MIM Entry: 156400
Title:
#156400 METAPHYSEAL CHONDRODYSPLASIA, JANSEN TYPE
;;METAPHYSEAL CHONDRODYSPLASIA, MURK JANSEN TYPE
Text:
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
constraints.
See Also:
Ozonoff (1969); Ozonoff (1974)
References:
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,
1969.
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:
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Severe short stature, postnatal onset;
Average adult height 125cm
HEAD AND NECK:
[Head];
Brachycephaly;
[Face];
Prominent supraorbital arches in adult;
Mild frontonasal hyperplasia in adult;
Micrognathia;
[Ears];
Deafness;
[Eyes];
Prominent eyes;
Hypertelorism;
[Nose];
Choanal stenosis;
Choanal atresia;
[Teeth];
Malposition of teeth
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Short ribs
GENITOURINARY:
[Kidneys];
Nephrocalcinosis
SKELETAL:
Generalized osteopenia;
Pathologic fracture;
[Skull];
Thick skull base;
Mandibular cyst;
[Pelvis];
Flexion contracture of hips;
[Limbs];
Flexion contracture of knees;
Bowing of long bones, especially lower limb;
Markedly expanded cup-shaped metaphyses, infancy;
Short, mildly broad diaphyses;
Short tubular bones;
[Hands];
Clinodactyly;
Short, clubbed fingers
LABORATORY ABNORMALITIES:
Hypercalcemia;
Hypophosphatemia;
Hypercalciuria;
Hyperphosphaturia;
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
MISCELLANEOUS:
Waddling gait;
Majority of cases are sporadic
MOLECULAR BASIS:
Caused by mutations in the parathyoid hormone receptor 1 gene (PTHR1,
168468.0001)
Contributors:
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
Contributors:
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
OMIM
