PTH RESISTANCE SYNDROMES: AGE-DEPENDENT CLINICAL PICTURE AND EMERGING UNCOMMON FEATURES

BACKGROUND: The term “PTH resistance syndromes” refers to a group of diseases so far named pseudohypoparathyroidism (PHP). The improvement of knowledge on pathophysiology and genetic background led to the proposal of a new classification that encompasses all the diseases caused by mutations within the PTH/PTHrP signaling cascade (iPPSD). PTH resistance is the hallmark of these disorders, but clinical picture is wider and more complex, with high variability and age-dependent presentation. A diagnostic delay is commonly reported; thus, our studies aim to describe some emerging uncommon clinical features with the final goal to improve diagnostic and management of these syndromes. METHODS: We conducted three retrospective analysis collecting data from large cohorts of PHP/iPPSD patients and exploring some still undescribed aspects (neonatal complications, early infancy features, hypercalcitoninemia, skeletal phenotype). As for Study A and Study B, we have collaborated with a referral Paediatric Center in France, therefore we could describe also paediatric features and rely on a very large cohort of patients. Study A focused on the rate of neonatal complications occurring in each PHP/iPPSD category during the first month of life, trying to estimate potential predictors and to correlate neonatal complications with the severity of the disease. Moreover, in Study A, we extracted from each medical record data about the age of onset or the age of diagnosis of the main clinical and biochemical features, aiming to describe early natural history of the disease and to explore the need of age-dependent criteria for diagnosis. The main aim of Study B was to investigate the prevalence and the dynamics of hypercalcitoninemia in PHP/iPPSD patients, and to define the clinical impact of this hormonal feature, also by analyzing data about thyroid ultrasound (US) and calcium stimulation test performed in a subset of patients. Study C is still ongoing, but we present preliminary data and an interesting case report. This study attempts to define the extent of bone responsiveness to elevated PTH levels, through the analysis of bone turnover markers, bone mineral density and fractures’ prevalence. Most of our patients had received a molecular diagnosis. RESULTS: • Study A: the first cohort was made up of 136 patients with a diagnosis of PHP/iPPSD. At least one neonatal complication occurred in 36% of patients and in 38.7% of cases neonatal complications were considered as severe, because they required prolonged hospitalization or intensive care assistance. PHP1A/iPPSD2 patients represent the majority of our cohort and 47% of them experienced neonatal complications, being the category the most affected (p=0.002). Neonatal hypoglycemia and transient respiratory distress appeared significantly frequent in this latter group, i.e., 10.5% and 18.4%, respectively. Neonatal complications were associated with the risk of developing neurocognitive impairment later in life (p=0.02) and earlier TSH resistance (p<0.001). In the second cohort (n=117) the median age at diagnosis was 5.9 years old. Age of 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, respectively). Minor diagnostic criteria were more represented than major criteria in children before 2 years (p=0.002). Indeed, in 64% of patients before 2 years none of the major criteria was described, conversely 71% had already developed at least 1 minor criteria; in particular, 20% had developed TSH resistance and obesity. • Study B: in the paediatric cohort 65.9% had hypercalcitoninemia (median CT 15 ng/L); in the adult cohort 53.5% (mean CT 21.6 ng/L). There was no difference between CT in paediatric and adult population; we observed stable CT levels over a median follow-up of 134.5 months in adults. Notably, no correlations were detected between CT and PTH levels. Other etiologies of hypercalcitoninemia were excluded, adult patients underwent regular thyroid US to screen for medullary thyroid cancer (MTC). We performed 20 calcium stimulation tests in adult patients. While there was a significant difference in basal and peak CT between our patients, healthy subjects and subjects with MTC, there was no difference with patients with C-cell hyperplasia. • Study C: we have preliminarily analysed data about 24 patients with PHP/iPPSDs. PTH levels show significant positive correlation with bone alkaline phosphatase (bALP) levels (rho = 0.66, p<0.001) but no correlation with CTX values. Bone turnover markers, bone mineral density and TBS were not significantly different between PHP1A/iPPSD2 and PHP1B/iPPSD3 patients. One patient was diagnosed with osteoporosis and two patients with osteopenia according to Z and T-scores respectively, as expected for age and sex. Fractures were described in 2 patients with pre-existing comorbidities. As for vertebral morphometry, we described rickets-like signs in 38% of patients, with no difference between various subtypes. It is worth report one patient of our study cohort affected by PHP1B/iPPSD3, who presented PTH levels >1000 pg/ml at diagnosis with concomitant cystic bone lesions (compatible with brown tumors/osteitis fibrosa cystica) at multiple sites. CONCLUSIONS: Clinical picture of PTH resistance syndromes is extremely variable and not limited to PTH resistance or physical characteristics. There are many others uncommon features emerging over years, which is important to focus on. From our studies we can conclude that: - patients affected by PHP/iPPSDs seem to experience a high rate of neonatal complications; - diagnostic criteria have to be updated accounting the difference in clinical presentation between children and adults; - PHP/iPPSD is an independent cause of hypercalcitoninemia and resistance to calcitonin should be added to the list of hormone resistances typical of these rare disorders; - bone responsiveness to elevated levels of PTH is an aspect to better investigate as inconsistent results have been provided until now.