Abstract
Recent classification of skeletal dysplasias has reclassified disorders according to their underlying pathophysiologic mechanisms. The latest nosology of skeletal dysplasias introduced a new pathogenic category termed "skeletal disorders of the parathyroid hormone (PTH) signaling cascade." The group encompasses genetic defects associated with abnormal signaling of PTH, PTH-related protein (PTHrP) encoded by the PTHLH (PTH-like hormone) gene, and their common receptor termed parathyroid hormone 1 receptor (PTH1R). PTH1R is a guanine nucleotide-binding protein (G protein)-coupled receptor; and thus, defects of the a-subunit of stimulatory G protein (Gsα) and its downstream effectors cause disorders that overlap with those of the PTH signaling cascade. PTH and PTHrP have both catabolic and anabolic effects on bone metabolism, while PTHrP inhibits maturation of chondrocytes. Therefore, increased signaling of the cascade includes osteolysis that may be accompanied by focal osteosclerosis and/or delayed ossification of the growth plate or metaphyseal dysplasia. Partial loss of signaling can present as type E brachydactyly due to premature maturation of the growth plate of short tubular bones, typically exemplified by pseudohypoparathyroidism. Total loss of signaling leads to osteosclerosis and significantly accelerated bone maturation seen in a lethal sclerosing bone dysplasia termed Blomstrand dysplasia.