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= PSEUDOHYPOPARATHYROIDISM =

Background
Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by hypocalcemia, hyperphosphatemia, increased serum concentration of parathyroid hormone (PTH), and insensitivity to the biologic activity of PTH.Several variants of PHP have been identified. The molecular defects in the gene (GNAS1) encoding the alpha subunit of the stimulatory G protein (Gsa) contribute to at least 3 different forms of the disease: PHP type 1a, PHP type 1b, and pseudopseudohypoparathyroidism (pseudo-PHP).undefinedPHP type 1a is the best understood form of the disease.

In 1942, Fuller Albright first introduced the term pseudohypoparathyroidism to describe patients who presented with PTH-resistant hypocalcemia and hyperphosphatemia along with an unusual constellation of developmental and skeletal defects, collectively termed Albright hereditary osteodystrophy (AHO). These features included short stature, rounded face, shortened fourth metacarpals and other bones of the hands and feet, obesity, dental hypoplasia, and soft-tissue calcifications/ossifications. In addition, administration of PTH failed to produce the expected phosphaturia or to stimulate renal production of cyclic adenosine monophosphate (cAMP).

Pseudohypoparathyroidism
Pseudohypoparathyroidism is a genetic disorder in which the body fails to respond to parathyroid hormone.

A related condition is hypoparathyroidism, in which the body does not make enough parathyroid hormone.

Causes
The parathyroid glands produce parathyroid hormone (PTH). PTH helps control calcium, phosphorus, and vitamin D levels in the blood and bone.

having pseudohypoparathyroidism, body produces the right amount of PTH, but is "resistant" to its effect. This causes low blood calcium levels and high blood phosphate levels.

Pseudohypoparathyroidism is caused by abnormal genes.

Types
There are different types of pseudohypoparathyroidism. All forms are rare.

Type1a-

 * Type Ia is inherited in an autosomal dominant manner. That means only one parent needs to pass you the faulty gene for you to have the condition. It is also called Albright hereditary osteodystrophy.
 * The condition causes short stature, round face, obesity, developmental delay, and short hand bones.
 * Symptoms depend on whether you inherit the gene from your mother or father.

Type1b-

 * Type Ib involves resistance to PTH only in the kidneys.
 * Less is known about type Ib than type Ia.
 * Calcium in the blood is low, but there are no symptoms of Albright hereditary osteodystrophy.

Type2

 * Type II pseudohypoparathyroidism also involves low blood calcium and high blood phosphate levels.
 * People with this form of the disorder do not have the physical traits common to people with Type Ia.
 * The genetic abnormality that causes it is not known.

Symptoms
Symptoms are related to a low level of calcium and include:
 * Cataracts
 * Dental problems
 * Numbness
 * Seizures
 * Tetany(a collection of symptoms including muscle twitches and hand and foot spasms).

Persons with Albright hereditary osteodystrophy may have the following symptoms:
 * Calcium deposits under the skin
 * Dimples that can replace knuckles on affected fingers
 * Round face and short neck
 * Short hand bones, especially the bone below the 4th finger
 * Short height

Diagnosis
Blood tests will be done to check calcium, phosphorus, and PTH levels. You may also need urine tests.

Other tests may include:
 * Genetic testing
 * Head MRI or CT scan of the brain

Treatment
it is recommended calcium and vitamin D supplements to maintain a proper calcium level. If the blood phosphate level is high, it is required to follow a low-phosphorus diet or take medicines called phosphate binders (such as calcium carbonate or calcium acetate).

Metabolism
The term pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of various hormones (primarily PTH) that activate cAMP-dependent pathways via Gsα protein. The two main subtypes of PHP, PHP type Ia, and Ib (PHP-Ia, PHP-Ib) are caused by molecular alterations within or upstream of the imprinted GNAS gene, which encodes Gsα and other translated and untranslated products.

GNAS complex gene and imprinting
Identical Gsα deficiency may lead to such variable phenotypic expression, in particular in terms of the presence or absence (PHP-Ia and PPHP, respectively) of generalized hormone resistance and why PHP-Ia patients display a resistance to some (PTH, TSH, GHRH, and gonadotropins) but not all hormones that activate the Gs-coupled pathway.

Moreover, only maternal transmission of the disease leads to the complete expression (PHP-Ia), whereas paternal transmission is associated with PPHP in the offsprings. Paternal genomic imprinting was then proposed as the potential mechanism to explain the occurrence of PHP-Ia and PPHP in patients with identical GNAS mutations, the phenomenon being expected to be tissue specific, i.e. limited mainly to tissues in which there is a parent-of-origin-specific difference in hormone responsiveness, such as the renal proximal tubule and the thyroid. In other tissues, no imprinting would be expected, resulting in a 50% reduction of Gsα activity, sufficient for maintaining normal signaling activity in most cells but leading to haploinsufficiency in others

Indeed, the two main subtypes of PHP, i.e. PHP-Ia and PHP-Ib, are caused by mutations and methylation defects within the imprinted GNAS cluster, respectively. This locus, which is among the most complex eukaryotic genes, combines elaborate patterns of imprinting, alternative splicing, and antisense transcription with tissue- and developmental stage-specific expression. By a parent-specific methylation pattern of most of its different promoters, GNAS locus gives rise to several transcripts, including the α-subunit of heterotrimeric stimulatory G protein (Gsα), the Gsα extra large variant, and a second alternative gene product encoded by the XL-exon1 , the neuroendocrine protein 55 , the untranslated exon A/B , and an additional antisense transcript.

Reference
https://medlineplus.gov/ency/article/000364.htm

https://academic.oup.com/jcem/article-abstract/96/10/3020/2834845/Pseudohypoparathyroidism-Diagnosis-and-Treatment?redirectedFrom=fulltext

http://emedicine.medscape.com/article/124836-overview

http://www.nytimes.com/health/guides/disease/pseudohypoparathyroidism/overview.html