Chondrodysplasia Blomstrand type (BOCD)

(OMIM phenotype number #215045)

Chondrodysplasia Blomstrand type (BOCD) is a rare autosomal recessive disorder, caused by homozygous or compound heterozygous inactivating mutations in the parathyroid hormone receptor-1 gene. The estimated prevalence is <1/1.000.000. Until now, few cases have been reported in the literature. The disease is characterized by multiple malformations, very short limbs and dwarfism, a narrow thorax, facial anomalies (macroglossia, micrognathia, and depressed nasal bridge), polyhydramnios, hydrops fetalis, hypoplastic lungs, protruding eyes showing cataracts, and internal malformations such as preductal aortic coarctation. It has been described increased bone mineral density and advanced bone maturation in the fetues. Signs of the disease are present at birth, and it leads to neonatal death.

Gene

PTHR1 gene, 3p21.31 (OMIM gene/locus number #168468).
Chondrodysplasias with mineral ion homeostasis are abnormalities due to alterations of the PTH/PTHrP receptor gene (PTHR1) gene, which usually mediates the actions of the two ligands: PTH and PTH-related peptide. The PTH1R is a member of the G protein-coupled receptor family 2, and its activity is mediated by G proteins that activate adenylate (AC)/protein kinase A (PKA) and the phospholipase C beta (PLCβ)/protein kinase C (PKC) signaling pathway. The PTH receptor is expressed in most tissues but with particularly high levels in bone, kidneys, and growth plate. Recently it has been shown that signaling through the PTH/PTHrP receptor, in addition to its role in regulating mineral metabolism, has an important role in fetal development due to the regulatory effects of PTHrP on the development of cartilage and bone.

Phenotype

Early lethality, defects of mammary gland and of tooth development, hypoplasia of nasal, mandibular and facial bones, short thick ribs, hypoplasia of the vertebrae, hyperdensity of the whole skeleton, markedly advanced ossification. Long bones: extremely short and poorly modeled, no zones of chondrocyte proliferation and of column formation are lacking.

Main biochemical alterations

Low Ca, high PTH, low Ur Pi, high Ur cAMP.

References

  1. Jobert AS, Zhang P, Couvineau A, et al.  Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest. 1998 Jul 1;102(1):34-40.
  2. Loshkajian A, Roume J, Stanescu V, et al. Familial Blomstrand chondrodysplasia with advanced skeletal maturation: further delineation. Am J Med Genet. 1997 Aug 22;71(3):283-8.
  3. M.L. Brandi, E.M. Brown (eds.), Hypoparathyroidism, DOI 10.1007/978-88-470-5376-2_36, © Springer-Verlag Italia 2015
  4. Galera MF, de Silva Patrício FR, Lederman HM, et al. Blomstrand chondrodysplasia: a lethal sclerosing skeletal dysplasia. Case report and review. Pediatr Radiol. 1999 Nov;29(11):842-5.
  5. Oostra RJ, van der Harten JJ, Rijnders WP, et al. Blomstrand osteochondrodysplasia: three novel cases and histological evidence for heterogeneity. Virchows Arch. 2000 Jan;436(1):28-35.
  6. Mannstadt M, Jüppner H, Gardella TJ. Receptors for PTH and PTHrP: their biological importance and functional properties. Am J Physiol. 1999 Nov;277(5 Pt 2):F665-75.
  7. Weir EC, Philbrick WM, Amling M, et al. Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10240-5.
  8. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  9. http://www.omim.org