Editorial
Wind of change in pseudohypoparathyroidism and related disorders: New classification and first international management consensus
Vientos de cambio en pseudohipoparatiroidismo y enfermedades relacionadas: nueva clasificación y primer consenso internacional
Beatriz Lecumberria,b,c, Gabriel Ángel Martos-Morenod,e,f, Guiomar Perez de Nanclaresg,
Corresponding author
a Department of Endocrinology and Nutrition, La Paz University Hospital, Madrid, Spain
b Department of Medicine, Autonomous University of Madrid (UAM), Madrid, Spain
c Endocrine Diseases Research Group, Hospital La Paz Institute for Health Research (IdiPaZ), Madrid, Spain
d Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Endocrine Diseases Research Group, Hospital La Princesa Institute for Health research (IIS La Princesa), Madrid, Spain
e Department of Pediatrics, Universidad Autónoma de Madrid (UAM), Madrid, Spain
f CIBERobn, ISCIII, Madrid, Spain
g Molecular (Epi)Genetics Laboratory, Bioaraba National Health Institute, OSI Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain
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"tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "425" "paginaFinal" => "427" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Beatriz Lecumberri, Gabriel Ángel Martos-Moreno, Guiomar Perez de Nanclares" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Beatriz" "apellidos" => "Lecumberri" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 1 => array:3 [ "nombre" => "Gabriel Ángel" "apellidos" => "Martos-Moreno" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] 2 => array:4 [ "nombre" => "Guiomar Perez" "apellidos" => "de Nanclares" "email" => array:1 [ 0 => "gnanclares@osakidetza.eus" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "aff0035" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:7 [ 0 => array:3 [ "entidad" => "Department of Endocrinology and Nutrition, La Paz University Hospital, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Medicine, Autonomous University of Madrid (UAM), Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Endocrine Diseases Research Group, Hospital La Paz Institute for Health Research (IdiPaZ), Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Endocrine Diseases Research Group, Hospital La Princesa Institute for Health research (IIS La Princesa), Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Department of Pediatrics, Universidad Autónoma de Madrid (UAM), Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "CIBERobn, ISCIII, Madrid, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Molecular (Epi)Genetics Laboratory, Bioaraba National Health Institute, OSI Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Vientos de cambio en pseudohipoparatiroidismo y enfermedades relacionadas: nueva clasificación y primer consenso internacional" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The first description of patients affected with pseudohypoparathyroidism (PHP) dates back to 1942, when Fuller Albright and colleagues reported some patients that showed significantly reduced levels of plasmatic calcium with hyperphosphatemia associated with raised serum parathyroid hormone (PTH) levels and normal renal function, introducing, for the first time, the concept of end-organ resistance to a hormone. These individuals also displayed a clinical phenotype characterized by short stature, obesity, rounded face and brachydactyly, that was referred to as Albright's hereditary osteodystrophy (AHO).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the following years, the substantial increase in the research on this disease allowed the identification of different subtypes of PHP and additional clinical signs, such as ectopic subcutaneous ossifications and cognitive abnormalities in varying degrees, as well as the underlying pathophysiologic mechanism: a defective activation of the cAMP signal transduction pathway by PTH secondary to molecular defects affecting the alpha subunit of the stimulatory G protein (Gsα).<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–6</span></a> The discovery, in 1990, of inactivating mutations in <span class="elsevierStyleItalic">GNAS</span> (the gene encoding for Gsα) in patients with signs of AHO and with/without distinct hormone resistances (PHP1A and PPHP, respectively) can be considered a milestone in the study of this disease.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Further molecular studies demonstrated that Gsα was predominantly maternally expressed in specific human tissues, including proximal renal tubules, pituitary, gonads, and thyroid. This differential tissue expression according to the parental origin of the allele (genomic imprinting) explained, at least in part, the reported intra and interfamilial phenotypic variability: the hormone resistance was usually present when the mutation was inherited from the mother, but absent when paternally inherited. It was also discovered that the loss of the normal parental-specific imprinting methylation pattern at <span class="elsevierStyleItalic">GNAS</span> differentially methylated regions (DMRs) led to a PHP phenotype typically characterized by PTH resistance without AHO features (PHP1B). Although most GNAS methylation defects were sporadic, in some familial cases they were produced by deletions of imprinting control elements (ICR) within <span class="elsevierStyleItalic">STX16</span> or <span class="elsevierStyleItalic">NESP55</span> upstream genes, and in a few cases also due to <span class="elsevierStyleItalic">GNAS</span> paternal uniparental isodisomy (UPD).<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> Additionally, independent studies highlighted the clinical and molecular overlap among PHP classic subtypes, comprising the presence of GNAS imprinting defects with no mutations in Gsα-coding exons in patients with a likely clinical diagnosis of PHP1A,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and revealed novel causative molecular defects and their prevalence.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Despite the high detection rate of <span class="elsevierStyleItalic">GNAS</span> genetic and epigenetic defects, a subset of patients still lack(ed) a molecular diagnosis. The analysis of genes acting downstream Gsα in the cAMP-mediated signalling pathway, particularly <span class="elsevierStyleItalic">PRKAR1A</span> and <span class="elsevierStyleItalic">PDE4D</span> genes, enabled the identification of causative molecular alteration in a small (but increasing) subset of patients without <span class="elsevierStyleItalic">GNAS</span> defects. These results explained the phenotypic overlap between PHP and acrodysostosis, both phenotypically related skeletal disorders sometimes hard to distinguish only on the basis of clinical and radiological findings.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13–15</span></a> These findings also prompted the experts to develop a new classification for PHP and related disorders.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In an attempt to embrace and describe in a more effective and accurate way all the disorders known to be caused by abnormalities of their common signalling pathway, the term selected was “inactivating PTH/PTHrP signalling disorder (iPPSD)”. The diagnosis is based only on clinical features (major and minor clinical criteria are proposed), and the integration of molecular findings is achieved through numbering each subtype. This new classification includes a variety of diseases under the same umbrella of a common pathogenic mechanism, provides with a clinical unifying diagnose, minimizes the clinical and molecular overlap between subgroups, and is open and capable to incorporate new incoming information.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Even if a validation (and if obtained, internationalization) of this iPPSD classification is needed, it is clear that a substantial progress has been achieved on the pathophysiology of PHP and related disorders throughout the world by physicians and research networks since 1942, but especially in the past 30 years. However, until very recently, caregivers and patients were still lacking guidelines for diagnosis and daily life care and treatment. With the aim of helping them from the clinical diagnosis, to the molecular confirmation of the genetic/epigenetic defect, up to the management of the most frequent manifestations of these rare diseases, an international consensus has just been stated.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The approach comprised 2 years of work, 2 pre-consensus meetings, an expert consensus meeting, and a Delphi-like methodology, adjusted to rare diseases. An extensive literature search was employed to review more than 800 articles published between 1990 and 2016, and, after voting, 64 final recommendations with different levels of evidence and strength were approved: 14 on clinical diagnosis, 11 on molecular diagnosis and 39 on management and treatment. Globally, the maximum consensus and level of evidence, as considered by the experts, was reached for 8 recommendations on clinical diagnosis, 5 on clinical management and 1 on molecular diagnosis.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The concept that the diagnosis should be based on clinical and biochemical characteristics concentrated one of the strongest consensus among experts. Among them, the major criteria should be PTH resistance, subcutaneous ossifications (can include deeper ossifications) and early-onset obesity associated with TSH resistance or AHO alone. The rest of the features (endocrine, neurological and others) would be supportive to the diagnosis. Similarly, the definition of PTH resistance was highly agreed as the association of hypocalcaemia, hyperphosphataemia and elevated serum levels of PTH in the absence of vitamin D deficiency, with normal magnesium levels and renal function. But even in the absence of overt hypocalcaemia, PTH resistance should be suspected when PTH is at – or above – the upper limit of normal, with normal calcifediol levels and hyperphosphataemia. Interestingly, the variability in the degree of PTH resistance and the evolving changes in serum calcium level, phosphorus and PTH in time, with the subsequent requirement of repeated testing before a definitive diagnosis is remarked. Genetic diagnosis should be considered in the presence of at least one major criteria, and severe symptomatic hypocalcemia should be managed according to the general guidelines stated for hypoparathyroidism.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In summary, a historical view of these rare disorders from their first descriptions until nowadays, reinforces the importance of all the observations and contributions coming from clinicians, researchers and patients, as well as the acceleration of scientific progress in recent years. We hope that this wind of change, boosted by the spontaneous creation of active multidisciplinary international networks where patients and families have had a cohesive and decisive role, promotes further collaborations among groups and societies, and finally manages to significantly improve the quality of life of the affected individuals.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pseudohypoparathyroidism – an example of “Seabright-Bantam syndrome”" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "F. Albright" 1 => "C.H. Burnett" 2 => "P.H. Smith" 3 => "W. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 4 | 2 | 6 |
| 2024 September | 22 | 1 | 23 |
| 2024 August | 14 | 3 | 17 |
| 2024 July | 11 | 3 | 14 |
| 2024 June | 8 | 3 | 11 |
| 2024 May | 12 | 5 | 17 |
| 2024 April | 13 | 5 | 18 |
| 2024 March | 12 | 8 | 20 |
| 2024 February | 3 | 2 | 5 |
| 2024 January | 10 | 2 | 12 |
| 2023 December | 8 | 1 | 9 |
| 2023 November | 9 | 5 | 14 |
| 2023 October | 14 | 7 | 21 |
| 2023 September | 13 | 0 | 13 |
| 2023 August | 16 | 1 | 17 |
| 2023 July | 12 | 2 | 14 |
| 2023 June | 21 | 2 | 23 |
| 2023 May | 49 | 2 | 51 |
| 2023 April | 28 | 1 | 29 |
| 2023 March | 18 | 1 | 19 |
| 2023 February | 17 | 5 | 22 |
| 2023 January | 8 | 4 | 12 |
| 2022 December | 15 | 4 | 19 |
| 2022 November | 19 | 10 | 29 |
| 2022 October | 20 | 11 | 31 |
| 2022 September | 14 | 15 | 29 |
| 2022 August | 17 | 2 | 19 |
| 2022 July | 11 | 5 | 16 |
| 2022 June | 10 | 8 | 18 |
| 2022 May | 15 | 4 | 19 |
| 2022 April | 37 | 8 | 45 |
| 2022 March | 27 | 6 | 33 |
| 2022 February | 29 | 4 | 33 |
| 2022 January | 15 | 8 | 23 |
| 2021 December | 11 | 7 | 18 |
| 2021 November | 16 | 5 | 21 |
| 2021 October | 14 | 4 | 18 |
| 2021 September | 17 | 11 | 28 |
| 2021 August | 11 | 8 | 19 |
| 2021 July | 44 | 8 | 52 |
| 2021 June | 14 | 10 | 24 |
| 2021 May | 16 | 10 | 26 |
| 2021 April | 59 | 23 | 82 |
| 2021 March | 43 | 13 | 56 |
| 2021 February | 24 | 10 | 34 |
| 2021 January | 26 | 13 | 39 |
| 2020 December | 30 | 9 | 39 |
| 2020 November | 26 | 13 | 39 |
| 2020 October | 13 | 5 | 18 |
| 2020 September | 17 | 16 | 33 |
| 2020 August | 21 | 12 | 33 |
| 2020 July | 13 | 4 | 17 |
| 2020 June | 16 | 9 | 25 |
| 2020 May | 15 | 8 | 23 |
| 2020 April | 9 | 6 | 15 |
| 2020 March | 23 | 10 | 33 |
| 2020 February | 19 | 5 | 24 |
| 2020 January | 16 | 3 | 19 |
| 2019 December | 31 | 15 | 46 |
| 2019 November | 25 | 4 | 29 |
| 2019 October | 18 | 3 | 21 |
| 2019 September | 24 | 6 | 30 |
| 2019 August | 10 | 0 | 10 |
| 2019 July | 14 | 11 | 25 |
| 2019 June | 27 | 22 | 49 |
| 2019 May | 65 | 20 | 85 |
| 2019 April | 33 | 4 | 37 |
| 2019 March | 6 | 2 | 8 |
| 2019 February | 3 | 4 | 7 |
| 2019 January | 2 | 0 | 2 |
| 2018 December | 1 | 0 | 1 |
| 2018 November | 15 | 18 | 33 |
| 2018 October | 122 | 108 | 230 |
| 2018 September | 84 | 40 | 124 |
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