Jansen’s metaphyseal chondrodysplasia (JMC) is a rare autosomal dominant human disorder characterized short-limbed dwarfism due to delayed chondrocyte differentiation and an associated, usually severe hypercalcemia and hypophosphatemia, despite normal or undetectable serum levels of PTH or PTHrP. These abnormalities are caused by mutations in the PTHR1 that lead to constitutive, PTH- and PTHrP-independent receptor activation. Since the PTHR1 is most abundantly expressed in kidney and bone, and in the metaphyseal growth plate, these findings provide a likely explanation for the abnormalities observed in mineral homeostasis and growth plate development associated with this disorder.
At birth, some JMC patients appear to be healthy, while others show dysmorphic features which can include micrognathia, prominent eyes, high skull vault, hypertelorism, prominent cheeks, wide cranial sutures, and a high-arched palate. Due to choanal atresia and/or rib fractures, patients often develop post-partum respiratory distress and require intubation. During the first years of life, patients typically decline progressively from their normal growth curves, may have feeding difficulties, recurrent episodes of vomiting and dehydration, and present with short stature and with other findings which may include waddling gait, enlarged joints, prominent supraorbital ridges, frontonasal hyperplasia, and a “bell-shaped” thorax with widened costochondral junctions. The legs, in particular the tibiae, are typically bowed, and are short in comparison to the relatively long arms. Tooth development and enamel formation are affected as well with few cases presenting impacted teeth.
In the newborn period, blood calcium and phosphorus concentrations are typically in the upper normal range, while alkaline phosphatase activity, a marker of osteoblast activity, can already be elevated. Severe but asymptomatic hypercalcemia, usually develops during the first months after birth (especially if vitamin D treatment is initiated for suspected rickets), and is most pronounced during infancy and childhood when serum calcium can reach 20 mg/dl. Hypercalcemia is caused