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.

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

• Pseudohypoparathyroidism 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 subtypes.
  • 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 resulting in resistance of target tissues to parathyroid hormone evidenced by hypocalcemia and hyperphosphatemia, in the presence of high plasma PTH level.

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

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.

Differentiating ((Page name)) from Other Diseases

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

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[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

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

Seizures can occur in children. Associated resistance to thyrotropin can result in hypothyroidism.Some patients also develop gonadotropin or GHRH resistance. Patients may develop paresthesias, muscular cramping, tetany, or carpopedal spasm. Asymptomatic hypocalcemia in children or adolescents can occur. 

Subcutaneous calcification has been has been reported in the neonatal period.

Reproductive dysfunction is seen in patients with pseudohypoparathyroidism 1a. Women may experience delayed puberty, oligomenorrhea, and infertility.

Pseudohypoparathyroidism type 1b patients could develop tertiary hyperparathyroidism and/or hyperparathyroid bone disease. 

Features of hypogonadism may be less obvious in men. Testes may show evidence of maturation arrest or may fail to descend normally. Fertility appears to be decreased in men with PHP-1a.

Peudohypoparathyroidism-1a is also associated with variability in osteoclast responsiveness to PTH. Some patients develop osteopenia and rickets.

Prognosis

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

Diagnosis

Diagnostic Criteria

The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].

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The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

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The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

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There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

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The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Blomstrand's Chondrodystrophy

Blomstrand's chondrodystrophy is characterized by growth impairment, primarily in the form of short limbs. It has been lethal prenatally, and therefore the regulation of serum calcium has not been evaluated in vivo. It is caused by inactivating mutations of the type 1 parathyroid hormone receptor106 and is inherited as an autosomal recessive trait. The growth plates show accelerated calcification and a near-absence of proliferating chondrocytes.

Physical Examination

Patients with [disease name] usually Pseudohypoparathyroidism type1A presents with characteristic clinical features of Albright's hereditary osteodystrophy like short stature, subcutaneous ossifications,mental retardation and shortening of third, fourth, and fifth metacarpals and metatarsals,round face, frontal bossing, dental hypoplasia not present at birth but becomes apparent by the second decade of life.appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

uptodatePatients with PHP type 1a have a constellation of findings known as Albright hereditary osteodystrophy (AHO), which includes round facies, short stature, short fourth metacarpal bones, obesity, subcutaneous calcifications, and developmental delay [42,52]. In addition, the PTH resistance of the renal tubule leads to hyperphosphatemia and hypocalcemia, and secondary hyperparathyroidism and hyperparathyroid bone disease (osteitis fibrosa).

In humans, GNAS1 also is predominantly expressed from the maternal allele in the thyroid, gonads, and pituitary glands. As a result, patients with PHP type 1a show resistance to various other G-protein coupled hormones including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadotropin-releasing hormone (GnRH), as well as blunted response to beta-adrenergic agonists [53,54].

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Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

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The presence of [finding(s)] on physical examination is diagnostic of [disease name].

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The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

Laboratory findings consistent with the diagnosis of pseudohypoparathyroidism include hypocalcemia, hyperphosphatemia and elevated serum concentration of PTH and diminished urinary cAMP response after administration of the biosynthetic N-terminal fragment of PTH.

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

Following exogenous parathyroid hormone administration 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 PTH.

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

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

Electrocardiogram

An ECG may be helpful in the diagnosis of hypocalcemia associated with the pseudohypoparathyroidism. Prolonged QT interval secondary to hypocalcemia is seen on ECG..

X-ray

Radiography may also show small soft tissue opacities (calcifications/ossifications). Computed tomography (CT) scanning may reveal calcification of the basal ganglia.

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.

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There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

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Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

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There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

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

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There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

MRI may be helpful in the diagnosis of Chiari Malformation-Type I associated with psuedohypoparathyroidism type 1a. It is important to consider brain MRI in PHP-Ia patients, particularly those with abnormal neurological examination or developmental delay. While developmental delay may be a feature of PHP-Ia, detecting CM-I with hydrocephalus may help to maximize neurodevelopmental outcomes and prevent neurosurgical emergencies.. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

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There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

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[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

Genetic Testing

Genetic testing and analysis of the GNAS1 gene can confirm diagnosis and identify the different variants of PHP. Patients affected by PHP-1b require testing for GNAS methylation changes; some laboratories will analyze exon A/B only as a screen, because the loss of methylation of this DMR on the maternally derived GNAS allele is present in all reported cases of both inherited and sporadic forms of PHP-1b. Patients with PHP-1b can be further analyzed for paternal uniparental isodisomy of chromosome 20q or small deletions within STX16 and GNAS; these tests have furthermore been shown to identify deletions within GNAS as the cause of some PHP-1a cases. ^{null 3}

There are no other diagnostic studies associated with [disease name].

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[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

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Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

"In pseudohypoparathyroidism, monitoring serum PTH levels during treatment is critical with the aim of normalizing or reducing PTH levels as much as possible. This is done to avoid the long-term elevation of circulating PTH, that would likely cause bone resorption. Also, hypercalciuria as a result of the calcitriol and calcium treatment is a lesser concern because PTH actions in the distal tubule are functional, preventing the loss of calcium in the urine. Of note, calcitriol (and not other forms of vitamin D) should be used for the treatment, because the PTH resistance in the proximal tubule does not allow for the efficient synthesis of 1,25(OH)2D from 25-hydroxyvitamin D"

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

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Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

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The majority of cases of [disease name] are self-limited and require only supportive care.

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[Disease name] is a medical emergency and requires prompt treatment.

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The mainstay of treatment for [disease name] is [therapy].

OR   The optimal therapy for [malignancy name] depends on the stage at diagnosis.

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[Therapy] is recommended among all patients who develop [disease name].

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Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

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Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

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Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

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Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].

Surgery

Surgical intervention is not recommended for the management of [disease name].

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Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]

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The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].

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The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

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Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

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

Secondary Prevention

There are no established measures for the secondary prevention of psuedohypoparathyroidism.

References

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