Aetiology
Pseudohypoparathyroidism (PHP) occurs as a result of mutations in the downstream signalling cascade of parathyroid hormone (PTH)/PTH-related peptide receptor (PTHrP1). All mutations identified to date affect GNAS, the gene coding for the guanine nucleotide-binding protein (G-protein) Gs-alpha.[11][12][13] However, the causative mutation is not known for all forms of PHP. Gs-alpha gene (positioned on chromosome 20q13.3 at the GNAS locus) transcription is affected by genomic imprinting, an epigenetic (non-DNA-sequence determined) phenomenon, leading to aberrant or inadequate expression of Gs-alpha. Imprinting of a gene allows a cell to express only one allele, most commonly maternal origin, but paternal inheritance has also been described. These parent-of-origin metabolic effects are due to preferential expression from the maternal allele in a small number of tissues.[14] Ineffective silencing or methylation of GNAS genes may also result in the findings of PHP. Tissues involved in the parent-of-origin metabolic effects of Gs-alpha mutation are not known completely. The small number of affected tissues helps to explain the unique presentation of these patients. The aetiology for obesity has been suggested to be the result of reduced energy expenditure from an imprinted Gs-alpha mutation in the paraventricular nucleus of the hypothalamus.[15] The type of PHP depends on the GNAS mutation, the imprinted tissue, and the inheritance pattern.
Type 1a is caused by heterozygous loss-of-function mutations in Gs-alpha, inherited from the mother in humans and other mammals.[16][17][18][19][20] This reduction of G-protein-coupled signalling may result in lack of function of PTH, thyroid-stimulating hormone (TSH), gonadotrophins, and growth hormone-releasing hormone. A characteristic skeletal phenotype, including short stature, stocky habitus, obesity, round face, dental hypoplasia, brachymetacarpals, brachymetatarsals, and soft-tissue calcification/ossification also results. It is referred to as Albright's hereditary osteodystrophy.
Type 1b is caused by less-severe sporadic or autosomal dominant mutations at GNAS locus, resulting in reduced expression of Gs-alpha, affecting PTH-sensitive tissues (mostly the kidney), and sometimes TSH-sensitive tissues (the thyroid gland). Other tissues are spared, so there are no morphological abnormalities.
Type 1c is typically associated with normal Gs-alpha activity and absence of GNAS mutations. However, mutations in the GNAS carboxy terminus have been detected in a subgroup of type 1c patients.[7] The phenotype of type 1c is similar to that of type 1a, with generalised hormone resistance and Albright's hereditary osteodystrophy. The cyclic adenosine monophosphate (cAMP) response is blunted in type 1c, suggesting that there is a defect in the cAMP synthesis and breakdown cycle.
Type 2 is caused by as-yet unidentified loss-of-function mutations without a mutation of the coding exons of Gs-alpha. The phenotype of type 2 is milder, with normal morphology and selective PTH resistance. The cAMP response to PTH is preserved in type 2 PHP, suggesting that the defect is located downstream of cAMP.[21]
Pseudo-pseudohypoparathyroidism is caused by the same mutations as type 1a and 1b PHP, but the mutations are inherited from the father rather than from the mother. Paternal inheritance produces no hormone resistance, but the characteristic skeletal phenotype still occurs. The reason for this is that Gs-alpha is primarily expressed from the maternal allele in the kidney. If the maternal allele has a non-functioning mutation, Gs-alpha-mediated function will be lost in the target tissues, causing PHP. However, if the paternal allele carries the mutation, Gs-alpha-mediated function will be preserved in the target tissues.[22][23][24][25] Because the tissues affected by the characteristic skeletal phenotype require both alleles to be fully functional, these abnormalities are seen in some types of PHP and in patients with pseudo-PHP.
Pathophysiology
Parathyroid hormone (PTH) is primarily involved in calcium homeostasis. It is released from the parathyroid gland when a calcium receptor perceives decreased ionised calcium. PTH liberates calcium from bone, increases intestinal calcium absorption by promoting the synthesis and activation of vitamin D, and promotes calcium reabsorption and phosphate excretion in the kidneys. Binding of PTH or PTH-related peptide (PTHrP), a protein important for growth, to its receptor is followed by a cascade of events that are mediated by G-proteins. Once the ligand binds to its receptor, the G-protein is activated and stimulates the synthesis of the second messenger, cyclic adenosine monophosphate (cAMP). Defects in cAMP signalling may result in metabolic, skeletal, or higher mental function abnormalities due to the broad distribution of this signalling system. The most common defects observed in pseudohypoparathyroidism are PTH resistance (producing hypocalcaemia), thyroid-stimulating hormone resistance (producing hypothyroidism), and the characteristic skeletal phenotype (Albright's hereditary osteodystrophy). PTH resistance results in hypocalcaemia. PTH levels become chronically elevated because the hypocalcaemia and hyperphosphataemia continue to stimulate PTH production, which in turn is unable to restore calcium levels.
Many patients have chronic asymptomatic hypocalcaemia, but symptoms of hypersensitivity of nerve and muscle, paraesthesias, twitching, anxiety, and ECG abnormalities (QT prolongation) can occur. If calcium levels are not corrected in patients with symptomatic hypocalcaemia, cardiac arrhythmia and death can occur.
PTH resistance also leads to hyperphosphataemia, which stimulates PTH secretion in an effort to lower phosphate levels. Hyperphosphataemia leads to the increased formation of calcium phosphate in extraskeletal sites. Calcium phosphate can be deposited in the kidney (causing nephrolithiasis), the brain (causing calcification of the basal ganglia), the skin (causing subdermal calcification and ossification), and the eye (causing cataracts).
The characteristic skeletal phenotype is not related to PTH sensitivity. It occurs because of the crucial role of Gs-alpha signalling in the growth, differentiation, and structure of these tissues.[Figure caption and citation for the preceding image starts]: Overview of regulation of serum calcium. The double lines and dashed line indicate the defects in PTH signalling seen in pseudohypoparathyroidism. The defect in the kidney response is more pronouncedCreated at the BMJ Evidence Centre based on author information [Citation ends].
[Figure caption and citation for the preceding image starts]: The signalling cascade of parathyroid hormoneFrom the collection of Kent Wehmeier, University of Florida Jacksonville [Citation ends].
Classification
Types of pseudohypoparathyroidism (PHP) based on clinical features, parathyroid hormone (PTH) responsiveness, and genotype[3][4][5]
Type 1a:
Caused by heterozygous loss-of-function mutations upstream or within the GNAS locus, where the 13 exon gene encodes the stimulatory guanine nucleotide-binding protein (G-protein) alpha subunit, Gs-alpha
Associated Albright's hereditary osteodystrophy
Decreased response to exogenous PTH as measured by urine cyclic adenosine monophosphate (cAMP) and urine phosphorus
Serum calcium is low
Hormone resistance is generalised, affecting hormones that rely on Gs-alpha signalling, such as PTH/PTH-related peptide (PTHrP), thyroid-stimulating hormone (TSH), gonadotrophins, and growth hormone-releasing hormone
Autosomal dominant inheritance; linked to maternal allele.
Type 1b:
Caused by mutations in GNAS resulting in disruption of imprinting control elements
Decreased Gs-alpha transcription in certain tissues where the gene transcript is derived from the maternal allele
No significant change in activity of Gs-alpha is detected
Hormone resistance is limited to PTH activity in the renal cortex
No associated skeletal phenotype
Decreased response to exogenous PTH as measured by urine cAMP and urine phosphorus
Serum calcium is low
Hormone resistance is limited to PTH target tissue; however, there are an increasing number of cases associated with TSH resistance
Inheritance may be sporadic or familial autosomal dominant.
Type 1c:
Normal Gs-alpha activity together with the absence of GNAS mutations are the hallmarks of type 1c.[6] However, two nonsense and two missense mutations in the GNAS carboxy terminus have been detected in a few type 1c patients[6][7][8]
Associated Albright's hereditary osteodystrophy
Decreased response to exogenous PTH as measured by urine cAMP and urine phosphorus
Serum calcium is low
Hormone resistance is generalised (affecting any hormone that relies on Gs-alpha signalling)
Inheritance similar to type 1a (i.e., autosomal dominant, linked to maternal allele).
Type 2:
Underlying genetic mutation is unknown
No associated skeletal phenotype
Complex response to exogenous PTH; urine phosphorus response is decreased but urine cAMP response is normal
Serum calcium is low
Hormone resistance is limited to PTH target tissue
Inheritance is unknown.
Pseudo-pseudohypoparathyroidism:
Caused by mutations in GNAS
Associated Albright's hereditary osteodystrophy
Normal response to exogenous PTH as measured by urine cAMP and urine phosphorus
Serum calcium is normal
No hormone resistance
Autosomal dominant inheritance, linked to paternal allele.
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