Clinical picture of early infancy PTH resistance syndromes: is it time to improve diagnostic criteria?

Abstract Background Clinical presentation of inactivating PTH/PTHrP signaling disorders (iPPSDs, historically pseudohypoparathyroidism (PHP)) exhibits pronounced age-dependence. Indeed, main features, including PTH resistance and brachydactyly, develop during late childhood, whilst other features (ectopic ossifications, obesity and hypothyroidism) are the most prevalent in toddlers. The latter are included among minor diagnostic criteria; therefore, a significant diagnostic delay has been reported. Aim of this work is to describe the early natural history of a large cohort of iPPSD/PHP patients, in order to improve the diagnosis, with the final goal of proposing new diagnostic criteria for early infancy and reducing the diagnostic delay. Methods We included 117 patients regularly followed up in two European Endocrinology tertiary centres and we retrospectively collected data on the age of onset of main clinical and hormonal features. Results In our cohort the median age at diagnosis was 5.9 years. 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 were observed, conversely 71% had already developed at least one minor criterion; in particular, 20% had developed TSH resistance and obesity. Conclusion Clinical picture of iPPSD/PHP in early infancy differs from that of mid-late infancy and adults, thus current diagnostic criteria may not be appropriate for children. We suggest that the combination of early onset obesity and elevated TSH should raise the suspicion and trigger genetic screening before 2 years of age.