyroidism are:^[1][2][3][4]

• Seizures (children)
• Hypothyroidism due to associated resistance to thyrotropin
• Gonadotropin
• Growth hormone releasing hormone(GHRH) resistance
• Patients may develop hypocalcemia resulting in:
  • Paresthesias
  • Muscular cramping
  • Tetany
  • Carpopedal spasm 
• Patients with pseudohypoparathyroidism type Ia have an increased rate of other endocrine abnormalities (such as hypothyroidism and hypogonadism)

• Complications of hypocalcemia associated with pseudohypoparathyroidism may include:
  • Seizures
  • Lowered sexual drive
  • Delayed sexual development
  • Lowered energy levels
  • Increased weight
• Subcutaneous calcification in neonates

• Reproductive dysfunction is seen in patients with pseudohypoparathyroidism 1a
  • Women may experience:
    • Delayed puberty
    • Oligomenorrhea
    • Infertility
  • In men decreased fertility may present with:
    • Maturation arrest of testes
    • Cryptorchidism

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

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

• In few cases of pseudohypoparathyroidism, calcium homeostasis adapts to parathyroid hormone resistance resulting in resolution of hypocalcemia.
• Patients who do not adapt to parathyroid hormone resistance are managed with lifelong calcium supplementation.
• Long term levothyroxine is used in patients with associated hypothyroidism.

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