Jansen-type metaphyseal chondrodysplasia (JMC) has both delayed ossification in long bones and usually
hypercalcemia. We report a Japanese male patient with JMC who presented with rachitic signs on radiographs,
hypercalcemia (13 mg/dl) and low %TRP at age 3 months (mo).
Hypercalcemia was treated from age 3 mo to 11 yr. Progressive widening, splaying and fragmentation of the metaphyses have been recognized on radiographs which resulted in shortened tubular bones and consequent short stature [107 cm (-6.5 SD)] at age 13 yr.
Hypercalcemia tended to normalize, and %TRP became normal at age 13 yr. Repeated measurements of serum PTH and PTH-related
protein (
PTHrP) levels showed that they were low or normal in the face of
hypercalcemia and high urine cAMP excretion, which led us to suspect constitutive activation of the
PTH/PTHrP receptor. Direct sequencing of
PTH/PTHrP receptor complementary DNA from skin fibroblast cells revealed a CAC to CGC transversion yielding a strictly conserved His223 to Arg substitution found in 90% of
DNA fragment in the second transmembrane domain of the receptor. This mutation created a restriction site Sphl (G/CATG/C). Direct sequencing of genomic
DNA and also restriction
enzyme digestion revealed heterozygous transition. The mutation was absent in the parents with normal phenotype. We conclude that both dysplastic bone lesions and
calcium homeostasis are age-dependent in JMC, and that the His223-Arg substitution is the same as that found in four Caucasian patients with a similar phenotype irrespective of the ethnic difference, and that the preferential expression of an abnormal allele of the
PTH/PTHrP receptor mRNA in skin fibroblast despite heterogygotic transversion in the genomic
DNA suggests the importance of allele expression.