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Annales D'endocrinologie Feb 2021Rare diseases of phosphate/calcium metabolism correspond to a wide and heterogeneous spectrum of diseases. Recent knowledge in physiology and genetics has made it... (Review)
Review
Rare diseases of phosphate/calcium metabolism correspond to a wide and heterogeneous spectrum of diseases. Recent knowledge in physiology and genetics has made it possible to better characterize them and to propose attractive therapeutic approaches based on the underlying pathophysiology. These diseases are often at the interface between nephrology and endocrinology. In this spirit of a multidisciplinary care, each specialty can bring its own critical point of view and its own specificities to improve patient care. The objective of this manuscript is to "read" with a nephrologist's point of view the main frameworks of diseases of phosphate/calcium metabolism, to illustrate the three crucial messages of nephro-protection sent to endocrinologists. First, calciuria must be interpreted both in absolute value (concentration hypercalciuria) and in ratio (flow hypercalciuria). Second, renal monitoring of therapies inducing hypercalciuria on kidneys with normal renal function (e.g. active vitamin D analogs or teriparatide) should be systematic. Last, hyperphosphatemia, often latent in hypoparathyroidism and pseudo-hypoparathyroidism, should be detected and at least benefit from dietary measures, in the context of Western diets rich in phosphate hidden in food additives.
Topics: Calcium; Calcium Metabolism Disorders; Endocrinology; Humans; Interdisciplinary Communication; Kidney; Nephrology; Patient Care Team; Phosphates; Phosphorus Metabolism Disorders; Rare Diseases
PubMed: 33316222
DOI: 10.1016/j.ando.2020.12.005 -
Journal of Bone and Mineral Research :... Mar 2022Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved...
Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth-plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone-related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)-like skeletal malformations without a clear clinical diagnosis were analyzed by whole-exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho-rhino-phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)-binding zinc-containing domain) and Ikaros-like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO-like features, and the need for a close interdisciplinary workout in these rare patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Brachydactyly; DNA-Binding Proteins; Fingers; Hair Diseases; Humans; Langer-Giedion Syndrome; Nose; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Repressor Proteins
PubMed: 34897794
DOI: 10.1002/jbmr.4490 -
Seminars in Arthritis and Rheumatism Dec 2023Ectopic calcifications (ECs) and heterotopic ossifications (HOs) form in non-mineralized tissues, most often in subcutaneous and muscular areas. Local and systemic...
INTRODUCTION
Ectopic calcifications (ECs) and heterotopic ossifications (HOs) form in non-mineralized tissues, most often in subcutaneous and muscular areas. Local and systemic complications can cause severe disability. Systemic administration of sodium thiosulfate (STS) gives promising results but is difficult to use in clinical practice.
OBJECTIVE
Evaluation of the efficacy and safety of topical STS in ECs and HOs.
METHODS
Retrospective analysis of the CATSS-O registry that included patients receiving topical STS 25 % prepared by the pharmacy of Limoges hospital during 2014-2020. The efficacy of STS was assessed by imaging (radiography or CT) after at least 6 months' treatment.
RESULTS
Among 126 patients who received STS 25 %, 35 had complete clinical and radiographic data for analysis (28 with ECs and 7 with HOs; 18 children [mean age 8.9 years, range 1.5-16], 17 adults [mean age 52.4 years, range 24-90]). Calcifications or ossifications were due to dermatomyositis (8 children, 6 adults), systemic scleroderma (6 adults) or pseudo-hypoparathyroidism 1A (7 children). They were single (37.1 %) or multiple (62.9 %). Treated regions were in the lower limbs (31.4 %), upper limbs (37.1 %) or both (28.6 %) and the axial region (2.9 %). Topical STS was clinically effective in 9/28 (32.1 %) patients with ECs and 2/7 (28.6 %) children with HOs. Three patients experienced complete disappearance of their calcifications. Response for ECs was better in children than adults (54.5% vs 17.6 %, p = 0.035). Topical STS was well tolerated.
CONCLUSION
Local STS seems effective for ossifications, particularly pediatric calcifications or ossifications. Randomized and experimental studies are needed to confirm this observation and to identify the underlying mechanisms.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Humans; Infant; Middle Aged; Young Adult; Calcinosis; Ossification, Heterotopic; Osteogenesis; Retrospective Studies
PubMed: 37976811
DOI: 10.1016/j.semarthrit.2023.152306 -
Endocrine Connections Jul 2020Hypoparathyroidism and pseudohypoparathyroidism are rare endocrine disorders, characterized by low serum calcium due to inappropriate parathyroid hormone (PTH) levels or...
Hypoparathyroidism and pseudohypoparathyroidism are rare endocrine disorders, characterized by low serum calcium due to inappropriate parathyroid hormone (PTH) levels or resistance to its action. There is little epidemiological information regarding chronic hypoparathyroidism in Russia. This study aims to build a registry database of Russian patients with chronic hypoparathyroidism who were referred for hospital treatment in order to conduct initial analysis of clinical presentations and hospital management. The Italian registry model was taken to be able to integrate our data in the future. Two hundred patients with hypoparathyroidism (n = 194) and pseudohypoparathyroidism (n = 6) were enrolled over 2 years (2017-2019). The most frequent cause of hypoparathyroidism was neck surgery (82.5%, mostly females), followed by idiopathic hypoparathyroidism (10%), syndromic forms of genetic hypoparathyroidism (4.5%) and forms of defective PTH action (3%). Calcium supplements and alfacalcidol were prescribed in most cases. However, a minority of patients (n = 6) needed to receive teriparatide as the only way to maintain calcium levels and to prevent symptoms of hypocalcemia. Consequently, substitution treatment with parathyroid hormone should be available in certain cases of hypoparathyroidism. This database will be useful to estimate the potential requirement for recombinant PTH in Russia and standards for clinical and therapeutic approaches.
PubMed: 32580149
DOI: 10.1530/EC-20-0219 -
The Journal of Pediatrics Nov 2023We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening. (Observational Study)
Observational Study
OBJECTIVE
We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening.
STUDY DESIGN
This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated.
RESULTS
We describe the body mass index trajectories of 62 children with genetic obesity (29 nonsyndromic, 33 syndromic) and 298 controls. Median AoO was 1.2 years in nonsyndromic genetic obesity (0.4 and 0.6 years in biallelic LEPR and MC4R; 1.7 in heterozygous MC4R); 2.0 years in syndromic genetic obesity (0.9, 2.3, 4.3, and 6.8 years in pseudohypoparathyroidism, Bardet-Biedl syndrome, 16p11.2del syndrome, and Temple syndrome, respectively); and 3.8 years in controls. The optimal AoO cut-off was ≤3.9 years (sensitivity, 0.83; specificity, 0.49; area under the curve, 0.79; P < .001) for nonsyndromic and ≤4.7 years (sensitivity, 0.82; specificity, 0.37; area under the curve, 0.68; P = .001) for syndromic genetic obesity.
CONCLUSIONS
Optimal AoO cut-off as single parameter to determine which children should undergo genetic testing was ≤3.9 years. In case of older AoO, additional features indicative of genetic obesity should be present to warrant genetic testing. Optimal cut-offs might differ across different races and ethnicities.
Topics: Humans; Child; Body Mass Index; Age of Onset; Obesity; Genetic Testing; Heterozygote; Receptor, Melanocortin, Type 4
PubMed: 37473986
DOI: 10.1016/j.jpeds.2023.113619 -
European Journal of Endocrinology Nov 2023Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding...
BACKGROUND
Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding protein (Gsα) resulting from maternal GNAS gene variation. The clinical manifestations are related to PTH resistance (hypocalcemia, hyperphosphatemia, and elevated serum intact PTH) in the presence or absence of multihormone resistance, and Albright's hereditary osteodystrophy (AHO).
OBJECTIVES
To summarize the molecular genetics results and clinical characteristics as well as to explore the correlations between them.
METHODS
Articles pertaining to PHP1a until May, 31, 2021 were reviewed and 527 patients with genetic diagnosis were included in the data analysis. The clinical characteristics and molecular genetics results of these patients were analyzed and compared to explore the correlations between them.
RESULTS
A total of 258 GNAS rare variants (RVs) were identified in 527 patients. The RVs were most commonly found in exons 1 and 7 (17.6% each), with frameshift (36.8%), and missense (31.3%) being the main types of RVs. The median age of onset was 5.0 years old. The most common clinical manifestations were elevation of PTH (86.7%) and AHO (87.5%). Thyroid stimulating hormone resistance was the most common hormone resistance (75.5%) other than PTH resistance. Patients with missense and in-frame RVs had lower incidence rates of the round face (P = .001) and subcutaneous ossifications (P < .001) than those with loss-of-function (non-sense, frameshift, splicing site variants, and large deletions) variants.
CONCLUSIONS
This study revealed the correlation between loss-of-function RVs with round faces and subcutaneous ossifications in PHP 1a patients. Further exploration of genotype-phenotype correlations through more standardized and prospective studies with long-term follow-up is necessary.
Topics: Humans; Child, Preschool; Prospective Studies; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; Genetic Association Studies
PubMed: 37837607
DOI: 10.1093/ejendo/lvad142 -
Acta Bio-medica : Atenei Parmensis Jun 2022Pseudohypoparathyroidism (PHP) is a rare disease, which can occur in the youth, characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid...
BACKGROUND AND AIM
Pseudohypoparathyroidism (PHP) is a rare disease, which can occur in the youth, characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid hormone (PTH) in target organs. This condition encompasses different conditions which differ between one another by different clinical, biochemically, and genetic features.
METHODS
Herein we report the clinical history of a boy with PHP1B with an interesting clinical presentation. He came in fact to the attention of the Emergency Department because of a spontaneously resolving epileptic attack, lasting about 15 minutes, characterized by loss of consciousness, fall to the ground, tonic-clonic shocks, and sphincter release. Moreover, the personal history was characterized by congenital long QT syndrome (LQTS), with a documented mutation of the KCNQ1 gene, treated with beta-blockers (nadolol).
RESULTS
The simultaneous presence of symptomatic acute hypocalcemia and long QT syndrome undoubtedly required particular attention both in the management of the onset and in the more in-depth subsequent diagnostics. In this regard, laboratory tests and molecular analyzes have proved to be crucial in the diagnostic process. Conclusions: this case underlines the diagnostic path complexity in patients with PTH elevation and the importance of considering all the possible differential diagnoses in order to undertake a timely and correct course of treatment.
Topics: Adolescent; Humans; Hyperphosphatemia; Hypocalcemia; Long QT Syndrome; Male; Parathyroid Hormone; Pseudohypoparathyroidism
PubMed: 35666115
DOI: 10.23750/abm.v93iS3.13072 -
The Journal of Clinical Investigation Apr 2023Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes...
Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes pseudohypoparathyroidism type 1B (PHP1B), a prototype of mammalian end-organ hormone resistance. Hypomethylation at the maternally methylated GNAS A/B region is the only shared defect in patients with PHP1B. In autosomal dominant (AD) PHP1B kindreds, A/B hypomethylation is associated with maternal microdeletions at either the GNAS NESP55 differentially methylated region or the STX16 gene located approximately 170 kb upstream. Functional evidence is meager regarding the causality of these microdeletions. Moreover, the mechanisms linking A/B methylation and the putative imprinting control regions (ICRs) NESP-ICR and STX16-ICR remain unknown. Here, we generated a human embryonic stem cell model of AD-PHP1B by introducing ICR deletions using CRISPR/Cas9. With this model, we showed that the NESP-ICR is required for methylation and transcriptional silencing of A/B on the maternal allele. We also found that the SXT16-ICR is a long-range enhancer of NESP55 transcription, which originates from the maternal NESP-ICR. Furthermore, we demonstrated that the STX16-ICR is an embryonic stage-specific enhancer enabled by the direct binding of pluripotency factors. Our findings uncover an essential GNAS imprinting control mechanism and advance the molecular understanding of PHP1B pathogenesis.
Topics: Animals; Humans; Darbepoetin alfa; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; DNA Methylation; Genomic Imprinting; Mammals
PubMed: 36853809
DOI: 10.1172/JCI167953 -
BMC Oral Health Dec 2019Pseudohypoparathyroidism (PHP) is a rare and inherited disease caused by mutations in the GNAS-gene or upstream of the GNAS complex locus. It is characterized by...
BACKGROUND
Pseudohypoparathyroidism (PHP) is a rare and inherited disease caused by mutations in the GNAS-gene or upstream of the GNAS complex locus. It is characterized by end-organ resistance to PTH, resulting in hypocalcemia and hyperphosphatemia. We aimed to investigate the dental anomalies according to tooth types and the orthodontic characteristics of patients with PHP.
METHODS
Using a cross-sectional design, 29 patients (23 females) with PHP, living in Denmark, were included, and their clinical intraoral photos and radiographs were examined.
RESULTS
Pulp calcification was found in 76% of the patients. Blunting of root apex was present in 55% and shortening of root in 48% of the examined patients. Blunting and shortening of roots were seen more often in premolars than in other tooth types (p < 0.01). Crowding of lower anterior teeth was frequently observed (36%) as well as diastema in the upper arch (25%), midline diastema (18%), and Class III malocclusion (11%).
CONCLUSION
In the present study population, the teeth were frequently affected by pulp calcification and/or deviation of the root morphology. Blunting and shortening of root(s) were more often seen in premolars than in other tooth types. Class III malocclusion was relatively prevalent. It is important to pay attention to dental anomalies and occlusion in order to provide adequate care for patients with PHP.
Topics: Chromogranins; Cross-Sectional Studies; Denmark; Diastema; Female; GTP-Binding Protein alpha Subunits, Gs; Humans; Male; Malocclusion; Mutation; Pseudohypoparathyroidism; Tooth Abnormalities
PubMed: 31892351
DOI: 10.1186/s12903-019-0978-z -
Experimental and Clinical Endocrinology... Feb 2021The gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. inactivation disorders are a heterogeneous group of rare disorders...
BACKGROUND
The gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright's hereditary osteodystrophy (AHO), and ectopic ossification.
METHODS
This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively.
RESULTS
Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at A/B:TSS-DMR.
CONCLUSIONS
Clinical and molecular characteristics of Korean patients with inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.
Topics: Adolescent; Child; Child, Preschool; Chromogranins; Cohort Studies; DNA Methylation; Female; GTP-Binding Protein alpha Subunits, Gs; Gene Silencing; Genetic Association Studies; Humans; Infant; Male; Mutation; Parathyroid Hormone; Phenotype; Pseudohypoparathyroidism; Republic of Korea; Retrospective Studies; Thyrotropin
PubMed: 31546270
DOI: 10.1055/a-1001-3575