Pseudohypoparathyroidism

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Pseudohypoparathyroidism
Specialty Endocrinology

Pseudohypoparathyroidism is a rare autosomal dominant genetic condition associated primarily with resistance to the parathyroid hormone. [1] Those with the condition have a low serum calcium and high phosphate, but the parathyroid hormone level (PTH) is inappropriately high (due to the low level of calcium in the blood). Its pathogenesis has been linked to dysfunctional G proteins (in particular, Gs alpha subunit). Pseudohypoparathyroidism is a very rare disorder, with estimated prevalence between 0.3 and 1.1 cases per 100,000 population depending on geographic location. [2]

Contents

Types

Types include:

Type 1a (OMIM 103580)
Has a characteristic phenotypic appearance (Albright's hereditary osteodystrophy), including short fourth and fifth metacarpals and a rounded facies. It is most likely an autosomal dominant disorder. [3] It is also associated with thyroid stimulating hormone resistance. Caused by GNAS1 mutation. [4]
Type 1b (OMIM 603233)
Lacks the physical appearance of type 1a, but is biochemically similar. [5] It is associated with a methylation defect in the A/B exon of GNAS1, caused by STX16 disruption. [6] [7]
Type 2 (OMIM 203330)
Also lacks the physical appearance of type 1a. [8] Since the genetic defect in type 2 is further down the signalling pathway than in type 1, there is a normal cAMP response to PTH stimulation despite the inherent abnormality in calcium regulation. The specific gene is not identified.

While biochemically similar, type 1 and 2 disease may be distinguished by the differing urinary excretion of cyclic AMP in response to exogenous PTH.[ citation needed ]

Some sources also refer to a "type 1c" (OMIM 612462). [9] The phenotype is the same as in type 1a, but red blood cells show normal Gs activity. As it is also caused by a GNAS mutation, it is not clear whether it should be considered an entity separate from Ia. [10]

Presentation

Patients may present with features of hypocalcaemia including carpo-pedal muscular spasms, cramping, tetany, and if the calcium deficit is severe, generalized seizures. IQ is typically mildly depressed or unaffected. Additional characteristics include short stature, obesity, developmental delay, and calcification of the basal ganglia in the deep white matter of the brain.[ citation needed ]

Type 1a pseudohypoparathyroidism is clinically manifest by bone resorption with blunting of the fourth and fifth knuckles of the hand, most notable when the dorsum of the hand is viewed in closed fist position. This presentation is known as 'knuckle knuckle dimple dimple' sign (Archibald's sign). This is as opposed to Turner syndrome which is characterized by blunting of only the fourth knuckle, and Down syndrome, which is associated with a hypoplastic middle phalanx.[ citation needed ]

The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but is biochemically normal.

ConditionAppearance PTH levels Calcitriol Calcium Phosphates Imprinting
Hypoparathyroidism NormalLowLowLowHighNot applicable
PseudohypoparathyroidismType 1A Skeletal defects HighLowLowHighGene defect from mother (GNAS1)
Type 1BNormalHighLowLowHighLikely a gene defect from mother (GNAS1 and STX16) however it can also be the result of an imprinting issue of (GNAS1) due to mother and father in equal measure
Type 2NormalHighLowLowHigh ?
Pseudopseudohypoparathyroidism Skeletal defects NormalNormalNormal [11] Normalgene defect from father

Diagnosis

Biochemical findings

Treatment

Calcium and Calcitriol supplements, the latter with a larger dose than for treatment of hypoparathyroidism.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Parathyroid gland</span> Endocrine gland

Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes parathyroid hormone in response to low blood calcium, which plays a key role in regulating the amount of calcium in the blood and within the bones.

<span class="mw-page-title-main">Parathyroid hormone</span> Mammalian protein found in humans

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

<span class="mw-page-title-main">Hypocalcemia</span> Low calcium levels in ones blood serum

Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L, while levels less than 2.1 mmol/L are defined as hypocalcemic. Mildly low levels that develop slowly often have no symptoms. Otherwise symptoms may include numbness, muscle spasms, seizures, confusion, or in extreme cases cardiac arrest.

Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.

Disorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body. In a healthy physiology, extracellular calcium levels are maintained within a tight range through the actions of parathyroid hormone, vitamin D and the calcium sensing receptor. Disorders in calcium metabolism can lead to hypocalcemia, decreased plasma levels of calcium or hypercalcemia, elevated plasma calcium levels.

<span class="mw-page-title-main">Parathyroid chief cell</span>

Parathyroid chief cells are one of the two cell types of the parathyroid glands, along with oxyphil cells. The chief cells are much more prevalent in the parathyroid gland than the oxyphil cells. It is perceived that oxyphil cells may be derived from chief cells at puberty, as they are not present at birth like chief cells.

<span class="mw-page-title-main">Oxyphil cell (parathyroid)</span> Cell type

Parathyroid oxyphil cells are one out of the two types of cells found in the parathyroid gland, the other being parathyroid chief cell. Oxyphil cells are only found in a select few number of species and humans are one of them.

Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany, and several other symptoms. It is a very rare disease. The condition can be inherited, but it is also encountered after thyroid or parathyroid gland surgery, and it can be caused by immune system-related damage as well as a number of rarer causes. The diagnosis is made with blood tests, and other investigations such as genetic testing depending on the results. The primary treatment of hypoparathyroidism is calcium and vitamin D supplementation. Calcium replacement or vitamin D can ameliorate the symptoms but can increase the risk of kidney stones and chronic kidney disease. Additionally, medications such as recombinant human parathyroid hormone or teriparatide may be given by injection to replace the missing hormone.

<span class="mw-page-title-main">Calcitriol</span> Active form of vitamin D

Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood calcium (Ca2+) mainly by increasing the uptake of calcium from the intestines.

Renal osteodystrophy is currently defined as an alteration of bone morphology in patients with chronic kidney disease (CKD). It is one measure of the skeletal component of the systemic disorder of chronic kidney disease-mineral and bone disorder (CKD-MBD). The term "renal osteodystrophy" was coined in 1943, 60 years after an association was identified between bone disease and kidney failure.

<span class="mw-page-title-main">Primary hyperparathyroidism</span> Medical condition

Primary hyperparathyroidism is a medical condition where the parathyroid gland produce excess amounts of parathyroid hormone (PTH). The symptoms of the condition relate to the resulting elevated serum calcium (hypercalcemia), which can cause digestive symptoms, kidney stones, psychiatric abnormalities, and bone disease.

<span class="mw-page-title-main">Osteitis fibrosa cystica</span> Medical condition

Osteitis fibrosa cystica is a skeletal disorder resulting in a loss of bone mass, a weakening of the bones as their calcified supporting structures are replaced with fibrous tissue, and the formation of cyst-like brown tumors in and around the bone. Osteitis fibrosis cystica (OFC), also known as osteitis fibrosa, osteodystrophia fibrosa, and von Recklinghausen's disease of bone, is caused by hyperparathyroidism, which is a surplus of parathyroid hormone from over-active parathyroid glands. This surplus stimulates the activity of osteoclasts, cells that break down bone, in a process known as osteoclastic bone resorption. The hyperparathyroidism can be triggered by a parathyroid adenoma, hereditary factors, parathyroid carcinoma, or renal osteodystrophy. Osteoclastic bone resorption releases minerals, including calcium, from the bone into the bloodstream, causing both elevated blood calcium levels, and the structural changes which weaken the bone. The symptoms of the disease are the consequences of both the general softening of the bones and the excess calcium in the blood, and include bone fractures, kidney stones, nausea, moth-eaten appearance in the bones, appetite loss, and weight loss.

<span class="mw-page-title-main">Albright's hereditary osteodystrophy</span> Form of osteodystrophy and a rare human disease

Albright's hereditary osteodystrophy is a form of osteodystrophy, and is classified as the phenotype of pseudohypoparathyroidism type 1A; this is a condition in which the body does not respond to parathyroid hormone.

Pseudopseudohypoparathyroidism (PPHP) is an inherited disorder, named for its similarity to pseudohypoparathyroidism in presentation. It is more properly Albright hereditary osteodystrophy, although without resistance of parathyroid hormone (PTH), as frequently seen in that affliction. The term is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but has normal labs, including calcium and PTH.

There are two known parathyroid hormone receptors in mammals termed PTH1R and PTH2R. These receptors bind parathyroid hormone and are members of the GPCR family of transmembrane proteins.

<span class="mw-page-title-main">Parathyroid hormone 1 receptor</span> Protein-coding gene in the species Homo sapiens

Parathyroid hormone/parathyroid hormone-related peptide receptor, also known as parathyroid hormone 1 receptor (PTH1R), is a protein that in humans is encoded by the PTH1R gene. PTH1R functions as a receptor for parathyroid hormone (PTH) and for parathyroid hormone-related protein (PTHrP), also called parathyroid hormone-like hormone (PTHLH).

<span class="mw-page-title-main">Parathyroid hormone 2 receptor</span> Protein-coding gene in the species Homo sapiens

Parathyroid hormone 2 receptor is a protein that in humans is encoded by the PTH2R gene.

<span class="mw-page-title-main">TIP39</span> Protein-coding gene in the species Homo sapiens

Tuberoinfundibular peptide of 39 residues is a protein that in humans is encoded by the PTH2 gene.

<span class="mw-page-title-main">GCM2</span> Protein-coding gene in the species Homo sapiens

Chorion-specific transcription factor GCMb is a protein that in humans is encoded by the GCM2 gene.

<span class="mw-page-title-main">Parathyroid disease</span> Medical condition

Many conditions are associated with disorders of the function of the parathyroid gland. Some disorders may be purely anatomical resulting in an enlarged gland which will raise concern. Such benign disorders, such as parathyroid cyst, are not discussed here. Parathyroid diseases can be divided into those causing hyperparathyroidism, and those causing hypoparathyroidism.

References

  1. ↑ Bastepe M (2008). "The GNAS Locus and Pseudohypoparathyroidism". Genomic Imprinting. Advances in Experimental Medicine and Biology. Vol. 626. pp. 27–40. doi:10.1007/978-0-387-77576-0_3. ISBN   978-0-387-77575-3. PMID   18372789.
  2. ↑ Ucciferro, Peter; Anastasolpoulou, Catherine (10 August 2020). Pseudohypoparathyroidism. Treasure Island (FL): StatPearls Publishing. PMID   31613489 . Retrieved 2 May 2021.
  3. ↑ Online Mendelian Inheritance in Man (OMIM): 103580
  4. ↑ de Nanclares GP, Fernández-Rebollo E, Santin I, et al. (June 2007). "Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy". J. Clin. Endocrinol. Metab. 92 (6): 2370–3. doi: 10.1210/jc.2006-2287 . PMID   17405843.
  5. ↑ Online Mendelian Inheritance in Man (OMIM): 603233
  6. ↑ Laspa E, Bastepe M, Jüppner H, Tsatsoulis A (December 2004). "Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type Ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance". J. Clin. Endocrinol. Metab. 89 (12): 5942–7. doi: 10.1210/jc.2004-0249 . PMID   15579741.
  7. ↑ Fröhlich LF, Bastepe M, Ozturk D, Abu-Zahra H, Jüppner H (June 2007). "Lack of Gnas epigenetic changes and pseudohypoparathyroidism type Ib in mice with targeted disruption of syntaxin-16". Endocrinology. 148 (6): 2925–35. doi: 10.1210/en.2006-1298 . PMID   17317779.
  8. ↑ Online Mendelian Inheritance in Man (OMIM): 203330
  9. ↑ Aldred MA (May 2006). "Genetics of pseudohypoparathyroidism types Ia and Ic". J. Pediatr. Endocrinol. Metab. 19 (Suppl 2): 635–40. doi:10.1515/jpem.2006.19.s2.635. PMID   16789628. S2CID   26538688.
  10. ↑ Bastepe, M (2008). "The GNAS Locus and Pseudohypoparathyroidism". Genomic Imprinting. Advances in Experimental Medicine and Biology. Vol. 626. pp. 27–40. doi:10.1007/978-0-387-77576-0_3. ISBN   978-0-387-77575-3. PMID   18372789.
  11. ↑ Shahid Hussain; Sharif Aaron Latif; Adrian Hall (1 July 2010). Rapid Review of Radiology. Manson Publishing. pp. 262–. ISBN   978-1-84076-120-7 . Retrieved 30 October 2010.
  12. ↑ Levine, Michael. "Pseudohypoparathyroidism: A Variation on the Theme of Hypoparathyroidism" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2014-11-10.

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