Endocrine Abstracts

Since the first description of inactivating PTH/PTHrP signaling disorders (iPPSDs, historically named pseudohypoparathyroidism (PHP)) a remarkable clinical variability was observed, especially in clinical presentation, which seems to be age-dependent. The main clinical features, including PTH resistance, brachydactyly and short stature, develop during mid and late childhood, whilst minor clinical features such as a round face, rapid weight gain and subclinical hypothyroidism are the most prevalent signs in toddlers, e.g., age<2 years. The latter are included among minor criteria for diagnosis and present a large overlap with other conditions, therefore a significant delay in diagnosis has been reported. The aim of our study was to analyse a large cohort of iPPSD patients and to describe early natural history of the disease, to improve the diagnosis and reduce the diagnostic delay, through the development of new diagnostic criteria for early infancy. We collected data from 117 patients diagnosed with iPPSDs regularly followed-up at the Endocrinology Unit of two European tertiary centres. We retrospectively collected data on the age of onset of main clinical and hormonal features. In our cohort the mean age at diagnosis was 7.2±6.7 years old. The onset of PTH resistance and brachydactyly, major criteria for diagnosis, was significantly different from that of both TSH resistance and obesity (median age 6.1, 5.8, 1.85 and 2 years old, respectively). In contrast, no statistically significant difference was detected between the age onset of PTH resistance and brachydactyly and the age onset of TSH resistance and obesity. We can therefore speculate that these two pairs of symptoms are tightly age-related. As for diagnostic criteria, we studied the distribution of both major and minor criteria in patients before 2 years. Minor criteria were more represented than major criteria in this population (P=0.002). Indeed, in 64% of patients before 2 years none of the major criteria was described, conversely 71% of these population had already developed at least 1 minor criteria. In details, 20% of patients had developed TSH resistance and obesity before 2 years, while only 2% of patients had developed PTH resistance, brachydactyly and ectopic ossifications before 2 years. In conclusion, the clinical picture of iPPSDs in early infancy differs from that of adults, thus current diagnostic criteria may not be appropriate for children. In detail, the combination of early onset obesity and elevated TSH levels, currently included among minor criteria, should trigger the genetic screening in infants before 2 years old.