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Subcutaneous ossifications in patients with PHP1A or POH. All patients presented carry a loss-of-function mutation at the coding sequence of the GNAS gene. (A-C) Different features of subcutaneous ossifications in infants; note the red/purple color of the lesions. (D-F) Subcutaneous ossifications in children and adolescents. Small lesions become more pale. (G, H) Organized painful ossification below the heel; surgical excision was performed and the ossification did not recur. (I) Severe extended ossification of the foot and ankle, one part is extruding white material. (J) Painful ossification surrounding the metatarsal joint of the second toe.
Source publication
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 h...
Contexts in source publication
Context 1
... of ectopic membranous bone, most commonly in the dermis and subcutaneous fat. They may present as small and asymptomatic nodules or as large, coalescent plaques of bone that evolve deeply into muscles and around joints. Subcutaneous ossifications preferentially affect the periarticular areas of the hands and feet and the feet plantar region 53 (Fig. 1). There is no evidence that environmental factors such as trauma or inflammation affect their progression. Some lesions occasionally extrude a chalky material. 6,48,53 Ectopic ossi- fications have been reported only so far in patients who have PHP1A or PPHP due to inactivating mutations involving GNAS exon 1 to 13 and are not observed ...
Context 2
... of ectopic membranous bone, most commonly in the dermis and subcutaneous fat. They may present as small and asymptomatic nodules or as large, coalescent plaques of bone that evolve deeply into muscles and around joints. Subcutaneous ossifications preferentially affect the periarticular areas of the hands and feet and the feet plantar region 53 (Fig. 1). There is no evidence that environmental factors such as trauma or inflammation affect their progression. Some lesions occasionally extrude a chalky material. 6,48,53 Ectopic ossifications have been reported only so far in patients who have PHP1A or PPHP due to inactivating mutations involving GNAS exon 1 to 13 and are not observed in ...
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Introduction:
Pseudohypoparathyroidism (PHP) indicates a group of rare disorders characterized by end-organ resistance to various hormones, primarily parathyroid hormone (PTH). One of its most common type is PHP-Ia, which is caused by maternally inherited inactivating mutations in GNAS. In this report, we present a Chinese girl with typical featur...
Basal ganglia calcification (BGC) can be seen up to 20% of the general population, with most cases being asymptomatic. Some have been reported to be associated with diseases of the endocrine system or neurological disorders. The underlying causes of calcium deposition in these conditions are not well understood. This case report describes a 26-year...
Citations
... In some cases, resistance to other hormones such as thyroid-stimulating hormone (TSH), growth hormone-releasing hormone (GHRH), and folliclestimulating hormone (FSH)/luteinizing hormone (LH) may also occur. 3,4 another hospital 4 years ago because of facial and limb convulsions. At that time, the following parameters were measured: calcium, 1.43 (2.11-2.52) ...
Pseudohypoparathyroidism (PHP) is a rare genetic disease characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) in serum. Here, we report a case of a patient with pseudohypoparathyroidism type IB (PHPIB) and subclinical hypothyroidism, analyze the clinical and genetic data of his family members, review the relevant literature, and classify and discuss the pathogenesis and clinical characteristics of each subtype. Finally, we discuss the treatment approach to improve clinicians’ understanding of the disease.
... Patients with PHP1A and PHP1C show variable expression of phenotypic features of AHO [2,5]. In PHP1B, patients typically manifest no evidence of AHO but show exclusive hormonal resistance to PTH and TSH [6]. In a subgroup of patients with PHP and various features of AHO, epigenetic mutations of GNAS similar to those classically detected in PHP1B patients were identified, suggesting a genetic overlie between PHP1A and PHP1B [7][8][9][10][11]. ...
Background
Pseudohypoparathyroidism (PHP) is caused by loss-of-function mutations at the GNAS gene (as in the PHP type 1A; PHP1A), de novo or inherited at heterozygous state, or by epigenetic alterations at the GNAS locus (as in the PHP1B). The condition of PHP refers to a heterogeneous group of disorders that share common clinical and biological features of PTH resistance. Manifestations related to resistance to other hormones are also reported in many patients with PHP, in association with the phenotypic picture of Albright hereditary osteodystrophy characterized by short stature, round facies, subcutaneous ossifications, brachydactyly, mental retardation and, in some subtypes, obesity. The purpose of our study is to report a new mutation in the GNAS gene and to describe the significant phenotypic variability of three sisters with PHP1A bearing the same mutation.
Case presentation
We describe the cases of three sisters with PHP1A bearing the same mutation but characterized by a significantly different phenotypic picture at onset and during follow-up in terms of clinical features, auxological pattern and biochemical changes. Clinical exome sequencing revealed a never before described heterozygote mutation in the GNAS gene (NM_000516.5 c.118_139 + 51del) of autosomal dominant maternal transmission in the three siblings, confirming the diagnosis of PHP1A.
Conclusions
This study reported on a novel mutation of GNAS gene and highlighted the clinical heterogeneity of PHP1A characterized by wide genotype–phenotype variability. The appropriate diagnosis has crucial implications for patient care and long-term multidisciplinary follow-up.
... This condition involves excessive testicular stimulation by LH and FSH, resulting in precocious puberty and virilization in males (70,71). PHP Ia subtype is identified by sluggish urinary cAMP and phosphate excretion in response to exogenous PTH administration (72). Since PTH inhibits phosphate reabsorption and induces 25dihydroxy vitamin D 1-a-hydroxylase (Cyp27b1) mRNA expression through the cAMP-dependent cellular mechanism, patients may develop not only hyperphosphatemia but also hypocalcemia. ...
GNAS is a complex locus characterized by multiple transcripts and an imprinting effect. It orchestrates a variety of physiological processes via numerous signaling pathways. Human diseases associated with the GNAS gene encompass fibrous dysplasia (FD), Albright’s Hereditary Osteodystrophy (AHO), parathyroid hormone(PTH) resistance, and Progressive Osseous Heteroplasia (POH), among others. To facilitate the study of the GNAS locus and its associated diseases, researchers have developed a range of mouse models. In this review, we will systematically explore the GNAS locus, its related signaling pathways, the bone diseases associated with it, and the mouse models pertinent to these bone diseases.
... Pseudohypoparathyroidism 1A (PHP1A) is caused by inactivating variants involving the maternal allele of the GNAS gene encoding Gsα, the alpha-subunit of the stimulatory G protein. 2,3 Pseudohypoparathyroidism 1A belongs to a large group of rare diseases that share common clinical features such as brachydactyly and end-organ resistance to PTH because of impaired signaling downstream of the PTH1R and other G protein-coupled receptors (GPCRs). The molecular defects causing these disorders all affect the PTH/ PTHrP-signaling pathway, which involves Gsα, cAMP, and protein kinase A (PKA), and is necessary for the actions of other hormones, such as thyroid-stimulating hormone (TSH), growth hormone-releasing hormone (GHRH), gonadotropins, and calcitonin. ...
... The molecular defects causing these disorders all affect the PTH/ PTHrP-signaling pathway, which involves Gsα, cAMP, and protein kinase A (PKA), and is necessary for the actions of other hormones, such as thyroid-stimulating hormone (TSH), growth hormone-releasing hormone (GHRH), gonadotropins, and calcitonin. 2,[4][5][6][7][8][9][10][11] Because of the clinical and molecular overlap of these diseases, a novel disease classification has been established under the term "inactivating PTH/PTHrP-signaling disorder" (iPPSD) based on the common impaired signaling of the PTH/ PTHrP receptor; the advantages and limitations, including the impaired signaling downstream of other GPCRs, of this classification have been described. 12 iPPSD2mat refers to patients bearing loss-of-function mutations in the GNAS gene, 11,12 and we will refer to this patient group as iPPSD2/PHP1A. ...
... A progressive decline of height velocity and an adult height below −2 standard deviation scores (SDS) in individuals with iPPSD2/PHP1A have been previously reported, mostly as published series of cases. 2,9,11,13,14 Few observational studies have been conducted using larger cohorts. [15][16][17] Our research group published in 2018 the progression of height and body mass index (BMI) in the largest cohort investigated up to that point, showing that more than half of iPPSD2/PHP1A individuals present with short stature and early-onset obesity. ...
Background:
Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating PTH/PTHrP signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height.
Objectives:
Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls.
Methods:
We included 190 patients; 26 received rhGH. Height, weight, body mass index (BMI) at various time-points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models.
Results:
Adult height was available for 11/26 of rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 SDS after one year (CI +0.5 to +0.8, p<0.001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, p<0.001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared to untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, p<0.001). BMI SDS did not vary significantly upon rhGH therapy.
Conclusion:
rhGH treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety.
... Albright hereditary osteodystrophy (AHO) is a disorder caused by heterozygous inactivation of GNAS, which encodes the α-subunit of the stimulatory G protein (Gα s ) and couples heptahelical receptors to stimulate adenylyl cyclase [1][2][3][4][5][6][7]. AHO is classically associated with a constellation of skeletal manifestations that include shortened adult stature, brachydactyly, brachymetacarpia, and the formation of subcutaneous ossifications [8], for review [1-5, 7, 9, 10]. ...
... In addition, both PHP1A and PPHP patients have rapidly advancing bone ages and lack of pubertal growth spurts secondary to early epiphyseal fusion due to premature chondrocyte differentiation [1,3,4,9,17,62,63]. It is hypothesized that the biallelic expression of GNAS in chondrocytes leads to this occurrence in both PHP1A and PPHP patients [4,[64][65][66][67]. ...
... Our investigations of the SOS in one-week and two-week-old WT and Gnas E1+/-mice revealed accelerated proliferative chondrocyte differentiation as the cause of premature closure of the SOS. This correlates with clinical findings in AHO patients of rapidly advancing bone ages and premature chondrocyte differentiation at the epiphyses, especially of the hand/wrist [1,3,4,9,17,[64][65][66]. Given these findings clinically and in our mouse model of the premature closure of the SOS, our data suggest that this premature fusion may play a role in the cranial abnormalities observed in PHP1A. ...
Background:
Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with multi-hormone resistance and aberrant craniofacial and skeletal development among other abnormalities. Chiari malformation type 1 (CM1), a condition in which brain tissue extends into the spinal canal when the skull is too small, has been reported in isolated cases of PHP1A. It has been hypothesized to be associated with growth hormone (GH) deficiency. Given the adverse clinical sequelae that can occur if CM1 goes unrecognized, we investigated the previously undetermined prevalence of CM1, as well as any potential correlations with GH status, given the known increased prevalence of GH deficiency in PHP1A. We also investigated these metrics for low lying cerebellar tonsils (LLCT), defined as tonsillar descent less than 5 mm below the foramen magnum. In addition, we investigated possible correlations of CM1/LLCT with advanced hand/wrist bone ages and craniofacial abnormalities known to occur in PHP1A to determine whether premature chondrocyte differentiation and/or aberrant craniofacial development could be potential etiologies of CM1/LLCT through both human studies and investigations of our AHO mouse model.
Methods:
We examined patients with PHP1A in our clinic and noticed CM1 more frequently than expected. Therefore, we set out to determine the true prevalence of CM1 and LLCT in a cohort of 54 mutation-confirmed PHP1A participants who had clinically-indicated brain imaging. We examined potential correlations with GH status, clinical features, biological sex, genotype, and hand/wrist bone age determinations. In addition, we investigated the craniofacial development in our mouse model of AHO (Gnas E1+/-m) by histologic analyses, dynamic histomorphometry, and micro-computerized tomographic imaging (MCT) in order to determine potential etiologies of CM1/LLCT in PHP1A.
Results:
In our cohort of PHP1A, the prevalence of CM1 is 10.8%, which is at least 10-fold higher than in the general population. If LLCT is included, the prevalence increases to 21.7%. We found no correlation with GH status, biological sex, genotype, or hand/wrist bone age. Through investigations of our Gnas E1+/-m mice, the correlate to PHP1A, we identified a smaller cranial vault and increased cranial dome angle with evidence of hyperostosis due to increased osteogenesis. We also demonstrated that there was premature closure of the spheno-occipital synchondrosis (SOS), a cartilaginous structure essential to the development of the cranial base. These findings lead to craniofacial abnormalities and could contribute to CM1 and LLCT development in PHP1A.
Conclusion:
The prevalence of CM1 is at least 10-fold higher in PHP1A compared to the general population and 20-fold higher when including LLCT. This is independent of the GH deficiency that is found in approximately two-thirds of patients with PHP1A. In light of potential serious consequences of CM1, clinicians should have a low threshold for brain imaging. Investigations of our AHO mouse model revealed aberrant cranial formation including a smaller cranium, increased cranial dome angle, hyperostosis, and premature SOS closure rates, providing a potential etiology for the increased prevalence of CM1 and LLCT in PHP1A.
... Pacientai, sergantys PHP, pasižymi neįprastais kūno bruožais: žemas ūgis, nutukimas, apvalus veidas, brachidaktilija, heterotopinė (poodinė) osifikacija. Gali būti rečiau pasitaikančių simptomų: sulėtėjęs vaisiaus augimas, metabolinis sindromas, miego apnėja, kognityviniai sutrikimai, astma, dantų būklės pokyčiai (dantų emalio defektai, trumpesnės šaknys, hipodontija ar oligodontija, dantų dygymo sutrikimai, ankilozės), kaukolės, skeleto ir neurologinės anomalijos (makrocefalija, kraniosinostozė, akrodizostozė, riešo tunelinis sindromas, stuburo kanalo stenozė, klausos sutrikimai) [1,2,6,7,8]. PHP sergančių vaikų intelekto koeficientas yra mažesnis, vėluoja adaptyvaus elgesio įgūdžiai, dažniau kyla elgesio problemų [2,9]. ...
... PHP sergančių vaikų intelekto koeficientas yra mažesnis, vėluoja adaptyvaus elgesio įgūdžiai, dažniau kyla elgesio problemų [2,9]. Būdingas atsparumas įvairiems hormonams: TSH, kalcitoninui, gonadotropinui, LH, FSH, GHRH, IGF-1, IGFB-3, epinefrinui, gliukagonui [1][2][3]6,10]. ...
... Biocheminiuose tyrimuose randama hipokalcemija (kliniškai pasireiškia parestezijomis, mėšlungiu, tetanija, hiperrefleksija), hiperfosfatemija, padidėjęs PTH (parathormono) kiekis, hiperfosfatemija [5,6]. Padidėjęs TSH kiekis gali būti nustatytas jau visuotiniame naujagimių tikrinimo dėl įgimtų medžiagų apykaitos ligų tyrime, tačiau tai gali būti klaidingai diagnozuota kaip įgimtas hipotiroidizmas. ...
Tyrimo tikslas. Apžvelgti naujausius mokslinės literatūros duomenis ir aptarti pseudohipoparatiroidizmo diagnostiką ir gydymą vaikų amžiuje. PHP diagnostika remiasi pagrindiniais kriterijais: atsparumu PTH, ektopine osifikacija, brachidaktilija, ankstyvu nutukimu. Galimas genetinis ištyrimas. Pacientai turėtų būti tikrinami dėl TSH atsparumo, augimo hormono nepakankamumo, hipogonadizmo, skeleto deformacijų, dantų būklės, svorio priaugio, gliukozės tolerancijos sutrikimo ar 2 tipo CD, hipertenzijos ir neurokognityvinių sutrikimų. Pagrindiniai PHP gydymo tikslai yra palaikyti normalią kalcio, fosforo koncentraciją, išvengti hiperkalciurijos, sunormalizuoti PTH koncentraciją.
... Pseudohypoparathyroidism type 1A (PHP1A) is a rare inheritable disease characterized by Albright's hereditary osteodystrophy (AHO) and hormonal resistance, including PTH, TSH, gonadotropins, calcitonin, growth hormone-releasing hormone, and possibly others (Linglart et al., 2018). PHP1A is caused by loss-of-function variants in the imprinted GNAS, which encodes Gsα, in the maternal allele (Spiegel, 1990). ...
Pseudohypoparathyroidism 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by loss-of-function variants of GNAS, which encodes Gsα. We present two unrelated Japanese families with PHP1A and PPHP harboring unreported pathogenic variants of GNAS (c.1141delG, p.Asp381Thrfs*23 and c.1117delC, p.Arg373Alafs*31). These variants introduce abnormal amino acids in the β6 strand/α5 helix of Gsα, which interact with G protein coupling receptor (GPCR). We conclude that these variants alter the association of Gsα with GPCR and cause PHP1A or PPHP.
... The GNAS gene encode the Gsα-part of the PTH receptor, resulting in PTH resistance. The defect G protein receptor does not only affect PTH, as Gsα deficiency in mesenchymal stem cells leads to de novo differentiation of osteoblasts in soft tissue, thereby causing ossifications [35]. Accordingly, patients with PHP may have a high occurrence of ossifications which may be misinterpreted as vascular calcifications when evaluating findings on HR-pQCT scans. ...
Hypoparathyroidism (HypoPT) and pseudohypoparathyroidism (PHP) are diseases with abnormal calcium and phosphate homeostasis and low and high PTH levels, respectively. It has been hypothesized that this could dispose to vascular calcifications and thereby perhaps also cardiovascular morbidity. The aim of this study was to assess lower leg arterial calcifications (LLAC) in patients with HypoPT or PHP. Using a cross-sectional design, we measured the LLAC using a high-resolution peripheral quantitative computed tomography (HR-pQCT) scanner in 72 patients with HypoPT and 25 patients with PHP and compared them with findings in 61 controls. LLAC were found in only two (3%) of the controls. Compared to the controls, LLAC were significantly more prevalent in patients with HypoPT (N = 12, [17%], p < 0.01) and PHP (N = 4, [16%], p < 0.04). Compared to the patients without calcifications, patients with calcifications had higher plasma calcium levels and a lower eGFR, as well as they were older and more often males. Plasma phosphate levels and the calcium-phosphate product were not associated with LLAC. In conclusion, we found that HypoPT and PHP are associated with an increased prevalence of vascular calcifications.
... With regard to Sneezy's extraordinary bouts of sneezing, it is of interest that increased prevalence of asthma and allergies are observed in patients with PHP1A (59). Finally, these patients may be hyporesponsive to the biologic effects of other peptide hormones that use Gsα to enhance cAMP production (60). Hypogonadism due to resistance to the action of gonadotropins is highly variable and has been poorly investigated, although it appears to be a compatible diagnosis with the absence of beard, as seen in Dopey. ...
'Snow White and the Seven Dwarfs', a fairytale that is widely known across the Western world, was originally written by the Brothers Grimm, and published in 1812. Though each dwarf was first given an individual name in the 1912 Broadway play by the same title, in Walt Disney's 1937 film 'Snow White and the Seven Dwarfs', they were renamed, and their names have become household words. As it is well known, myths, fables, and fairytales, though appearing to be merely children’s tales about made-up and magical beings and places, have, more often than not, originated from real facts. Therefore, the presence in the story of seven brothers with short stature is, from an endocrinological point of view, highly intriguing, in fact, thrilling. The diversity of the phenotypes among the seven dwarfs is also stimulating , although puzzling. We undertook a differential diagnosis of their common underlying disorder based on the original Disney production drawings and the unique characteristics of these little gentlemen, while we additionally evaluated several causes of short stature and, focusing on endocrine disorders that could lead to these clinical features among siblings, and we have, we believe, been able to reveal the underlying disease depicted in this archetypal tale.
... The POH mouse model used in our current study formed subcutaneous HO through either local subcutaneous inactivation of Gnas or through global/systemic inactivation, suggesting that the HO may be more dependent on local effects of Gnas inactivation. However, we note that POH is classified among the pseudohypoparathyroidism (PHP) disorders, caused by deficiencies in Gnas/Gsα and/or downstream signaling effectors, some of which are accompanied by resistance to PTH and/or other hormones and by altered serum biochemistries (Linglart et al., 2018;Mantovani and Elli, 2018). Although endocrine abnormalities have not been associated with POH (Adegbite et al., 2008;Linglart et al., 2018), the POH mouse model provides an opportunity to more closely investigate whether changes in endocrine function accompany the progressive formation of HO and this will be examined in future studies. ...
... However, we note that POH is classified among the pseudohypoparathyroidism (PHP) disorders, caused by deficiencies in Gnas/Gsα and/or downstream signaling effectors, some of which are accompanied by resistance to PTH and/or other hormones and by altered serum biochemistries (Linglart et al., 2018;Mantovani and Elli, 2018). Although endocrine abnormalities have not been associated with POH (Adegbite et al., 2008;Linglart et al., 2018), the POH mouse model provides an opportunity to more closely investigate whether changes in endocrine function accompany the progressive formation of HO and this will be examined in future studies. ...
Heterotopic ossification (HO), the formation of bone outside of the skeleton, occurs in response to severe trauma and in rare genetic diseases such as progressive osseous heteroplasia (POH). In POH, which is caused by inactivation of GNAS, a gene that encodes the alpha stimulatory subunit of G proteins (Gsα), HO typically initiates within subcutaneous soft tissues before progressing to deeper connective tissues. To mimic POH, we used conditional Gnas-null mice which form HO in subcutaneous tissues upon Gnas inactivation. In response to Gnas inactivation, we determined that prior to detection of heterotopic bone, dermal adipose tissue changed dramatically, with progressively decreased adipose tissue volume and increased density of extracellular matrix over time. Upon depletion of the adipose tissue, heterotopic bone progressively formed in those locations. To investigate the potential relevance of the tissue microenvironment for HO formation, we implanted Gnas-null or control mesenchymal progenitor cells into Gnas-null or control host subcutaneous tissues. We found that mutant cells in a Gnas-null tissue environment induced a robust HO response while little/no HO was detected in control hosts. Additionally, a Gnas-null tissue environment appeared to support the recruitment of control cells to heterotopic bone, although control cell implants were associated with less HO formation compared to mutant cells. Our data support that Gnas inactivation alters the tissue microenvironment to influence mutant and wild-type progenitor cells to contribute to HO formation.
