Metaphyseal chondrodysplasia Jansen type (JMC)

(OMIM phenotype number #156400)

Metaphyseal chondrodysplasia Jansen type (JMC) is a rare autosomal dominant skeletal disease caused by mutations in the PTH/PTHrP receptor (PTH1R) gene. The mutation leads to constitutive activation of the receptor independent of PTH or PTHrP. JMC is usually characterized by short stature, bowed legs, waddling gait, contracture deformities of the joints, and short hands with clubbed fingers. Until now, four distinct mutations in PTH1R have been described in patients affected by JMC. Three of these mutations were identified in the classic form of the disease (p.His223Arg, p.Thr410Pro, p.Ile458Arg) while the fourth one (p.Thr410Arg) appears to be associated with less pronounced skeletal and laboratory abnormalities. A nearlier diagnosis is often driven by presence of complications in the neonatal period (i.e. respiratory distress or difficulty in feeding).

Gene

PTHR1 gene, 3p21.31 (OMIM gene/locus number #168468). Chondrodysplasias with mineral ion homeostasis are abnormalities due to alterations of the PTHR1 gene, which usually mediates the actions of the two ligands: PTH and PTH-related peptide. PTHR1 activates several signal transduction pathways, including adenyl cyclase (AC)/protein kinase A (PKA) and phospholipase C (PLC)/protein kinase C (PKC). (see also BOCD)

Phenotype

High skull vault, flattening of the nose and forehead, low-set ears, hypertelorism, high arched palate, micrognathia, retrognathia, kyphoscoliosis with bell-shaped thorax and widened costochondral junctions, metaphyseal enlargement of the joints, frontonasal hyperplasia, short legs and relatively long arms; in younger patients: enlargement of metaphyses with a wide zone of irregular calcifications (lesions similar to rickets). At puberty: partially calcified cartilage that protrude into diaphysis. Late adolescence: cartilaginous tissue in the metaphysis disappears, sclerosis and thickening of the base of skull with cranial auditory and optical nerve compression.

Main biochemical alterations

High Ca, low Pi, high Ur Pi, high Ur Ca, high Ur cAMP, suppressed/low-normal PTH.

References

  1. Schipani E, Kruse K, Jüppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science. 1995 Apr 7;268(5207):98-100.
  2. Schipani E, Jensen GS, Pincus J, et al.  Constitutive activation of the cyclic adenosine 3',5'-monophosphate signaling pathway by parathyroid hormone (PTH)/PTH-related peptide receptors mutated at the two loci for Jansen's metaphyseal chondrodysplasia. Mol Endocrinol. 1997 Jun;11(7):851-8.
  3. Savoldi G, Izzi C, Signorelli M, et al. Prenatal presentation and postnatal evolution of a patient with Jansen metaphyseal dysplasia with a novel missense mutation in PTH1R. Am J Med Genet A. 2013 Oct;161A(10):2614-9.
  4. Jüppner H. Functional properties of the PTH/PTHrP receptor. Bone. 1995 Aug;17(2 Suppl):39S-42S.
  5. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  6. http://www.omim.org