Defect of Receptor-Cyclase Coupling Protein in Pseudohypoparathyroidism

Farfel, Zvi; Brickman, Arnold S.; Kaslow, Harvey R.; BROTHERS, VIRGINIA M.; Bourne, Henry R.

doi:10.1097/00006254-198102000-00017

Cited by 48 publications

(77 citation statements)

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“…A defect in this protein is reported in patients with pseudohypoparathyroidism (PHP), which is characterized by reduced expression or function of the a subunit of the stimulatory G-protein (Gsa) in the action of parathyroid and other hormones that use cyclic AMP as an intracellular second messenger. A defect in the G-protein could cause multiple hormone resistance in patients with PHP [23][24][25][26][27][28]. Because of the hormonal data and cAMP response in our patients, it seems that they do not have a defect in the G-proteins.…”

Section: Discussionmentioning

confidence: 62%

Siblings with ACTH Insensitivity Due to Lack of ACTH Binding to the Receptor.

et al. 1995

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Abstract. We report two siblings, a 9-year-old boy and 4-year-old girl, with ACTH insensitivity. They were referred to our hospital because of pigmentation of the skin. They had normal plasma cortisol and urinary 17-OHCS levels despite markedly high plasma ACTH, and these did not respond to consecutive 3-day ACTH-Z administration, but plasma aldosterone responded normally to increased plasma renin activity after a low sodium diet. We examined the characteristics of ACTH receptors in peripheral blood mononuclear leukocytes (MNLs) obtained from the patients and their family. Adenylate cyclase generation caused by an addition of ACTH did not occur in MNLs from the patients.In studies on ACTH binding to MNLs, a lack of high-affinity ACTH binding was observed in the patients. These results suggest that the patients have a defect in ACTH binding to the receptors, resulting in ACTH insensitivity. The reason for this defect in ACTH binding remains unclear because no significant mutation in the ACTH receptor DNA sequence was detected in the MNLs of these patients.

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Section: Discussionmentioning

confidence: 62%

Siblings with ACTH Insensitivity Due to Lack of ACTH Binding to the Receptor.

et al. 1995

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“…The first classification system distinguished PHP variants as PHP1A, PHP1B, PHP1C and PPHP 1,2,27,29,69,132,133 . The subtype assignment is based on the presence or absence of AHO together with characterization of hormone resistance and determination of G s α protein activity using in vitro assays 132,133 .…”

Section: Evolution Of Php Classificationmentioning

confidence: 99%

“…The subtype assignment is based on the presence or absence of AHO together with characterization of hormone resistance and determination of G s α protein activity using in vitro assays 132,133 . In addition, this classification excludes phenocopies of PHP, such as acrodysostosis and POH.…”

Section: Evolution Of Php Classificationmentioning

confidence: 99%

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Mantovani¹,

Lecumberri²,

Baştepe³

et al. 2018

EJEA

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Pseu do hy popar ath yroi dism (PHP) and related disorders are associated with a spectrum of abnormal physical characteristics as well as neurocognitive and endocrine abnormalities that are caused primarily by molecular defects that impair hormonal signalling via receptors that are coupled, through the α-subunit of the stimulatory G protein (G s α), to activation of adenylyl cyclase (Fig. 1). 6,7,20,48 * Abstract | This Consensus Statement covers recommendations for the diagnosis and management of patients with pseu do hy popar ath yroi dism (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.

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“…But, in PHP type II the same test as above fails to increase serum calcium level or increase the urinary phosphate secretion whereas the cAMP urinary secretion is normal, these means the defect is distal to cAMP generation point [37,40]. In PHP Ia (OMIM #103580) and PHP Ic (OMIM #612462) the feature of AHO including short stature, rounded face, foreshortened metacarpals and metatarsals, obesity [41], stocky habitus, obesity, developmental delay, dental hypoplasia, soft tissue calcification/ossification and subcutaneous calcifications are present, but in PHP type Ib (OMIM #603233) there are not [42][43][44][45][46]. Hypocalcemic patients may have sign and symptoms of decreased ionized calcium such as tetany or seizure [47].…”

Section: Gene Rolementioning

confidence: 99%

Calcification of Soft Tissues in a Family, Case Report and Review of Pseudohypoparathyroidism

Navaeifar¹,

Zamanfar²

2017

J Rare Disord Diagn Ther

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Pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism are rare genetic disorders of calcium metabolism and resistance to the action of Parathormone. Although the genetic details of these conditions are not fully diagnosed, role of gene coding for stimulatory G protein locus was studied and imprinting in its inheritance was proved. We report three cases of a family member with calcification in soft tissues that show Pseudohypoparathyroidism in father and his sister and pseudo-pseudohypoparathyroidism in his son. history of two times seizure in the past years. The patient's paternal aunt had similar objective finding similar to patient's father but she didn't agree to involve in our assessment. The parents was non-consanguineous and the mother had not the same problems and was normal in physical examination and anthropometric evaluation. The other 3.5 year old boy of this parent had not objective specific finding. In evaluation of 33 year old father, low total calcium level (6.9 mg/dL), high phosphorus (5.5 mg/dL), normal Alkaline phosphatase (277 U/L), very high PTH (650 pg/ml), normal kidney and thyroid function tests were found. The 25-OH-Vit D was in mid-normal range and ultrasound evaluation of kidneys do not demonstrate significant pathology. The brain CT scan showed calcification of basal ganglia and cerebellum nuclei (Figure 2). KeywordsAccording to clinical and para-clinical findings, such as hypocalcemia, hyperphosphatemia, elevated PTH, shortening of metacarpus, facial sign and subcutaneous calcification, the father's disease is a classic form of PHP type I (a or c) with AHO features but without obvious other evaluated hormone resistance. Differential diagnosis for subcutaneous ossification in our target child were: dystrophic soft tissue calcification, causing chondro-calcinosis, Fibrodysplasia ossificans progressive, posttraumatic osteoma cutis, metastatic calcification, idiopathic tumoural calcinosis, scleroderma, dermatomyositis, cysticercosis, myositis ossificans and soft tissue sarcoma. These wide range of differential diagnosis from trauma to malignancy were simply narrowed when his father's observed after a simple family history taking! Multiple subcutaneous calcifications in a child when his father shows a classic form of PHP, strike PPHP in the mind because of its genetic nature. As we discuss it in the next section, in a family with history of PHP when the father is the origin of gene, its imprinting led to PPHP in child. When a child has PPHP, and the father shows PHP features, the father's type of PHP is Ia. In the absence of genetic study and evaluation of urine cAMP after synthetic PTH administration it is difficult to say our diagnosis is definite. According to European PHP network classification for PHP the father case has two major criteria and is a case of "inactivating PTH/PTHrP signaling disorder" (iPPSD) without genetic study. PathophysiologyBecause of critical function of calcium ion in much vital enzymatic process and electrical activity of neuron, muscle conducti...

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Defect of Receptor-Cyclase Coupling Protein in Pseudohypoparathyroidism

Cited by 48 publications

References 0 publications

Siblings with ACTH Insensitivity Due to Lack of ACTH Binding to the Receptor.

Siblings with ACTH Insensitivity Due to Lack of ACTH Binding to the Receptor.

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Calcification of Soft Tissues in a Family, Case Report and Review of Pseudohypoparathyroidism

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