Publications by authors named "Agnes Linglart"

127 Publications

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.

J Exp Med 2021 07;218(7)

Pediatric Medicine Unit, University Hospital of Besançon, Besançon, France.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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http://dx.doi.org/10.1084/jem.20210554DOI Listing
July 2021

Perception of medical education by learners and teachers during the COVID-19 pandemic: a cross-sectional survey of online teaching.

Med Educ Online 2021 Dec;26(1):1919042

Université de Paris, UFR Médecine Santé, 75006, Paris, France.

COVID-19 lockdowns have deeply impacted teaching programs. Online teaching has suddenly become the main form of medical education, a form that may be used as long as the pandemic continues. We aimed at analyzing how online teaching was perceived by both teachers and learners to help determine how to adapt curricula in the next few years. An anonymous cross-sectional survey of medical students, pediatric residents, neonatal fellows, and their respective teachers was conducted between June and August 2020 to assess feelings about quality, attendance, equivalence, and sustainability of online teaching programs. 146 Students and 26 teachers completed the survey. 89% of students agreed that the offered online teaching was an appropriate way of teaching during the pandemic. Less than half of learners and teachers felt they have received or provided a training of an equivalent level and quality as in usual courses. About one-third thought that this online teaching should continue after the crisis ends. Medical school students had significantly more mixed opinions on online teaching than residents and fellows did. Attendance of learners significantly improved with synchronous online classes (p < 0.001), and among more advanced learners (p < 0.002). Our study is the first of this kind to assess simultaneously the feelings of learners at different levels (medical students, residents, and fellows) and their respective teachers of pediatric on programs taught online. It showed that online programs were perceived as appropriate ways of teaching during the COVID pandemic. Further studies are, however, needed to assess the efficacy of such teaching methods on medical skills and communication capabilities.
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http://dx.doi.org/10.1080/10872981.2021.1919042DOI Listing
December 2021

Impact of Early Conventional Treatment on Adult Bone and Joints in a Murine Model of X-Linked Hypophosphatemia.

Front Cell Dev Biol 2020 18;8:591417. Epub 2021 Feb 18.

Université de Paris, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP 2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France.

X-linked hypophosphatemia (XLH) is the most common form of genetic rickets. Mainly diagnosed during childhood because of growth retardation and deformities of the lower limbs, the disease affects adults with early enthesopathies and joint structural damage that significantly alter patient quality of life. The conventional treatment, based on phosphorus supplementation and active vitamin D analogs, is commonly administered from early childhood to the end of growth; unfortunately, it does not allow complete recovery from skeletal damage. Despite adequate treatment during childhood, bone and joint complications occur in adults and become a dominant feature in the natural history of the disease. Our previous data showed that the mouse is a relevant model of XLH for studying early enthesophytes and joint structural damage. Here, we studied the effect of conventional treatment on the development of bone and joint alterations in this mouse model during growth and young adulthood. Mice were supplemented with oral phosphorus and calcitriol injections, following two timelines: (i) from weaning to 3 months of age and (ii) from 2 to 3 months to evaluate the effects of treatment on the development of early enthesophytes and joint alterations, and on changes in bone and joint deformities already present, respectively. We showed that early conventional treatment improved bone microarchitecture, and partially prevented bone and joint complications, but with no noticeable improvement in enthesophytes. In contrast, later administration had limited efficacy in ameliorating bone and joint alterations. Despite the improvement in bone microarchitecture, the conventional treatment, early or late, had no effect on osteoid accumulation. Our data underline the usefulness of the murine model for preclinical studies on skeletal and extraskeletal lesions. Although the early conventional treatment is important for the improvement of bone microarchitecture, the persistence of osteomalacia implies seeking new therapeutic strategies, in particular anti-FGF23 approach, in order to optimize the treatment of XLH.
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http://dx.doi.org/10.3389/fcell.2020.591417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930336PMC
February 2021

A novel familial PHP1B variant with incomplete loss-of-methylation at GNAS-A/B and enhanced methylation at GNAS-AS2.

J Clin Endocrinol Metab 2021 Mar 2. Epub 2021 Mar 2.

Université Paris-Saclay, Inserm, Physiologie et physiopathologie endocrinienne, Le Kremlin-Bicêtre, France.

Context: Pseudohypoparathyroidism type 1B (PHP1B), also referred to as inactivating PTH/PTHrP Signaling Disorder (iPPSD), is characterized by proximal renal tubular resistance to parathyroid hormone (PTH) leading to hypocalcemia, hyperphosphatemia and elevated PTH values. Autosomal dominant PHP1B (AD-PHP1B) with loss-of-methylation at the maternal GNAS A/B:TSS-DMR (transcription start site-differentially methylated region) alone can be caused by maternal deletions involving STX16.

Objectives: Characterize a previously not reported AD-PHP1B family with loss-of-methylation at GNAS A/B:TSS-DMR, but without evidence for a STX16 deletion on the maternal allele and assess GNAS-AS2:TSS-DMR methylation.

Patients And Methods: DNAs from 24 patients and 10 controls were investigated. AD-PHP1B patients without STX16 deletion from a single family (n=3), AD-PHP1B patients with STX16 deletion (n=9), sporPHP1B (n=10), unaffected controls (n=10), patUPD20 (n=1), and matUPD20 (n=1). Methylation and copy number analyses were performed by pyrosequencing, MS-MPLA, and MLPA, respectively.

Results: Molecular cloning of PCR-amplified, bisulfite-treated genomic DNA from healthy controls revealed evidence for two distinct GNAS-AS2:TSS-DMR subdomains, named AS2-1 and AS2-2, which showed 16.0±2.3% and 31.0±2.2% methylation, respectively. DNA from affected members of a previously not reported AD-PHP1B family without the known genetic defects revealed incomplete LOM (loss-of-methylation) at GNAS A/B:TSS-DMR, normal methylation at the three well-established maternal and paternal DMRs, and, surprisingly, increased methylation at AS2-1 (32.9±3.5%), but not at AS2-2 (30.5±2.9%).

Conclusion: The distinct methylation changes at the novel GNAS-AS2:TSS-DMR will help characterize further different PHP1B/iPPSD3 variants and will guide the search for underlying genetic defects, which may provide novel insights into the mechanisms underlying GNAS methylation.
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http://dx.doi.org/10.1210/clinem/dgab136DOI Listing
March 2021

Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population.

Eur J Endocrinol 2021 Feb;184(2):347-355

Paediatric Unit, Limoges University Hospital, Limoges, France.

Aim: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.

Methods: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.

Results: Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively).

Conclusion: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.
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http://dx.doi.org/10.1530/EJE-20-1119DOI Listing
February 2021

Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.

Nat Commun 2020 12 7;11(1):6249. Epub 2020 Dec 7.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.

The bioactive vitamin D, 1α,25(OH)D, plays a central role in calcium homeostasis by controlling the activity of the vitamin D receptor (VDR) in various tissues. Hypercalcemia secondary to high circulating levels of vitamin D leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH)D synthesis, but are poorly efficient. In this study, we identify WBP4 as a new VDR interactant, and demonstrate that it controls VDR subcellular localization. Moreover, we show that the vitamin D analogue ZK168281 enhances the interaction between VDR and WBP4 in the cytosol, and normalizes the expression of VDR target genes and serum calcium levels in 1α,25(OH)D-intoxicated mice. As ZK168281 also blunts 1α,25(OH)D-induced VDR signaling in fibroblasts of a patient with impaired vitamin D degradation, this VDR antagonist represents a promising therapeutic option for 1α,25(OH)D-induced hypercalcemia.
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http://dx.doi.org/10.1038/s41467-020-20069-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721737PMC
December 2020

Inactivating PTH/PTHrP signaling disorders (iPPSDs): evaluation of the new classification in a multicenter large series of 544 molecularly characterized patients.

Eur J Endocrinol 2021 Feb;184(2):311-320

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy.

Objective: Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification.

Design: Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized.

Methods: Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients.

Results: More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease.

Conclusions: The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.
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http://dx.doi.org/10.1530/EJE-20-0625DOI Listing
February 2021

Demographic Characteristics, Risk Factors, and Presenting Features of Children with Symptomatic Nutritional Rickets: A French Series.

Horm Res Paediatr 2020 29;93(5):304-312. Epub 2020 Oct 29.

Reference and Competence Centers for Rare Diseases of the Calcium and Phosphate Metabolism, OSCAR Network for Rare Diseases, Paris, France,

Aim: To describe the demographic characteristics, risk factors, and presenting features of children with symptomatic nutritional rickets in France.

Methods: This is a retrospective study of 38 children diagnosed with nutritional rickets from 1998 to 2019.

Results: We observed a higher frequency of rickets in males (74 vs. 26%), in young children (median age at diagnosis: 23 months; 82% were younger than 5 years), and in children with a non-Caucasian ethnic background (89%). Most children were exclusively breastfed (78%) without adequate vitamin D supplementation (89%). The most common presentations were bowed legs (63%), hypocalcemic seizures (21%), and growth retardation (11%). Approximately half (62%) of the children were hypocalcemic. The children presenting with hypocalcemic seizures were significantly younger (0.8 vs. 2.2 years; p = 0.041) and had lower total serum calcium levels (1.44 vs. 2.17 mmol/L; p < 0.0001), higher phosphatemia (1.43 vs. 1.23 mmol/L; p = 0.020), and lower 25-hydroxy vitamin D levels (3 vs. 7 ng/mL; p = 0.020) but similar parathyroid hormone levels (357 vs. 289 ng/mL; p = 0.940) compared to rickets cases who did not experience hypocalcemic seizures. A dilated cardiomyopathy was detected in 14% of the children who had undergone echocardiography.

Conclusion: Nutritional rickets remains endemic in the pediatric population and its most severe forms can have life-threatening sequelae. Health practitioners need to be cognizant of these facts to raise awareness and screen high-risk populations.
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http://dx.doi.org/10.1159/000511419DOI Listing
October 2020

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort.

Clin Endocrinol (Oxf) 2021 Feb 21;94(2):277-289. Epub 2020 Dec 21.

Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Faculté des Sciences médicales et paramédicales, Institut Marseille Maladies Rares (MarMaRa), Marseille, France.

Context: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism.

Aims: To describe main phenotype patterns and their evolution through life.

Design: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.

Results: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations.

Conclusion: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.
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http://dx.doi.org/10.1111/cen.14355DOI Listing
February 2021

Development of Enthesopathies and Joint Structural Damage in a Murine Model of X-Linked Hypophosphatemia.

Front Cell Dev Biol 2020 22;8:854. Epub 2020 Sep 22.

Université de Paris, Laboratory Orofacial Pathologies, Imaging and Biotherapies UR 2496, Dental School, Montrouge, France.

X-linked hypophosphatemia (XLH) is characterized by rickets and osteomalacia, caused by inactivating mutations in the Phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. With aging, adult patients develop paradoxical heterotopic calcifications of tendons and ligaments at their insertion sites (enthesophytes), and joint alterations. Understanding the progression of this structural damage that severely affects patients' quality of life will help to improve the management of XLH. Here, we characterized the occurrence of enthesophytes and joint alterations through a 12 month micro-CT follow-up in the mouse, a murine model of XLH ( = 5 mice per group). Similar to adult patients with XLH, mice developed calcaneal enthesophytes, hip joint alterations, erosions of the sacroiliac joints and periarticular calcifications. These lesions were already present at month 3 and gradually worsened over time. In sharp contrast, no abnormalities were observed in control mice at early time points. Histological analyses confirmed the presence of bone erosions, calcifications and expansion of mineralizing enthesis fibrocartilage in mice and their absence in controls and suggested that new bone formation is driven by altered mechanical strain. Interestingly, despite a strong deformation of the curvature, none of the mice displayed enthesophyte at the spine. Peripheral enthesophytes and joint alterations develop at the early stages of the disease and gradually worsen overtime. Overall, our findings highlight the relevance of this preclinical model to test new therapies aiming to prevent bone and joint complications in XLH.
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http://dx.doi.org/10.3389/fcell.2020.00854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536578PMC
September 2020

Pseudohypoparathyroidism type 1B (PHP1B), a rare disorder encountered in adolescence.

J Pediatr Endocrinol Metab 2020 Nov;33(11):1475-1479

2nd Department of Paediatrics, University of Athens, "P & A Kyriakou" Children's Hospital, Athens, Greece.

Objectives The objective of this paper is to report a peculiar case of a patient with pseudohypoparathyroidism type 1b (PHP1B). Pseudohypoparathyroidism (PHP) refers to a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) concentrations as the result of end-organ unresponsiveness to PTH. Case presentation We present a 14-year-old boy, who was admitted with severe symptomatic hypocalcaemia, absence of dysmorphic features and Albright's hereditary osteodystrophy features. Laboratory investigations revealed markedly low serum calcium, high phosphate, markedly elevated PTH levels and vitamin D insufficiency, while magnesium, albumin, ALP and TSH were normal. The clinical and laboratory findings were consistent with PHP1B. Molecular analysis revealed loss of methylation at the AB DMR of the GNAS locus, confirming the diagnosis. Yet no STX16 deletion was detected. Conclusions It is possible that delSTX16- patients carry a defect in an element that controls the methylation both at the GNAS-A/B DMR and at the GNAS-AS2. This rare case emphasizes the need of individualized molecular analysis in PHP1B patients in order to elucidate the possible molecular defect.
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http://dx.doi.org/10.1515/jpem-2020-0192DOI Listing
November 2020

Hydrolyzed Rice Protein-Based Formulas, a Vegetal Alternative in Cow's Milk Allergy.

Nutrients 2020 Aug 31;12(9). Epub 2020 Aug 31.

Department of Paediatrics, Saint Antoine Paediatric Hospital, Saint Vincent de Paul Hospital, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Catholic University of Lille, 59000 Lille, France.

Formulas adapted to infant feeding, although most of the time made from cow's milk proteins, can be made from hydrolyzed rice protein but they must be classified as "formulas for specific medical needs", according to European regulations. The nutritional quality of rice proteins is thus suitable to be used in infant formulas giving that it is supplemented by certain amino acids which can be lacking. Besides, hydrolysis is required to facilitate their water solubility and digestibility. Owing to a low allergenicity of rice and to the absence of the cross-allergy between milk proteins and rice proteins, these formulas are adapted to the diet of children with cow's milk protein allergy (CMPA), which explains their growing use in some countries. However, CMPA, an expanding disorder, has consequences for growth, bone mineralization, and often has an association with allergy to other foods, including cow's milk extensive hydrolysate, so that a surveillance of the adaption of hydrolyzed rice protein formulas (HRPF) to CMPA, the absence of unexpected side effects, and the appropriate response to its various health hazards seems mandatory. This paper analyses the health problem deriving from CMPA, the industrial development of hydrolyzed rice protein formulas, and the limited number of clinical studies, which confirms, at the moment, a good allergic tolerance and safety. The goal is to better advise heath care professionals on their use of HRPFs during CMPA.
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http://dx.doi.org/10.3390/nu12092654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551844PMC
August 2020

Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients.

Horm Res Paediatr 2020 5;93(3):182-196. Epub 2020 Aug 5.

Molecular (Epi)Genetics Laboratory, BioAraba Research Health Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Spain.

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.
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http://dx.doi.org/10.1159/000508985DOI Listing
August 2020

Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry.

J Bone Miner Res 2020 11 10;35(11):2171-2178. Epub 2020 Aug 10.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by deficient tissue non-specific alkaline phosphatase activity. This study aims to assess patient-reported pain, disability and health-related quality of life (HRQoL) in a real-world cohort of adults with HPP who were not receiving asfotase alfa during the analysis. Adults (≥18 years old) with HPP (confirmed by ALPL gene mutation and/or low serum alkaline phosphatase activity for age/sex) were identified from the Global HPP Registry (NCT02306720). Demographics, clinical characteristics, and data on patient-reported pain, disability, and HRQoL (assessed by Brief Pain Inventory Short Form [BPI-SF], Health Assessment Questionnaire Disability Index [HAQ-DI], and 36-Item Short-Form Health Survey version 2 [SF-36v2], respectively) were stratified by pediatric- and adult-onset HPP and summarized descriptively. Of the 304 adults included (median [min, max] age 48.6 [18.8, 79.8] years; 74% women), 45% had adult-onset HPP and 33% had pediatric-onset HPP (unknown age of onset, 22%). Of those with data, 38% had experienced ≥5 HPP manifestations and 62% had a history of ≥1 fracture/pseudofracture. Median (Q1, Q3) BPI-SF scores were 3.5 (1.5, 5.3) for pain severity and 3.3 (0.9, 6.2) for pain interference. Median (Q1, Q3) disability on the HAQ-DI was 0.3 (0.0, 0.7). Median (Q1, Q3) physical and mental component summary scores on the SF-36v2 were 42.4 (32.7, 49.9) and 45.3 (36.3, 54.8), respectively. Greater numbers of HPP manifestations experienced/body systems affected correlated significantly with poorer scores on the BPI-SF, HAQ-DI, and SF-36v2 (all p < 0.05). No significant differences between adults with pediatric- and adult-onset HPP were observed for patient-reported outcomes, except for disability and the BPI-SF question "pain at its worst," which were significantly higher among adults with pediatric- versus adult-onset HPP (p = 0.03 and 0.04, respectively). These data from the Global HPP Registry show that adults with HPP have a substantial burden of illness that is associated with reduced patient-reported HRQoL, regardless of age of disease onset. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4130DOI Listing
November 2020

FGF23 measurement in burosumab-treated patients: an emerging treatment may induce a new analytical interference.

Clin Chem Lab Med 2020 Oct;58(11):e267-e269

AP-HP, Department of Endocrinology and Diabetology for children and Department of Adolescent Medicine, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR and Platform of Expertise for Rare Diseases Paris-Sud, Bicêtre Paris-Saclay Hospital, Paris Saclay University, Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1515/cclm-2020-0460DOI Listing
October 2020

Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients.

Clin Endocrinol (Oxf) 2020 09 14;93(3):248-260. Epub 2020 May 14.

Department of Endocrinology, Larrey Hospital, CardioMet Institute, University Hospital Centre of Toulouse, Toulouse, France.

Objective: Familial hypocalciuric hypercalcaemia type 1 (FHH1), related to heterozygous loss-of-function mutations of the calcium-sensing receptor gene, is the main differential diagnosis for primary hyperparathyroidism. The aim of our study was to describe clinical characteristics of adult patients living in France with a genetically confirmed FHH1.

Design And Patients: This observational, retrospective, multicentre study included 77 adults, followed up in 32 clinical departments in France, with a genetic FHH1 diagnosis between 2001 and 2012.

Results: Hypercalcaemia was diagnosed at a median age of 53 years [IQR: 38-61]. The diagnosis was made after clinical manifestations, routine analysis or familial screening in 56, 34 and 10% of cases, respectively, (n = 58; data not available for 19 patients). Chondrocalcinosis was present in 11/51 patients (22%), bone fractures in 8/56 (14%) and renal colic in 6/55 (11%). The median serum calcium was 2.74 mmol/L [IQR: 2.63-2.86 mmol/L], the median plasma parathyroid hormone level was 4.9 pmol/L [3.1-7.1], and the median 24-hour urinary calcium excretion was 2.8 mmol/24 hours [IQR: 1.9-4.0]. Osteoporosis (dual X-ray absorptiometry) or kidney stones (renal ultrasonography) were found in 6/38 patients (16%) and 9/32 patients (28%), respectively. Fourteen patients (18%) underwent parathyroid surgery; parathyroid adenoma was found in three patients (21%) and parathyroid hyperplasia in nine patients (64%). No correlation between genotype and phenotype was established.

Conclusion: This large cohort study demonstrates that FHH1 clinical characteristics can be atypical in 33 patients (43%). Clinicians should be aware of this rare differential diagnosis in order to adopt an appropriate treatment strategy.
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http://dx.doi.org/10.1111/cen.14211DOI Listing
September 2020

Hyperparathyroidism in Patients With X-Linked Hypophosphatemia.

J Bone Miner Res 2020 07 27;35(7):1263-1273. Epub 2020 Mar 27.

Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphate, Filière OSCAR, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre, France.

X-linked hypophosphatemia (XLH) is characterized by increased activity of circulating FGF23 resulting in renal phosphate wasting and abnormal bone mineralization. Hyperparathyroidism may develop in XLH patients; however, its prevalence, pathogenesis, and clinical presentation are not documented. This observational study (CNIL 171036 v 0) recruited XLH adult patients in a single tertiary referral center. Each patient was explored in standardized conditions and compared with two healthy volunteers, matched for sex, age, and 25-OH vitamin D concentrations. The primary endpoint was the proportion of patients with hyperparathyroidism. The secondary endpoints were the factors influencing serum parathyroid hormone (PTH) concentrations and the prevalence of hypercalcemic hyperparathyroidism. Sixty-eight patients (51 women, 17 men) were enrolled and matched with 136 healthy volunteers. Patients had higher PTH concentrations compared with healthy controls (53.5 ng/L, interquartile range [IQR] 36.7-72.7 versus 36.0 ng/L, IQR 27.7-44.0, p < .0001). Hyperparathyroidism was observed in 17 patients of 68 (25%). In patients, a positive relationship between PTH and calcium concentrations and a negative relationship between PTH and phosphate concentrations were observed. Seven (10%) patients (3 premenopausal women, 1 postmenopausal woman, and 3 men) were diagnosed with hypercalcemic hyperparathyroidism. All underwent parathyroid surgery, with consecutive normalization of calcium and PTH concentrations. Hyperparathyroidism is a frequent complication in XLH adult patients. Disruption of the physiological regulation of PTH secretion contributes to parathyroid disease. Early-onset hypercalcemic hyperparathyroidism can be effectively and safely cured by surgical resection. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3992DOI Listing
July 2020

Increased prevalence of overweight and obesity in children with X-linked hypophosphatemia.

Endocr Connect 2020 Feb;9(2):144-153

APHP, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, FilièreOSCAR and Platform of Expertise for Rare Diseases Paris-Saclay, Bicêtre Paris-Saclay Hospital, Le Kremlin-Bicêtre, France.

Background/aim: X-linked hypophosphatemia (XLH) is a rare disease characterized by low phosphate levels. Scientific evidence points to a link between hypophosphatemia and obesity in general population. The aim of our longitudinal observational study was to investigate the prevalence of obesity and associated factors in a large cohort of children with XLH.

Patients/methods: We studied 172 XLH-children 5-20 years of age (113 girls/59 boys). Anthropometric parameters (weight, height, and BMI) were collected at birth and during follow-up at mean ages of 5.3, 8.2, 11.3, and 15.9 years (groups 1, 2, 3, and 4, respectively). In each group, subjects were classified based on International Obesity Taskforce (IOTF) cut off values of BMI for age and sex as overweight or obese (IOTF 25-30 or ≥30 kg/m2, respectively).

Results: In each age-group, almost 1/3 of XLH-patients were classified as overweight or obese (29.4, 28.7, 27.5, and 36.7% in groups 1, 2, 3, and 4, respectively). Children without a XLH-family history had higher BMI-IOTF at every point of follow-up, compared to those with positive XLH-family history. Similarly, higher BMI-IOTF was significantly associated with treatment duration (23.3 ± 4.4 vs 23.8 ± 3.8 vs 25.2 ± 4.5 kg/m2, for subjects with treatment duration of <5, 5-10 and >10 years, respectively, P for trend = 0.025). Multiple regression analysis confirmed an association of treatment duration and lack of XLH-family history with higher BMI-IOTF.

Conclusion: One out of three of XLH-children have phenotypically unfavourable metabolic profile expressed as increased prevalence of overweight or obesity in comparison to general population. Both the lack of XLH family history and the duration of treatment increase the risk of higher BMI-IOTF. BMI should be carefully monitored in children, and later in adults, with XLH.
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http://dx.doi.org/10.1530/EC-19-0481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993252PMC
February 2020

Management of X-linked hypophosphatemia in adults.

Metabolism 2020 02 18;103S:154049. Epub 2019 Dec 18.

AP-HP, Department of Endocrinology and Reproductive Diseases, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, filière OSCAR, and Platform of Expertise for Rare Disorders, Bicêtre Paris Saclay Hospital, Le Kremlin-Bicêtre, France; Université Paris-Saclay, INSERM, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France. Electronic address:

X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene which result in Fibroblast Growth Factor-23 (FG-F23) excess and phosphate wasting. Clinically, XLH children present with rickets, bone deformities and short stature. In adulthood, patients may still be symptomatic with bone and joint pain, osteomalacia-related fractures or pseudofractures, precocious osteoarthrosis, enthesopathy, muscle weakness and severe dental anomalies. Besides these musculoskeletal and dental manifestations, adult XLH patients are also prone to secondary and tertiary hyperparathyroidism, cardiovascular and metabolic disorders. Pathophysiology of hyperparathyroidism is only partially understood but FGF23 excess and deficient production of calcitriol likely contributes to its development. Similarly, the pathophysiological mechanisms of potential cardiovascular and metabolic involvements are not clear, but FGF-23 excess may play an essential role. Treatment should be considered in symptomatic patients, patients undergoing orthopedic or dental surgery and women during pregnancy and lactation. Treatment with oral phosphate salts and active vitamin D analogs has incomplete efficacy and potential risks. Burosumab, a recombinant human monoclonal antibody against FGF-23, has proven its efficacy in phase 2 and phase 3 clinical trials in adult patients with XLH, but currently its position as first line or second line treatment differ among the countries.
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http://dx.doi.org/10.1016/j.metabol.2019.154049DOI Listing
February 2020

GHD Diagnostics in Europe and the US: An Audit of National Guidelines and Practice.

Horm Res Paediatr 2019 8;92(3):150-156. Epub 2019 Nov 8.

Dipartimento Pediatrico Universitario Ospedaliero, "Bambino Gesù" Children's Hospital - Tor Vergata University, Rome, Italy.

Introduction: Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure.

Methods: A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants.

Results: National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries.

Conclusions: GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence.
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http://dx.doi.org/10.1159/000503783DOI Listing
May 2020

Dental and craniofacial features associated with GNAS loss of function mutations.

Eur J Orthod 2020 11;42(5):525-533

APHP, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR and Plateforme d'Expertise Maladies Rares Paêris-Sud, Bicêtre Paris Sud Hospital, Le Kremlin Bicetre.

Background: Pseudohypoparathyroidism (PHP, OMIM #103580) is a very rare disease (incidence 0.3-1/100,000). Heterozygous inactivating mutations involving the maternal GNAS exons 1-13 that encodes the alpha subunit of the stimulatory G protein (Gsα) cause inactivating parathyroid hormone (PTH)/PTHrP signalling disorder type 2 (iPPSD2 or PHP type 1A), which is characterized by Albright hereditary osteodystrophy and resistance to multiple hormones that act through the Gsα signalling pathway (including PTH, thyroid-stimulating hormone, and α-melanocyte-stimulating hormone). To date, little information is available on craniofacial features in patients with PHP. The small number of patients studied in previous reports as well as the lack of molecular characterization of the patients may have precluded the detection of specific orofacial manifestations in the different PHP subtypes.

Materials/methods: We conducted a systematic analysis of dental and craniofacial features in 19 patients with iPPSD2 and maternal GNAS inactivating mutations to assess the frequency and specificity of the anomalies.

Results: Facial examinations showed reduced vertical, sagittal, and transverse development of the mid-facial structures. Intraoral and radiographic examinations revealed that 89 per cent of the patients had at least one dental anomaly, including tooth submergence leading to severe infraocclusion in 83 per cent of cases. Craniofacial analysis of lateral cephalometric radiographs also showed a significant alteration in the development of the cranial base and maxillary and mandibular structures in these patients.

Conclusions: Patients with iPPSD2 and maternal GNAS mutations had specific craniofacial alterations and dental abnormalities. These specific defects should be assessed in order to provide appropriate dental and orthodontic care to these patients. (clinical trial registration: 1920371 v 0, French Nationale Data Processing and Liberties Commission - CNIL).
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http://dx.doi.org/10.1093/ejo/cjz084DOI Listing
November 2020

The Lifelong Impact of X-Linked Hypophosphatemia: Results From a Burden of Disease Survey.

J Endocr Soc 2019 Jul 7;3(7):1321-1334. Epub 2019 May 7.

Ultragenyx Pharmaceutical Inc., Novato, California.

Context: X-linked hypophosphatemia (XLH) is characterized by excess fibroblast growth factor 23 (FGF23), hypophosphatemia, skeletal abnormalities, and growth impairment. We aimed to understand the burden of disease of XLH across the lifespan.

Methods: Responses were collected from adults with XLH and parents/caregivers of a child with XLH in an online survey, including multiple-choice and open-ended questions on demographics, disease manifestations, treatment history, assistive device use, and age-specific patient-reported outcomes (PROs).

Results: Data were collected from 232 adults with XLH (mean age, 45.6 years; 76% female) and 90 parents/caregivers of a child with XLH (mean age, 9.1 years; 56% female). Mean age recalled for symptom onset was 3.2 years for adults and 1.3 years for children. When surveyed, nearly all children (99%) and 64% of adults were receiving oral phosphate, active vitamin D, or both. Prior participation in a trial investigating burosumab, a fully human monoclonal antibody against FGF23, was reported in 3% of children and 10% of adults; of these respondents, only one child reported current treatment with burosumab at the time of the survey. Both children and adults reported typical features of XLH, including abnormal gait (84% and 86%, respectively), bowing of the tibia/fibula (72% and 77%), and short stature (80% and 86%). Nearly all adults (97%) and children (80%) reported bone or joint pain/stiffness. Adults reported a history of fractures (n/N = 102/232; 44%), with a mean (SD) age at first fracture of 26 (16) years. Adults reported osteophytes (46%), enthesopathy (27%), and spinal stenosis (19%). Mean scores for PROs evaluating pain, stiffness, and physical function were worse than population norms. Analgesics were taken at least once a week by 67% of adults.

Conclusions: Despite the common use of oral phosphate and active vitamin D established in the 1980s, children with XLH demonstrate a substantial disease burden, including pain and impaired physical functioning that persists, as demonstrated by similar responses reported in adults with XLH.
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http://dx.doi.org/10.1210/js.2018-00365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595532PMC
July 2019

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia.

Nat Rev Nephrol 2019 07;15(7):435-455

APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, Paris, France.

X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.
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http://dx.doi.org/10.1038/s41581-019-0152-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136170PMC
July 2019

Diagnosis, treatment-monitoring and follow-up of children and adolescents with X-linked hypophosphatemia (XLH).

Metabolism 2020 02 27;103S:153892. Epub 2019 Mar 27.

APHP, Endocrinology and Diabetology for Children, Bicêtre Paris Sud Hospital, Le Kremlin-Bicêtre, France; APHP, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, filière OSCAR, Paris, France; APHP, Platform of Expertise for Rare Disorders Paris-Sud, Bicêtre Paris Sud Hospital, Le Kremlin-Bicêtre, France.

Early diagnosis, optimal therapeutic management and regular follow up of children with X-linked hypophosphatemia (XLH) determine their long term outcomes and future quality of life. Biochemical screening of potentially affected newborns in familial cases and improving physician's knowledge on clinical signs, symptoms and biochemical characteristics of XLH for de novo cases should lead to earlier diagnosis and treatment initiation. The follow-up of children with XLH includes clinical, biochemical and radiological monitoring of treatment (efficacy and complications) and screening for XLH-related dental, neurosurgical, rheumatological, cardiovascular, renal and ENT complications. In 2018, the European Union approved the use of burosumab, a humanized monoclonal anti-FGF23 antibody, as an alternative therapy to conventional therapy (active vitamin D analogues and phosphate supplements) in growing children with XLH and insufficiently controlled disease. Diagnostic criteria of XLH and the principles of disease management with conventional treatment or with burosumab are reviewed in this paper.
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http://dx.doi.org/10.1016/j.metabol.2019.03.009DOI Listing
February 2020

Transcriptional profiling at the domain explains clinical overlap between imprinting disorders.

Sci Adv 2019 02 20;5(2):eaau9425. Epub 2019 Feb 20.

Sorbonne Université, INSERM, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France.

Imprinting disorders (IDs) often affect growth in humans, leading to diseases with overlapping features, regardless of the genomic region affected. IDs related to hypomethylation of the human 14q32.2 region and its domain are associated with Temple syndrome (TS14). TS14 is a rare type of growth retardation, the clinical signs of which overlap considerably with those of Silver-Russell syndrome (SRS), another ID related to down-regulation at 11p15.5 region. We show that 14q32.2 hypomethylation affects expression, not only for genes at this locus but also for other imprinted genes, and especially lowers levels at 11p15.5. Furthermore, expression of nonimprinted genes is also affected, some of which are also deregulated in SRS patients. These findings highlight the epigenetic regulation of gene expression at the domain. Expression profiling of TS14 and SRS patients highlights common signatures, which may account for the clinical overlap observed between TS14 and SRS.
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http://dx.doi.org/10.1126/sciadv.aau9425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382400PMC
February 2019

Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry.

BMC Musculoskelet Disord 2019 Feb 14;20(1):80. Epub 2019 Feb 14.

Department of Pediatrics, Duke University Medical Center, 2301 Erwin Rd, Durham, NC, 27710, USA.

Background: Hypophosphatasia (HPP) is a rare, systemic disease caused by mutation(s) within the ALPL gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP has a heterogeneous presentation, which coupled with its rarity, often leads to missed/delayed diagnosis and an incomplete understanding of its natural history. To better understand the epidemiology and clinical course of HPP, including timing of diagnosis after first reported manifestation, we present baseline data for patients enrolled in the Global HPP Registry.

Methods: Data were analyzed from patients with an HPP diagnosis confirmed by low serum ALP activity and/or an ALPL pathogenic variant, regardless of prior or current treatment, according to age at enrollment (children: < 18 y; adult: ≥18 y). All analyses were descriptive.

Results: Of 269 patients from 11 countries enrolled January 2015-September 2017, 121 (45.0%) were children and 148 (55.0%) were adults. The majority of children and adults were female (61.2 and 73.0%, respectively) and white (57.7 and 90.0%, respectively). Children had a median (min, max) age at earliest reported HPP manifestation of 7.2 months (- 2.3 mo, 16.0 y), which was > 12 months before diagnosis at age 20.4 months (- 0.2 mo, 16.0 y). In adults, the earliest reported manifestation occurred at a median (min, max) age of 37.6 years (0.2 y, 75.2 y), which preceded age at diagnosis (47.5 years [0.2 y, 75.2 y]) by ~ 10 years. Premature loss of deciduous teeth (48.2%, age ≥ 6 mo), bone deformity (32.5%), and failure to thrive (26.7%) were most commonly reported in the HPP-related disease history of children. Pain (74.5%), orthopedic procedures and therapies (44.6%), and recurrent and poorly healing fractures (36.5%) were most commonly reported in the HPP-related disease history of adults.

Conclusions: The Global HPP Registry represents the largest observational study of patients with HPP, capturing real world data. This analysis shows that diagnostic delay is common, reflecting limited awareness of HPP, and that HPP is associated with systemic manifestations across all ages. Many patients diagnosed in adulthood had HPP manifestations in childhood, highlighting the importance of taking thorough medical histories to ensure timely diagnosis.

Trial Registration: Clinicaltrials.gov : NCT02306720 , December 2014; ENCePP.eu: EUPAS13526 , May 2016 (retrospectively registered).
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http://dx.doi.org/10.1186/s12891-019-2420-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376686PMC
February 2019

X-linked hypophosphatemia: Management and treatment prospects.

Joint Bone Spine 2019 Nov 31;86(6):731-738. Epub 2019 Jan 31.

Centre de référence des maladies rares du métabolisme du calcium et du phosphate, filière OSCAR and plateforme d'expertise maladies rares Paris-Sud, hôpital Bicêtre Paris Sud, AP-HP, 94270 Le Kremlin Bicêtre, France; Endocrinologie et diabète de l'enfant, hôpital Bicêtre Paris Sud, AP-HP, 94270 Le Kremlin Bicêtre, France; Inserm U1185 et université Paris Sud Paris-Saclay, Hôpital Bicêtre Paris Sud, 94270 Le Kremlin Bicêtre, France.

X-linked hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. Treatment options include active vitamin D analogs and phosphate supplementation to correct the 1.25(OH) vitamin D deficiency and to compensate for the renal phosphate wasting, respectively. The recently introduced FGF23 antagonist burosumab is designed to restore renal phosphate reabsorption by the proximal tubule and to stimulate endogenous calcitriol production. In Europe, burosumab is licensed for use in pediatric patients older than 1 year who have XLH. This review discusses the diagnosis and treatment of XLH and describes the indications of the various available treatments.
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http://dx.doi.org/10.1016/j.jbspin.2019.01.012DOI Listing
November 2019

Parathyroid hormone resistance syndromes - Inactivating PTH/PTHrP signaling disorders (iPPSDs).

Best Pract Res Clin Endocrinol Metab 2018 12 28;32(6):941-954. Epub 2018 Sep 28.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Electronic address:

Metabolic disorders caused by impairments of the Gsα/cAMP/PKA pathway affecting the signaling of PTH/PTHrP lead to features caused by non-responsiveness of target organs, in turn leading to manifestations similar to the deficiency of the hormone itself. Pseudohypoparathyroidism (PHP) and related disorders derive from a defect of the α subunit of the stimulatory G protein (Gsα) or of downstream effectors of the same pathway, such as the PKA regulatory subunit 1A and the phosphodiesterase type 4D. The increasing knowledge on these diseases made the actual classification of PHP outdated as it does not include related conditions such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), so that a new nomenclature and classification has been recently proposed grouping these disorders under the term "inactivating PTH/PTHrP signaling disorder" (iPPSD). This review will focus on the pathophysiology, clinical and molecular aspects of these rare, heterogeneous but closely related diseases.
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http://dx.doi.org/10.1016/j.beem.2018.09.008DOI Listing
December 2018

Pseudohypoparathyroidism.

Endocrinol Metab Clin North Am 2018 12 12;47(4):865-888. Epub 2018 Oct 12.

Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, 50 Blossom street, Boston, MA 02114, USA; Pediatric Nephrology Unit, Massachusetts General Hospital, Harvard Medical School, 50 Blossom street, Boston, MA 02114, USA.

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.
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http://dx.doi.org/10.1016/j.ecl.2018.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305568PMC
December 2018