Alternative titles; symbols
SNOMEDCT: 24629003; ORPHA: 33067; DO: 0080020;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.31 | Metaphyseal chondrodysplasia, Murk Jansen type | 156400 | Autosomal dominant | 3 | PTH1R | 168468 |
A number sign (#) is used with this entry because of evidence that the Jansen type of metaphyseal chondrodysplasia (MCDJ) is caused by constitutively active heterozygous mutations in the parathyroid hormone-1 receptor gene (PTH1R; 168468) on chromosome 3p21.
The Murk Jansen type of metaphyseal chondrodysplasia is characterized by severe short stature, short bowed limbs, clinodactyly, prominent upper face, and small mandible. Hypercalcemia and hypophosphatemia occur despite the lack of parathyroid abnormalities (summary by Cohen, 2002).
Stoeckenius (1966) described affected mother and child with this disorder, which was formerly known as metaphyseal dysostosis. 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).
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.
Charrow and Poznanski (1984) observed affected mother and daughter.
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, highly 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.
Csukasi et al. (2018) performed histologic analysis of a growth plate from a patient with MCDJ and observed severe disorganization with a hypocellular reserve zone, a reduced proliferative region with clusters of late-proliferating chondrocytes as well as diminished numbers of hypertrophic chondrocytes that failed to organize into columns, and invasion into the cartilaginous growth plate of bone territories, such as spicules or the mineralization front.
The transmission pattern of MCDJ in the patient reported by Schipani et al. (1995) was consistent with autosomal dominant inheritance.
Schipani et al. (1995) demonstrated an activating mutation of the PTH1R gene in a patient with Jansen metaphyseal chondrodysplasia. The patient was heterozygous for a his223-to-arg (H223R) substitution in the first intracellular loop of the PTH receptor (168468.0001). Both parents lacked the mutation. COS-7 cells expressing the mutant PTH1R showed ligand-independent cAMP accumulation that was approximately 4-fold higher than that observed with cells expressing the wildtype PTH1R. 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 H223R 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.
Csukasi et al. (2018) performed immunolocalization of DEPTOR (DEPDC6; 612974) in human cartilage growth plate and observed higher expression in resting and proliferative chondrocytes in control tissues, decreasing upon commitment to the hypertrophic program. In contrast, MCDJ patient growth plate showed a constant expression of DEPTOR throughout the poorly organized growth plate, concordant with Western blot analyses that showed increased amounts of DEPTOR. The authors concluded that in wildtype chondrocytes, PTH/PTHrP inhibits SIK3 (614776) phosphorylation and acts as a negative regulator of mTORC1/mTORC2 (see 601231) activity. In MCDJ, because of constitutive activation of the PTH/PTHrP pathway, there is exaggerated and persistent inhibition of SIK3, leading to DEPTOR accumulation and subsequent decrease in mTOR activity.
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.
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. [PubMed: 6331768] [Full Text: https://doi.org/10.1002/ajmg.1320180216]
Cohen, M. M., Jr. Some chondrodysplasias with short limbs: molecular perspectives. Am. J. Med. Genet. 112: 304-313, 2002. [PubMed: 12357475] [Full Text: https://doi.org/10.1002/ajmg.10780]
Csukasi, F., Duran, I., Barad, M., Barta, T., Gudernova, I., Trantirek, L., Martin, J. H., Kuo, C. Y., Woods, J., Lee, H., Cohn, D. H., Krejci, P., Krakow, D. The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. Sci. Transl. Med. 10: eaat9356, 2018. Note: Electronic Article. [PubMed: 30232230] [Full Text: https://doi.org/10.1126/scitranslmed.aat9356]
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. [PubMed: 5770408]
Gordon, S. L., Varano, L. A., Alandete, A., Maisels, M. J. Jansen's metaphyseal dysostosis. Pediatrics 58: 556-560, 1976. [PubMed: 972797]
Holthusen, W., Holt, J. F., Stoeckenius, M. The skull in metaphyseal chondrodysplasia type Jansen. Pediat. Radiol. 3: 137-144, 1975. [PubMed: 1233427] [Full Text: https://doi.org/10.1007/BF01006898]
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.
Juppner, H. Personal Communication. Boston, Mass. 6/26/1995.
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. [PubMed: 8314082] [Full Text: https://doi.org/10.1101/gad.8.3.277]
Kruse, K., Schutz, C. Calcium metabolism in the Jansen type of metaphyseal dysplasia. Europ. J. Pediat. 152: 912-915, 1993. [PubMed: 8276022] [Full Text: https://doi.org/10.1007/BF01957529]
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.
Lenz, W. Discussion. Birth Defects Orig. Art. Ser. V(4): 71-72, 1969.
Ozonoff, M. B. Metaphyseal dysostosis of Jansen. Radiology 93: 1047-1050, 1969. [PubMed: 5350670] [Full Text: https://doi.org/10.1148/93.5.1047]
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.
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. [PubMed: 9178745] [Full Text: https://doi.org/10.1210/mend.11.7.9934]
Schipani, E., Kruse, K., Juppner, H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268: 98-100, 1995. [PubMed: 7701349] [Full Text: https://doi.org/10.1126/science.7701349]
Stoeckenius, N. I. Cited by Lenz, W.: Symposion ueber generalisierte Anomalien des Skeletes. Mschr. Kinderheilk. 114: 157-158, 1966.