From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

Abstract

Objective: 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

A case of Adult onset Pseudohypoparathyroidism yet to be resolved: “No money no genetics”

“…Unfortunately in our patient a distinction between PHP type 1b and PHP type 2 and eventually further genetic testing cannot be made until the renewal of her public health insurance. By that time we hope more light will be shed on the diagnostic criteria and classification of these rare and highly heterogeneous diseases as recently proposed by the European PHP network 36 .…”

Multiple hormonal resistance and metabolic disorders in pseudogypoparatiosis

“…В ходе обследования была выявлена деком-пенсация по кальций-фосфорному обмену и гипотиреозу: гипокальциемия (Са ион. 0,87 ммоль/л при норме 1,03-1,29), гиперфосфатемия (1,81 ммоль/л при норме 0,74-1,52), повышение уровня ПТГ до 136 пг/мл , гипотиреоз (ТТГ 7,37 мМЕ/л при норме 0,64-5,76, св.Т4 8,72 пмоль/л при норме 11,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]4) при нормальном уровне аутоантител (АТ) (АТ к тиреопероксидазе (ТПО) 1,77 МЕ/мл, при норме 0-5,6) и отсутствии эхо-признаков аутоиммунного тиреоидита по данным УЗИ щитовидной железы (рис. 7).…”

“…7). В суточном ана-лизе мочи гипокальциурия 0,804 ммоль/сут (2,(5)(6)(7)(8), 0,37 мг/ кг/сут, гипофосфатурия -12,52 ммоль/сут . Беседа с пациенткой выявила ряд психологических проблем, появ-ление которых сама женщина связывала с тяжелым пере-живанием последнего аборта: на фоне депрессии переста-ла следить за питанием и регулярным приемом препаратов, отмечались прогрессирующий набор веса и периодическая боль в мышцах, развившаяся в итоге в карпопедальный спазм.…”

A de novo 50-bp <b><i>GNAS</i></b> Intragenic Duplication in a Patient with Pseudohypoparathyroidism Type 1a

“…The GNAS gene encodes the alpha subunit of the stimulatory GTP-binding protein (Gs-alpha) [Weinstein et al, 2001;Mantovani et al, 2016;Thiele et al, 2016]. Gsalpha is a key regulator of the cAMP pathway that functions downstream of the parathyroid hormone (PTH) receptor [Weinstein et al, 2001;Mantovani et al, 2016;Thiele et al, 2016].…”

“…Gsalpha is a key regulator of the cAMP pathway that functions downstream of the parathyroid hormone (PTH) receptor [Weinstein et al, 2001;Mantovani et al, 2016;Thiele et al, 2016]. The GNAS locus undergoes complex tissue-specific imprinting, and therefore, germline intra-…”