Database: OMIM
Entry: 156400
LinkDB: 156400
MIM Entry: 156400
  A number sign (#) is used with this entry because of evidence that the
  disorder is caused by constitutively active mutations in the parathyroid
  hormone receptor (PTHR; 168468).
  This disorder was formerly known as metaphyseal dysostosis. Stoeckenius
  (1966) described affected mother and child. The mother's condition may
  have been the result of new dominant mutation. Her father was 40 years
  old at her birth. Lenz (1967) saw the same family. The mother was only
  102 cm tall. The extreme disorganization of the metaphyses of the long
  bones and of the metacarpal and metatarsal bones is in sharp contrast to
  the almost normal appearance of the epiphyseal centers, which on x-ray
  appear widely separated from the long bones. The chin is receding. The
  fingers, especially the distal phalanges, are very short. The spine,
  pelvis, and lower legs are distorted. De Haas et al. (1969) gave a
  follow-up of the original case of Murk Jansen (1934). The striking
  feature at age 44 was the development of nearly normal bone structure
  with, however, marked deformity and dwarfing. Sclerosis in the cranial
  bones, including the petrous bone, leading to deafness, was
  demonstrated. Sclerosis of the skull is a common finding in older
  patients (Holthusen et al., 1975). Charrow and Poznanski (1984) observed
  affected mother and daughter. Gordon et al. (1976) described a case in
  which severe radiographic manifestations were detected at birth. Linear
  growth was significantly retarded at 2 years of age.
  Hypercalcemia has been noted in cases in childhood (Lenz, 1969; Holt and
  Dent in discussion of Lenz, 1969). See the follow-up by Lenz (1969).
  Kruse and Schutz (1993) noted that 7 of 16 patients described to that
  time presented with hypercalcemia. They reported studies of calcium
  metabolism in a hypercalcemic girl with this disorder during the first
  year of life. Biochemical indices of bone turnover indicated increased
  bone resorption without sufficient compensatory bone formation.
  Hypercalcemia, hypercalciuria, elevated urinary phosphate and cyclic AMP
  excretion, and increased 1,25-dihydroxyvitamin D concentrations in serum
  despite suppressed or low normal values of circulating parathyroid
  hormone (PTH; 168450) and PTH-related peptide (PTHRP; 168470) were
  found. Kruse and Schutz (1993) suggested that the hypercalcemia was
  caused by an unknown factor, which was not PTH or PTHRP, with osteolytic
  activity and stimulatory effect on the proximal renal tubule. The
  patient in their study presented at birth with prominent eyes, choanal
  stenosis, wide cranial sutures, high arched palate, micrognathia, rib
  fractures, and irregularities of the metaphyses of the long bones
  resembling rickets. At the age of 3.5 years, she showed height of 86 cm,
  waddling gait, enlarged joints, prominent supraorbital ridges, and
  frontonasal hyperplasia.
  Karaplis et al. (1994) disrupted the parathyroid hormone-related peptide
  in murine embryonic stem cells by homologous recombination, and
  introduced the null allele into a mouse germline. Mice homozygous for
  the null mutation died postnatally, probably from asphyxia, and
  exhibited widespread abnormalities of endochondral bone development.
  Histologic examination revealed a diminution of chondrocyte
  proliferation, associated with premature maturation of chondrocytes and
  accelerated bone formation. Analysis of earlier developmental stages
  revealed that disturbance in cartilage growth preceded abnormal
  endochondral bone formation. There was no morphologic abnormality
  apparent in other tissues. Schipani et al. (1995) demonstrated an
  activating mutation of the PTH receptor gene (PTHR) in a patient with
  Jansen metaphyseal chondrodysplasia. A patient with this disorder was
  heterozygous for a nucleotide change that caused a his223-to-arg
  substitution in the first intracellular loop of the PTH receptor
  (168468.0001). Both parents lacked the mutation. COS-7 cells expressing
  the mutant PTHR showed ligand-independent cAMP accumulation that was
  approximately 4-fold higher than that observed with cells expressing the
  wildtype PTHR. Although no mutation was identified in the DNA from 2
  other patients with Jansen type metaphyseal chondrodysplasia (Juppner,
  1995), 2 patients were found to have the his223-to-arg mutation.
  To further characterize the roles of positions 223 and 410 of human
  PTH/PTHRP in activation of the cAMP pathway, Schipani et al. (1997)
  replaced the native residues at these sites, histidine and threonine,
  respectively, by all 19 natural amino acids. At position 223, only
  arginine and lysine led to agonist-independent cAMP accumulation. All
  other substitutions resulted in receptor mutants that lacked
  constitutive activity or were uninformative due to poor cell surface
  expression. In contrast, most substitutions at position 410 conferred
  constitutive cAMP accumulation with little effect on receptor
  expression. Schipani et al. (1997) stated that the PTH/PTHRP receptor
  residues mutated in Jansen disease are conserved in all mammalian
  members of this family of G protein-coupled receptors. The authors
  concluded that residues 223 and 410 of the human PTH/PTHRP receptor have
  critical roles in signal transduction, but different sequence
See Also:
  Ozonoff  (1969); Ozonoff  (1974)
  1. Charrow, J.; Poznanski, A. K.: The Jansen type of metaphyseal
  chondrodysplasia: confirmation of dominant inheritance and review
  of radiographic manifestations in the newborn and adult. Am. J. Med.
  Genet. 18: 321-327, 1984.
  2. De Haas, W. H. D.; De Boer, W.; Griffioen, F.: Metaphyseal dysostosis:
  a late follow-up of the first reported case. J. Bone Joint Surg.
  Br. 51: 290-299, 1969.
  3. Gordon, S. L.; Varano, L. A.; Alandete, A.; Maisels, M. J.: Jansen's
  metaphyseal dysostosis. Pediatrics 58: 556-560, 1976.
  4. Holthusen, W.; Holt, J. F.; Stoeckenius, M.: The skull in metaphyseal
  chondrodysplasia type Jansen. Pediat. Radiol. 3: 137-144, 1975.
  5. Jansen, M.: Ueber atypische Chondrodystrophie (Achondroplasie)
  und ueber eine noch nicht beschriebene angeborene Wachstumsstoerung
  des Knochensystems: Metaphysaere Dysostosis. Z. Orthop. Chir. 61:
  253-286, 1934.
  6. Juppner, H.: Personal Communication. Boston, Mass.  6/26/1995.
  7. Karaplis, A. C.; Luz, A.; Glowacki, J.; Bronson, R. T.; Tybulewicz,
  V. L. J.; Kronenberg, H. M.; Mulligan, R. C.: Lethal skeletal dysplasia
  from targeted disruption of the parathyroid hormone-related peptide
  gene. Genes Dev. 8: 277-289, 1994.
  8. Kruse, K.; Schutz, C.: Calcium metabolism in the Jansen type of
  metaphyseal dysplasia. Europ. J. Pediat. 152: 912-915, 1993.
  9. Lenz, W.: Discussion. Birth Defects Orig. Art. Ser. V(4): 71-72,
  10. Lenz, W. L.: Diagnosis in medical genetics.In: Crow, J. F.; Neel,
  J. V.: Proceedings of the Third International Congress of Human Genetics,
  September 5-10, 1966.  Baltimore: Johns Hopkins Press (pub.)  1967.
  Pp. 29-36.
  11. Ozonoff, M. B.: Metaphyseal dysostosis of Jansen. Radiology 93:
  1047-1050, 1969.
  12. Ozonoff, M. B.: Asphyxiating thoracic dysplasia as a complication
  of metaphyseal chondrodysplasia (Jansen type).In: Bergsma, D.: Skeletal
  Dysplasias.  Amsterdam: Excerpta Medica (pub.)  1974. Pp. 72-77.
  13. Schipani, E.; Jensen, G. S.; Pincus, J.; Nissenson, R. A.; Gardella,
  T. J.; Juppner, H.: Constitutive activation of the cyclic adenosine
  3-prime,5-prime monophosphate signaling pathway by parathyroid hormone
  (PTH)/PTH-related peptide receptors mutated at the two loci for Jansen's
  metaphyseal chondrodysplasia. Molec. Endocr. 11: 851-858, 1997.
  14. Schipani, E.; Kruse, K.; Juppner, H.: A constitutively active
  mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 2  68:
  98-100, 1995.
  15. Stoeckenius, N. I.: Cited by Lenz, W.: Symposion ueber generalisierte
  Anomalien des Skeletes. Mschr. Kinderheilk. 114: 157-158, 1966.
Clinical Synopsis:
     Autosomal dominant
     Severe short stature, postnatal onset;
     Average adult height 125cm
     Prominent supraorbital arches in adult;
     Mild frontonasal hyperplasia in adult;
     Prominent eyes;
     Choanal stenosis;
     Choanal atresia;
     Malposition of teeth
     [Ribs, sternum, clavicles, and scapulae];
     Short ribs
     Generalized osteopenia;
     Pathologic fracture;
     Thick skull base;
     Mandibular cyst;
     Flexion contracture of hips;
     Flexion contracture of knees;
     Bowing of long bones, especially lower limb;
     Markedly expanded cup-shaped metaphyses, infancy;
     Short, mildly broad diaphyses;
     Short tubular bones;
     Short, clubbed fingers
     Increased urinary excretion of cAMP;
     Elevated 1,25(OH)2 D3;
     Elevated alkaline phosphatase;
     Parathyroid hormone (PTH) absent to low;
     Parathyroid hormone-related peptide (PTHrP) absent to low
     Waddling gait;
     Majority of cases are sporadic
     Caused by mutations in the parathyoid hormone receptor 1 gene (PTHR1,
  Kelly A. Przylepa - revised: 6/27/2001
Creation Date: 
  John F. Jackson: 6/15/1995
Edit Dates: 
  joanna: 03/14/2005
  joanna: 3/30/2004
  joanna: 6/27/2001
  John A. Phillips, III - updated: 11/8/1997
Creation Date: 
  Victor A. McKusick: 6/2/1986
Edit Dates: 
  terry: 01/13/2011
  alopez: 1/19/2001
  alopez: 1/27/1998
  terry: 1/17/1997
  mark: 7/20/1995
  carol: 12/14/1994
  terry: 11/22/1994
  mimadm: 11/6/1994
  warfield: 3/15/1994
  carol: 12/13/1993
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