Pseudohypoparathyroidism (PHP) covers a heterogeneous group of disorders, which have in common resistance to parathyroid hormone (PTH). However, they differ in many aspects such as site of the defect in signal transduction, clinical picture (with or without Albright's hereditary osteodystrophy (AHO)), extension of hormone resistance, and the tissue activity of protein Gs. PHP type Ic, a rare subtype, is characterized by resistance to several hormones, the presence of AHO, and normal activity of protein Gs. We present the case of a patient with PHP type Ic. Although resistance to TSH was suggested at the age of 12 months, diagnosis was made when she presented with hypocalcemia and resistance to PTH. Resistance to GH was also detected, and partial resistance to gonadotropins became clear after puberty. We demonstrated a defective lipolytic response to epinephrine, suggesting a role of this resistance in the pathogenesis of her morbid obesity. In view of the difficulties in the management of overweight in this disorder, treatment with a cannabinoid receptor type 1 (CB1) antagonist was started, and it proved to be highly effective, lowering the patient's body mass index from 40.5 to 33.5, which was quite impressive. We propose that an underactive melanocortin-4 receptor, which is found in certain patients with PHP, leads to upregulation of the CB1 receptor and consequently to a good response to treatment with CB1 antagonists. Another interesting finding was the GNAS mutation that was identified in this patient. A nonsense mutation resulted in a truncated Gsa that was able to stimulate adenylyl cyclase efficiently, but could not bind to receptors in a normal way.
Abdallah Al-Salameh, F Despert, Marie-Laure Kottler, Agnès Linglart, Jean-Claude Carel, and Pierre Lecomte
Hélène Che, Christian Roux, Adrien Etcheto, Anya Rothenbuhler, Peter Kamenicky, Agnès Linglart, and Karine Briot
Adults with X-linked hypophosphatemia (XLH) may suffer from skeletal symptoms leading to functional disability. No data on their quality of life (QoL) have been reported so far. Our objectives were to evaluate the QoL and its determinants in XLH adults.
Patients and methods
We conducted a prospective study in XLH adults, who consulted for musculoskeletal symptoms between 2013 and 2014. We assessed their QoL using HAQ, RAPID3 and SF36, and analysed the variables associated with low QoL. We compared their QoL to that of patients affected with axial spondyloarthritis (ax-SpA) (paired on age and gender), a rheumatologic disorder with a known low QoL.
Fifty-two XLH adults (37 women (71.1%); mean age 41.8±13.3 years) were included; 44 (84.6%) patients had an altered QoL. Increased age and presence of structural lesions were significantly associated with worse QoL (HAQ, RAPID3) (P<0.05). Presence of enthesopathies was significantly associated with worse RAPID3 (OR=4.45 (1.09–18.29), P=0.038). Treatment with phosphate supplements and vitamin D in XLH adults were significantly associated with a better SF36-mental component score (OR=0.14 (0.03–0.57), P=0.007 and OR=0.26 (0.07–0.98), P=0.047 respectively). QoL was significantly worse in XLH than in ax-SpA adults (VAS pain, SF36-PCS, RAPID3) (P<0.05).
Our study showed i) QoL of XLH adults is altered and significantly worse than that of ax-SpA patients (VAS pain, SF36-PCS and RAPID3), ii) structural lesions and especially enthesopathies are associated with a worse QoL and iii) treatment using phosphate supplements and/or vitamin D is associated with a better mental health score.
Anne-Lise Lecoq, Jérôme Bouligand, Mirella Hage, Laure Cazabat, Sylvie Salenave, Agnès Linglart, Jacques Young, Anne Guiochon-Mantel, Philippe Chanson, and Peter Kamenický
Recently, germline and somatic GPR101 p.(E308D) mutation was found in patients with isolated acromegaly. It is not known whether GPR101 point mutations are associated with other histological types of pituitary adenoma.
We sought germline GPR101 mutations in patients with sporadic pituitary adenomas, and compared the phenotypes of GPR101 mutation carriers and AIP mutation carriers.
An observational cohort study performed between 2007 and 2014 in a single referral center.
This prospective study involved 766 unselected patients (413 women) with sporadic pituitary adenomas of all histotypes.
Entire GPR101 and AIP coding sequence were screened for germline mutations.
Twelve patients (1.6%) were found to carry the GPR101 p.(E308D) mutation or rare GPR101 variants. The minor allele frequency of the GPR101 mutation and variants was higher in patients with pituitary adenomas than in unaffected individuals included in the Exome Aggregation Consortium database. Three of the six patients with the GPR101 p.(E308D) mutation had adult-onset acromegaly, two had adrenocorticotropin-secreting adenomas, and one had a nonfunctioning macroadenoma. Six patients carried rare GPR101 variants. Germline AIP mutations or rare AIP variants were identified in 32 patients (4.2%). AIP mutation carriers were younger at diagnosis than GPR101 mutation carriers and non carriers. None of the patients harbored mutations in both the GPR101 and AIP genes.
Germline GPR101 mutations are very rare in patients with sporadic pituitary adenomas of various histotypes. No digenism with AIP was identified. Further studies are required to establish whether and how genetic variation in GPR101 gene contributes to pituitary tumorigenesis.
Arrate Pereda, Francesca M Elli, Suzanne Thiele, Luisa de Sanctis, Anya Rothenbuhler, Patrick Hanna, Bruno Francou, Diana Alexandra Ertl, Guiomar Perez de Nanclares, Agnès Linglart, and Giovanna Mantovani
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.
Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized.
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.
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.
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.
Susanne Thiele, Giovanna Mantovani, Anne Barlier, Valentina Boldrin, Paolo Bordogna, Luisa De Sanctis, Francesca M Elli, Kathleen Freson, Intza Garin, Virginie Grybek, Patrick Hanna, Benedetta Izzi, Olaf Hiort, Beatriz Lecumberri, Arrate Pereda, Vrinda Saraff, Caroline Silve, Serap Turan, Alessia Usardi, Ralf Werner, Guiomar Perez de Nanclares, and Agnès Linglart
Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity. However, this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), as well as recent findings of clinical and genetic/epigenetic background of the different subtypes. Therefore, the EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway.
Design and methods
Extensive review of the literature was performed. Several meetings were organised to discuss about a new, more effective and accurate way to describe disorders caused by abnormalities of the PTH/PTHrP signalling pathway.
Results and conclusions
After determining the major and minor criteria to be considered for the diagnosis of these disorders, we proposed to group them under the term ‘inactivating PTH/PTHrP signalling disorder’ (iPPSD). This terminology: (i) defines the common mechanism responsible for all diseases; (ii) does not require a confirmed genetic defect; (iii) avoids ambiguous terms like ‘pseudo’ and (iv) eliminates the clinical or molecular overlap between diseases. We believe that the use of this nomenclature and classification will facilitate the development of rationale and comprehensive international guidelines for the diagnosis and treatment of iPPSDs.
Yasmine El Allali, Coralie Hermetet, Justine Bacchetta, Cyril Amouroux, Anya Rothenbuhler, Valérie Porquet-Bordes, Marie-Alexandrine Champigny, Sabine Baron, Pascal Barat, Helene Bony-Trifunovic, Karine Bourdet, Kanetee Busiah, Maryse Cartigny-maciejewski, Florence Compain, Regis Coutant, Jessica Amsellem-jager, Marc De Kerdanet, Nathalie Magontier, Brigitte Mignot, Odile Richard, Sylvie Rossignol, Soskin Sylvie, Aurélie Berot, Naud-saudreau Catherine, Jean-pierre Salles, Agnès Linglart, Thomas Edouard, and Anne Lienhardt-Roussie
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 mutated infants) 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 mutated children and adolescents). Although serum calcium levels did not differ between the 2 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.