Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia

Abstract

Context: Jansen's metaphyseal chondrodysplasia (JMC) is a rare skeletal dysplasia characterized by abnormal endochondral bone formation and typically severe hypercalcemia despite normal/low levels of PTH. Five different heterozygous activating PTH/PTHrP receptor (PTH1R) mutations that change one of three different amino acid residues are known to cause JMC.

Objectives: Establishing the diagnosis of JMC during infancy or early childhood can be challenging, especially in the absence of family history and/or overt hypercalcemia. We therefore sought to provide radiographic findings supporting this diagnosis early in life.

Patients and methods: Three patients, a mother and her two sons, had radiographic evidence for JMC. However, obvious hypercalcemia and suppressed PTH levels were encountered only in both affected children. Sanger sequencing and endonuclease (SphI) digestion of PCR-amplified genomic DNA were performed to search for the H223R-PTH1R mutation.

Results: The heterozygous H223R mutation was identified in all three affected individuals. Surprisingly, however, the now 38-year-old mother was never overtly hypercalcemic and was therefore not diagnosed until her sons were found to be affected by JMC at the ages of 28 months and 40 days, respectively. The presented radiographic findings at different ages will help diagnose other infants/toddlers suspected of having JMC.

Conclusion: The H223R mutation is typically associated with profound hypercalcemia despite low/normal PTH levels. However, the findings presented herein show that overt hypercalcemia is not always encountered in JMC, even if caused by this relatively frequent mutation, which is similar to observations with other PTH1R mutations that show less constitutive activity.

Figure 1.

Radiographs of patient 1 showing metaphyseal expansion and calcification of upper and lower ends of femur with bowing and ragged acetabular roof (A), wide separation of epiphyseal center from metaphysis at the distal ends of the metacarpals and proximal phalanges with cupping and fraying of distal radius and ulna (B), similar changes in feet (C), thick arrows depicting medullary nephrocalcinosis (D), sclerosis of the base and skull vault with antegonial notching of mandible (E), a bell-shaped thorax (F), and a photograph of the index case showing microretrognathia, squatting stance, narrow thorax, and sloping shoulders (G).

Figure 2.

Radiographs of patient 2 showing massive sclerosis of the base of skull, calvarium, supraorbital ridges, and complete absence of all paranasal sinuses with antegonial notching of mandible (A), a photograph showing microretrognathia, prominent supraorbital ridges (B), a short physically disabled radius and ulna with bulbous distal ends (C), a bowed femur with coxa vara and flattened femoral heads and short neck (D), short metacarpals and phalanges (E), nephrocalcinosis (F), and an orthopantomogram showing retained left upper canine (G).

Figure 3.

Infantogram of patient 3 showing rachitiform changes in the anterior ends of ribs and dense base of skull (A), cupping and fraying of metaphysis at knee and ankle with bowing of femur (B), metaphyseal cupping in the metacarpals and proximal phalanges (C), and a photograph showing microretrognathia (D).