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

in European Journal of Endocrinology
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  • 1 Molecular (Epi)Genetics Laboratory, BioAraba Research Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain
  • 2 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy
  • 3 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
  • 4 Department of Pediatrics, University of Lübeck, Lübeck, Germany
  • 5 Department of Public Health and Pediatric Sciences, University of Torino, Regina Margherita Children’s Hospital-AOU Città della Salute e della Scienza, Torino, Italy
  • 6 AP-HP, Service d’endocrinologie et diabète de l’enfant et Centre de référence des maladies rares du métabolisme du calcium et du phosphate, filière OSCAR, EndoRare and BOND ERN, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France
  • 7 Université Paris-Saclay, Hôpital de Bicêtre, INSERM U1185, Le Kremlin-Bicêtre, France
  • 8 AP-HP, Service de génétique moléculaire, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France
  • 9 University Clinic of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

Correspondence should be addressed to G Perez de Nanclares; Email: gnanclares@osakidetza.eus
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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.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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