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Endocrinology and Metabolism Clinics of... Dec 2018Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of uncommon, yet related metabolic disorders that are characterized by impaired activation of the... (Review)
Review
Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of uncommon, yet related metabolic disorders that are characterized by impaired activation of the Gsα/cAMP/PKA signaling pathway by parathyroid hormone (PTH) and other hormones that interact with Gsa-coupled receptors. Proximal renal tubular resistance to PTH and thus hypocalcemia and hyperphosphatemia, frequently in presence of brachydactyly, ectopic ossification, early-onset obesity, or short stature are common features of PHP. Registries and large cohorts of patients are needed to conduct clinical and genetic research, to improve the still limited knowledge regarding the underlying disease mechanisms, and allow the development of novel therapies.
Topics: Adult; Bone Diseases; Child; Drug Resistance; Humans; Parathyroid Hormone; Pseudohypoparathyroidism
PubMed: 30390819
DOI: 10.1016/j.ecl.2018.07.011 -
Nature Reviews. Endocrinology Aug 2018This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise... (Review)
Review
This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.
Topics: Consensus; Delayed Diagnosis; Drug Resistance; Female; Genetic Predisposition to Disease; Humans; Infant, Newborn; Male; Neonatal Screening; Parathyroid Hormone; Practice Guidelines as Topic; Prognosis; Program Development; Pseudohypoparathyroidism; Risk Assessment
PubMed: 29959430
DOI: 10.1038/s41574-018-0042-0 -
The Journal of Clinical Endocrinology... May 2021Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome... (Review)
Review
Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several differentially methylated regions (DMRs). GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. PHP type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal exons 1-13. Heterozygosity of these maternal GNAS mutations cause PTH-resistant hypocalcemia and hyperphosphatemia because paternal Gsα expression is suppressed in certain organs thus leading to little or no Gsα protein in the proximal renal tubules and other tissues. Besides biochemical abnormalities, PHP1A patients show developmental abnormalities, referred to as Albright's hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who carry paternal Gsα-specific mutations and typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss of methylation at the A/B DMR alone or at all maternally methylated GNAS exons. Loss of methylation of exon A/B and the resulting biallelic expression of A/B transcript reduces Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, which is the most frequent PHP1B variant. However, this disease variant remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).
Topics: Chromogranins; DNA Methylation; Epigenesis, Genetic; GTP-Binding Protein alpha Subunits, Gs; Humans; Molecular Diagnostic Techniques; Pseudohypoparathyroidism
PubMed: 33529330
DOI: 10.1210/clinem/dgab060 -
Minerva Endocrinologica Jun 2018The term pseudohypoparathyroidism (PHP) refers to a spectrum of rare disorders of mineral metabolism, characterized by features due to end-organ resistance to PTH. The... (Review)
Review
The term pseudohypoparathyroidism (PHP) refers to a spectrum of rare disorders of mineral metabolism, characterized by features due to end-organ resistance to PTH. The phenotypes of Albright hereditary osteodystrophy (AHO), originally described as associated to the disease, and progressive osseous heteroplasia, can be associated to the endocrine manifestations of hormonal resistance. Genetic or epigenetic alterations in the complex imprinted GNAS locus, encoding the alpha-subunit of the stimulatory G protein (GSα) and several other transcripts, give rise to the different forms oh PHP, which can be differentiated according to the phenotype, the response to PTH infusion and in vitro assays testing Gsα activity. Since PHP-related phenotypes are overlapping and other non GNAS-dependent disorders mimicking AHO, such as acrodysostosis, have been genetically characterized, the term PHP is today considered obsolete and better referred to the more comprehensive "inactivating PTH/PTHrP signaling disorder (iPPSD)" as proposed in a recent classification. This broad term include all the congenital rare disorders due to impaired PTH/PTHrP cAMP pathway. Genetic and epigenetic analyses, although not necessary for diagnosis made on the basis of major and minor criteria according to clinical and biochemical signs, will let to differentiate among the different forms for proper therapeutic planning, counseling and follow-up.
Topics: Humans; Hypocalcemia; Parathyroid Hormone; Pseudohypoparathyroidism
PubMed: 29125274
DOI: 10.23736/S0391-1977.17.02768-7 -
Current Opinion in Pediatrics Aug 2019This review is timely given the 2018 publication of the first international Consensus Statement for the diagnosis and management of pseudohypoparathyroidism (PHP) and... (Review)
Review
PURPOSE OF REVIEW
This review is timely given the 2018 publication of the first international Consensus Statement for the diagnosis and management of pseudohypoparathyroidism (PHP) and related disorders. The purpose of this review is to provide the knowledge needed to recognize and manage PHP1A, pseudopseudohypoparathyroidism (PPHP) and PHP1B - the most common of the subtypes - with an overview of the entire spectrum and to provide a concise summary of management for clinical use. This review will draw from recent literature as well as personal experience in evaluating hundreds of children and adults with PHP.
RECENT FINDINGS
Progress is continually being made in understanding the mechanisms underlying the PHP spectrum. Every year, through clinical and laboratory studies, the phenotypes are elucidated in more detail, as are clinical issues such as short stature, brachydactyly, subcutaneous ossifications, cognitive/behavioural impairments, obesity and metabolic disturbances. Headed by a European PHP consortium, experts worldwide published the first international Consensus that provides detailed guidance in a systematic manner and will lead to exponential progress in understanding and managing these disorders.
SUMMARY
As more knowledge is gained from clinical and laboratory investigations, the mechanisms underlying the abnormalities associated with PHP are being uncovered as are improvements in management.
Topics: Adult; Animals; Child; Child, Preschool; Chromogranins; Female; GTP-Binding Protein alpha Subunits, Gs; Growth Hormone; Humans; Infant; Male; Mice; Obesity; Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism
PubMed: 31145125
DOI: 10.1097/MOP.0000000000000783 -
Annual Review of Medicine 1983Pseudohypoparathyroidism includes a genotypically diverse group of syndromes of primary resistance to hormones whose actions are mediated by cyclic adenosine... (Review)
Review
Pseudohypoparathyroidism includes a genotypically diverse group of syndromes of primary resistance to hormones whose actions are mediated by cyclic adenosine 3':5'-monophosphate. In most cases, clinical presentation results from resistance to actions of parathyroid hormone, while resistance to other hormones remains subclinical. The largest subgroup of patients with this disorder, characterized by a typical somatic phenotype termed Albright's hereditary osteodystrophy, exhibits generalized deficient activity of a membrane protein that couples hormone receptors to stimulation of adenylate cyclase. Phenotypic expression of the disease varies greatly between families, within families, and even during the clinical course of individual patients. Genetic transmission occurs via several distinct loci, which produce different patterns of inheritance.
Topics: Humans; Hypothyroidism; Parathyroid Hormone; Phenotype; Pseudohypoparathyroidism; Thyrotropin; Vitamin D
PubMed: 6344759
DOI: 10.1146/annurev.me.34.020183.001355 -
Annales D'endocrinologie May 2015The term pseudohypoparathryoidism (PHP) refers to a group of rare genetic and epigenetic disorders characterized by resistance to the action of parathyroid hormone (PTH)... (Review)
Review
The term pseudohypoparathryoidism (PHP) refers to a group of rare genetic and epigenetic disorders characterized by resistance to the action of parathyroid hormone (PTH) that activates cAMP signaling in target cells. Together with pseudohypoparathyroidism, Albright hereditary osteodystrophy (AHO) and progressive osseous heteroplasia (POH) represent rare, related and deeply impairing disorders encompassing heterogeneous features, such as brachydactyly, ectopic ossifications, short stature, mental retardation and endocrine deficiencies due to resistance to the action of different hormones. The two main subtypes, PHP-Ia and PHP-Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster respectively, while mutations in the PRKAR1A and PDE4D genes (also involved in mediating cAMP signalling) have been demonstrated in patients with acrodysostosis, a disease of bone formation with characteristics similar to AHO. The molecular overlap among these disorders indicates the need for different classification models and seriously alters our understanding of the mechanisms through which GNAS defects, together with the new recently described defects involving other components of the cAMP signalling cascade, cause AHO-related disorders.
Topics: Chromogranins; Disease Progression; GTP-Binding Protein alpha Subunits, Gs; Humans; Pseudohypoparathyroidism; Receptor, Parathyroid Hormone, Type 1
PubMed: 25910998
DOI: 10.1016/j.ando.2015.03.028 -
Endocrine Jun 2021Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the α subunit of the stimulatory G protein... (Review)
Review
Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key component of the PTH/PTHrP signaling pathway. Since its first description, different studies unveiled, beside the molecular basis for PHP, the existence of different subtypes and of diseases in differential diagnosis associated with genetic alterations in other genes of the PTH/PTHrP pathway. The clinical and molecular overlap among PHP subtypes and with different but related disorders make both differential diagnosis and genetic counseling challenging. Recently, a proposal to group all these conditions under the novel term "inactivating PTH/PTHrP signaling disorders (iPPSD)" was promoted and, soon afterwards, the first international consensus statement on the diagnosis and management of these disorders has been published. This review will focus on the major and minor features characterizing PHP/iPPSDs as a group and on the specificities as well as the overlap associated with the most frequent subtypes.
Topics: Bone Diseases, Metabolic; Dysostoses; Humans; Intellectual Disability; Ossification, Heterotopic; Osteochondrodysplasias; Parathyroid Hormone; Pseudohypoparathyroidism; Skin Diseases, Genetic
PubMed: 33179219
DOI: 10.1007/s12020-020-02533-9 -
Acta Paediatrica Japonica : Overseas... Aug 1997Hypoparathyroidism is a clinical disorder characterized by hypocalcemia and hyperphosphatemia in the absence of renal failure and hypomagnesemia. The causes of... (Review)
Review
Hypoparathyroidism is a clinical disorder characterized by hypocalcemia and hyperphosphatemia in the absence of renal failure and hypomagnesemia. The causes of hypoparathyroidism can be classified as two groups: (i) insufficient parathyroid hormone (PTH) secretion in relation to the serum calcium level (hypoparathyroidism); and (ii) impaired PTH action (pseudohypoparathyroidism). The main emphasis in this report is to distinguish subgroups based on the etiology and pathophysiology of the various aspects of the disease.
Topics: Diagnosis, Differential; Humans; Hypoparathyroidism; Parathyroid Hormone; Pseudohypoparathyroidism; Receptors, Parathyroid Hormone
PubMed: 9316298
DOI: 10.1111/j.1442-200x.1997.tb03625.x -
The American Journal of the Medical... Aug 1989Following a brief discussion of the diagnosis and classification of hypoparathyroidism, this review will focus on current concepts of pseudohypoparathyroidism. Topics to... (Review)
Review
Following a brief discussion of the diagnosis and classification of hypoparathyroidism, this review will focus on current concepts of pseudohypoparathyroidism. Topics to be covered will include differing resistance of kidney and bone to parathyroid hormone, relationship of estrogen and pregnancy to Ca homeostasis, normocalcemic pseudohypoparathyroidism, and current understanding of pathogenesis based on various defects in the hormone receptor-adenylate cyclase system. Evidence for physiologic derangements beyond the impaired generation of cyclic AMP will be reviewed, as well as involvement of nonendocrine systems by the deficiency of the stimulatory guanine nucleotide connecting protein. Finally, semantic confusion resulting from the faulty term "pseudopseudohypoparathyroidism" will be addressed.
Topics: Female; Humans; Male; Pregnancy; Pregnancy Complications; Pseudohypoparathyroidism
PubMed: 2669477
DOI: 10.1097/00000441-198908000-00011